MASTERKEY-265: Pembrolizumab With Talimogene Laherparepvec or Placebo in Unresected Melanoma
Sponsor
Amgen (Industry)
Overall Status
Terminated
CT.gov ID
NCT02263508
Collaborator
Merck Sharp & Dohme LLC (Industry)
713
161
3
75.1
4.4
0.1
Study Details
Study Description
Brief Summary
The primary objectives of the Phase 1b part of the study are to evaluate the safety, as assessed by incidence of dose limiting toxicity (DLT), of talimogene laherparepvec in combination with pembrolizumab in adults with previously untreated, unresectable, stage IIIB to IVM1c melanoma.
The primary objective of Phase 3 are to evaluate the efficacy of talimogene laherparepvec with pembrolizumab versus placebo with pembrolizumab, as assessed by progression-free survival (PFS) (response evaluation by blinded independent central review using modified Response Evaluation Criteria in Solid Tumors [RECIST] 1.1) and overall survival (OS).
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 3 |
Study Design
Study Type:
Interventional
Actual Enrollment
:
713 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Intervention Model Description:
Phase 1b was an open-label, single-arm study. Phase 3 was a randomized, double-blind, placebo-controlled study design.Phase 1b was an open-label, single-arm study. Phase 3 was a randomized, double-blind, placebo-controlled study design.
Masking:
Double (Participant, Investigator)
Primary Purpose:
Treatment
Official Title:
A Phase 1b/3, Multicenter, Trial of Talimogene Laherparepvec in Combination With Pembrolizumab (MK-3475) for Treatment of Unresectable Stage IIIB to IVM1c Melanoma (MASTERKEY-265)
Actual Study Start Date
:
Dec 8, 2014
Actual Primary Completion Date
:
Mar 11, 2021
Actual Study Completion Date
:
Mar 11, 2021
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Phase 1b: Talimogene Laherparepvec + Pembrolizumab Participants received talimogene laherparepvec at an initial dose of up to 4 mL 10⁶ plaque-forming units (PFU)/mL by intralesional injection. Subsequent doses of talimogene laherparepvec at up to 4 mL of 10⁸ PFU/mL began 3 weeks after the first dose and were administered every 2 weeks until disappearance of injectable lesions, complete response (CR), confirmed disease progression (PD) per modified Immune-related Response Criteria (irRC), intolerance of study treatment, 24 months from the date of the first dose of pembrolizumab, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 2 weeks starting at the time of the third dose of talimogene laherparepvec (week 6) until confirmed PD per modified irRC, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first. |
Drug: Talimogene Laherparepvec
Talimogene laherparepvec administered by intratumoral injection
Other Names:
Drug: Pembrolizumab
Administered at a dose of 200 mg as an intravenous infusion over approximately 30 minutes.
Other Names:
|
| Placebo Comparator: Phase 3 : Placebo + Pembrolizumab Participants received up to 4 mL placebo to talimogene laherparepvec by intralesional injection on day 1 of week 0. Subsequent doses of placebo (up to 4 mL) began 3 weeks after the first dose and were administered every 2 weeks until the fifth injection (week 9), and then synchronously with pembrolizumab thereafter every 3 weeks until disappearance of injectable lesions, complete response per modified Immune-related Response Criteria simulating Response Evaluation Criteria in Solid Tumors (irRC-RECIST) (iCR), confirmed iPD per modified irRC-RECIST, intolerance of study treatment, 24 months from the date of the first dose of placebo, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 3 weeks starting on day 1 of week 0, until confirmed iPD per modified irRC-RECIST, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first. |
Drug: Pembrolizumab
Administered at a dose of 200 mg as an intravenous infusion over approximately 30 minutes.
Other Names:
Drug: Placebo
Administered by intratumoral injection
|
| Experimental: Phase 3: Talimogene Laherparepvec + Pembrolizumab Participants received talimogene laherparepvec at an initial dose of up to 4 mL 10⁶ PFU/mL by intralesional injection on day 1. Subsequent doses of talimogene laherparepvec at 10⁸ PFU/mL (up to 4 mL) began 3 weeks after the first dose and were administered every 2 weeks until the fifth injection of talimogene laherparepvec (week 9), and then synchronously with pembrolizumab thereafter every 3 weeks until disappearance of injectable lesions, iCR, confirmed iPD per modified irRC-RECIST, intolerance of study treatment, 24 months from the date of the first dose of talimogene laherparepvec, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 3 weeks starting on day 1 of week 0, until confirmed iPD per modified irRC-RECIST, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first. |
Drug: Talimogene Laherparepvec
Talimogene laherparepvec administered by intratumoral injection
Other Names:
Drug: Pembrolizumab
Administered at a dose of 200 mg as an intravenous infusion over approximately 30 minutes.
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Phase 1b: Number of Participants With Dose-limiting Toxicities (DLTs) [The DLT evaluation period was 6 weeks from the initial administration of pembrolizumab (week 6 to 12).]
A DLT was defined as any toxicity related to study drug which met any of the following criteria based on Common Terminology Criteria for Adverse Events (CTCAE) version 4.0: Grade 4 non-hematologic toxicity. Grade 3 or higher pneumonitis. Grade 3 non-hematologic toxicity lasting > 3 days despite optimal supportive care, excluding grade 3 fatigue. Any grade 3 or higher non-hematologic laboratory value if medical intervention was required, or the abnormality lead to hospitalization, or the abnormality persisted for > 1 week. Febrile neutropenia grade 3 or grade 4. Thrombocytopenia < 25 x 10^9/L if associated with a bleeding event which does not result in hemodynamic instability but required an elective platelet infusion, or a life-threatening bleeding event which resulted in urgent intervention and admission to intensive care unit. Grade 5 toxicity (ie, death). Any other intolerable toxicity leading to permanent discontinuation of talimogene laherparepvec or pembrolizumab.
- Phase 3: Progression Free Survival (PFS) by Blinded Independent Central Review (BICR) Assessed Using Modified RECIST 1.1 [From randomization until the data-cut-off date of 02 March 2020; median (range) time on follow-up was 25.5 (0.6, 44.7) months in the Placebo + Pembrolizumab arm and 25.6 (0.3, 45.8) months in the Talimogene Laherparepvec + Pembrolizumab arm.]
PFS per modified Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 is defined as the interval from randomization to the earlier event of progressive disease (PD) per modified RECIST 1.1 or death from any cause. PD: Increase in size of target lesions from nadir by ≥ 20% and ≥ 5 mm absolute increase above nadir, or the appearance of a new lesion. Median PFS was calculated using the Kaplan-Meier method. Participants without an event were censored at their last evaluable tumor assessment if available; otherwise on their randomization date. The primary analysis of PFS was specified to be conducted when 407 PFS events had occurred (data cut-off date 02 March 2020).
- Phase 3: Overall Survival [From randomization until the end of study; median (range) time on follow-up was 34.8 (0.6, 58.3) months in the Placebo + Pembrolizumab arm and 36.8 (0.3, 58.4) months in the Talimogene Laherparepvec + Pembrolizumab arm.]
Overall survival (OS) is defined as the interval from randomization to death from any cause. Median overall survival was calculated using the Kaplan-Meier method. Participants without an event were censored at their last known alive date.
Secondary Outcome Measures
- Phase 1b: Objective Response Rate (ORR) [Tumor assessments were performed at week 6 (prior to initiation of pembrolizumab), week 18, and every 12 weeks thereafter until confirmed PD or start of new anticancer treatment; median (range) time on follow-up was 58.6 (1.4, 61.6) months.]
ORR is defined as the percentage of participants with a best overall response of complete response (CR) or partial response (PR) using the modified Immune-related Response Criteria (irRC), by Investigator assessment. CR was defined as the disappearance of all lesions; PR was defined as a decrease in tumor area ≥ 50% relative to baseline, response must have been confirmed by a second, consecutive assessment at least 4 weeks apart. Radiographic imaging for assessment of lesions was performed using computed tomography (CT), positron emission tomography (PET), magnetic resonance imaging (MRI), or ultrasound. Clinical measurement of cutaneous, subcutaneous, and palpable nodal tumor lesions was conducted with calipers.
- Phase 1b: Best Overall Response (BOR) [Tumor assessments were performed at week 6 (prior to initiation of pembrolizumab), week 18, and every 12 weeks thereafter until confirmed PD or start of new anticancer treatment; median (range) time on follow-up was 58.6 (1.4, 61.6) months.]
Best overall response is defined as the best overall visit response in the following order: CR, PR, stable disease (SD), progressive disease (PD), or unevaluable (UE), based on investigator assessment using the modified irRC up to the start of any subsequent anti-cancer therapy. CR was defined as the disappearance of all lesions; PR was defined as a decrease in tumor area ≥ 50% relative to baseline; PD was defined as an increase in tumor area ≥ 25% relative to nadir; and SD was defined as any outcome not meeting the criteria for response or PD with ≥ 77 days elapsed after enrollment. Responses and PD must have been confirmed by a second, consecutive assessment at least 4 weeks apart.
- Phase 1b: Durable Response Rate (DRR) [Tumor assessments were performed at week 6 (prior to initiation of pembrolizumab), week 18, and every 12 weeks thereafter until confirmed PD or start of new anticancer treatment; median (range) time on follow-up was 58.6 (1.4, 61.6) months.]
DRR is defined as the percentage of participants with a best overall response of CR or PR using the modified irRC per Investigator assessment with a duration of response of at least 6 months. CR was defined as the disappearance of all lesions; PR was defined as a decrease in tumor area ≥ 50% relative to baseline, response must have been confirmed by a second, consecutive assessment at least 4 weeks apart.
- Phase 1b: Duration of Response (DOR) [Tumor assessments were performed at week 6 (prior to initiation of pembrolizumab), week 18, and every 12 weeks thereafter until confirmed PD or start of new anticancer treatment; median (range) time on follow-up was 58.6 (1.4, 61.6) months.]
Duration of response (DOR) is defined as the time from the date of an initial response (CR or PR) that is subsequently confirmed to the earlier of confirmed PD or death. Participants who had not ended their response at the time of analysis were censored at their last evaluable tumor assessment before start of the first subsequent anticancer therapy. CR was defined as the disappearance of all lesions; PR was defined as a decrease in tumor area ≥ 50% relative to baseline; PD was defined as an increase in tumor area ≥ 25% relative to nadir. Response and PD must have been confirmed by a second, consecutive assessment at least 4 weeks apart.
- Phase 1b: Disease Control Rate (DCR) [Tumor assessments were performed at week 6 (prior to initiation of pembrolizumab), week 18, and every 12 weeks thereafter until confirmed PD or start of new anticancer treatment; median (range) time on follow-up was 58.6 (1.4, 61.6) months.]
DCR is defined as the percentage of participants with a best overall response of CR, PR, or SD using the modified irRC per Investigator assessment. CR was defined as the disappearance of all lesions; PR was defined as a decrease in tumor area ≥ 50% relative to baseline, response must have been confirmed by a second, consecutive assessment at least 4 weeks apart; and SD was defined as any outcome not meeting the criteria for response or PD with ≥ 84 days elapsed after enrollment.
- Phase 1b: Progression-free Survival (PFS) [From first dose until the end of study; median (range) time on follow-up was 70.6 (1.4, 74.5) months.]
Progression-free survival is defined as the time from first dose to the earlier event of confirmed PD per modified irRC or death from any cause. PFS was estimated using the Kaplan-Meier method. Participants without an event were censored at their last evaluable tumor assessment.
- Phase 1b: Overall Survival (OS) [From first dose until the end of study; median (range) time on follow-up was 70.6 (1.4, 74.5) months.]
Overall survival is defined as the interval from first dose to death from any cause. OS was estimated using the Kaplan-Meier method. Participants without an event were censored at their last known alive date.
- Phase 3: Complete Response Rate Assessed Using Modified irRC-RECIST (iCRR) [Tumor assessments were performed every 12 weeks after initiation of treatment until confirmed PD or start of new anticancer treatment; median (range) time on follow-up was 30.6 (0.6, 53.0) months and 31.4 (0.3, 52.5) months in each group, respectively.]
Complete response rate per modified Immune-related Response Criteria (irRC) simulating RECIST 1.1 (irRC-RECIST) is defined as the percentage of participants with a best overall response of complete response assessed using the modified irRC-RECIST (iCR) evaluated by blinded independent central review. iCR: Disappearance of all lesions (whether measurable or not and whether baseline or new) and confirmation by a repeat, consecutive assessment at least 4 weeks after the criteria were first met. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Modifications to the irRC-RECIST 1.1 included an increase in the total number of target lesions and new measurable lesions to 10 with a maximum of 5 target lesions per organ, and target lesions must have been measurable by CT or MRI only.
- Phase 3: Progression Free Survival Assessed Using Modified irRC-RECIST (iPFS) [From randomization until the data cut-off date of 29 September 2020; median time on follow-up was 30.6 (0.6, 53.0) months in the Placebo + Pembrolizumab arm and 31.4 (0.3, 52.5) months in the Talimogene Laherparepvec + Pembrolizumab arm.]
PFS per modified irRC-RECIST is defined as the interval from randomization to the earlier event of progressive disease assessed by modified irRC-RECIST (iPD) evaluated by blinded independent central review, or death from any cause. iPD: Increase in tumor burden ≥ 20% and at least 5 mm absolute increase relative to nadir (minimum recorded tumor burden) confirmed by a repeat, consecutive assessment at least 4 weeks after the initial detection. Median iPFS was calculated using the Kaplan-Meier method. Participants without an event were censored at their last evaluable tumor assessment if available; otherwise on their randomization date. The primary analysis of iPFS was specified to be conducted when 256 iPFS events had occurred (data cut-off date 29 September 2020).
- Phase 3: Overall Survival Excluding Stage IVM1c Participants [From randomization until the end of study; median (range) time on follow-up was 34.8 (0.6, 58.3) months in the Placebo + Pembrolizumab arm and 36.8 (0.3, 58.4) months in the Talimogene Laherparepvec + Pembrolizumab arm.]
Overall survival is defined as the interval from randomization to death from any cause. Median OS was calculated using the Kaplan-Meier method. Participants without an event were censored at the last known alive date.
- Phase 3: Objective Response Rate Assessed Using Modified RECIST 1.1 [Tumor assessments were performed every 12 weeks after initiation of treatment until confirmed PD or start of new anticancer treatment; median (range) time on follow-up was 30.6 (0.6, 53.0) months and 31.4 (0.3, 52.5) months in each group, respectively.]
ORR is defined as the percentage of participants with a best overall response of complete response (CR) or partial response (PR) assessed using modified RECIST version 1.1, evaluated by blinded independent central review. CR was defined as the disappearance of all lesions except lymph node short axis < 10 mm; PR was defined as a ≥ 30% reduction in sum of diameters in target lesions. Confirmation of CR or PR was not required. Modifications to conventional RECIST 1.1 included the following: target lesions were measurable on CT or MRI; otherwise, they were considered as nontarget lesions. A maximum of 10 target lesions was allowed with up to 5 per organ.
- Phase 3: Best Overall Response Assessed Using Modified RECIST 1.1 [Tumor assessments were performed every 12 weeks after initiation of treatment until confirmed PD or start of new anticancer treatment; median (range) time on follow-up was 30.6 (0.6, 53.0) months and 31.4 (0.3, 52.5) months in each group, respectively.]
BOR is defined as the best overall visit response up to and including the first overall visit response of PD in the following order: CR, PR, SD, non-CR/Non-PD (NN), PD or UE per modified RECIST 1.1, evaluated by BICR. CR: Disappearance of all lesions except lymph node short axis < 10 mm; PR: ≥ 30% reduction in sum of diameters in target lesions. Confirmation of CR or PR was not required; NN: Persistence of ≥ 1 non-target lesions and/or maintenance of tumor marker level above normal limits; SD: Neither sufficient shrinkage of target lesions to qualify for CR or PR nor sufficient increase to qualify for PD and ≥ 84 days from randomization; PD: Increase from nadir by ≥ 20% or ≥ 5 mm of target lesions or any new lesion; Missing: No postbaseline assessment, or assessments on or after the start of first subsequent anticancer therapy, including complete or partial removal/reduction of any target lesion which contained melanoma on pathology evaluation or pathology results were unknown.
- Phase 3: Durable Response Rate (DRR) Assessed Using Modified RECIST 1.1 [Tumor assessments were performed every 12 weeks after initiation of treatment until confirmed PD or start of new anticancer treatment; median (range) time on follow-up was 30.6 (0.6, 53.0) months and 31.4 (0.3, 52.5) months in each group, respectively.]
DRR is defined as the percentage of participants with a CR or PR per modified RECIST 1.1 evaluated by blinded independent central review, with a duration of response of ≥ 6 months. CR was defined as the disappearance of all lesions except lymph node short axis < 10 mm; PR was defined as a ≥ 30% reduction in sum of diameters in target lesions. Confirmation of CR or PR was not required.
- Phase 3: Duration of Response (DOR) Assessed Using Modified RECIST 1.1 [From randomization until the data cut-off date of 29 September 2020; median time on follow-up was 30.6 (0.6, 53.0) months in the Placebo + Pembrolizumab arm and 31.4 (0.3, 52.5) months in the Talimogene Laherparepvec + Pembrolizumab arm.]
Duration of response (DOR) is defined as the time from the date of an initial response of CR or PR to the earlier of PD per modified RECIST 1.1, or death. Participants who had not ended their response at the time of analysis were censored at their last evaluable tumor assessment date before start of the first subsequent anticancer therapy. CR was defined as the disappearance of all lesions except lymph node short axis < 10 mm; PR was defined as a ≥ 30% reduction in sum of diameters in target lesions. Confirmation of CR or PR was not required. PD was defined as an increase from nadir by ≥ 20% or ≥ 5 mm absolute increase above nadir of target lesions or appearance of any new lesion.
- Phase 3: Disease Control Rate (DCR) Assessed Using RECIST 1.1 [Tumor assessments were performed every 12 weeks after initiation of treatment until confirmed PD or start of new anticancer treatment; median (range) time on follow-up was 30.6 (0.6, 53.0) months and 31.4 (0.3, 52.5) months in each group, respectively.]
Disease control rate (DCR) per modified RECIST 1.1 is defined as the percentage of participants with a best overall response of CR, PR or SD evaluated by blinded independent central review. CR was defined as the disappearance of all lesions except lymph node short axis < 10 mm; PR was defined as a ≥ 30% reduction in sum of diameters in target lesions. Confirmation of CR or PR was not required. SD was defined as neither sufficient shrinkage of target lesions to qualify for CR or PR nor sufficient increase to qualify for PD with ≥ 84 days elapsed after randomization.
- Phase 3: Objective Response Rate Assessed Using Modified irRC-RECIST (iORR) [Tumor assessments were performed every 12 weeks after initiation of treatment until confirmed PD or start of new anticancer treatment; median (range) time on follow-up was 30.6 (0.6, 53.0) months and 31.4 (0.3, 52.5) months in each group, respectively.]
Objective response rate per modified irRC-RECIST is defined as the percentage of participants with a best overall response of iCR or partial response assessed using modified irRC-RECIST (iPR) evaluated by blinded independent central review. iCR: Disappearance of all lesions (whether measurable or not and whether baseline or new) and confirmation by a repeat, consecutive assessment at least 4 weeks from the date first documented. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. iPR: Decrease in tumor burden ≥ 30% relative to baseline confirmed by a consecutive assessment at least 4 weeks after first documentation. Modifications to the irRC-RECIST 1.1 included an increase in the total number of target lesions and new measurable lesions to 10 with a maximum of 5 target lesions per organ, and target lesions must be measurable by CT or MRI only.
- Phase 3: Best Overall Response Assessed Using Modified irRC-RECIST [Tumor assessments were performed every 12 weeks after initiation of treatment until confirmed PD or start of new anticancer treatment; median (range) time on follow-up was 30.6 (0.6, 53.0) months and 31.4 (0.3, 52.5) months in each group, respectively.]
BOR is defined as the best overall visit response in the following order: iCR, iPR, stable disease per modified irRC-RECIST (iSD), iPD, or UE per modified irRC-RECIST (iUE), evaluated by BICR. iCR: Disappearance of all lesions confirmed by consecutive assessment ≥ 4 weeks from the date first documented. Reduction of any pathological lymph node to <10 mm. iPR: Decrease in tumor burden ≥ 30% relative to baseline confirmed ≥ 4 weeks after first documentation. iPD: Increase in tumor burden ≥ 20 % and at least 5 mm absolute increase relative to nadir confirmed ≥ 4 weeks from initial detection. iSD: Neither sufficient shrinkage to qualify for iCR or iPR nor sufficient increase to qualify for iPD and ≥ 84 days from randomization. Missing: No postbaseline assessment, or assessments after start of first subsequent anticancer therapy, including complete or partial removal/reduction of any target lesion which contained melanoma on pathology evaluation or pathology results were unknown.
- Phase 3: Durable Response Rate Assessed Using Modified irRC-RECIST (iDRR) [Tumor assessments were performed every 12 weeks after initiation of treatment until confirmed PD or start of new anticancer treatment; median (range) time on follow-up was 30.6 (0.6, 53.0) months and 31.4 (0.3, 52.5) months in each group, respectively.]
Durable response rate per modified irRC-RECIST is defined as the percentage of participants with a best overall response of iCR or iPR per modified irRC-RECIST evaluated by blinded independent central review with a duration of response ≥ 6 months. iCR: Disappearance of all lesions (whether measurable or not and whether baseline or new) and confirmation by a repeat, consecutive assessment at least 4 weeks from the date first documented. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. iPR: Decrease in tumor burden ≥ 30% relative to baseline confirmed by a consecutive assessment at least 4 weeks after first documentation.
- Phase 3: Duration of Response Assessed Using Modified irRC-RECIST (iDOR) [From randomization until the data cut-off date of 29 September 2020; median time on follow-up was 30.6 (0.6, 53.0) months in the Placebo + Pembrolizumab arm and 31.4 (0.3, 52.5) months in the Talimogene Laherparepvec + Pembrolizumab arm.]
Duration of response per modified irRC-RECIST is defined as the time from the date of an initial response of iCR or iPR that was subsequently confirmed to the earlier of iPD per modified irRC-RECIST evaluated by blinded independent central review, or death. Participants who had not ended their response at the time of analysis were censored at their last evaluable tumor assessment date before the start of the first subsequent anticancer therapy. iCR: Disappearance of all lesions (whether measurable or not and whether baseline or new) and confirmation by a repeat, consecutive assessment at least 4 weeks from the date first documented. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. iPR: Decrease in tumor burden ≥ 30% relative to baseline confirmed by a consecutive assessment at least 4 weeks after first documentation.
- Phase 3: Disease Control Rate Assessed Using Modified irRC-RECIST (iDCR) [Tumor assessments were performed every 12 weeks after initiation of treatment until confirmed PD or start of new anticancer treatment; median (range) time on follow-up was 30.6 (0.6, 53.0) months and 31.4 (0.3, 52.5) months in each group, respectively.]
Disease control rate per modified irRC-RECIST is defined as the percentage of participants with a best overall response of iCR, iCR, or iSD assessed using modified irRC-RECIST evaluated by blinded independent central review. iCR: Disappearance of all lesions (whether measurable or not and whether baseline or new) and confirmation by a repeat, consecutive assessment at least 4 weeks from the date first documented. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. iPR: Decrease in tumor burden ≥ 30% relative to baseline confirmed by a consecutive assessment at least 4 weeks after first documentation. iSD: Neither sufficient shrinkage to qualify for iCR or iPR nor sufficient increase to qualify for iPD with ≥ 84 days elapsed after randomization.
- Phase 3: Change From Baseline in European Organisation for Research and Treatment of Cancer Quality of Life Core Module (EORTC QLQ-C30) Global Health Status (GHS)/Quality of Life (QOL) Score [Baseline and day 1 of weeks 3, 6, 9, 12, then every 6 weeks until end of study treatment; median (range) duration of treatment was 39.0 (0.1, 107.3) weeks in Placebo + Pembrolizumab and 54.1 (0.1, 109.6) weeks in Talimogene Laherparepvec + Pembrolizumab.]
The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30) is a 30-question tool used to assess the overall quality of life in cancer patients. It consists of 15 domains: 1 global health status/quality of life scale, 5 functional scales, and 9 symptom scales/items. The global health/QoL scale consists of 2 questions that ask participants to rate their overall health and overall quality of life during the past week on a scale from 1 (very poor) to 7 (excellent). The GHS/QoL subscale score was derived as the mean of each score then transformed to a scale from 0 to 100 where higher scores represent a better health status and a positive change from baseline indicates improvement. The overall change from baseline (calculated from all on-treatment visits) was calculated using a restricted maximum likelihood-based mixed model for repeated measures (MMRM) (see model details in statistical analysis section).
- Number of Participants With Treatment-emergent Adverse Events (TEAEs) [From first dose to 30 days after last dose (90 days for SAEs); median (range) duration was 48 (5.1, 110.1) weeks in Phase 1b, 39 (0.1, 107.3) weeks in Placebo + Pembrolizumab and 56 (0.1, 109.6) weeks in Phase 3 Talimogene Laherparepvec + Pembrolizumab.]
An adverse event (AE) is any untoward medical occurrence in a clinical trial subject, including worsening of a pre-existing medical condition. The event does not necessarily have a causal relationship with study treatment. TEAEs include AEs from the first dose of study drug to 30 days after the last dose. A serious adverse event (SAE) is an AE that met at least 1 of the following criteria: fatal life threatening required in-patient hospitalization or prolongation of existing hospitalization resulted in persistent or significant disability/incapacity congenital anomaly/birth defect other medically important serious event. Treatment-emergent SAEs are any SAE occurring from first dose of study drug through 90 days after the last dose or 30 days after the last dose if new anticancer therapy was started, whichever was earlier. AEs were graded for severity using CTCAE version 4.0, where Grade 1 = Mild; Grade 2 = Moderate; Grade 3 = Severe; Grade 4 = Life-threatening; Grade 5 = Fatal.
Eligibility Criteria
Criteria
Ages Eligible for Study:
18 Years
to 95 Years
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
Key Inclusion Criteria:
-
Age ≥ 18 years with histologically confirmed diagnosis of melanoma and stage IIIB to IVM1c for whom surgery is not recommended.
-
Subjects must have measurable disease and be a candidate for intralesional therapy administration into cutaneous, subcutaneous, or nodal lesions.
-
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
-
Adequate hematologic, hepatic, renal, and coagulation function.
-
Subjects with serine/threonine protein kinase B-Raf V600 (BRAFV600) wild-type tumors must not have received any prior systemic anticancer treatment consisting of chemotherapy, immunotherapy, or targeted therapy given in a non-adjuvant setting for unresectable stage IIIB to IVM1c melanoma.
-
Subjects with B-Raf V600 (BRAFV600) mutated tumors who have received prior BRAF inhibitor therapy either alone or in combination with mitogen-activated protein kinase kinase (MEK) inhibitor as their only prior systemic therapy are eligible.
-
Subjects who received prior adjuvant therapy for melanoma will not be excluded (including, but not limited to, interferon, ipilimumab, limb infusion/perfusion, or use of investigational agents in the adjuvant setting) with the exception that prior adjuvant therapy with inhibitors of programmed cell death-1 (PD-1) or programmed cell death ligand 1 (PD-L1) is not allowed. However, if the subject received adjuvant therapy, the subject must have completed therapy at least 28 days prior to enrollment.
-
Subjects must have a tumor sample that is adequate for PD-L1 assessment prior to randomization.
Key Exclusion Criteria:
-
Subjects must not have clinically active cerebral metastases.
-
Subjects must not have primary uveal or mucosal melanoma, history or evidence of melanoma associated with immunodeficiency states or history of other malignancy within the past 3 years.
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Subjects may not have been previously treated with talimogene laherparepvec, any other oncolytic virus, pembrolizumab, or any other inhibitor of PD-1, PD-L1, or PD-L2.
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Subjects must not have history or evidence of symptomatic autoimmune pneumonitis, glomerulonephritis, vasculitis, other symptomatic autoimmune disease, documented history of autoimmune disease or syndrome requiring systemic treatment in the past 2 years (ie, with use of disease modifying agents, steroids or immunosuppressive agents) except vitiligo or resolved childhood asthma/atopy, or evidence of clinically significant immunosuppression.
-
Subjects must not have active herpetic skin lesions or prior complications of herpetic infection and must not require intermittent or chronic treatment with an antiherpetic drug (eg, acyclovir), other than intermittent topical use.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Research Site | Birmingham | Alabama | United States | 35243 |
| 2 | Research Site | Mobile | Alabama | United States | 36608 |
| 3 | Research Site | Beverly Hills | California | United States | 90211 |
| 4 | Research Site | Duarte | California | United States | 91010 |
| 5 | Research Site | Encinitas | California | United States | 92024 |
| 6 | Research Site | La Jolla | California | United States | 92037 |
| 7 | Research Site | Los Angeles | California | United States | 90024 |
| 8 | Research Site | Los Angeles | California | United States | 90025 |
| 9 | Research Site | Riverside | California | United States | 92505 |
| 10 | Research Site | San Francisco | California | United States | 94115 |
| 11 | Research Site | San Francisco | California | United States | 94117 |
| 12 | Research Site | Santa Monica | California | United States | 90404 |
| 13 | Research Site | Miami Beach | Florida | United States | 33140 |
| 14 | Research Site | Miami | Florida | United States | 33136 |
| 15 | Research Site | Orlando | Florida | United States | 32806 |
| 16 | Research Site | Atlanta | Georgia | United States | 30322 |
| 17 | Research Site | Chicago | Illinois | United States | 60611 |
| 18 | Research Site | Chicago | Illinois | United States | 60637 |
| 19 | Research Site | Louisville | Kentucky | United States | 40202 |
| 20 | Research Site | Baltimore | Maryland | United States | 21237 |
| 21 | Research Site | Boston | Massachusetts | United States | 02215 |
| 22 | Research Site | Detroit | Michigan | United States | 48201 |
| 23 | Research Site | Fridley | Minnesota | United States | 55432 |
| 24 | Research Site | Saint Louis | Missouri | United States | 63110-1093 |
| 25 | Research Site | Hackensack | New Jersey | United States | 07601 |
| 26 | Research Site | Buffalo | New York | United States | 14263 |
| 27 | Research Site | New York | New York | United States | 10016 |
| 28 | Research Site | New York | New York | United States | 10032 |
| 29 | Research Site | New York | New York | United States | 10065 |
| 30 | Research Site | Cincinnati | Ohio | United States | 45209 |
| 31 | Research Site | Cleveland | Ohio | United States | 44195 |
| 32 | Research Site | Philadelphia | Pennsylvania | United States | 19107 |
| 33 | Research Site | Philadelphia | Pennsylvania | United States | 19111 |
| 34 | Research Site | Pittsburgh | Pennsylvania | United States | 15232 |
| 35 | Research Site | Germantown | Tennessee | United States | 38138 |
| 36 | Research Site | Knoxville | Tennessee | United States | 37920 |
| 37 | Research Site | Nashville | Tennessee | United States | 37232 |
| 38 | Research Site | Dallas | Texas | United States | 75246 |
| 39 | Research Site | Murray | Utah | United States | 84107 |
| 40 | Research Site | Salt Lake City | Utah | United States | 84112 |
| 41 | Research Site | Seattle | Washington | United States | 98109-1023 |
| 42 | Research Site | North Sydney | New South Wales | Australia | 2060 |
| 43 | Research Site | Waratah | New South Wales | Australia | 2298 |
| 44 | Research Site | Wollongong | New South Wales | Australia | 2500 |
| 45 | Research Site | Southport | Queensland | Australia | 4215 |
| 46 | Research Site | Woolloongabba | Queensland | Australia | 4102 |
| 47 | Research Site | Woodville South | South Australia | Australia | 5011 |
| 48 | Research Site | Geelong | Victoria | Australia | 3220 |
| 49 | Research Site | Heidelberg | Victoria | Australia | 3084 |
| 50 | Research Site | Melbourne | Victoria | Australia | 3000 |
| 51 | Research Site | Prahran | Victoria | Australia | 3181 |
| 52 | Research Site | Murdoch | Western Australia | Australia | 6150 |
| 53 | Research Site | Graz | Austria | 8036 | |
| 54 | Research Site | Innsbruck | Austria | 6020 | |
| 55 | Research Site | Salzburg | Austria | 5020 | |
| 56 | Research Site | Wien | Austria | 1090 | |
| 57 | Research Site | Bruxelles | Belgium | 1200 | |
| 58 | Research Site | Liege | Belgium | 4000 | |
| 59 | Research Site | Edmonton | Alberta | Canada | T6G 1Z2 |
| 60 | Research Site | Kingston | Ontario | Canada | K7L 2V7 |
| 61 | Research Site | London | Ontario | Canada | N6A 4L6 |
| 62 | Research Site | Ottawa | Ontario | Canada | K1H 8L6 |
| 63 | Research Site | Toronto | Ontario | Canada | M5G 2M9 |
| 64 | Research Site | Montreal | Quebec | Canada | H3T 1E2 |
| 65 | Research Site | Quebec | Canada | G1R 2J6 | |
| 66 | Research Site | Brno | Czechia | 656 53 | |
| 67 | Research Site | Olomouc | Czechia | 775 20 | |
| 68 | Research Site | Ostrava-Poruba | Czechia | 708 52 | |
| 69 | Research Site | Praha 10 | Czechia | 100 34 | |
| 70 | Research Site | Praha 2 | Czechia | 128 08 | |
| 71 | Research Site | Praha 8 | Czechia | 180 81 | |
| 72 | Research Site | Helsinki | Finland | 00290 | |
| 73 | Research Site | Bordeaux Cedex | France | 33075 | |
| 74 | Research Site | Grenoble Cedex 9 | France | 38043 | |
| 75 | Research Site | Lille | France | 59037 | |
| 76 | Research Site | Lyon cedex 08 | France | 69373 | |
| 77 | Research Site | Marseille cedex 05 | France | 13385 | |
| 78 | Research Site | Nantes Cedex 1 | France | 44093 | |
| 79 | Research Site | Paris | France | 75010 | |
| 80 | Research Site | Pierre Benite Cedex | France | 69495 | |
| 81 | Research Site | Toulouse cedex 9 | France | 31059 | |
| 82 | Research Site | Vandoeuvre les Nancy | France | 54511 | |
| 83 | Research Site | Berlin | Germany | 10117 | |
| 84 | Research Site | Dresden | Germany | 01307 | |
| 85 | Research Site | Erlangen | Germany | 91054 | |
| 86 | Research Site | Essen | Germany | 45147 | |
| 87 | Research Site | Hannover | Germany | 30625 | |
| 88 | Research Site | Heidelberg | Germany | 69120 | |
| 89 | Research Site | Kiel | Germany | 24105 | |
| 90 | Research Site | Leipzig | Germany | 04103 | |
| 91 | Research Site | Mainz | Germany | 55131 | |
| 92 | Research Site | Mannheim | Germany | 68167 | |
| 93 | Research Site | München | Germany | 80337 | |
| 94 | Research Site | Regensburg | Germany | 93053 | |
| 95 | Research Site | Tübingen | Germany | 72076 | |
| 96 | Research Site | Würzburg | Germany | 97080 | |
| 97 | Research Site | Athens | Greece | 11527 | |
| 98 | Research Site | Athens | Greece | 18547 | |
| 99 | Research Site | Heraklion - Crete | Greece | 71110 | |
| 100 | Research Site | Ioannina | Greece | 45500 | |
| 101 | Research Site | Thessaloniki | Greece | 54622 | |
| 102 | Research Site | Budapest | Hungary | 1122 | |
| 103 | Research Site | Pecs | Hungary | 7632 | |
| 104 | Research Site | Szeged | Hungary | 6720 | |
| 105 | Research Site | Bergamo | Italy | 24127 | |
| 106 | Research Site | Brescia | Italy | 25123 | |
| 107 | Research Site | Meldola FC | Italy | 47014 | |
| 108 | Research Site | Milano | Italy | 20133 | |
| 109 | Research Site | Milano | Italy | 20141 | |
| 110 | Research Site | Siena | Italy | 53100 | |
| 111 | Research Site | Seoul | Korea, Republic of | 03722 | |
| 112 | Research Site | Seoul | Korea, Republic of | 05505 | |
| 113 | Research Site | Amsterdam | Netherlands | 1066 CX | |
| 114 | Research Site | Amsterdam | Netherlands | 1081 HV | |
| 115 | Research Site | Groningen | Netherlands | 9713 GZ | |
| 116 | Research Site | Nijmegen | Netherlands | 6525 GA | |
| 117 | Research Site | Bielsko-Biala | Poland | 43-300 | |
| 118 | Research Site | Bydgoszcz | Poland | 85-796 | |
| 119 | Research Site | Gdansk | Poland | 80-952 | |
| 120 | Research Site | Konin | Poland | 62-500 | |
| 121 | Research Site | Krakow | Poland | 31-501 | |
| 122 | Research Site | Poznan | Poland | 60-848 | |
| 123 | Research Site | Poznan | Poland | 61-866 | |
| 124 | Research Site | Szczecin | Poland | 71-730 | |
| 125 | Research Site | Warszawa | Poland | 02-781 | |
| 126 | Research Site | Wroclaw | Poland | 50-368 | |
| 127 | Research Site | Almada | Portugal | 2801-951 | |
| 128 | Research Site | Lisboa | Portugal | 1099-023 | |
| 129 | Research Site | Lisboa | Portugal | 1649-035 | |
| 130 | Research Site | Porto | Portugal | 4200-072 | |
| 131 | Research Site | Moscow | Russian Federation | 115478 | |
| 132 | Research Site | Saint-Petersburg | Russian Federation | 197758 | |
| 133 | Research Site | Groenkloof | Gauteng | South Africa | 0181 |
| 134 | Research Site | Johannesburg | Gauteng | South Africa | 2196 |
| 135 | Research Site | Parktown | Gauteng | South Africa | 2193 |
| 136 | Research Site | Kraaifontein | South Africa | 7570 | |
| 137 | Research Site | Pretoria | South Africa | 0002 | |
| 138 | Research Site | Pretoria | South Africa | 0081 | |
| 139 | Research Site | Badalona | Cataluña | Spain | 08916 |
| 140 | Research Site | Barcelona | Cataluña | Spain | 08036 |
| 141 | Research Site | Valencia | Comunidad Valenciana | Spain | 46014 |
| 142 | Research Site | Pamplona | Navarra | Spain | 31008 |
| 143 | Research Site | San Sebastian | País Vasco | Spain | 20014 |
| 144 | Research Site | Madrid | Spain | 28009 | |
| 145 | Research Site | Madrid | Spain | 28046 | |
| 146 | Research Site | Madrid | Spain | 28050 | |
| 147 | Research Site | Bellinzona | Switzerland | 6500 | |
| 148 | Research Site | Bern | Switzerland | 3010 | |
| 149 | Research Site | Geneva 14 | Switzerland | 1211 | |
| 150 | Research Site | Lausanne | Switzerland | 1011 | |
| 151 | Research Site | Zürich | Switzerland | 8091 | |
| 152 | Research Site | Birmingham | United Kingdom | B15 2TH | |
| 153 | Research Site | Guildford | United Kingdom | GU2 7XX | |
| 154 | Research Site | Leeds | United Kingdom | LS9 7TF | |
| 155 | Research Site | Leicester | United Kingdom | LE1 5WW | |
| 156 | Research Site | London | United Kingdom | SE1 9RT | |
| 157 | Research Site | London | United Kingdom | SW3 6JJ | |
| 158 | Research Site | Manchester | United Kingdom | M20 4BX | |
| 159 | Research Site | Oxford | United Kingdom | OX3 7LJ | |
| 160 | Research Site | Preston | United Kingdom | PR2 9HT | |
| 161 | Research Site | Southampton | United Kingdom | SO16 6YD |
Sponsors and Collaborators
- Amgen
- Merck Sharp & Dohme LLC
Investigators
- Study Director: MD, Amgen
Study Documents (Full-Text)
More Information
Additional Information:
Publications
- Dummer R, Hoeller C, Gruter IP, Michielin O. Combining talimogene laherparepvec with immunotherapies in melanoma and other solid tumors. Cancer Immunol Immunother. 2017 Jun;66(6):683-695. doi: 10.1007/s00262-017-1967-1. Epub 2017 Feb 25. Review.
- Ribas A, Dummer R, Puzanov I, VanderWalde A, Andtbacka RHI, Michielin O, Olszanski AJ, Malvehy J, Cebon J, Fernandez E, Kirkwood JM, Gajewski TF, Chen L, Gorski KS, Anderson AA, Diede SJ, Lassman ME, Gansert J, Hodi FS, Long GV. Oncolytic Virotherapy Promotes Intratumoral T Cell Infiltration and Improves Anti-PD-1 Immunotherapy. Cell. 2017 Sep 7;170(6):1109-1119.e10. doi: 10.1016/j.cell.2017.08.027. Erratum in: Cell. 2018 Aug 9;174(4):1031-1032.
Responsible Party:
Amgen
ClinicalTrials.gov Identifier:
NCT02263508
Other Study ID Numbers:
- 20110265
- 2014-000185-22
- KEYNOTE-034
First Posted:
Oct 13, 2014
Last Update Posted:
May 16, 2022
Last Verified:
Apr 1, 2022
Individual Participant Data (IPD) Sharing Statement:
Yes
Plan to Share IPD:
Yes
Studies a U.S. FDA-regulated Drug Product:
Yes
Studies a U.S. FDA-regulated Device Product:
No
Keywords provided by Amgen
Additional relevant MeSH terms:
Study Results
Participant Flow
| Recruitment Details | This study was conducted at 134 centers in Australia, Canada, Europe, South Africa, South Korea, and the United States. Phase 1b was an open-label, single-arm study and Phase 3 was a randomized, double-blind, placebo-controlled study. |
|---|---|
| Pre-assignment Detail | In Phase 3 participants were randomized equally to 1 of 2 arms. Randomization was stratified by stage of disease: less advanced stages (IIIB, IIIC, and IVM1a) versus more advanced stages (IVM1b and IVM1c) and by prior serine/threonine protein kinase B-Raf (BRAF) inhibitor therapy (no prior BRAF inhibitor versus BRAF inhibitor with or without mitogen-activated extracellular signal-regulated kinase [MEK] inhibitor). |
| Arm/Group Title | Phase 1b: Talimogene Laherparepvec + Pembrolizumab | Phase 3: Placebo + Pembrolizumab | Phase 3: Talimogene Laherparepvec + Pembrolizumab |
|---|---|---|---|
| Arm/Group Description | Participants received talimogene laherparepvec at an initial dose of up to 4 mL 10⁶ plaque-forming units (PFU)/mL by intralesional injection on day 1 of week 1. Subsequent doses of talimogene laherparepvec at up to 4 mL of 10⁸ PFU/mL began 3 weeks after the first dose and were administered every 2 weeks until disappearance of injectable lesions, complete response (CR), confirmed disease progression (PD) per modified Immune-related Response Criteria (irRC), intolerance of study treatment, 24 months from the date of the first dose of pembrolizumab, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 2 weeks starting at the time of the third dose of talimogene laherparepvec (week 6) until confirmed PD per modified irRC, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first. | Participants received up to 4 mL placebo to talimogene laherparepvec by intralesional injection on day 1 of week 0. Subsequent doses of placebo (up to 4 mL) began 3 weeks after the first dose and were administered every 2 weeks until the fifth injection (week 9), and then synchronously with pembrolizumab thereafter every 3 weeks until disappearance of injectable lesions, complete response per modified Immune-related Response Criteria simulating Response Evaluation Criteria in Solid Tumors (irRC-RECIST) (iCR), confirmed iPD per modified irRC-RECIST, intolerance of study treatment, 24 months from the date of the first dose of placebo, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 3 weeks starting on day 1 of week 0, until confirmed iPD per modified irRC-RECIST, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first. | Participants received talimogene laherparepvec at an initial dose of up to 4 mL 10⁶ PFU/mL by intralesional injection on day 1. Subsequent doses of talimogene laherparepvec at 10⁸ PFU/mL (up to 4 mL) began 3 weeks after the first dose and were administered every 2 weeks until the fifth injection of talimogene laherparepvec (week 9), and then synchronously with pembrolizumab thereafter every 3 weeks until disappearance of injectable lesions, iCR, confirmed iPD per modified irRC-RECIST, intolerance of study treatment, 24 months from the date of the first dose of talimogene laherparepvec, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 3 weeks starting on day 1 of week 0, until confirmed iPD per modified irRC-RECIST, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first. |
| Period Title: Overall Study | |||
| STARTED | 21 | 346 | 346 |
| Received Talimogene Laherparepvec/Placebo | 21 | 345 | 343 |
| Received Pembrolizumab | 21 | 345 | 343 |
| COMPLETED | 0 | 0 | 0 |
| NOT COMPLETED | 21 | 346 | 346 |
Baseline Characteristics
| Arm/Group Title | Phase 1b: Talimogene Laherparepvec + Pembrolizumab | Phase 3: Placebo + Pembrolizumab | Phase 3: Talimogene Laherparepvec + Pembrolizumab | Total |
|---|---|---|---|---|
| Arm/Group Description | Participants received talimogene laherparepvec at an initial dose of up to 4 mL 10⁶ plaque-forming units (PFU)/mL by intralesional injection on day 1 of week 1. Subsequent doses of talimogene laherparepvec at up to 4 mL of 10⁸ PFU/mL began 3 weeks after the first dose and were administered every 2 weeks until disappearance of injectable lesions, complete response (CR), confirmed disease progression (PD) per modified Immune-related Response Criteria (irRC), intolerance of study treatment, 24 months from the date of the first dose of pembrolizumab, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 2 weeks starting at the time of the third dose of talimogene laherparepvec (week 6) until confirmed PD per modified irRC, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first. | Participants received up to 4 mL placebo to talimogene laherparepvec by intralesional injection on day 1 of week 0. Subsequent doses of placebo (up to 4 mL) began 3 weeks after the first dose and were administered every 2 weeks until the fifth injection (week 9), and then synchronously with pembrolizumab thereafter every 3 weeks until disappearance of injectable lesions, complete response per modified Immune-related Response Criteria simulating Response Evaluation Criteria in Solid Tumors (irRC-RECIST) (iCR), confirmed iPD per modified irRC-RECIST, intolerance of study treatment, 24 months from the date of the first dose of placebo, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 3 weeks starting on day 1 of week 0, until confirmed iPD per modified irRC-RECIST, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first. | Participants received talimogene laherparepvec at an initial dose of up to 4 mL 10⁶ PFU/mL by intralesional injection on day 1. Subsequent doses of talimogene laherparepvec at 10⁸ PFU/mL (up to 4 mL) began 3 weeks after the first dose and were administered every 2 weeks until the fifth injection of talimogene laherparepvec (week 9), and then synchronously with pembrolizumab thereafter every 3 weeks until disappearance of injectable lesions, iCR, confirmed iPD per modified irRC-RECIST, intolerance of study treatment, 24 months from the date of the first dose of talimogene laherparepvec, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 3 weeks starting on day 1 of week 0, until confirmed iPD per modified irRC-RECIST, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first. | Total of all reporting groups |
| Overall Participants | 21 | 346 | 346 | 713 |
| Age (years) [Mean (Standard Deviation) ] | ||||
| Mean (Standard Deviation) [years] |
60.2
(13.4)
|
62.3
(14.5)
|
63.1
(13.7)
|
62.6
(14.1)
|
| Sex: Female, Male (Count of Participants) | ||||
| Female |
13
61.9%
|
127
36.7%
|
147
42.5%
|
287
40.3%
|
| Male |
8
38.1%
|
219
63.3%
|
199
57.5%
|
426
59.7%
|
| Ethnicity (NIH/OMB) (Count of Participants) | ||||
| Hispanic or Latino |
0
0%
|
9
2.6%
|
13
3.8%
|
22
3.1%
|
| Not Hispanic or Latino |
21
100%
|
337
97.4%
|
331
95.7%
|
689
96.6%
|
| Unknown or Not Reported |
0
0%
|
0
0%
|
2
0.6%
|
2
0.3%
|
| Race/Ethnicity, Customized (Count of Participants) | ||||
| American Indian or Alaska Native |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Asian |
0
0%
|
4
1.2%
|
7
2%
|
11
1.5%
|
| Black (or African American) |
0
0%
|
1
0.3%
|
2
0.6%
|
3
0.4%
|
| Native Hawaiian or Other Pacific Islander |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| White |
21
100%
|
335
96.8%
|
327
94.5%
|
683
95.8%
|
| Other |
0
0%
|
6
1.7%
|
10
2.9%
|
16
2.2%
|
| Disease Stage per the American Joint Committee on Cancer (AJCC) 7th Edition (Count of Participants) | ||||
| Stage IIIB - IVM1a |
9
42.9%
|
169
48.8%
|
169
48.8%
|
347
48.7%
|
| Stage IVM1b/c |
12
57.1%
|
177
51.2%
|
177
51.2%
|
366
51.3%
|
| Prior Serine/Threonine Protein Kinase B-Raf (BRAF) Inhibitor Therapy (Count of Participants) | ||||
| Yes |
29
138.1%
|
29
8.4%
|
58
16.8%
|
|
| No |
317
1509.5%
|
317
91.6%
|
634
183.2%
|
|
| Programmed Cell Death-1 Ligand 1 (PD-L1) Status (Count of Participants) | ||||
| Positive |
17
81%
|
218
63%
|
231
66.8%
|
466
65.4%
|
| Not Positive |
4
19%
|
128
37%
|
115
33.2%
|
247
34.6%
|
| BRAF V600 Mutation Status (Count of Participants) | ||||
| Mutation |
4
19%
|
116
33.5%
|
124
35.8%
|
244
34.2%
|
| Mutation not present |
17
81%
|
215
62.1%
|
211
61%
|
443
62.1%
|
| Missing/unknown |
0
0%
|
15
4.3%
|
11
3.2%
|
26
3.6%
|
Outcome Measures
| Title | Phase 1b: Number of Participants With Dose-limiting Toxicities (DLTs) |
|---|---|
| Description | A DLT was defined as any toxicity related to study drug which met any of the following criteria based on Common Terminology Criteria for Adverse Events (CTCAE) version 4.0: Grade 4 non-hematologic toxicity. Grade 3 or higher pneumonitis. Grade 3 non-hematologic toxicity lasting > 3 days despite optimal supportive care, excluding grade 3 fatigue. Any grade 3 or higher non-hematologic laboratory value if medical intervention was required, or the abnormality lead to hospitalization, or the abnormality persisted for > 1 week. Febrile neutropenia grade 3 or grade 4. Thrombocytopenia < 25 x 10^9/L if associated with a bleeding event which does not result in hemodynamic instability but required an elective platelet infusion, or a life-threatening bleeding event which resulted in urgent intervention and admission to intensive care unit. Grade 5 toxicity (ie, death). Any other intolerable toxicity leading to permanent discontinuation of talimogene laherparepvec or pembrolizumab. |
| Time Frame | The DLT evaluation period was 6 weeks from the initial administration of pembrolizumab (week 6 to 12). |
Outcome Measure Data
| Analysis Population Description |
|---|
| The DLT analysis set included DLT-evaluable participants enrolled in Phase 1b who had the opportunity to be on treatment for at least 6 weeks from the initial dose of pembrolizumab and received at least 2 doses of talimogene laherparepvec and 2 doses of pembrolizumab in combination (ie, on the same day), or those who otherwise experienced a DLT within 6 weeks after starting the combination therapy. |
| Arm/Group Title | Phase 1b: Talimogene Laherparepvec + Pembrolizumab |
|---|---|
| Arm/Group Description | Participants received talimogene laherparepvec at an initial dose of up to 4 mL 10⁶ plaque-forming units (PFU)/mL by intralesional injection on day 1 of week 1. Subsequent doses of talimogene laherparepvec at up to 4 mL of 10⁸ PFU/mL began 3 weeks after the first dose and were administered every 2 weeks until disappearance of injectable lesions, complete response (CR), confirmed disease progression (PD) per modified Immune-related Response Criteria (irRC), intolerance of study treatment, 24 months from the date of the first dose of pembrolizumab, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 2 weeks starting at the time of the third dose of talimogene laherparepvec (week 6) until confirmed PD per modified irRC, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first. |
| Measure Participants | 21 |
| Count of Participants [Participants] |
0
0%
|
| Title | Phase 3: Progression Free Survival (PFS) by Blinded Independent Central Review (BICR) Assessed Using Modified RECIST 1.1 |
|---|---|
| Description | PFS per modified Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 is defined as the interval from randomization to the earlier event of progressive disease (PD) per modified RECIST 1.1 or death from any cause. PD: Increase in size of target lesions from nadir by ≥ 20% and ≥ 5 mm absolute increase above nadir, or the appearance of a new lesion. Median PFS was calculated using the Kaplan-Meier method. Participants without an event were censored at their last evaluable tumor assessment if available; otherwise on their randomization date. The primary analysis of PFS was specified to be conducted when 407 PFS events had occurred (data cut-off date 02 March 2020). |
| Time Frame | From randomization until the data-cut-off date of 02 March 2020; median (range) time on follow-up was 25.5 (0.6, 44.7) months in the Placebo + Pembrolizumab arm and 25.6 (0.3, 45.8) months in the Talimogene Laherparepvec + Pembrolizumab arm. |
Outcome Measure Data
| Analysis Population Description |
|---|
| All participants randomized in Phase 3. |
| Arm/Group Title | Phase 3: Placebo + Pembrolizumab | Phase 3: Talimogene Laherparepvec + Pembrolizumab |
|---|---|---|
| Arm/Group Description | Participants received up to 4 mL placebo to talimogene laherparepvec by intralesional injection on day 1 of week 0. Subsequent doses of placebo (up to 4 mL) began 3 weeks after the first dose and were administered every 2 weeks until the fifth injection (week 9), and then synchronously with pembrolizumab thereafter every 3 weeks until disappearance of injectable lesions, complete response per modified Immune-related Response Criteria simulating Response Evaluation Criteria in Solid Tumors (irRC-RECIST) (iCR), confirmed iPD per modified irRC-RECIST, intolerance of study treatment, 24 months from the date of the first dose of placebo, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 3 weeks starting on day 1 of week 0, until confirmed iPD per modified irRC-RECIST, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first. | Participants received talimogene laherparepvec at an initial dose of up to 4 mL 10⁶ PFU/mL by intralesional injection on day 1. Subsequent doses of talimogene laherparepvec at 10⁸ PFU/mL (up to 4 mL) began 3 weeks after the first dose and were administered every 2 weeks until the fifth injection of talimogene laherparepvec (week 9), and then synchronously with pembrolizumab thereafter every 3 weeks until disappearance of injectable lesions, iCR, confirmed iPD per modified irRC-RECIST, intolerance of study treatment, 24 months from the date of the first dose of talimogene laherparepvec, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 3 weeks starting on day 1 of week 0, until confirmed iPD per modified irRC-RECIST, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first. |
| Measure Participants | 346 | 346 |
| Median (95% Confidence Interval) [months] |
8.5
|
14.3
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Phase 1b: Talimogene Laherparepvec + Pembrolizumab, Phase 3: Talimogene Laherparepvec + Pembrolizumab |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.13 |
| Comments | ||
| Method | Stratified log-rank test | |
| Comments | Stratified by randomization factors (disease stage, prior BRAF inhibitor therapy) and baseline PD-L1 status. | |
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 0.86 | |
| Confidence Interval |
(2-Sided) 95% 0.71 to 1.04 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Cox proportional hazards model stratified by randomization factors (disease stage, prior BRAF inhibitor therapy) and baseline PD-L1 status. | |
| Title | Phase 3: Overall Survival |
|---|---|
| Description | Overall survival (OS) is defined as the interval from randomization to death from any cause. Median overall survival was calculated using the Kaplan-Meier method. Participants without an event were censored at their last known alive date. |
| Time Frame | From randomization until the end of study; median (range) time on follow-up was 34.8 (0.6, 58.3) months in the Placebo + Pembrolizumab arm and 36.8 (0.3, 58.4) months in the Talimogene Laherparepvec + Pembrolizumab arm. |
Outcome Measure Data
| Analysis Population Description |
|---|
| All participants randomized in Phase 3 |
| Arm/Group Title | Phase 3: Placebo + Pembrolizumab | Phase 3: Talimogene Laherparepvec + Pembrolizumab |
|---|---|---|
| Arm/Group Description | Participants received up to 4 mL placebo to talimogene laherparepvec by intralesional injection on day 1 of week 0. Subsequent doses of placebo (up to 4 mL) began 3 weeks after the first dose and were administered every 2 weeks until the fifth injection (week 9), and then synchronously with pembrolizumab thereafter every 3 weeks until disappearance of injectable lesions, complete response per modified Immune-related Response Criteria simulating Response Evaluation Criteria in Solid Tumors (irRC-RECIST) (iCR), confirmed iPD per modified irRC-RECIST, intolerance of study treatment, 24 months from the date of the first dose of placebo, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 3 weeks starting on day 1 of week 0, until confirmed iPD per modified irRC-RECIST, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first. | Participants received talimogene laherparepvec at an initial dose of up to 4 mL 10⁶ PFU/mL by intralesional injection on day 1. Subsequent doses of talimogene laherparepvec at 10⁸ PFU/mL (up to 4 mL) began 3 weeks after the first dose and were administered every 2 weeks until the fifth injection of talimogene laherparepvec (week 9), and then synchronously with pembrolizumab thereafter every 3 weeks until disappearance of injectable lesions, iCR, confirmed iPD per modified irRC-RECIST, intolerance of study treatment, 24 months from the date of the first dose of talimogene laherparepvec, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 3 weeks starting on day 1 of week 0, until confirmed iPD per modified irRC-RECIST, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first. |
| Measure Participants | 346 | 346 |
| Median (95% Confidence Interval) [months] |
NA
|
NA
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Phase 1b: Talimogene Laherparepvec + Pembrolizumab, Phase 3: Talimogene Laherparepvec + Pembrolizumab |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.77 |
| Comments | ||
| Method | Stratified log-rank test | |
| Comments | Stratified by randomization factors (disease stage, prior BRAF inhibitor therapy) and baseline PD-L1 status. | |
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 0.97 | |
| Confidence Interval |
(2-Sided) 95% 0.77 to 1.21 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Cox proportional hazards model stratified by randomization factors (disease stage, prior BRAF inhibitor therapy) and baseline PD-L1 status. | |
| Title | Phase 1b: Objective Response Rate (ORR) |
|---|---|
| Description | ORR is defined as the percentage of participants with a best overall response of complete response (CR) or partial response (PR) using the modified Immune-related Response Criteria (irRC), by Investigator assessment. CR was defined as the disappearance of all lesions; PR was defined as a decrease in tumor area ≥ 50% relative to baseline, response must have been confirmed by a second, consecutive assessment at least 4 weeks apart. Radiographic imaging for assessment of lesions was performed using computed tomography (CT), positron emission tomography (PET), magnetic resonance imaging (MRI), or ultrasound. Clinical measurement of cutaneous, subcutaneous, and palpable nodal tumor lesions was conducted with calipers. |
| Time Frame | Tumor assessments were performed at week 6 (prior to initiation of pembrolizumab), week 18, and every 12 weeks thereafter until confirmed PD or start of new anticancer treatment; median (range) time on follow-up was 58.6 (1.4, 61.6) months. |
Outcome Measure Data
| Analysis Population Description |
|---|
| All participants enrolled in Phase 1b who received ≥ 1 dose of talimogene laherparepvec or pembrolizumab. Participants with no post-baseline tumor assessments were counted as non-responders. |
| Arm/Group Title | Phase 1b: Talimogene Laherparepvec + Pembrolizumab |
|---|---|
| Arm/Group Description | Participants received talimogene laherparepvec at an initial dose of up to 4 mL 10⁶ plaque-forming units (PFU)/mL by intralesional injection on day 1 of week 1. Subsequent doses of talimogene laherparepvec at up to 4 mL of 10⁸ PFU/mL began 3 weeks after the first dose and were administered every 2 weeks until disappearance of injectable lesions, complete response (CR), confirmed disease progression (PD) per modified Immune-related Response Criteria (irRC), intolerance of study treatment, 24 months from the date of the first dose of pembrolizumab, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 2 weeks starting at the time of the third dose of talimogene laherparepvec (week 6) until confirmed PD per modified irRC, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first. |
| Measure Participants | 21 |
| Number (95% Confidence Interval) [percentage of participants] |
61.9
294.8%
|
| Title | Phase 1b: Best Overall Response (BOR) |
|---|---|
| Description | Best overall response is defined as the best overall visit response in the following order: CR, PR, stable disease (SD), progressive disease (PD), or unevaluable (UE), based on investigator assessment using the modified irRC up to the start of any subsequent anti-cancer therapy. CR was defined as the disappearance of all lesions; PR was defined as a decrease in tumor area ≥ 50% relative to baseline; PD was defined as an increase in tumor area ≥ 25% relative to nadir; and SD was defined as any outcome not meeting the criteria for response or PD with ≥ 77 days elapsed after enrollment. Responses and PD must have been confirmed by a second, consecutive assessment at least 4 weeks apart. |
| Time Frame | Tumor assessments were performed at week 6 (prior to initiation of pembrolizumab), week 18, and every 12 weeks thereafter until confirmed PD or start of new anticancer treatment; median (range) time on follow-up was 58.6 (1.4, 61.6) months. |
Outcome Measure Data
| Analysis Population Description |
|---|
| All participants enrolled in Phase 1b who received ≥ 1 dose of talimogene laherparepvec or pembrolizumab. |
| Arm/Group Title | Phase 1b: Talimogene Laherparepvec + Pembrolizumab |
|---|---|
| Arm/Group Description | Participants received talimogene laherparepvec at an initial dose of up to 4 mL 10⁶ plaque-forming units (PFU)/mL by intralesional injection on day 1 of week 1. Subsequent doses of talimogene laherparepvec at up to 4 mL of 10⁸ PFU/mL began 3 weeks after the first dose and were administered every 2 weeks until disappearance of injectable lesions, complete response (CR), confirmed disease progression (PD) per modified Immune-related Response Criteria (irRC), intolerance of study treatment, 24 months from the date of the first dose of pembrolizumab, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 2 weeks starting at the time of the third dose of talimogene laherparepvec (week 6) until confirmed PD per modified irRC, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first. |
| Measure Participants | 21 |
| Complete Response (CR) |
9
42.9%
|
| Partial Response (PR) |
4
19%
|
| Stable Disease (SD) |
1
4.8%
|
| Progressive Disease (PD) |
6
28.6%
|
| Unable to Evaluate (UE) |
1
4.8%
|
| Title | Phase 1b: Durable Response Rate (DRR) |
|---|---|
| Description | DRR is defined as the percentage of participants with a best overall response of CR or PR using the modified irRC per Investigator assessment with a duration of response of at least 6 months. CR was defined as the disappearance of all lesions; PR was defined as a decrease in tumor area ≥ 50% relative to baseline, response must have been confirmed by a second, consecutive assessment at least 4 weeks apart. |
| Time Frame | Tumor assessments were performed at week 6 (prior to initiation of pembrolizumab), week 18, and every 12 weeks thereafter until confirmed PD or start of new anticancer treatment; median (range) time on follow-up was 58.6 (1.4, 61.6) months. |
Outcome Measure Data
| Analysis Population Description |
|---|
| All participants enrolled in Phase 1b who received ≥ 1 dose of talimogene laherparepvec or pembrolizumab. |
| Arm/Group Title | Phase 1b: Talimogene Laherparepvec + Pembrolizumab |
|---|---|
| Arm/Group Description | Participants received talimogene laherparepvec at an initial dose of up to 4 mL 10⁶ plaque-forming units (PFU)/mL by intralesional injection on day 1 of week 1. Subsequent doses of talimogene laherparepvec at up to 4 mL of 10⁸ PFU/mL began 3 weeks after the first dose and were administered every 2 weeks until disappearance of injectable lesions, complete response (CR), confirmed disease progression (PD) per modified Immune-related Response Criteria (irRC), intolerance of study treatment, 24 months from the date of the first dose of pembrolizumab, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 2 weeks starting at the time of the third dose of talimogene laherparepvec (week 6) until confirmed PD per modified irRC, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first. |
| Measure Participants | 21 |
| Number (95% Confidence Interval) [percentage of participants] |
57.1
271.9%
|
| Title | Phase 1b: Duration of Response (DOR) |
|---|---|
| Description | Duration of response (DOR) is defined as the time from the date of an initial response (CR or PR) that is subsequently confirmed to the earlier of confirmed PD or death. Participants who had not ended their response at the time of analysis were censored at their last evaluable tumor assessment before start of the first subsequent anticancer therapy. CR was defined as the disappearance of all lesions; PR was defined as a decrease in tumor area ≥ 50% relative to baseline; PD was defined as an increase in tumor area ≥ 25% relative to nadir. Response and PD must have been confirmed by a second, consecutive assessment at least 4 weeks apart. |
| Time Frame | Tumor assessments were performed at week 6 (prior to initiation of pembrolizumab), week 18, and every 12 weeks thereafter until confirmed PD or start of new anticancer treatment; median (range) time on follow-up was 58.6 (1.4, 61.6) months. |
Outcome Measure Data
| Analysis Population Description |
|---|
| All participants enrolled in Phase 1b who received ≥ 1 dose of talimogene laherparepvec or pembrolizumab with a CR or PR. |
| Arm/Group Title | Phase 1b: Talimogene Laherparepvec + Pembrolizumab |
|---|---|
| Arm/Group Description | Participants received talimogene laherparepvec at an initial dose of up to 4 mL 10⁶ plaque-forming units (PFU)/mL by intralesional injection on day 1 of week 1. Subsequent doses of talimogene laherparepvec at up to 4 mL of 10⁸ PFU/mL began 3 weeks after the first dose and were administered every 2 weeks until disappearance of injectable lesions, complete response (CR), confirmed disease progression (PD) per modified Immune-related Response Criteria (irRC), intolerance of study treatment, 24 months from the date of the first dose of pembrolizumab, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 2 weeks starting at the time of the third dose of talimogene laherparepvec (week 6) until confirmed PD per modified irRC, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first. |
| Measure Participants | 13 |
| Median (95% Confidence Interval) [months] |
NA
|
| Title | Phase 1b: Disease Control Rate (DCR) |
|---|---|
| Description | DCR is defined as the percentage of participants with a best overall response of CR, PR, or SD using the modified irRC per Investigator assessment. CR was defined as the disappearance of all lesions; PR was defined as a decrease in tumor area ≥ 50% relative to baseline, response must have been confirmed by a second, consecutive assessment at least 4 weeks apart; and SD was defined as any outcome not meeting the criteria for response or PD with ≥ 84 days elapsed after enrollment. |
| Time Frame | Tumor assessments were performed at week 6 (prior to initiation of pembrolizumab), week 18, and every 12 weeks thereafter until confirmed PD or start of new anticancer treatment; median (range) time on follow-up was 58.6 (1.4, 61.6) months. |
Outcome Measure Data
| Analysis Population Description |
|---|
| All participants enrolled in Phase 1b who received ≥ 1 dose of talimogene laherparepvec or pembrolizumab. |
| Arm/Group Title | Phase 1b: Talimogene Laherparepvec + Pembrolizumab |
|---|---|
| Arm/Group Description | Participants received talimogene laherparepvec at an initial dose of up to 4 mL 10⁶ plaque-forming units (PFU)/mL by intralesional injection on day 1 of week 1. Subsequent doses of talimogene laherparepvec at up to 4 mL of 10⁸ PFU/mL began 3 weeks after the first dose and were administered every 2 weeks until disappearance of injectable lesions, complete response (CR), confirmed disease progression (PD) per modified Immune-related Response Criteria (irRC), intolerance of study treatment, 24 months from the date of the first dose of pembrolizumab, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 2 weeks starting at the time of the third dose of talimogene laherparepvec (week 6) until confirmed PD per modified irRC, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first. |
| Measure Participants | 21 |
| Number (95% Confidence Interval) [percentage of participants] |
66.7
317.6%
|
| Title | Phase 1b: Progression-free Survival (PFS) |
|---|---|
| Description | Progression-free survival is defined as the time from first dose to the earlier event of confirmed PD per modified irRC or death from any cause. PFS was estimated using the Kaplan-Meier method. Participants without an event were censored at their last evaluable tumor assessment. |
| Time Frame | From first dose until the end of study; median (range) time on follow-up was 70.6 (1.4, 74.5) months. |
Outcome Measure Data
| Analysis Population Description |
|---|
| All participants enrolled in Phase 1b who received ≥ 1 dose of talimogene laherparepvec or pembrolizumab. |
| Arm/Group Title | Phase 1b: Talimogene Laherparepvec + Pembrolizumab |
|---|---|
| Arm/Group Description | Participants received talimogene laherparepvec at an initial dose of up to 4 mL 10⁶ plaque-forming units (PFU)/mL by intralesional injection on day 1 of week 1. Subsequent doses of talimogene laherparepvec at up to 4 mL of 10⁸ PFU/mL began 3 weeks after the first dose and were administered every 2 weeks until disappearance of injectable lesions, complete response (CR), confirmed disease progression (PD) per modified Immune-related Response Criteria (irRC), intolerance of study treatment, 24 months from the date of the first dose of pembrolizumab, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 2 weeks starting at the time of the third dose of talimogene laherparepvec (week 6) until confirmed PD per modified irRC, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first. |
| Measure Participants | 21 |
| Median (95% Confidence Interval) [months] |
NA
|
| Title | Phase 1b: Overall Survival (OS) |
|---|---|
| Description | Overall survival is defined as the interval from first dose to death from any cause. OS was estimated using the Kaplan-Meier method. Participants without an event were censored at their last known alive date. |
| Time Frame | From first dose until the end of study; median (range) time on follow-up was 70.6 (1.4, 74.5) months. |
Outcome Measure Data
| Analysis Population Description |
|---|
| All participants enrolled in Phase 1b who received ≥ 1 dose of talimogene laherparepvec or pembrolizumab |
| Arm/Group Title | Phase 1b: Talimogene Laherparepvec + Pembrolizumab |
|---|---|
| Arm/Group Description | Participants received talimogene laherparepvec at an initial dose of up to 4 mL 10⁶ plaque-forming units (PFU)/mL by intralesional injection on day 1 of week 1. Subsequent doses of talimogene laherparepvec at up to 4 mL of 10⁸ PFU/mL began 3 weeks after the first dose and were administered every 2 weeks until disappearance of injectable lesions, complete response (CR), confirmed disease progression (PD) per modified Immune-related Response Criteria (irRC), intolerance of study treatment, 24 months from the date of the first dose of pembrolizumab, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 2 weeks starting at the time of the third dose of talimogene laherparepvec (week 6) until confirmed PD per modified irRC, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first. |
| Measure Participants | 21 |
| Median (95% Confidence Interval) [months] |
NA
|
| Title | Phase 3: Complete Response Rate Assessed Using Modified irRC-RECIST (iCRR) |
|---|---|
| Description | Complete response rate per modified Immune-related Response Criteria (irRC) simulating RECIST 1.1 (irRC-RECIST) is defined as the percentage of participants with a best overall response of complete response assessed using the modified irRC-RECIST (iCR) evaluated by blinded independent central review. iCR: Disappearance of all lesions (whether measurable or not and whether baseline or new) and confirmation by a repeat, consecutive assessment at least 4 weeks after the criteria were first met. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Modifications to the irRC-RECIST 1.1 included an increase in the total number of target lesions and new measurable lesions to 10 with a maximum of 5 target lesions per organ, and target lesions must have been measurable by CT or MRI only. |
| Time Frame | Tumor assessments were performed every 12 weeks after initiation of treatment until confirmed PD or start of new anticancer treatment; median (range) time on follow-up was 30.6 (0.6, 53.0) months and 31.4 (0.3, 52.5) months in each group, respectively. |
Outcome Measure Data
| Analysis Population Description |
|---|
| All participants randomized in Phase 3 |
| Arm/Group Title | Phase 3: Placebo + Pembrolizumab | Phase 3: Talimogene Laherparepvec + Pembrolizumab |
|---|---|---|
| Arm/Group Description | Participants received up to 4 mL placebo to talimogene laherparepvec by intralesional injection on day 1 of week 0. Subsequent doses of placebo (up to 4 mL) began 3 weeks after the first dose and were administered every 2 weeks until the fifth injection (week 9), and then synchronously with pembrolizumab thereafter every 3 weeks until disappearance of injectable lesions, complete response per modified Immune-related Response Criteria simulating Response Evaluation Criteria in Solid Tumors (irRC-RECIST) (iCR), confirmed iPD per modified irRC-RECIST, intolerance of study treatment, 24 months from the date of the first dose of placebo, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 3 weeks starting on day 1 of week 0, until confirmed iPD per modified irRC-RECIST, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first. | Participants received talimogene laherparepvec at an initial dose of up to 4 mL 10⁶ PFU/mL by intralesional injection on day 1. Subsequent doses of talimogene laherparepvec at 10⁸ PFU/mL (up to 4 mL) began 3 weeks after the first dose and were administered every 2 weeks until the fifth injection of talimogene laherparepvec (week 9), and then synchronously with pembrolizumab thereafter every 3 weeks until disappearance of injectable lesions, iCR, confirmed iPD per modified irRC-RECIST, intolerance of study treatment, 24 months from the date of the first dose of talimogene laherparepvec, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 3 weeks starting on day 1 of week 0, until confirmed iPD per modified irRC-RECIST, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first. |
| Measure Participants | 346 | 346 |
| Number (95% Confidence Interval) [percentage of participants] |
8.1
38.6%
|
14.5
4.2%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Phase 1b: Talimogene Laherparepvec + Pembrolizumab, Phase 3: Talimogene Laherparepvec + Pembrolizumab |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.012 |
| Comments | ||
| Method | Regression, Logistic | |
| Comments | Logistic regression stratified by randomization stratification factors (disease stage and prior BRAF inhibitor therapy) and the baseline PD-L1 status. | |
| Method of Estimation | Estimation Parameter | Odds Ratio (OR) |
| Estimated Value | 1.88 | |
| Confidence Interval |
(2-Sided) 95% 1.15 to 3.07 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Adjusted odds ratio estimated using logistic regression with randomization stratification factors and baseline PD-L1 status. | |
| Title | Phase 3: Progression Free Survival Assessed Using Modified irRC-RECIST (iPFS) |
|---|---|
| Description | PFS per modified irRC-RECIST is defined as the interval from randomization to the earlier event of progressive disease assessed by modified irRC-RECIST (iPD) evaluated by blinded independent central review, or death from any cause. iPD: Increase in tumor burden ≥ 20% and at least 5 mm absolute increase relative to nadir (minimum recorded tumor burden) confirmed by a repeat, consecutive assessment at least 4 weeks after the initial detection. Median iPFS was calculated using the Kaplan-Meier method. Participants without an event were censored at their last evaluable tumor assessment if available; otherwise on their randomization date. The primary analysis of iPFS was specified to be conducted when 256 iPFS events had occurred (data cut-off date 29 September 2020). |
| Time Frame | From randomization until the data cut-off date of 29 September 2020; median time on follow-up was 30.6 (0.6, 53.0) months in the Placebo + Pembrolizumab arm and 31.4 (0.3, 52.5) months in the Talimogene Laherparepvec + Pembrolizumab arm. |
Outcome Measure Data
| Analysis Population Description |
|---|
| All participants randomized in Phase 3 |
| Arm/Group Title | Phase 3 : Placebo + Pembrolizumab | Phase 3: Talimogene Laherparepvec + Pembrolizumab |
|---|---|---|
| Arm/Group Description | Participants received up to 4 mL placebo to talimogene laherparepvec by intralesional injection on day 1 of week 0. Subsequent doses of placebo (up to 4 mL) began 3 weeks after the first dose and were administered every 2 weeks until the fifth injection (week 9), and then synchronously with pembrolizumab thereafter every 3 weeks until disappearance of injectable lesions, complete response per modified Immune-related Response Criteria simulating Response Evaluation Criteria in Solid Tumors (irRC-RECIST) (iCR), confirmed iPD per modified irRC-RECIST, intolerance of study treatment, 24 months from the date of the first dose of placebo, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 3 weeks starting on day 1 of week 0, until confirmed iPD per modified irRC-RECIST, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first. | Participants received talimogene laherparepvec at an initial dose of up to 4 mL 10⁶ PFU/mL by intralesional injection on day 1. Subsequent doses of talimogene laherparepvec at 10⁸ PFU/mL (up to 4 mL) began 3 weeks after the first dose and were administered every 2 weeks until the fifth injection of talimogene laherparepvec (week 9), and then synchronously with pembrolizumab thereafter every 3 weeks until disappearance of injectable lesions, iCR, confirmed iPD per modified irRC-RECIST, intolerance of study treatment, 24 months from the date of the first dose of talimogene laherparepvec, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 3 weeks starting on day 1 of week 0, until confirmed iPD per modified irRC-RECIST, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first. |
| Measure Participants | 346 | 346 |
| Median (95% Confidence Interval) [months] |
25.3
|
NA
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Phase 1b: Talimogene Laherparepvec + Pembrolizumab, Phase 3: Talimogene Laherparepvec + Pembrolizumab |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.14 |
| Comments | ||
| Method | Stratified log-rank test | |
| Comments | Stratified by randomization factors (disease stage, prior BRAF inhibitor therapy) and baseline PD-L1 status. | |
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 1.05 | |
| Confidence Interval |
(2-Sided) 95% 0.82 to 1.34 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Cox proportional hazards model stratified by randomization factors (disease stage, prior BRAF inhibitor therapy) and baseline PD-L1 status. | |
| Title | Phase 3: Overall Survival Excluding Stage IVM1c Participants |
|---|---|
| Description | Overall survival is defined as the interval from randomization to death from any cause. Median OS was calculated using the Kaplan-Meier method. Participants without an event were censored at the last known alive date. |
| Time Frame | From randomization until the end of study; median (range) time on follow-up was 34.8 (0.6, 58.3) months in the Placebo + Pembrolizumab arm and 36.8 (0.3, 58.4) months in the Talimogene Laherparepvec + Pembrolizumab arm. |
Outcome Measure Data
| Analysis Population Description |
|---|
| Participants randomized in Phase 3 with stage IIIB to IVM1a/b. |
| Arm/Group Title | Phase 3: Placebo + Pembrolizumab | Phase 3: Talimogene Laherparepvec + Pembrolizumab |
|---|---|---|
| Arm/Group Description | Participants received up to 4 mL placebo to talimogene laherparepvec by intralesional injection on day 1 of week 0. Subsequent doses of placebo (up to 4 mL) began 3 weeks after the first dose and were administered every 2 weeks until the fifth injection (week 9), and then synchronously with pembrolizumab thereafter every 3 weeks until disappearance of injectable lesions, complete response per modified Immune-related Response Criteria simulating Response Evaluation Criteria in Solid Tumors (irRC-RECIST) (iCR), confirmed iPD per modified irRC-RECIST, intolerance of study treatment, 24 months from the date of the first dose of placebo, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 3 weeks starting on day 1 of week 0, until confirmed iPD per modified irRC-RECIST, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first. | Participants received talimogene laherparepvec at an initial dose of up to 4 mL 10⁶ PFU/mL by intralesional injection on day 1. Subsequent doses of talimogene laherparepvec at 10⁸ PFU/mL (up to 4 mL) began 3 weeks after the first dose and were administered every 2 weeks until the fifth injection of talimogene laherparepvec (week 9), and then synchronously with pembrolizumab thereafter every 3 weeks until disappearance of injectable lesions, iCR, confirmed iPD per modified irRC-RECIST, intolerance of study treatment, 24 months from the date of the first dose of talimogene laherparepvec, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 3 weeks starting on day 1 of week 0, until confirmed iPD per modified irRC-RECIST, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first. |
| Measure Participants | 203 | 201 |
| Median (95% Confidence Interval) [months] |
NA
|
NA
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Phase 1b: Talimogene Laherparepvec + Pembrolizumab, Phase 3: Talimogene Laherparepvec + Pembrolizumab |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.47 |
| Comments | ||
| Method | Stratified log-rank test | |
| Comments | Stratified by randomization factors (disease stage, prior BRAF inhibitor therapy) and baseline PD-L1 status. | |
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 0.88 | |
| Confidence Interval |
(2-Sided) 95% 0.63 to 1.24 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Cox proportional hazards model stratified by randomization factors (disease stage, prior BRAF inhibitor therapy) and baseline PD-L1 status. | |
| Title | Phase 3: Objective Response Rate Assessed Using Modified RECIST 1.1 |
|---|---|
| Description | ORR is defined as the percentage of participants with a best overall response of complete response (CR) or partial response (PR) assessed using modified RECIST version 1.1, evaluated by blinded independent central review. CR was defined as the disappearance of all lesions except lymph node short axis < 10 mm; PR was defined as a ≥ 30% reduction in sum of diameters in target lesions. Confirmation of CR or PR was not required. Modifications to conventional RECIST 1.1 included the following: target lesions were measurable on CT or MRI; otherwise, they were considered as nontarget lesions. A maximum of 10 target lesions was allowed with up to 5 per organ. |
| Time Frame | Tumor assessments were performed every 12 weeks after initiation of treatment until confirmed PD or start of new anticancer treatment; median (range) time on follow-up was 30.6 (0.6, 53.0) months and 31.4 (0.3, 52.5) months in each group, respectively. |
Outcome Measure Data
| Analysis Population Description |
|---|
| All participants randomized in Phase 3; Participants with no post-baseline tumor assessments were counted as non-responders. |
| Arm/Group Title | Phase 3: Placebo + Pembrolizumab | Phase 3: Talimogene Laherparepvec + Pembrolizumab |
|---|---|---|
| Arm/Group Description | Participants received up to 4 mL placebo to talimogene laherparepvec by intralesional injection on day 1 of week 0. Subsequent doses of placebo (up to 4 mL) began 3 weeks after the first dose and were administered every 2 weeks until the fifth injection (week 9), and then synchronously with pembrolizumab thereafter every 3 weeks until disappearance of injectable lesions, complete response per modified Immune-related Response Criteria simulating Response Evaluation Criteria in Solid Tumors (irRC-RECIST) (iCR), confirmed iPD per modified irRC-RECIST, intolerance of study treatment, 24 months from the date of the first dose of placebo, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 3 weeks starting on day 1 of week 0, until confirmed iPD per modified irRC-RECIST, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first. | Participants received talimogene laherparepvec at an initial dose of up to 4 mL 10⁶ PFU/mL by intralesional injection on day 1. Subsequent doses of talimogene laherparepvec at 10⁸ PFU/mL (up to 4 mL) began 3 weeks after the first dose and were administered every 2 weeks until the fifth injection of talimogene laherparepvec (week 9), and then synchronously with pembrolizumab thereafter every 3 weeks until disappearance of injectable lesions, iCR, confirmed iPD per modified irRC-RECIST, intolerance of study treatment, 24 months from the date of the first dose of talimogene laherparepvec, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 3 weeks starting on day 1 of week 0, until confirmed iPD per modified irRC-RECIST, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first. |
| Measure Participants | 346 | 346 |
| Number (95% Confidence Interval) [percentage of participants] |
41.3
196.7%
|
48.6
14%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Phase 1b: Talimogene Laherparepvec + Pembrolizumab, Phase 3: Talimogene Laherparepvec + Pembrolizumab |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.081 |
| Comments | ||
| Method | Regression, Logistic | |
| Comments | Logistic regression stratified by randomization stratification factors (disease stage and prior BRAF inhibitor therapy) and the baseline PD-L1 status. | |
| Method of Estimation | Estimation Parameter | Odds Ratio (OR) |
| Estimated Value | 1.32 | |
| Confidence Interval |
(2-Sided) 95% 0.97 to 1.79 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Adjusted odds ratio estimated using logistic regression with randomization stratification factors and baseline PD-L1 status. | |
| Title | Phase 3: Best Overall Response Assessed Using Modified RECIST 1.1 |
|---|---|
| Description | BOR is defined as the best overall visit response up to and including the first overall visit response of PD in the following order: CR, PR, SD, non-CR/Non-PD (NN), PD or UE per modified RECIST 1.1, evaluated by BICR. CR: Disappearance of all lesions except lymph node short axis < 10 mm; PR: ≥ 30% reduction in sum of diameters in target lesions. Confirmation of CR or PR was not required; NN: Persistence of ≥ 1 non-target lesions and/or maintenance of tumor marker level above normal limits; SD: Neither sufficient shrinkage of target lesions to qualify for CR or PR nor sufficient increase to qualify for PD and ≥ 84 days from randomization; PD: Increase from nadir by ≥ 20% or ≥ 5 mm of target lesions or any new lesion; Missing: No postbaseline assessment, or assessments on or after the start of first subsequent anticancer therapy, including complete or partial removal/reduction of any target lesion which contained melanoma on pathology evaluation or pathology results were unknown. |
| Time Frame | Tumor assessments were performed every 12 weeks after initiation of treatment until confirmed PD or start of new anticancer treatment; median (range) time on follow-up was 30.6 (0.6, 53.0) months and 31.4 (0.3, 52.5) months in each group, respectively. |
Outcome Measure Data
| Analysis Population Description |
|---|
| All participants randomized in Phase 3 |
| Arm/Group Title | Phase 3: Placebo + Pembrolizumab | Phase 3: Talimogene Laherparepvec + Pembrolizumab |
|---|---|---|
| Arm/Group Description | Participants received up to 4 mL placebo to talimogene laherparepvec by intralesional injection on day 1 of week 0. Subsequent doses of placebo (up to 4 mL) began 3 weeks after the first dose and were administered every 2 weeks until the fifth injection (week 9), and then synchronously with pembrolizumab thereafter every 3 weeks until disappearance of injectable lesions, complete response per modified Immune-related Response Criteria simulating Response Evaluation Criteria in Solid Tumors (irRC-RECIST) (iCR), confirmed iPD per modified irRC-RECIST, intolerance of study treatment, 24 months from the date of the first dose of placebo, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 3 weeks starting on day 1 of week 0, until confirmed iPD per modified irRC-RECIST, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first. | Participants received talimogene laherparepvec at an initial dose of up to 4 mL 10⁶ PFU/mL by intralesional injection on day 1. Subsequent doses of talimogene laherparepvec at 10⁸ PFU/mL (up to 4 mL) began 3 weeks after the first dose and were administered every 2 weeks until the fifth injection of talimogene laherparepvec (week 9), and then synchronously with pembrolizumab thereafter every 3 weeks until disappearance of injectable lesions, iCR, confirmed iPD per modified irRC-RECIST, intolerance of study treatment, 24 months from the date of the first dose of talimogene laherparepvec, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 3 weeks starting on day 1 of week 0, until confirmed iPD per modified irRC-RECIST, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first. |
| Measure Participants | 346 | 346 |
| Complete response (CR) |
40
190.5%
|
62
17.9%
|
| Partial response (PR) |
103
490.5%
|
106
30.6%
|
| Stable disease (SD) |
30
142.9%
|
28
8.1%
|
| Non-CR/Non-PD (NN) |
16
76.2%
|
11
3.2%
|
| Progressive disease (PD) |
120
571.4%
|
106
30.6%
|
| Unevaluable (UE) |
11
52.4%
|
3
0.9%
|
| Missing |
26
123.8%
|
30
8.7%
|
| Title | Phase 3: Durable Response Rate (DRR) Assessed Using Modified RECIST 1.1 |
|---|---|
| Description | DRR is defined as the percentage of participants with a CR or PR per modified RECIST 1.1 evaluated by blinded independent central review, with a duration of response of ≥ 6 months. CR was defined as the disappearance of all lesions except lymph node short axis < 10 mm; PR was defined as a ≥ 30% reduction in sum of diameters in target lesions. Confirmation of CR or PR was not required. |
| Time Frame | Tumor assessments were performed every 12 weeks after initiation of treatment until confirmed PD or start of new anticancer treatment; median (range) time on follow-up was 30.6 (0.6, 53.0) months and 31.4 (0.3, 52.5) months in each group, respectively. |
Outcome Measure Data
| Analysis Population Description |
|---|
| All participants randomized in Phase 3 |
| Arm/Group Title | Phase 3: Placebo + Pembrolizumab | Phase 3: Talimogene Laherparepvec + Pembrolizumab |
|---|---|---|
| Arm/Group Description | Participants received up to 4 mL placebo to talimogene laherparepvec by intralesional injection on day 1 of week 0. Subsequent doses of placebo (up to 4 mL) began 3 weeks after the first dose and were administered every 2 weeks until the fifth injection (week 9), and then synchronously with pembrolizumab thereafter every 3 weeks until disappearance of injectable lesions, complete response per modified Immune-related Response Criteria simulating Response Evaluation Criteria in Solid Tumors (irRC-RECIST) (iCR), confirmed iPD per modified irRC-RECIST, intolerance of study treatment, 24 months from the date of the first dose of placebo, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 3 weeks starting on day 1 of week 0, until confirmed iPD per modified irRC-RECIST, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first. | Participants received talimogene laherparepvec at an initial dose of up to 4 mL 10⁶ PFU/mL by intralesional injection on day 1. Subsequent doses of talimogene laherparepvec at 10⁸ PFU/mL (up to 4 mL) began 3 weeks after the first dose and were administered every 2 weeks until the fifth injection of talimogene laherparepvec (week 9), and then synchronously with pembrolizumab thereafter every 3 weeks until disappearance of injectable lesions, iCR, confirmed iPD per modified irRC-RECIST, intolerance of study treatment, 24 months from the date of the first dose of talimogene laherparepvec, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 3 weeks starting on day 1 of week 0, until confirmed iPD per modified irRC-RECIST, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first. |
| Measure Participants | 346 | 346 |
| Number (95% Confidence Interval) [percentage of participants] |
34.1
162.4%
|
42.2
12.2%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Phase 1b: Talimogene Laherparepvec + Pembrolizumab, Phase 3: Talimogene Laherparepvec + Pembrolizumab |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.039 |
| Comments | ||
| Method | Regression, Logistic | |
| Comments | Logistic regression stratified by randomization stratification factors (disease stage and prior BRAF inhibitor therapy) and the baseline PD-L1 status. | |
| Method of Estimation | Estimation Parameter | Odds Ratio (OR) |
| Estimated Value | 1.39 | |
| Confidence Interval |
(2-Sided) 95% 1.02 to 1.90 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Adjusted odds ratio estimated using logistic regression with randomization stratification factors and baseline PD-L1 status. | |
| Title | Phase 3: Duration of Response (DOR) Assessed Using Modified RECIST 1.1 |
|---|---|
| Description | Duration of response (DOR) is defined as the time from the date of an initial response of CR or PR to the earlier of PD per modified RECIST 1.1, or death. Participants who had not ended their response at the time of analysis were censored at their last evaluable tumor assessment date before start of the first subsequent anticancer therapy. CR was defined as the disappearance of all lesions except lymph node short axis < 10 mm; PR was defined as a ≥ 30% reduction in sum of diameters in target lesions. Confirmation of CR or PR was not required. PD was defined as an increase from nadir by ≥ 20% or ≥ 5 mm absolute increase above nadir of target lesions or appearance of any new lesion. |
| Time Frame | From randomization until the data cut-off date of 29 September 2020; median time on follow-up was 30.6 (0.6, 53.0) months in the Placebo + Pembrolizumab arm and 31.4 (0.3, 52.5) months in the Talimogene Laherparepvec + Pembrolizumab arm. |
Outcome Measure Data
| Analysis Population Description |
|---|
| Participants randomized in Phase 3 with a CR or PR per modified RECIST. |
| Arm/Group Title | Phase 3: Placebo + Pembrolizumab | Phase 3: Talimogene Laherparepvec + Pembrolizumab |
|---|---|---|
| Arm/Group Description | Participants received up to 4 mL placebo to talimogene laherparepvec by intralesional injection on day 1 of week 0. Subsequent doses of placebo (up to 4 mL) began 3 weeks after the first dose and were administered every 2 weeks until the fifth injection (week 9), and then synchronously with pembrolizumab thereafter every 3 weeks until disappearance of injectable lesions, complete response per modified Immune-related Response Criteria simulating Response Evaluation Criteria in Solid Tumors (irRC-RECIST) (iCR), confirmed iPD per modified irRC-RECIST, intolerance of study treatment, 24 months from the date of the first dose of placebo, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 3 weeks starting on day 1 of week 0, until confirmed iPD per modified irRC-RECIST, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first. | Participants received talimogene laherparepvec at an initial dose of up to 4 mL 10⁶ PFU/mL by intralesional injection on day 1. Subsequent doses of talimogene laherparepvec at 10⁸ PFU/mL (up to 4 mL) began 3 weeks after the first dose and were administered every 2 weeks until the fifth injection of talimogene laherparepvec (week 9), and then synchronously with pembrolizumab thereafter every 3 weeks until disappearance of injectable lesions, iCR, confirmed iPD per modified irRC-RECIST, intolerance of study treatment, 24 months from the date of the first dose of talimogene laherparepvec, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 3 weeks starting on day 1 of week 0, until confirmed iPD per modified irRC-RECIST, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first. |
| Measure Participants | 143 | 168 |
| Median (95% Confidence Interval) [months] |
NA
|
43.7
|
| Title | Phase 3: Disease Control Rate (DCR) Assessed Using RECIST 1.1 |
|---|---|
| Description | Disease control rate (DCR) per modified RECIST 1.1 is defined as the percentage of participants with a best overall response of CR, PR or SD evaluated by blinded independent central review. CR was defined as the disappearance of all lesions except lymph node short axis < 10 mm; PR was defined as a ≥ 30% reduction in sum of diameters in target lesions. Confirmation of CR or PR was not required. SD was defined as neither sufficient shrinkage of target lesions to qualify for CR or PR nor sufficient increase to qualify for PD with ≥ 84 days elapsed after randomization. |
| Time Frame | Tumor assessments were performed every 12 weeks after initiation of treatment until confirmed PD or start of new anticancer treatment; median (range) time on follow-up was 30.6 (0.6, 53.0) months and 31.4 (0.3, 52.5) months in each group, respectively. |
Outcome Measure Data
| Analysis Population Description |
|---|
| All participants randomized in Phase 3 |
| Arm/Group Title | Phase 3: Placebo + Pembrolizumab | Phase 3: Talimogene Laherparepvec + Pembrolizumab |
|---|---|---|
| Arm/Group Description | Participants received up to 4 mL placebo to talimogene laherparepvec by intralesional injection on day 1 of week 0. Subsequent doses of placebo (up to 4 mL) began 3 weeks after the first dose and were administered every 2 weeks until the fifth injection (week 9), and then synchronously with pembrolizumab thereafter every 3 weeks until disappearance of injectable lesions, complete response per modified Immune-related Response Criteria simulating Response Evaluation Criteria in Solid Tumors (irRC-RECIST) (iCR), confirmed iPD per modified irRC-RECIST, intolerance of study treatment, 24 months from the date of the first dose of placebo, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 3 weeks starting on day 1 of week 0, until confirmed iPD per modified irRC-RECIST, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first. | Participants received talimogene laherparepvec at an initial dose of up to 4 mL 10⁶ PFU/mL by intralesional injection on day 1. Subsequent doses of talimogene laherparepvec at 10⁸ PFU/mL (up to 4 mL) began 3 weeks after the first dose and were administered every 2 weeks until the fifth injection of talimogene laherparepvec (week 9), and then synchronously with pembrolizumab thereafter every 3 weeks until disappearance of injectable lesions, iCR, confirmed iPD per modified irRC-RECIST, intolerance of study treatment, 24 months from the date of the first dose of talimogene laherparepvec, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 3 weeks starting on day 1 of week 0, until confirmed iPD per modified irRC-RECIST, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first. |
| Measure Participants | 346 | 346 |
| Number (95% Confidence Interval) [percentage of participants] |
50.0
238.1%
|
56.6
16.4%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Phase 1b: Talimogene Laherparepvec + Pembrolizumab, Phase 3: Talimogene Laherparepvec + Pembrolizumab |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.11 |
| Comments | ||
| Method | Regression, Logistic | |
| Comments | Logistic regression stratified by randomization stratification factors (disease stage and prior BRAF inhibitor therapy) and the baseline PD-L1 status. | |
| Method of Estimation | Estimation Parameter | Odds Ratio (OR) |
| Estimated Value | 1.28 | |
| Confidence Interval |
(2-Sided) 95% 0.94 to 1.75 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Adjusted odds ratio estimated using logistic regression with randomization stratification factors and baseline PD-L1 status. | |
| Title | Phase 3: Objective Response Rate Assessed Using Modified irRC-RECIST (iORR) |
|---|---|
| Description | Objective response rate per modified irRC-RECIST is defined as the percentage of participants with a best overall response of iCR or partial response assessed using modified irRC-RECIST (iPR) evaluated by blinded independent central review. iCR: Disappearance of all lesions (whether measurable or not and whether baseline or new) and confirmation by a repeat, consecutive assessment at least 4 weeks from the date first documented. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. iPR: Decrease in tumor burden ≥ 30% relative to baseline confirmed by a consecutive assessment at least 4 weeks after first documentation. Modifications to the irRC-RECIST 1.1 included an increase in the total number of target lesions and new measurable lesions to 10 with a maximum of 5 target lesions per organ, and target lesions must be measurable by CT or MRI only. |
| Time Frame | Tumor assessments were performed every 12 weeks after initiation of treatment until confirmed PD or start of new anticancer treatment; median (range) time on follow-up was 30.6 (0.6, 53.0) months and 31.4 (0.3, 52.5) months in each group, respectively. |
Outcome Measure Data
| Analysis Population Description |
|---|
| All participants randomized in Phase 3 |
| Arm/Group Title | Phase 3: Placebo + Pembrolizumab | Phase 3: Talimogene Laherparepvec + Pembrolizumab |
|---|---|---|
| Arm/Group Description | Participants received up to 4 mL placebo to talimogene laherparepvec by intralesional injection on day 1 of week 0. Subsequent doses of placebo (up to 4 mL) began 3 weeks after the first dose and were administered every 2 weeks until the fifth injection (week 9), and then synchronously with pembrolizumab thereafter every 3 weeks until disappearance of injectable lesions, complete response per modified Immune-related Response Criteria simulating Response Evaluation Criteria in Solid Tumors (irRC-RECIST) (iCR), confirmed iPD per modified irRC-RECIST, intolerance of study treatment, 24 months from the date of the first dose of placebo, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 3 weeks starting on day 1 of week 0, until confirmed iPD per modified irRC-RECIST, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first. | Participants received talimogene laherparepvec at an initial dose of up to 4 mL 10⁶ PFU/mL by intralesional injection on day 1. Subsequent doses of talimogene laherparepvec at 10⁸ PFU/mL (up to 4 mL) began 3 weeks after the first dose and were administered every 2 weeks until the fifth injection of talimogene laherparepvec (week 9), and then synchronously with pembrolizumab thereafter every 3 weeks until disappearance of injectable lesions, iCR, confirmed iPD per modified irRC-RECIST, intolerance of study treatment, 24 months from the date of the first dose of talimogene laherparepvec, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 3 weeks starting on day 1 of week 0, until confirmed iPD per modified irRC-RECIST, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first. |
| Measure Participants | 346 | 346 |
| Number (95% Confidence Interval) [percentage of participants] |
39.9
190%
|
49.1
14.2%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Phase 1b: Talimogene Laherparepvec + Pembrolizumab, Phase 3: Talimogene Laherparepvec + Pembrolizumab |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.020 |
| Comments | ||
| Method | Regression, Logistic | |
| Comments | Logistic regression stratified by randomization stratification factors (disease stage and prior BRAF inhibitor therapy) and the baseline PD-L1 status. | |
| Method of Estimation | Estimation Parameter | Odds Ratio (OR) |
| Estimated Value | 1.44 | |
| Confidence Interval |
(2-Sided) 95% 1.06 to 1.96 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Adjusted odds ratio estimated using logistic regression with randomization stratification factors and baseline PD-L1 status. | |
| Title | Phase 3: Best Overall Response Assessed Using Modified irRC-RECIST |
|---|---|
| Description | BOR is defined as the best overall visit response in the following order: iCR, iPR, stable disease per modified irRC-RECIST (iSD), iPD, or UE per modified irRC-RECIST (iUE), evaluated by BICR. iCR: Disappearance of all lesions confirmed by consecutive assessment ≥ 4 weeks from the date first documented. Reduction of any pathological lymph node to <10 mm. iPR: Decrease in tumor burden ≥ 30% relative to baseline confirmed ≥ 4 weeks after first documentation. iPD: Increase in tumor burden ≥ 20 % and at least 5 mm absolute increase relative to nadir confirmed ≥ 4 weeks from initial detection. iSD: Neither sufficient shrinkage to qualify for iCR or iPR nor sufficient increase to qualify for iPD and ≥ 84 days from randomization. Missing: No postbaseline assessment, or assessments after start of first subsequent anticancer therapy, including complete or partial removal/reduction of any target lesion which contained melanoma on pathology evaluation or pathology results were unknown. |
| Time Frame | Tumor assessments were performed every 12 weeks after initiation of treatment until confirmed PD or start of new anticancer treatment; median (range) time on follow-up was 30.6 (0.6, 53.0) months and 31.4 (0.3, 52.5) months in each group, respectively. |
Outcome Measure Data
| Analysis Population Description |
|---|
| All participants randomized in Phase 3 |
| Arm/Group Title | Phase 3: Placebo + Pembrolizumab | Phase 3: Talimogene Laherparepvec + Pembrolizumab |
|---|---|---|
| Arm/Group Description | Participants received up to 4 mL placebo to talimogene laherparepvec by intralesional injection on day 1 of week 0. Subsequent doses of placebo (up to 4 mL) began 3 weeks after the first dose and were administered every 2 weeks until the fifth injection (week 9), and then synchronously with pembrolizumab thereafter every 3 weeks until disappearance of injectable lesions, complete response per modified Immune-related Response Criteria simulating Response Evaluation Criteria in Solid Tumors (irRC-RECIST) (iCR), confirmed iPD per modified irRC-RECIST, intolerance of study treatment, 24 months from the date of the first dose of placebo, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 3 weeks starting on day 1 of week 0, until confirmed iPD per modified irRC-RECIST, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first. | Participants received talimogene laherparepvec at an initial dose of up to 4 mL 10⁶ PFU/mL by intralesional injection on day 1. Subsequent doses of talimogene laherparepvec at 10⁸ PFU/mL (up to 4 mL) began 3 weeks after the first dose and were administered every 2 weeks until the fifth injection of talimogene laherparepvec (week 9), and then synchronously with pembrolizumab thereafter every 3 weeks until disappearance of injectable lesions, iCR, confirmed iPD per modified irRC-RECIST, intolerance of study treatment, 24 months from the date of the first dose of talimogene laherparepvec, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 3 weeks starting on day 1 of week 0, until confirmed iPD per modified irRC-RECIST, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first. |
| Measure Participants | 346 | 346 |
| Complete response (iCR) |
28
133.3%
|
50
14.5%
|
| Partial response (iPR) |
110
523.8%
|
120
34.7%
|
| Stable disease (iSD) |
57
271.4%
|
51
14.7%
|
| Progressive disease (iPD) |
56
266.7%
|
65
18.8%
|
| Unevaluable (iUE) |
69
328.6%
|
30
8.7%
|
| Missing |
26
123.8%
|
30
8.7%
|
| Title | Phase 3: Durable Response Rate Assessed Using Modified irRC-RECIST (iDRR) |
|---|---|
| Description | Durable response rate per modified irRC-RECIST is defined as the percentage of participants with a best overall response of iCR or iPR per modified irRC-RECIST evaluated by blinded independent central review with a duration of response ≥ 6 months. iCR: Disappearance of all lesions (whether measurable or not and whether baseline or new) and confirmation by a repeat, consecutive assessment at least 4 weeks from the date first documented. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. iPR: Decrease in tumor burden ≥ 30% relative to baseline confirmed by a consecutive assessment at least 4 weeks after first documentation. |
| Time Frame | Tumor assessments were performed every 12 weeks after initiation of treatment until confirmed PD or start of new anticancer treatment; median (range) time on follow-up was 30.6 (0.6, 53.0) months and 31.4 (0.3, 52.5) months in each group, respectively. |
Outcome Measure Data
| Analysis Population Description |
|---|
| All participants randomized in Phase 3 |
| Arm/Group Title | Phase 3: Placebo + Pembrolizumab | Phase 3: Talimogene Laherparepvec + Pembrolizumab |
|---|---|---|
| Arm/Group Description | Participants received up to 4 mL placebo to talimogene laherparepvec by intralesional injection on day 1 of week 0. Subsequent doses of placebo (up to 4 mL) began 3 weeks after the first dose and were administered every 2 weeks until the fifth injection (week 9), and then synchronously with pembrolizumab thereafter every 3 weeks until disappearance of injectable lesions, complete response per modified Immune-related Response Criteria simulating Response Evaluation Criteria in Solid Tumors (irRC-RECIST) (iCR), confirmed iPD per modified irRC-RECIST, intolerance of study treatment, 24 months from the date of the first dose of placebo, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 3 weeks starting on day 1 of week 0, until confirmed iPD per modified irRC-RECIST, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first. | Participants received talimogene laherparepvec at an initial dose of up to 4 mL 10⁶ PFU/mL by intralesional injection on day 1. Subsequent doses of talimogene laherparepvec at 10⁸ PFU/mL (up to 4 mL) began 3 weeks after the first dose and were administered every 2 weeks until the fifth injection of talimogene laherparepvec (week 9), and then synchronously with pembrolizumab thereafter every 3 weeks until disappearance of injectable lesions, iCR, confirmed iPD per modified irRC-RECIST, intolerance of study treatment, 24 months from the date of the first dose of talimogene laherparepvec, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 3 weeks starting on day 1 of week 0, until confirmed iPD per modified irRC-RECIST, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first. |
| Measure Participants | 346 | 346 |
| Number (95% Confidence Interval) [percentage of participants] |
34.4
163.8%
|
45.7
13.2%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Phase 1b: Talimogene Laherparepvec + Pembrolizumab, Phase 3: Talimogene Laherparepvec + Pembrolizumab |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.004 |
| Comments | ||
| Method | Regression, Logistic | |
| Comments | Logistic regression stratified by randomization stratification factors (disease stage and prior BRAF inhibitor therapy) and the baseline PD-L1 status. | |
| Method of Estimation | Estimation Parameter | Odds Ratio (OR) |
| Estimated Value | 1.59 | |
| Confidence Interval |
(2-Sided) 95% 1.16 to 2.17 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Adjusted odds ratio estimated using logistic regression with randomization stratification factors and baseline PD-L1 status. | |
| Title | Phase 3: Duration of Response Assessed Using Modified irRC-RECIST (iDOR) |
|---|---|
| Description | Duration of response per modified irRC-RECIST is defined as the time from the date of an initial response of iCR or iPR that was subsequently confirmed to the earlier of iPD per modified irRC-RECIST evaluated by blinded independent central review, or death. Participants who had not ended their response at the time of analysis were censored at their last evaluable tumor assessment date before the start of the first subsequent anticancer therapy. iCR: Disappearance of all lesions (whether measurable or not and whether baseline or new) and confirmation by a repeat, consecutive assessment at least 4 weeks from the date first documented. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. iPR: Decrease in tumor burden ≥ 30% relative to baseline confirmed by a consecutive assessment at least 4 weeks after first documentation. |
| Time Frame | From randomization until the data cut-off date of 29 September 2020; median time on follow-up was 30.6 (0.6, 53.0) months in the Placebo + Pembrolizumab arm and 31.4 (0.3, 52.5) months in the Talimogene Laherparepvec + Pembrolizumab arm. |
Outcome Measure Data
| Analysis Population Description |
|---|
| Participants randomized in Phase 3 with a iCR or iPR per modified irRC-RECIST. |
| Arm/Group Title | Phase 3: Placebo + Pembrolizumab | Phase 3: Talimogene Laherparepvec + Pembrolizumab |
|---|---|---|
| Arm/Group Description | Participants received up to 4 mL placebo to talimogene laherparepvec by intralesional injection on day 1 of week 0. Subsequent doses of placebo (up to 4 mL) began 3 weeks after the first dose and were administered every 2 weeks until the fifth injection (week 9), and then synchronously with pembrolizumab thereafter every 3 weeks until disappearance of injectable lesions, complete response per modified Immune-related Response Criteria simulating Response Evaluation Criteria in Solid Tumors (irRC-RECIST) (iCR), confirmed iPD per modified irRC-RECIST, intolerance of study treatment, 24 months from the date of the first dose of placebo, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 3 weeks starting on day 1 of week 0, until confirmed iPD per modified irRC-RECIST, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first. | Participants received talimogene laherparepvec at an initial dose of up to 4 mL 10⁶ PFU/mL by intralesional injection on day 1. Subsequent doses of talimogene laherparepvec at 10⁸ PFU/mL (up to 4 mL) began 3 weeks after the first dose and were administered every 2 weeks until the fifth injection of talimogene laherparepvec (week 9), and then synchronously with pembrolizumab thereafter every 3 weeks until disappearance of injectable lesions, iCR, confirmed iPD per modified irRC-RECIST, intolerance of study treatment, 24 months from the date of the first dose of talimogene laherparepvec, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 3 weeks starting on day 1 of week 0, until confirmed iPD per modified irRC-RECIST, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first. |
| Measure Participants | 138 | 170 |
| Median (95% Confidence Interval) [months] |
NA
|
43.7
|
| Title | Phase 3: Disease Control Rate Assessed Using Modified irRC-RECIST (iDCR) |
|---|---|
| Description | Disease control rate per modified irRC-RECIST is defined as the percentage of participants with a best overall response of iCR, iCR, or iSD assessed using modified irRC-RECIST evaluated by blinded independent central review. iCR: Disappearance of all lesions (whether measurable or not and whether baseline or new) and confirmation by a repeat, consecutive assessment at least 4 weeks from the date first documented. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. iPR: Decrease in tumor burden ≥ 30% relative to baseline confirmed by a consecutive assessment at least 4 weeks after first documentation. iSD: Neither sufficient shrinkage to qualify for iCR or iPR nor sufficient increase to qualify for iPD with ≥ 84 days elapsed after randomization. |
| Time Frame | Tumor assessments were performed every 12 weeks after initiation of treatment until confirmed PD or start of new anticancer treatment; median (range) time on follow-up was 30.6 (0.6, 53.0) months and 31.4 (0.3, 52.5) months in each group, respectively. |
Outcome Measure Data
| Analysis Population Description |
|---|
| All participants randomized in Phase 3 |
| Arm/Group Title | Phase 3: Placebo + Pembrolizumab | Phase 3: Talimogene Laherparepvec + Pembrolizumab |
|---|---|---|
| Arm/Group Description | Participants received up to 4 mL placebo to talimogene laherparepvec by intralesional injection on day 1 of week 0. Subsequent doses of placebo (up to 4 mL) began 3 weeks after the first dose and were administered every 2 weeks until the fifth injection (week 9), and then synchronously with pembrolizumab thereafter every 3 weeks until disappearance of injectable lesions, complete response per modified Immune-related Response Criteria simulating Response Evaluation Criteria in Solid Tumors (irRC-RECIST) (iCR), confirmed iPD per modified irRC-RECIST, intolerance of study treatment, 24 months from the date of the first dose of placebo, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 3 weeks starting on day 1 of week 0, until confirmed iPD per modified irRC-RECIST, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first. | Participants received talimogene laherparepvec at an initial dose of up to 4 mL 10⁶ PFU/mL by intralesional injection on day 1. Subsequent doses of talimogene laherparepvec at 10⁸ PFU/mL (up to 4 mL) began 3 weeks after the first dose and were administered every 2 weeks until the fifth injection of talimogene laherparepvec (week 9), and then synchronously with pembrolizumab thereafter every 3 weeks until disappearance of injectable lesions, iCR, confirmed iPD per modified irRC-RECIST, intolerance of study treatment, 24 months from the date of the first dose of talimogene laherparepvec, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 3 weeks starting on day 1 of week 0, until confirmed iPD per modified irRC-RECIST, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first. |
| Measure Participants | 346 | 346 |
| Number (95% Confidence Interval) [percentage of participants] |
56.4
268.6%
|
63.9
18.5%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Phase 1b: Talimogene Laherparepvec + Pembrolizumab, Phase 3: Talimogene Laherparepvec + Pembrolizumab |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.058 |
| Comments | ||
| Method | Regression, Logistic | |
| Comments | Logistic regression stratified by randomization stratification factors (disease stage and prior BRAF inhibitor therapy) and the baseline PD-L1 status. | |
| Method of Estimation | Estimation Parameter | Odds Ratio (OR) |
| Estimated Value | 1.35 | |
| Confidence Interval |
(2-Sided) 95% 0.99 to 1.85 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Adjusted odds ratio estimated using logistic regression with randomization stratification factors and baseline PD-L1 status. | |
| Title | Phase 3: Change From Baseline in European Organisation for Research and Treatment of Cancer Quality of Life Core Module (EORTC QLQ-C30) Global Health Status (GHS)/Quality of Life (QOL) Score |
|---|---|
| Description | The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30) is a 30-question tool used to assess the overall quality of life in cancer patients. It consists of 15 domains: 1 global health status/quality of life scale, 5 functional scales, and 9 symptom scales/items. The global health/QoL scale consists of 2 questions that ask participants to rate their overall health and overall quality of life during the past week on a scale from 1 (very poor) to 7 (excellent). The GHS/QoL subscale score was derived as the mean of each score then transformed to a scale from 0 to 100 where higher scores represent a better health status and a positive change from baseline indicates improvement. The overall change from baseline (calculated from all on-treatment visits) was calculated using a restricted maximum likelihood-based mixed model for repeated measures (MMRM) (see model details in statistical analysis section). |
| Time Frame | Baseline and day 1 of weeks 3, 6, 9, 12, then every 6 weeks until end of study treatment; median (range) duration of treatment was 39.0 (0.1, 107.3) weeks in Placebo + Pembrolizumab and 54.1 (0.1, 109.6) weeks in Talimogene Laherparepvec + Pembrolizumab. |
Outcome Measure Data
| Analysis Population Description |
|---|
| Participants randomized in Phase 3 who received at least one dose of study therapy and had both a baseline and at least one on-treatment assessment. |
| Arm/Group Title | Phase 3: Placebo + Pembrolizumab | Phase 3: Talimogene Laherparepvec + Pembrolizumab |
|---|---|---|
| Arm/Group Description | Participants received up to 4 mL placebo to talimogene laherparepvec by intralesional injection on day 1 of week 0. Subsequent doses of placebo (up to 4 mL) began 3 weeks after the first dose and were administered every 2 weeks until the fifth injection (week 9), and then synchronously with pembrolizumab thereafter every 3 weeks until disappearance of injectable lesions, complete response per modified Immune-related Response Criteria simulating Response Evaluation Criteria in Solid Tumors (irRC-RECIST) (iCR), confirmed iPD per modified irRC-RECIST, intolerance of study treatment, 24 months from the date of the first dose of placebo, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 3 weeks starting on day 1 of week 0, until confirmed iPD per modified irRC-RECIST, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first. | Participants received talimogene laherparepvec at an initial dose of up to 4 mL 10⁶ PFU/mL by intralesional injection on day 1. Subsequent doses of talimogene laherparepvec at 10⁸ PFU/mL (up to 4 mL) began 3 weeks after the first dose and were administered every 2 weeks until the fifth injection of talimogene laherparepvec (week 9), and then synchronously with pembrolizumab thereafter every 3 weeks until disappearance of injectable lesions, iCR, confirmed iPD per modified irRC-RECIST, intolerance of study treatment, 24 months from the date of the first dose of talimogene laherparepvec, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 3 weeks starting on day 1 of week 0, until confirmed iPD per modified irRC-RECIST, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first. |
| Measure Participants | 329 | 328 |
| Least Squares Mean (Standard Error) [score on a scale] |
-0.20
(1.02)
|
-0.02
(1.02)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Phase 1b: Talimogene Laherparepvec + Pembrolizumab, Phase 3: Talimogene Laherparepvec + Pembrolizumab |
|---|---|---|
| Comments | Mixed Model for Repeated Measures include the fixed and categorical effects of treatment, visit and treatment-by-visit interaction, the fixed and continuous covariates of baseline HRQL score, randomization stratification factors (stage of disease and prior BRAF inhibitor therapy per IVRS) and baseline PD-L1 status (positive and not positive). Random subject effect was modeled using within subject-error correlation structure. | |
| Type of Statistical Test | Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.84 |
| Comments | ||
| Method | Mixed Model for Repeated Measures | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Difference |
| Estimated Value | 0.19 | |
| Confidence Interval |
(2-Sided) 95% -1.67 to 2.05 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 0.95 |
|
| Estimation Comments | ||
| Title | Number of Participants With Treatment-emergent Adverse Events (TEAEs) |
|---|---|
| Description | An adverse event (AE) is any untoward medical occurrence in a clinical trial subject, including worsening of a pre-existing medical condition. The event does not necessarily have a causal relationship with study treatment. TEAEs include AEs from the first dose of study drug to 30 days after the last dose. A serious adverse event (SAE) is an AE that met at least 1 of the following criteria: fatal life threatening required in-patient hospitalization or prolongation of existing hospitalization resulted in persistent or significant disability/incapacity congenital anomaly/birth defect other medically important serious event. Treatment-emergent SAEs are any SAE occurring from first dose of study drug through 90 days after the last dose or 30 days after the last dose if new anticancer therapy was started, whichever was earlier. AEs were graded for severity using CTCAE version 4.0, where Grade 1 = Mild; Grade 2 = Moderate; Grade 3 = Severe; Grade 4 = Life-threatening; Grade 5 = Fatal. |
| Time Frame | From first dose to 30 days after last dose (90 days for SAEs); median (range) duration was 48 (5.1, 110.1) weeks in Phase 1b, 39 (0.1, 107.3) weeks in Placebo + Pembrolizumab and 56 (0.1, 109.6) weeks in Phase 3 Talimogene Laherparepvec + Pembrolizumab. |
Outcome Measure Data
| Analysis Population Description |
|---|
| All participants who received at least 1 dose of talimogene laherparepvec or pembrolizumab. One participant who was randomized in Phase 3 to receive placebo received talimogene laherparepvec; thus, the Safety Analysis Set consisted of 344 participants in the Talimogene Laherparepvec + Pembrolizumab group and 344 participants in the Placebo + Pembrolizumab group. |
| Arm/Group Title | Phase 1b: Talimogene Laherparepvec + Pembrolizumab | Phase 3: Placebo + Pembrolizumab | Phase 3: Talimogene Laherparepvec + Pembrolizumab |
|---|---|---|---|
| Arm/Group Description | Participants received talimogene laherparepvec at an initial dose of up to 4 mL 10⁶ plaque-forming units (PFU)/mL by intralesional injection on day 1 of week 1. Subsequent doses of talimogene laherparepvec at up to 4 mL of 10⁸ PFU/mL began 3 weeks after the first dose and were administered every 2 weeks until disappearance of injectable lesions, complete response (CR), confirmed disease progression (PD) per modified Immune-related Response Criteria (irRC), intolerance of study treatment, 24 months from the date of the first dose of pembrolizumab, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 2 weeks starting at the time of the third dose of talimogene laherparepvec (week 6) until confirmed PD per modified irRC, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first. | Participants received up to 4 mL placebo to talimogene laherparepvec by intralesional injection on day 1 of week 0. Subsequent doses of placebo (up to 4 mL) began 3 weeks after the first dose and were administered every 2 weeks until the fifth injection (week 9), and then synchronously with pembrolizumab thereafter every 3 weeks until disappearance of injectable lesions, complete response per modified Immune-related Response Criteria simulating Response Evaluation Criteria in Solid Tumors (irRC-RECIST) (iCR), confirmed iPD per modified irRC-RECIST, intolerance of study treatment, 24 months from the date of the first dose of placebo, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 3 weeks starting on day 1 of week 0, until confirmed iPD per modified irRC-RECIST, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first. | Participants received talimogene laherparepvec at an initial dose of up to 4 mL 10⁶ PFU/mL by intralesional injection on day 1. Subsequent doses of talimogene laherparepvec at 10⁸ PFU/mL (up to 4 mL) began 3 weeks after the first dose and were administered every 2 weeks until the fifth injection of talimogene laherparepvec (week 9), and then synchronously with pembrolizumab thereafter every 3 weeks until disappearance of injectable lesions, iCR, confirmed iPD per modified irRC-RECIST, intolerance of study treatment, 24 months from the date of the first dose of talimogene laherparepvec, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 3 weeks starting on day 1 of week 0, until confirmed iPD per modified irRC-RECIST, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first. |
| Measure Participants | 21 | 344 | 344 |
| Any treatment-emergent adverse events |
21
100%
|
331
95.7%
|
338
97.7%
|
| Grade ≥ 2 |
20
95.2%
|
279
80.6%
|
306
88.4%
|
| Grade ≥ 3 |
13
61.9%
|
151
43.6%
|
161
46.5%
|
| Grade ≥ 4 |
2
9.5%
|
29
8.4%
|
33
9.5%
|
| Serious adverse events |
8
38.1%
|
141
40.8%
|
154
44.5%
|
| Leading to discontinuation of talimogene laherparepvec/Placebo |
0
0%
|
24
6.9%
|
26
7.5%
|
| Leading to discontinuation of pembrolizumab |
2
9.5%
|
41
11.8%
|
43
12.4%
|
| Fatal adverse events |
1
4.8%
|
42
12.1%
|
45
13%
|
Adverse Events
| Time Frame | All-cause mortality: From enrollment (Phase 1b) or randomization (Phase 3) to end of study, up to 75 months in Phase 1b and 58 months in Phase 3. SAEs: From first dose of study drug to 90 days after last dose or 30 days after last dose if new anticancer therapy was started. AEs: From first dose to 30 days after last dose; median (range) duration of exposure was 48 (5.1, 110) weeks in Phase 1b, 39 (0.1, 107) weeks in Placebo + Pembrolizumab and 56 (0.1, 110) weeks in T-VEC + Pembrolizumab arm. | |||||
|---|---|---|---|---|---|---|
| Adverse Event Reporting Description | All-cause mortality is reported for all enrolled (Phase 1b) or randomized (Phase 3) participants. Adverse events are reported for all participants who received at least 1 dose of talimogene laherparepvec or pembrolizumab. One participant who was randomized in Phase 3 to receive placebo received talimogene laherparepvec; thus, the Safety Analysis Set consisted of 344 participants in the talimogene laherparepvec + pembrolizumab group and 344 participants in the placebo + pembrolizumab group. | |||||
| Arm/Group Title | Phase 1b: Talimogene Laherparepvec + Pembrolizumab | Phase 3: Placebo + Pembrolizumab | Phase 3: Talimogene Laherparepvec + Pembrolizumab | |||
| Arm/Group Description | Participants received talimogene laherparepvec at an initial dose of up to 4 mL 10⁶ plaque-forming units (PFU)/mL by intralesional injection on day 1 of week 1. Subsequent doses of talimogene laherparepvec at up to 4 mL of 10⁸ PFU/mL began 3 weeks after the first dose and were administered every 2 weeks until disappearance of injectable lesions, complete response (CR), confirmed disease progression (PD) per modified Immune-related Response Criteria (irRC), intolerance of study treatment, 24 months from the date of the first dose of pembrolizumab, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 2 weeks starting at the time of the third dose of talimogene laherparepvec (week 6) until confirmed PD per modified irRC, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first. | Participants received up to 4 mL placebo to talimogene laherparepvec by intralesional injection on day 1 of week 0. Subsequent doses of placebo (up to 4 mL) began 3 weeks after the first dose and were administered every 2 weeks until the fifth injection (week 9), and then synchronously with pembrolizumab thereafter every 3 weeks until disappearance of injectable lesions, complete response per modified Immune-related Response Criteria simulating Response Evaluation Criteria in Solid Tumors (irRC-RECIST) (iCR), confirmed iPD per modified irRC-RECIST, intolerance of study treatment, 24 months from the date of the first dose of placebo, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 3 weeks starting on day 1 of week 0, until confirmed iPD per modified irRC-RECIST, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first. | Participants received talimogene laherparepvec at an initial dose of up to 4 mL 10⁶ PFU/mL by intralesional injection on day 1. Subsequent doses of talimogene laherparepvec at 10⁸ PFU/mL (up to 4 mL) began 3 weeks after the first dose and were administered every 2 weeks until the fifth injection of talimogene laherparepvec (week 9), and then synchronously with pembrolizumab thereafter every 3 weeks until disappearance of injectable lesions, iCR, confirmed iPD per modified irRC-RECIST, intolerance of study treatment, 24 months from the date of the first dose of talimogene laherparepvec, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 3 weeks starting on day 1 of week 0, until confirmed iPD per modified irRC-RECIST, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first. | |||
All Cause Mortality |
||||||
| Phase 1b: Talimogene Laherparepvec + Pembrolizumab | Phase 3: Placebo + Pembrolizumab | Phase 3: Talimogene Laherparepvec + Pembrolizumab | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 6/21 (28.6%) | 156/346 (45.1%) | 146/346 (42.2%) | |||
Serious Adverse Events |
||||||
| Phase 1b: Talimogene Laherparepvec + Pembrolizumab | Phase 3: Placebo + Pembrolizumab | Phase 3: Talimogene Laherparepvec + Pembrolizumab | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 8/21 (38.1%) | 141/344 (41%) | 154/344 (44.8%) | |||
| Blood and lymphatic system disorders | ||||||
| Anaemia | 0/21 (0%) | 8/344 (2.3%) | 9/344 (2.6%) | |||
| Anaemia of malignant disease | 0/21 (0%) | 0/344 (0%) | 1/344 (0.3%) | |||
| Febrile neutropenia | 0/21 (0%) | 1/344 (0.3%) | 0/344 (0%) | |||
| Granulomatous lymphadenitis | 0/21 (0%) | 1/344 (0.3%) | 0/344 (0%) | |||
| Lymph node pain | 0/21 (0%) | 1/344 (0.3%) | 0/344 (0%) | |||
| Lymphadenopathy | 0/21 (0%) | 0/344 (0%) | 2/344 (0.6%) | |||
| Thrombocytopenia | 0/21 (0%) | 2/344 (0.6%) | 0/344 (0%) | |||
| Cardiac disorders | ||||||
| Acute coronary syndrome | 0/21 (0%) | 1/344 (0.3%) | 0/344 (0%) | |||
| Acute myocardial infarction | 0/21 (0%) | 2/344 (0.6%) | 1/344 (0.3%) | |||
| Angina pectoris | 0/21 (0%) | 0/344 (0%) | 1/344 (0.3%) | |||
| Atrial fibrillation | 0/21 (0%) | 2/344 (0.6%) | 1/344 (0.3%) | |||
| Atrial flutter | 0/21 (0%) | 1/344 (0.3%) | 1/344 (0.3%) | |||
| Atrioventricular block second degree | 0/21 (0%) | 0/344 (0%) | 1/344 (0.3%) | |||
| Cardiac arrest | 0/21 (0%) | 0/344 (0%) | 1/344 (0.3%) | |||
| Cardiac failure | 0/21 (0%) | 2/344 (0.6%) | 1/344 (0.3%) | |||
| Cardiac failure acute | 0/21 (0%) | 0/344 (0%) | 1/344 (0.3%) | |||
| Cardiac failure congestive | 0/21 (0%) | 0/344 (0%) | 1/344 (0.3%) | |||
| Cardiogenic shock | 0/21 (0%) | 1/344 (0.3%) | 0/344 (0%) | |||
| Left ventricular failure | 0/21 (0%) | 1/344 (0.3%) | 0/344 (0%) | |||
| Mitral valve prolapse | 0/21 (0%) | 0/344 (0%) | 1/344 (0.3%) | |||
| Myocardial infarction | 0/21 (0%) | 3/344 (0.9%) | 4/344 (1.2%) | |||
| Myocarditis | 0/21 (0%) | 1/344 (0.3%) | 0/344 (0%) | |||
| Supraventricular tachycardia | 0/21 (0%) | 0/344 (0%) | 1/344 (0.3%) | |||
| Ear and labyrinth disorders | ||||||
| Vertigo | 0/21 (0%) | 0/344 (0%) | 2/344 (0.6%) | |||
| Endocrine disorders | ||||||
| Addison's disease | 0/21 (0%) | 1/344 (0.3%) | 0/344 (0%) | |||
| Adrenal insufficiency | 0/21 (0%) | 1/344 (0.3%) | 0/344 (0%) | |||
| Adrenocortical insufficiency acute | 0/21 (0%) | 1/344 (0.3%) | 0/344 (0%) | |||
| Endocrine disorder | 0/21 (0%) | 1/344 (0.3%) | 0/344 (0%) | |||
| Hyperthyroidism | 0/21 (0%) | 1/344 (0.3%) | 0/344 (0%) | |||
| Hypophysitis | 0/21 (0%) | 2/344 (0.6%) | 0/344 (0%) | |||
| Hypopituitarism | 0/21 (0%) | 0/344 (0%) | 1/344 (0.3%) | |||
| Lymphocytic hypophysitis | 0/21 (0%) | 1/344 (0.3%) | 2/344 (0.6%) | |||
| Thyroid mass | 0/21 (0%) | 0/344 (0%) | 1/344 (0.3%) | |||
| Thyroiditis | 0/21 (0%) | 1/344 (0.3%) | 0/344 (0%) | |||
| Eye disorders | ||||||
| Papilloedema | 0/21 (0%) | 0/344 (0%) | 1/344 (0.3%) | |||
| Retinal oedema | 0/21 (0%) | 0/344 (0%) | 1/344 (0.3%) | |||
| Uveitis | 0/21 (0%) | 1/344 (0.3%) | 0/344 (0%) | |||
| Gastrointestinal disorders | ||||||
| Abdominal pain | 0/21 (0%) | 1/344 (0.3%) | 2/344 (0.6%) | |||
| Abdominal pain upper | 0/21 (0%) | 1/344 (0.3%) | 1/344 (0.3%) | |||
| Ascites | 0/21 (0%) | 2/344 (0.6%) | 1/344 (0.3%) | |||
| Autoimmune colitis | 0/21 (0%) | 1/344 (0.3%) | 0/344 (0%) | |||
| Colitis | 0/21 (0%) | 0/344 (0%) | 5/344 (1.5%) | |||
| Constipation | 0/21 (0%) | 0/344 (0%) | 2/344 (0.6%) | |||
| Diarrhoea | 0/21 (0%) | 0/344 (0%) | 4/344 (1.2%) | |||
| Gastritis | 0/21 (0%) | 1/344 (0.3%) | 1/344 (0.3%) | |||
| Gastrointestinal haemorrhage | 0/21 (0%) | 1/344 (0.3%) | 1/344 (0.3%) | |||
| Haematochezia | 0/21 (0%) | 1/344 (0.3%) | 1/344 (0.3%) | |||
| Haemoperitoneum | 0/21 (0%) | 0/344 (0%) | 1/344 (0.3%) | |||
| Ileus | 0/21 (0%) | 1/344 (0.3%) | 0/344 (0%) | |||
| Large intestine polyp | 0/21 (0%) | 0/344 (0%) | 1/344 (0.3%) | |||
| Mechanical ileus | 0/21 (0%) | 1/344 (0.3%) | 0/344 (0%) | |||
| Nausea | 0/21 (0%) | 0/344 (0%) | 2/344 (0.6%) | |||
| Oesophageal motility disorder | 0/21 (0%) | 0/344 (0%) | 1/344 (0.3%) | |||
| Pancreatitis | 0/21 (0%) | 0/344 (0%) | 1/344 (0.3%) | |||
| Rectal haemorrhage | 0/21 (0%) | 0/344 (0%) | 1/344 (0.3%) | |||
| Vomiting | 0/21 (0%) | 1/344 (0.3%) | 1/344 (0.3%) | |||
| General disorders | ||||||
| Asthenia | 0/21 (0%) | 2/344 (0.6%) | 1/344 (0.3%) | |||
| Chest pain | 0/21 (0%) | 0/344 (0%) | 1/344 (0.3%) | |||
| Chills | 0/21 (0%) | 0/344 (0%) | 1/344 (0.3%) | |||
| Condition aggravated | 0/21 (0%) | 0/344 (0%) | 1/344 (0.3%) | |||
| Death | 0/21 (0%) | 0/344 (0%) | 2/344 (0.6%) | |||
| Disease progression | 0/21 (0%) | 1/344 (0.3%) | 0/344 (0%) | |||
| Fatigue | 0/21 (0%) | 1/344 (0.3%) | 3/344 (0.9%) | |||
| General physical health deterioration | 1/21 (4.8%) | 2/344 (0.6%) | 1/344 (0.3%) | |||
| Generalised oedema | 0/21 (0%) | 1/344 (0.3%) | 1/344 (0.3%) | |||
| Inflammation | 0/21 (0%) | 0/344 (0%) | 2/344 (0.6%) | |||
| Influenza like illness | 0/21 (0%) | 0/344 (0%) | 1/344 (0.3%) | |||
| Multiple organ dysfunction syndrome | 0/21 (0%) | 2/344 (0.6%) | 1/344 (0.3%) | |||
| Pain | 0/21 (0%) | 1/344 (0.3%) | 0/344 (0%) | |||
| Performance status decreased | 0/21 (0%) | 0/344 (0%) | 1/344 (0.3%) | |||
| Pyrexia | 2/21 (9.5%) | 4/344 (1.2%) | 7/344 (2%) | |||
| Sudden death | 0/21 (0%) | 1/344 (0.3%) | 1/344 (0.3%) | |||
| Swelling | 0/21 (0%) | 1/344 (0.3%) | 0/344 (0%) | |||
| Hepatobiliary disorders | ||||||
| Autoimmune hepatitis | 1/21 (4.8%) | 1/344 (0.3%) | 1/344 (0.3%) | |||
| Cholecystitis | 1/21 (4.8%) | 1/344 (0.3%) | 1/344 (0.3%) | |||
| Cholecystitis acute | 0/21 (0%) | 1/344 (0.3%) | 0/344 (0%) | |||
| Cholelithiasis | 0/21 (0%) | 1/344 (0.3%) | 0/344 (0%) | |||
| Hepatic failure | 0/21 (0%) | 0/344 (0%) | 1/344 (0.3%) | |||
| Hepatitis | 0/21 (0%) | 0/344 (0%) | 1/344 (0.3%) | |||
| Jaundice | 0/21 (0%) | 0/344 (0%) | 1/344 (0.3%) | |||
| Immune system disorders | ||||||
| Anaphylactic shock | 0/21 (0%) | 1/344 (0.3%) | 0/344 (0%) | |||
| Cytokine release syndrome | 1/21 (4.8%) | 0/344 (0%) | 0/344 (0%) | |||
| Infections and infestations | ||||||
| Abscess | 0/21 (0%) | 1/344 (0.3%) | 0/344 (0%) | |||
| Anal abscess | 0/21 (0%) | 1/344 (0.3%) | 0/344 (0%) | |||
| Appendicitis | 0/21 (0%) | 1/344 (0.3%) | 0/344 (0%) | |||
| Atypical pneumonia | 0/21 (0%) | 0/344 (0%) | 1/344 (0.3%) | |||
| Bronchitis | 0/21 (0%) | 2/344 (0.6%) | 1/344 (0.3%) | |||
| Bronchopulmonary aspergillosis | 1/21 (4.8%) | 0/344 (0%) | 0/344 (0%) | |||
| Cellulitis | 1/21 (4.8%) | 4/344 (1.2%) | 4/344 (1.2%) | |||
| Chorioretinitis | 0/21 (0%) | 0/344 (0%) | 1/344 (0.3%) | |||
| Dermo-hypodermitis | 0/21 (0%) | 0/344 (0%) | 1/344 (0.3%) | |||
| Diverticulitis | 0/21 (0%) | 1/344 (0.3%) | 0/344 (0%) | |||
| Encephalitis | 0/21 (0%) | 0/344 (0%) | 1/344 (0.3%) | |||
| Erysipelas | 0/21 (0%) | 2/344 (0.6%) | 2/344 (0.6%) | |||
| Escherichia sepsis | 0/21 (0%) | 0/344 (0%) | 1/344 (0.3%) | |||
| Extradural abscess | 0/21 (0%) | 0/344 (0%) | 1/344 (0.3%) | |||
| Gastroenteritis | 0/21 (0%) | 0/344 (0%) | 1/344 (0.3%) | |||
| Herpes zoster | 0/21 (0%) | 1/344 (0.3%) | 0/344 (0%) | |||
| Infected cyst | 0/21 (0%) | 1/344 (0.3%) | 0/344 (0%) | |||
| Infection | 0/21 (0%) | 0/344 (0%) | 1/344 (0.3%) | |||
| Influenza | 0/21 (0%) | 0/344 (0%) | 1/344 (0.3%) | |||
| Localised infection | 0/21 (0%) | 1/344 (0.3%) | 0/344 (0%) | |||
| Lower respiratory tract infection | 0/21 (0%) | 0/344 (0%) | 1/344 (0.3%) | |||
| Lymph gland infection | 0/21 (0%) | 0/344 (0%) | 1/344 (0.3%) | |||
| Meningitis aseptic | 1/21 (4.8%) | 0/344 (0%) | 0/344 (0%) | |||
| Nasopharyngitis | 0/21 (0%) | 1/344 (0.3%) | 0/344 (0%) | |||
| Periorbital cellulitis | 0/21 (0%) | 0/344 (0%) | 1/344 (0.3%) | |||
| Pneumonia | 0/21 (0%) | 4/344 (1.2%) | 3/344 (0.9%) | |||
| Postoperative wound infection | 0/21 (0%) | 0/344 (0%) | 1/344 (0.3%) | |||
| Pulmonary sepsis | 0/21 (0%) | 0/344 (0%) | 1/344 (0.3%) | |||
| Pyelonephritis chronic | 0/21 (0%) | 0/344 (0%) | 1/344 (0.3%) | |||
| Respiratory tract infection | 0/21 (0%) | 1/344 (0.3%) | 0/344 (0%) | |||
| Scrotal abscess | 0/21 (0%) | 0/344 (0%) | 1/344 (0.3%) | |||
| Sepsis | 0/21 (0%) | 1/344 (0.3%) | 1/344 (0.3%) | |||
| Sinusitis | 0/21 (0%) | 1/344 (0.3%) | 1/344 (0.3%) | |||
| Tooth abscess | 0/21 (0%) | 0/344 (0%) | 1/344 (0.3%) | |||
| Tracheobronchitis | 0/21 (0%) | 0/344 (0%) | 1/344 (0.3%) | |||
| Upper respiratory tract infection | 0/21 (0%) | 0/344 (0%) | 1/344 (0.3%) | |||
| Ureteritis | 0/21 (0%) | 1/344 (0.3%) | 0/344 (0%) | |||
| Urinary tract infection | 0/21 (0%) | 3/344 (0.9%) | 5/344 (1.5%) | |||
| Urinary tract infection bacterial | 0/21 (0%) | 0/344 (0%) | 1/344 (0.3%) | |||
| Urosepsis | 0/21 (0%) | 1/344 (0.3%) | 1/344 (0.3%) | |||
| Wound infection | 0/21 (0%) | 0/344 (0%) | 2/344 (0.6%) | |||
| Injury, poisoning and procedural complications | ||||||
| Bone contusion | 0/21 (0%) | 1/344 (0.3%) | 0/344 (0%) | |||
| Contusion | 0/21 (0%) | 1/344 (0.3%) | 0/344 (0%) | |||
| Fall | 0/21 (0%) | 0/344 (0%) | 2/344 (0.6%) | |||
| Femur fracture | 0/21 (0%) | 0/344 (0%) | 3/344 (0.9%) | |||
| Hip fracture | 0/21 (0%) | 1/344 (0.3%) | 0/344 (0%) | |||
| Humerus fracture | 0/21 (0%) | 1/344 (0.3%) | 1/344 (0.3%) | |||
| Infusion related reaction | 0/21 (0%) | 0/344 (0%) | 1/344 (0.3%) | |||
| Lumbar vertebral fracture | 0/21 (0%) | 1/344 (0.3%) | 1/344 (0.3%) | |||
| Multiple fractures | 0/21 (0%) | 1/344 (0.3%) | 0/344 (0%) | |||
| Overdose | 0/21 (0%) | 1/344 (0.3%) | 0/344 (0%) | |||
| Pseudomeningocele | 0/21 (0%) | 0/344 (0%) | 1/344 (0.3%) | |||
| Radius fracture | 0/21 (0%) | 1/344 (0.3%) | 0/344 (0%) | |||
| Skin laceration | 0/21 (0%) | 1/344 (0.3%) | 0/344 (0%) | |||
| Spinal compression fracture | 0/21 (0%) | 1/344 (0.3%) | 2/344 (0.6%) | |||
| Synovial rupture | 0/21 (0%) | 1/344 (0.3%) | 0/344 (0%) | |||
| Toxicity to various agents | 0/21 (0%) | 0/344 (0%) | 1/344 (0.3%) | |||
| Traumatic arthritis | 0/21 (0%) | 1/344 (0.3%) | 0/344 (0%) | |||
| Upper limb fracture | 0/21 (0%) | 1/344 (0.3%) | 1/344 (0.3%) | |||
| Investigations | ||||||
| Alanine aminotransferase increased | 0/21 (0%) | 0/344 (0%) | 1/344 (0.3%) | |||
| Aspartate aminotransferase increased | 0/21 (0%) | 0/344 (0%) | 1/344 (0.3%) | |||
| General physical condition abnormal | 0/21 (0%) | 1/344 (0.3%) | 0/344 (0%) | |||
| Metabolism and nutrition disorders | ||||||
| Decreased appetite | 0/21 (0%) | 1/344 (0.3%) | 0/344 (0%) | |||
| Dehydration | 0/21 (0%) | 0/344 (0%) | 1/344 (0.3%) | |||
| Diabetes mellitus | 0/21 (0%) | 0/344 (0%) | 3/344 (0.9%) | |||
| Diabetic ketoacidosis | 0/21 (0%) | 0/344 (0%) | 2/344 (0.6%) | |||
| Hypercalcaemia | 0/21 (0%) | 1/344 (0.3%) | 0/344 (0%) | |||
| Hyperglycaemia | 0/21 (0%) | 2/344 (0.6%) | 1/344 (0.3%) | |||
| Hyperkalaemia | 0/21 (0%) | 1/344 (0.3%) | 0/344 (0%) | |||
| Hyponatraemia | 0/21 (0%) | 3/344 (0.9%) | 2/344 (0.6%) | |||
| Tumour lysis syndrome | 0/21 (0%) | 1/344 (0.3%) | 0/344 (0%) | |||
| Type 1 diabetes mellitus | 0/21 (0%) | 0/344 (0%) | 1/344 (0.3%) | |||
| Type 2 diabetes mellitus | 0/21 (0%) | 1/344 (0.3%) | 0/344 (0%) | |||
| Musculoskeletal and connective tissue disorders | ||||||
| Arthralgia | 0/21 (0%) | 0/344 (0%) | 1/344 (0.3%) | |||
| Arthritis | 0/21 (0%) | 0/344 (0%) | 1/344 (0.3%) | |||
| Arthropathy | 0/21 (0%) | 1/344 (0.3%) | 0/344 (0%) | |||
| Back pain | 0/21 (0%) | 0/344 (0%) | 2/344 (0.6%) | |||
| Intervertebral disc degeneration | 0/21 (0%) | 1/344 (0.3%) | 0/344 (0%) | |||
| Intervertebral disc protrusion | 0/21 (0%) | 0/344 (0%) | 2/344 (0.6%) | |||
| Joint effusion | 0/21 (0%) | 0/344 (0%) | 1/344 (0.3%) | |||
| Lumbar spinal stenosis | 1/21 (4.8%) | 0/344 (0%) | 0/344 (0%) | |||
| Myositis | 0/21 (0%) | 3/344 (0.9%) | 0/344 (0%) | |||
| Osteoarthritis | 0/21 (0%) | 1/344 (0.3%) | 0/344 (0%) | |||
| Pain in extremity | 0/21 (0%) | 0/344 (0%) | 1/344 (0.3%) | |||
| Pathological fracture | 0/21 (0%) | 0/344 (0%) | 2/344 (0.6%) | |||
| Polyarthritis | 0/21 (0%) | 0/344 (0%) | 1/344 (0.3%) | |||
| Psoriatic arthropathy | 0/21 (0%) | 0/344 (0%) | 1/344 (0.3%) | |||
| Spinal pain | 0/21 (0%) | 1/344 (0.3%) | 0/344 (0%) | |||
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||||||
| Adenocarcinoma gastric | 0/21 (0%) | 0/344 (0%) | 1/344 (0.3%) | |||
| Adenocarcinoma of colon | 0/21 (0%) | 1/344 (0.3%) | 0/344 (0%) | |||
| Basal cell carcinoma | 0/21 (0%) | 1/344 (0.3%) | 1/344 (0.3%) | |||
| Bladder adenocarcinoma stage unspecified | 0/21 (0%) | 0/344 (0%) | 1/344 (0.3%) | |||
| Breast cancer | 0/21 (0%) | 1/344 (0.3%) | 0/344 (0%) | |||
| Endometrial cancer | 0/21 (0%) | 1/344 (0.3%) | 0/344 (0%) | |||
| Intraductal proliferative breast lesion | 1/21 (4.8%) | 0/344 (0%) | 0/344 (0%) | |||
| Malignant melanoma | 0/21 (0%) | 26/344 (7.6%) | 27/344 (7.8%) | |||
| Malignant neoplasm progression | 1/21 (4.8%) | 0/344 (0%) | 1/344 (0.3%) | |||
| Melanoma recurrent | 0/21 (0%) | 1/344 (0.3%) | 0/344 (0%) | |||
| Metastases to bone | 0/21 (0%) | 0/344 (0%) | 1/344 (0.3%) | |||
| Metastases to central nervous system | 0/21 (0%) | 1/344 (0.3%) | 3/344 (0.9%) | |||
| Metastases to lung | 0/21 (0%) | 1/344 (0.3%) | 1/344 (0.3%) | |||
| Metastases to nervous system | 0/21 (0%) | 1/344 (0.3%) | 0/344 (0%) | |||
| Metastatic malignant melanoma | 0/21 (0%) | 10/344 (2.9%) | 7/344 (2%) | |||
| Squamous cell carcinoma of skin | 0/21 (0%) | 0/344 (0%) | 2/344 (0.6%) | |||
| Transitional cell carcinoma | 0/21 (0%) | 1/344 (0.3%) | 0/344 (0%) | |||
| Tumour associated fever | 0/21 (0%) | 0/344 (0%) | 1/344 (0.3%) | |||
| Tumour haemorrhage | 0/21 (0%) | 0/344 (0%) | 2/344 (0.6%) | |||
| Nervous system disorders | ||||||
| Altered state of consciousness | 0/21 (0%) | 1/344 (0.3%) | 0/344 (0%) | |||
| Basal ganglia infarction | 0/21 (0%) | 1/344 (0.3%) | 0/344 (0%) | |||
| Carotid artery stenosis | 0/21 (0%) | 0/344 (0%) | 1/344 (0.3%) | |||
| Central nervous system necrosis | 0/21 (0%) | 0/344 (0%) | 1/344 (0.3%) | |||
| Cerebral haemorrhage | 0/21 (0%) | 1/344 (0.3%) | 0/344 (0%) | |||
| Dementia | 0/21 (0%) | 1/344 (0.3%) | 0/344 (0%) | |||
| Dizziness | 0/21 (0%) | 0/344 (0%) | 2/344 (0.6%) | |||
| Embolic stroke | 0/21 (0%) | 0/344 (0%) | 1/344 (0.3%) | |||
| Epilepsy | 0/21 (0%) | 1/344 (0.3%) | 1/344 (0.3%) | |||
| Facial paralysis | 0/21 (0%) | 1/344 (0.3%) | 0/344 (0%) | |||
| Headache | 0/21 (0%) | 1/344 (0.3%) | 1/344 (0.3%) | |||
| Hemiparesis | 0/21 (0%) | 1/344 (0.3%) | 0/344 (0%) | |||
| Hydrocephalus | 0/21 (0%) | 0/344 (0%) | 1/344 (0.3%) | |||
| Ischaemic cerebral infarction | 0/21 (0%) | 0/344 (0%) | 1/344 (0.3%) | |||
| Ischaemic stroke | 0/21 (0%) | 1/344 (0.3%) | 0/344 (0%) | |||
| Migraine | 0/21 (0%) | 1/344 (0.3%) | 0/344 (0%) | |||
| Nervous system disorder | 0/21 (0%) | 0/344 (0%) | 1/344 (0.3%) | |||
| Neurological symptom | 0/21 (0%) | 1/344 (0.3%) | 0/344 (0%) | |||
| Paraesthesia | 0/21 (0%) | 1/344 (0.3%) | 0/344 (0%) | |||
| Paraparesis | 0/21 (0%) | 1/344 (0.3%) | 0/344 (0%) | |||
| Paraplegia | 0/21 (0%) | 1/344 (0.3%) | 0/344 (0%) | |||
| Seizure | 0/21 (0%) | 0/344 (0%) | 1/344 (0.3%) | |||
| Speech disorder | 0/21 (0%) | 1/344 (0.3%) | 0/344 (0%) | |||
| Spinal cord compression | 0/21 (0%) | 1/344 (0.3%) | 0/344 (0%) | |||
| Syncope | 0/21 (0%) | 2/344 (0.6%) | 1/344 (0.3%) | |||
| Transient ischaemic attack | 0/21 (0%) | 0/344 (0%) | 1/344 (0.3%) | |||
| Psychiatric disorders | ||||||
| Completed suicide | 0/21 (0%) | 1/344 (0.3%) | 1/344 (0.3%) | |||
| Confusional state | 0/21 (0%) | 1/344 (0.3%) | 0/344 (0%) | |||
| Delirium | 0/21 (0%) | 0/344 (0%) | 1/344 (0.3%) | |||
| Mental status changes | 0/21 (0%) | 0/344 (0%) | 1/344 (0.3%) | |||
| Obsessive-compulsive disorder | 0/21 (0%) | 1/344 (0.3%) | 0/344 (0%) | |||
| Somatic symptom disorder | 0/21 (0%) | 0/344 (0%) | 1/344 (0.3%) | |||
| Renal and urinary disorders | ||||||
| Acute kidney injury | 0/21 (0%) | 1/344 (0.3%) | 2/344 (0.6%) | |||
| Haematuria | 0/21 (0%) | 0/344 (0%) | 1/344 (0.3%) | |||
| Nephrotic syndrome | 0/21 (0%) | 1/344 (0.3%) | 0/344 (0%) | |||
| Renal colic | 0/21 (0%) | 1/344 (0.3%) | 0/344 (0%) | |||
| Renal failure | 0/21 (0%) | 1/344 (0.3%) | 0/344 (0%) | |||
| Renal impairment | 0/21 (0%) | 1/344 (0.3%) | 0/344 (0%) | |||
| Ureteric obstruction | 0/21 (0%) | 0/344 (0%) | 1/344 (0.3%) | |||
| Urinary retention | 0/21 (0%) | 0/344 (0%) | 1/344 (0.3%) | |||
| Reproductive system and breast disorders | ||||||
| Benign prostatic hyperplasia | 0/21 (0%) | 1/344 (0.3%) | 1/344 (0.3%) | |||
| Gynaecomastia | 0/21 (0%) | 0/344 (0%) | 1/344 (0.3%) | |||
| Respiratory, thoracic and mediastinal disorders | ||||||
| Chronic obstructive pulmonary disease | 0/21 (0%) | 0/344 (0%) | 2/344 (0.6%) | |||
| Dyspnoea | 0/21 (0%) | 3/344 (0.9%) | 5/344 (1.5%) | |||
| Immune-mediated pneumonitis | 0/21 (0%) | 1/344 (0.3%) | 0/344 (0%) | |||
| Interstitial lung disease | 0/21 (0%) | 1/344 (0.3%) | 0/344 (0%) | |||
| Lung infiltration | 1/21 (4.8%) | 0/344 (0%) | 0/344 (0%) | |||
| Pleural effusion | 0/21 (0%) | 2/344 (0.6%) | 1/344 (0.3%) | |||
| Pneumonitis | 1/21 (4.8%) | 4/344 (1.2%) | 5/344 (1.5%) | |||
| Pneumothorax spontaneous | 0/21 (0%) | 0/344 (0%) | 1/344 (0.3%) | |||
| Pulmonary embolism | 0/21 (0%) | 1/344 (0.3%) | 2/344 (0.6%) | |||
| Pulmonary oedema | 0/21 (0%) | 1/344 (0.3%) | 0/344 (0%) | |||
| Pulmonary sarcoidosis | 0/21 (0%) | 0/344 (0%) | 1/344 (0.3%) | |||
| Respiratory failure | 0/21 (0%) | 2/344 (0.6%) | 3/344 (0.9%) | |||
| Sleep apnoea syndrome | 0/21 (0%) | 1/344 (0.3%) | 0/344 (0%) | |||
| Skin and subcutaneous tissue disorders | ||||||
| Dermatitis | 0/21 (0%) | 0/344 (0%) | 2/344 (0.6%) | |||
| Dermatitis bullous | 0/21 (0%) | 1/344 (0.3%) | 0/344 (0%) | |||
| Drug eruption | 0/21 (0%) | 1/344 (0.3%) | 0/344 (0%) | |||
| Eczema | 0/21 (0%) | 1/344 (0.3%) | 0/344 (0%) | |||
| Rash | 0/21 (0%) | 1/344 (0.3%) | 0/344 (0%) | |||
| Skin hypopigmentation | 0/21 (0%) | 0/344 (0%) | 1/344 (0.3%) | |||
| Skin lesion | 0/21 (0%) | 1/344 (0.3%) | 0/344 (0%) | |||
| Skin ulcer | 0/21 (0%) | 0/344 (0%) | 1/344 (0.3%) | |||
| Stevens-Johnson syndrome | 0/21 (0%) | 1/344 (0.3%) | 0/344 (0%) | |||
| Surgical and medical procedures | ||||||
| Axillary lymphadenectomy | 0/21 (0%) | 1/344 (0.3%) | 0/344 (0%) | |||
| Vascular disorders | ||||||
| Arteritis | 0/21 (0%) | 0/344 (0%) | 1/344 (0.3%) | |||
| Deep vein thrombosis | 0/21 (0%) | 0/344 (0%) | 1/344 (0.3%) | |||
| Haemorrhage | 0/21 (0%) | 1/344 (0.3%) | 1/344 (0.3%) | |||
| Hypertensive crisis | 0/21 (0%) | 0/344 (0%) | 1/344 (0.3%) | |||
| Hypotension | 0/21 (0%) | 1/344 (0.3%) | 0/344 (0%) | |||
| Labile blood pressure | 0/21 (0%) | 1/344 (0.3%) | 0/344 (0%) | |||
| Peripheral artery occlusion | 0/21 (0%) | 2/344 (0.6%) | 0/344 (0%) | |||
| Subclavian vein thrombosis | 0/21 (0%) | 0/344 (0%) | 1/344 (0.3%) | |||
| Thrombophlebitis | 0/21 (0%) | 1/344 (0.3%) | 0/344 (0%) | |||
| Vena cava thrombosis | 0/21 (0%) | 0/344 (0%) | 1/344 (0.3%) | |||
Other (Not Including Serious) Adverse Events |
||||||
| Phase 1b: Talimogene Laherparepvec + Pembrolizumab | Phase 3: Placebo + Pembrolizumab | Phase 3: Talimogene Laherparepvec + Pembrolizumab | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 21/21 (100%) | 305/344 (88.7%) | 317/344 (92.2%) | |||
| Blood and lymphatic system disorders | ||||||
| Anaemia | 2/21 (9.5%) | 26/344 (7.6%) | 33/344 (9.6%) | |||
| Leukopenia | 2/21 (9.5%) | 2/344 (0.6%) | 0/344 (0%) | |||
| Endocrine disorders | ||||||
| Hyperthyroidism | 3/21 (14.3%) | 20/344 (5.8%) | 22/344 (6.4%) | |||
| Hypothyroidism | 6/21 (28.6%) | 49/344 (14.2%) | 48/344 (14%) | |||
| Eye disorders | ||||||
| Visual impairment | 2/21 (9.5%) | 2/344 (0.6%) | 6/344 (1.7%) | |||
| Gastrointestinal disorders | ||||||
| Abdominal pain | 2/21 (9.5%) | 24/344 (7%) | 23/344 (6.7%) | |||
| Abdominal pain upper | 2/21 (9.5%) | 12/344 (3.5%) | 7/344 (2%) | |||
| Constipation | 4/21 (19%) | 28/344 (8.1%) | 52/344 (15.1%) | |||
| Diarrhoea | 13/21 (61.9%) | 73/344 (21.2%) | 70/344 (20.3%) | |||
| Dry mouth | 1/21 (4.8%) | 19/344 (5.5%) | 14/344 (4.1%) | |||
| Frequent bowel movements | 2/21 (9.5%) | 1/344 (0.3%) | 0/344 (0%) | |||
| Nausea | 7/21 (33.3%) | 61/344 (17.7%) | 92/344 (26.7%) | |||
| Vomiting | 7/21 (33.3%) | 29/344 (8.4%) | 56/344 (16.3%) | |||
| General disorders | ||||||
| Asthenia | 2/21 (9.5%) | 29/344 (8.4%) | 27/344 (7.8%) | |||
| Chills | 8/21 (38.1%) | 17/344 (4.9%) | 73/344 (21.2%) | |||
| Face oedema | 2/21 (9.5%) | 0/344 (0%) | 3/344 (0.9%) | |||
| Fatigue | 15/21 (71.4%) | 94/344 (27.3%) | 137/344 (39.8%) | |||
| Influenza like illness | 5/21 (23.8%) | 26/344 (7.6%) | 64/344 (18.6%) | |||
| Injection site pain | 2/21 (9.5%) | 14/344 (4.1%) | 15/344 (4.4%) | |||
| Injection site reaction | 2/21 (9.5%) | 3/344 (0.9%) | 10/344 (2.9%) | |||
| Oedema peripheral | 5/21 (23.8%) | 22/344 (6.4%) | 27/344 (7.8%) | |||
| Pain | 1/21 (4.8%) | 18/344 (5.2%) | 24/344 (7%) | |||
| Pyrexia | 10/21 (47.6%) | 33/344 (9.6%) | 128/344 (37.2%) | |||
| Infections and infestations | ||||||
| Cellulitis | 2/21 (9.5%) | 9/344 (2.6%) | 14/344 (4.1%) | |||
| Influenza | 2/21 (9.5%) | 7/344 (2%) | 9/344 (2.6%) | |||
| Nasopharyngitis | 1/21 (4.8%) | 23/344 (6.7%) | 21/344 (6.1%) | |||
| Oral herpes | 2/21 (9.5%) | 16/344 (4.7%) | 15/344 (4.4%) | |||
| Rhinitis | 2/21 (9.5%) | 11/344 (3.2%) | 7/344 (2%) | |||
| Upper respiratory tract infection | 2/21 (9.5%) | 17/344 (4.9%) | 17/344 (4.9%) | |||
| Urinary tract infection | 1/21 (4.8%) | 17/344 (4.9%) | 22/344 (6.4%) | |||
| Injury, poisoning and procedural complications | ||||||
| Contusion | 2/21 (9.5%) | 3/344 (0.9%) | 4/344 (1.2%) | |||
| Infusion related reaction | 2/21 (9.5%) | 0/344 (0%) | 4/344 (1.2%) | |||
| Procedural pain | 2/21 (9.5%) | 5/344 (1.5%) | 9/344 (2.6%) | |||
| Investigations | ||||||
| Alanine aminotransferase increased | 3/21 (14.3%) | 23/344 (6.7%) | 26/344 (7.6%) | |||
| Aspartate aminotransferase increased | 3/21 (14.3%) | 16/344 (4.7%) | 20/344 (5.8%) | |||
| Blood alkaline phosphatase increased | 2/21 (9.5%) | 7/344 (2%) | 15/344 (4.4%) | |||
| Blood iron decreased | 2/21 (9.5%) | 1/344 (0.3%) | 0/344 (0%) | |||
| Metabolism and nutrition disorders | ||||||
| Decreased appetite | 0/21 (0%) | 26/344 (7.6%) | 43/344 (12.5%) | |||
| Hyperglycaemia | 3/21 (14.3%) | 11/344 (3.2%) | 19/344 (5.5%) | |||
| Hyperkalaemia | 2/21 (9.5%) | 5/344 (1.5%) | 2/344 (0.6%) | |||
| Hypophosphataemia | 2/21 (9.5%) | 3/344 (0.9%) | 14/344 (4.1%) | |||
| Musculoskeletal and connective tissue disorders | ||||||
| Arthralgia | 8/21 (38.1%) | 66/344 (19.2%) | 82/344 (23.8%) | |||
| Back pain | 3/21 (14.3%) | 30/344 (8.7%) | 35/344 (10.2%) | |||
| Muscle spasms | 2/21 (9.5%) | 5/344 (1.5%) | 9/344 (2.6%) | |||
| Myalgia | 2/21 (9.5%) | 16/344 (4.7%) | 33/344 (9.6%) | |||
| Pain in extremity | 4/21 (19%) | 21/344 (6.1%) | 29/344 (8.4%) | |||
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||||||
| Squamous cell carcinoma | 3/21 (14.3%) | 1/344 (0.3%) | 1/344 (0.3%) | |||
| Nervous system disorders | ||||||
| Headache | 9/21 (42.9%) | 44/344 (12.8%) | 62/344 (18%) | |||
| Neuropathy peripheral | 2/21 (9.5%) | 0/344 (0%) | 4/344 (1.2%) | |||
| Paraesthesia | 2/21 (9.5%) | 6/344 (1.7%) | 13/344 (3.8%) | |||
| Psychiatric disorders | ||||||
| Anxiety | 2/21 (9.5%) | 7/344 (2%) | 11/344 (3.2%) | |||
| Insomnia | 3/21 (14.3%) | 27/344 (7.8%) | 23/344 (6.7%) | |||
| Respiratory, thoracic and mediastinal disorders | ||||||
| Cough | 8/21 (38.1%) | 44/344 (12.8%) | 58/344 (16.9%) | |||
| Dyspnoea | 4/21 (19%) | 24/344 (7%) | 23/344 (6.7%) | |||
| Pneumonitis | 2/21 (9.5%) | 7/344 (2%) | 18/344 (5.2%) | |||
| Skin and subcutaneous tissue disorders | ||||||
| Actinic keratosis | 2/21 (9.5%) | 4/344 (1.2%) | 6/344 (1.7%) | |||
| Alopecia | 3/21 (14.3%) | 3/344 (0.9%) | 10/344 (2.9%) | |||
| Erythema | 2/21 (9.5%) | 15/344 (4.4%) | 15/344 (4.4%) | |||
| Pruritus | 7/21 (33.3%) | 55/344 (16%) | 61/344 (17.7%) | |||
| Rash | 9/21 (42.9%) | 42/344 (12.2%) | 61/344 (17.7%) | |||
| Rash erythematous | 2/21 (9.5%) | 1/344 (0.3%) | 4/344 (1.2%) | |||
| Rash macular | 2/21 (9.5%) | 1/344 (0.3%) | 6/344 (1.7%) | |||
| Rash maculo-papular | 3/21 (14.3%) | 17/344 (4.9%) | 20/344 (5.8%) | |||
| Skin lesion | 2/21 (9.5%) | 2/344 (0.6%) | 11/344 (3.2%) | |||
| Skin mass | 2/21 (9.5%) | 2/344 (0.6%) | 0/344 (0%) | |||
| Urticaria | 2/21 (9.5%) | 2/344 (0.6%) | 3/344 (0.9%) | |||
| Vitiligo | 5/21 (23.8%) | 32/344 (9.3%) | 44/344 (12.8%) | |||
| Vascular disorders | ||||||
| Hypertension | 1/21 (4.8%) | 22/344 (6.4%) | 19/344 (5.5%) | |||
Limitations/Caveats
[Not Specified]
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
The Clinical Trial Agreement generally does not restrict an investigator's discussion of trial results after completion. The Agreement permits Amgen a limited period of time to review material discussing trial results (typically up to 45 days and possible extension). Amgen may remove confidential information, but authors have final control and approval of publication content. For multicenter studies, the investigator agrees not to publish any results before the first multi-center publication.
Results Point of Contact
| Name/Title | Study Director |
|---|---|
| Organization | Amgen Inc. |
| Phone | 866-572-6436 |
| medinfo@amgen.com |
Responsible Party:
Amgen
ClinicalTrials.gov Identifier:
NCT02263508
Other Study ID Numbers:
- 20110265
- 2014-000185-22
- KEYNOTE-034
First Posted:
Oct 13, 2014
Last Update Posted:
May 16, 2022
Last Verified:
Apr 1, 2022