Study of Pembrolizumab (MK-3475) in Participants With Relapsed or Refractory Primary Mediastinal Large B-cell Lymphoma or Relapsed or Refractory Richter Syndrome (MK-3475-170/KEYNOTE-170)

• Sponsor: Merck Sharp & Dohme LLC (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02576990
• Collaborator: (none)
• Enrollment: 80
• Arms: 2
• Actual Duration (Months): 58.7

Study Details

Study Description

Brief Summary

In this study, participants with relapsed or refractory primary mediastinal large B-cell lymphoma (rrPMBCL) or relapsed or refractory Richter Syndrome (rrRS) will receive pembrolizumab (MK-3475). The efficacy of pembrolizumab in the treatment of rrPMBCL and rrRS will be evaluated. The primary study hypothesis is that intravenous (IV) administration of single agent pembrolizumab to the rrPMBCL cohort will result in an Objective Response Rate (ORR) of greater than 15% using the International Working Group (IWG) response criteria (Cheson, 2007) by independent central review.

Effective with Protocol Amendment 04, enrollment into the rrRS cohort was closed.

Condition or Disease	Intervention/Treatment	Phase
Mediastinal Large B-cell Lymphoma; Richter Syndrome	Biological: Pembrolizumab	Phase 2

Detailed Description

Treatment with pembrolizumab will continue for a maximum of 35 administrations (approximately 2 years) or until documented disease progression by investigator assessment, unacceptable adverse event(s) (AEs), intercurrent illness that prevents further administration of treatment, participant withdraws consent, pregnancy of the participant, noncompliance with study treatment or procedure requirements, or administrative reasons.

Study Design

• Study Type: Interventional
• Actual Enrollment: 80 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Study of Pembrolizumab (MK-3475) in Subjects With Relapsed or Refractory Primary Mediastinal Large B-cell Lymphoma (rrPMBCL) or Relapsed or Refractory Richter Syndrome (rrRS)
• Actual Study Start Date: Dec 2, 2015
• Actual Primary Completion Date: May 28, 2019
• Actual Study Completion Date: Oct 23, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Pembrolizumab: Relapsed or Refractory Primary Mediastinal Large B-cell Lymphoma (rrPMBCL) Participants with rrPMBCL receive pembrolizumab 200 mg every 3 weeks (Q3W), intravenous infusion (IV) on Day 1 of each 3-week cycle for up to a maximum of 35 administrations (approximately 2 years).	Biological: Pembrolizumab; IV infusion; Other Names: MK-3475 KEYTRUDA® SCH 900475
Experimental: Pembrolizumab: Relapsed or Refractory Richter Syndrome (rrRS) Participants with rrRS receive pembrolizumab 200 mg Q3W, IV for each 3-week cycle for up to a maximum of 35 administrations (approximately 2 years). Effective with Protocol Amendment 04, enrollment into this cohort was closed.	Biological: Pembrolizumab; IV infusion; Other Names: MK-3475 KEYTRUDA® SCH 900475

Outcome Measures

Primary Outcome Measures

1. Objective Response Rate (ORR) Based on International Working Group (IWG) Response Assessment Criteria Per Independent Central Review [Up to approximately 27 months (Database Cutoff: 28MAY2019)]

   The ORR was assessed by independent central review utilizing the International Working Group [IWG] response assessment criteria per Cheson 2007 of pembrolizumab in participants with rrPMBCL. For participants with rrRS, IWG criteria with special considerations for RS was used for progression. The ORR was defined as the percentage of participants who had a response (complete response, CR or partial response, PR) prior to disease progression. CR is the disappearance of all evidence of disease and PR is the regression of measurable disease and no new sites. Participants with missing data were considered non-responders. In the rrPMBCL cohort, an exact binomial test was conducted versus a fixed historical control rate. For the rrPMBCL cohort, the ORR was estimated as well as a 95% 2-sided exact confidence interval (CI) using the Clopper-Pearson method whereas the rrRS cohort was estimated with a 90% 2-sided CI.

Secondary Outcome Measures

1. ORR Based on IWG Response Assessment Criteria by Investigator Assessment [Up to approximately 27 months (Database Cutoff Date: 28MAY2019)]

   The ORR was assessed by Investigator assessment utilizing the IWG response assessment criteria per Cheson 2007 of pembrolizumab in participants with rrPMBCL. For participants with rrRS, IWG criteria with special considerations for RS was used for progression. The ORR was defined as the percentage of participants who had a response (CR or PR) prior to disease progression. CR is the disappearance of all evidence of disease and PR is the regression of measurable disease and no new sites. Participants with missing data were considered non-responders. In the rrPMBCL cohort, an exact binomial test was conducted versus a fixed historical control rate.

2. Progression Free Survival (PFS) Based on IWG Response Assessment Criteria by Independent Central Review [Up to approximately 27 months (Database Cutoff Date: 28MAY2019)]

   PFS was defined as the time from first dose to the first documented progressive disease (PD) or death due to any cause, whichever occurs first. PD is the appearance of any new lesion or increase by ≥ 50% of previously involved site from nadir. Calculated from the product-limit (Kaplan-Meier) method for censored data.

3. Progression Free Survival (PFS) Based on IWG Response Assessment Criteria by Investigator Assessment [Up to approximately 27 months (Database Cutoff Date: 28MAY2019)]

   PFS was defined as the time from the first dose to the first documented PD or death due to any cause, whichever occurs first. PD is the appearance of any new lesion or increase by ≥ 50% of previously involved site from nadir. Calculated from the product-limit (Kaplan-Meier) method for censored data.

4. Duration of Response (DOR) Based on IWG Response Assessment Criteria by Independent Central Review in Participants With Responses [Up to approximately 27 months (Database Cutoff Date: 28MAY2019)]

   The DOR was defined, only for the subgroup of participants who achieved a CR or PR by independent central review, as the time from start of the first documentation of objective tumor response (CR or PR) to the first documentation of PD or to death due to any cause, whichever comes first. CR is the disappearance of all evidence of disease and PR is the regression of measurable disease and no new sites. PD is the appearance any new lesion or increase by ≥ 50% of previously involved site from nadir. The analysis consisted of Kaplan-Meier estimates. DOR data was censored on the date of the last disease assessment documenting absence of PD for participants who did not have tumor progression and were still on study at the time of an analysis, were given antitumor treatment other than the study treatment, or were removed from study prior to documentation of tumor progression.

5. Duration of Response (DOR) Based on IWG Response Assessment Criteria by Investigator Assessment in Participants With Responses [Up to approximately 27 months (Database Cutoff Date: 28MAY2019)]

   The DOR was defined, only for the subgroup of participants who achieved a CR or PR by investigator assessment, as the time from start of the first documentation of objective tumor response (CR or PR) to the first documentation of PD or to death due to any cause, whichever comes first. CR is the disappearance of all evidence of disease and PR is the regression of measurable disease and no new sites. PD is the appearance any new lesion or increase by ≥ 50% of previously involved site from nadir. The analysis consisted of Kaplan-Meier estimates. DOR data was censored on the date of the last disease assessment documenting absence of PD for participants who did not have tumor progression and were still on study at the time of an analysis, were given antitumor treatment other than the study treatment, or were removed from study prior to documentation of tumor progression.

6. Disease Control Rate (DCR) Based on IWG Response Assessment Criteria by Independent Central Review [Up to approximately 27 months (Database Cutoff Date: 28MAY2019)]

   The DCR was defined as the percentage of participants in the analysis population who have achieved a CR, PR or stable disease (SD) response prior to PD. CR is the disappearance of all evidence of disease and PR is the regression of measurable disease and no new sites. SD is the failure to attain CR/PR or PD. PD is the appearance any new lesion or increase by ≥ 50% of previously involved site from nadir. Participants with missing data were considered non-responders.

7. Disease Control Rate (DCR) Based on IWG Response Assessment Criteria by Investigator Assessment [Up to approximately 27 months (Database Cutoff Date: 28MAY2019)]

   The DCR was defined as the percentage of participants in the analysis population who have achieved a CR, PR or SD response prior to PD. CR is the disappearance of all evidence of disease and PR is the regression of measurable disease and no new sites. SD is the failure to attain CR/PR or PD. PD is the appearance any new lesion or increase by ≥ 50% of previously involved site from nadir. Participants with missing data were considered non-responders.

8. Overall Survival (OS) [Up to approximately 27 months (Database Cutoff Date: 28MAY2019)]

   OS was defined as the time from the first dose to death due to any cause. OS is presented from product limit (Kaplan-Meier) method for censored data (censored at the last assessment).

9. Number of Participants Who Experienced an Adverse Event (AE) [Up to approximately 30 months (Up to 90 days after last dose of study treatment) (Database Cutoff Date: 28MAY2019)]

   An adverse event (AE) is defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it is considered related to the medical treatment or procedure, that occurs during the course of the study. The number of participants who experienced an AE were reported.

10. Number of Participants Who Discontinued Study Drug Due to an AE [Up to approximately 27 months (Database Cutoff Date: 28MAY2019)]

    An AE is defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it is considered related to the medical treatment or procedure, that occurs during the course of the study. The number of participants who discontinued study drug due to an AE were reported.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Primary mediastinal large B-cell lymphoma (PMBCL):

• Diagnosis of relapsed or refractory primary mediastinal large B-cell lymphoma (rrPMBCL) AND

• Has relapsed after autologous stem cell transplant (auto-SCT) or has failed to achieve a Complete Response or Partial Response within 60 days of auto-SCT. Participants may have received intervening therapy after auto-SCT for relapsed or refractory disease, in which case they must have relapsed after or be refractory to their last treatment OR

• For participants who are ineligible for auto-SCT, has received at least ≥2 lines of prior therapy and has failed to respond to or relapsed after their last line of treatment. For participants who received consolidative local radiotherapy after systemic therapy, local radiotherapy will not be considered as a separate line of treatment

• Previously exposed to rituximab as part of prior lines of treatment

• Richter syndrome (RS):

• Pathologic diagnosis per local institutional review of RS that transformed from chronic lymphocytic leukemia (CLL)

• Relapsed or refractory Richter syndrome and has received ≥1 previous treatment for RS

• All Participants:

• Radiographically measurable disease

• Performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale

• Life expectancy >3 months

• Adequate organ function

• Female participants of childbearing potential must be willing to use an adequate method of contraception for the course of the study through 120 days after the last dose of study drug

• Male participants of childbearing potential must agree to use an adequate method of contraception, starting with the first dose of study drug through 120 days after the last dose of study drug

Exclusion Criteria:

• Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of study drug

• Is receiving systemic steroid therapy <3 days before the first dose of study drug or receiving any other form of immunosuppressive medication

• Prior monoclonal antibody within 4 weeks prior to study Day 1 (2 weeks for RS participants) or who has not recovered (i.e. ≤ Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier (2 weeks for RS participants)

• Prior chemotherapy or targeted small molecule therapy within 2 weeks prior to study Day 1 or prior radiation therapy within 4 weeks prior to study Day 1

• Allogeneic hematopoietic stem cell transplantation within the last 5 years.

• Has a known additional malignancy (except underlying CLL for RS) that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy

• Known clinically active central nervous system involvement

• Active autoimmune disease requiring systemic treatment in past 2 years

• History of (non-infectious) pneumonitis that required steroids, or current pneumonitis

• Active infection requiring intravenous systemic therapy

• Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the study, starting with the pre-screening or screening visit through 120 days after the last dose of study drug

• Has received prior therapy with an anti-programmed cell death 1 (anti-PD-1), anti-programmed cell death ligand 1 (anti-PD-L1), anti-programmed cell death ligand 2 (anti-PD-L2), anti-CD137, or anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways)

• Known human immunodeficiency virus (HIV), or Hepatitis B or C

• Has received a live vaccine within 30 days prior to first dose of study drug

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• Merck Sharp & Dohme LLC

Investigators

• Study Director: Medical Director, Merck Sharp & Dohme LLC

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jul 8, 2020

More Information

Additional Information:

• Merck Oncology Clinical Trials Information

Publications

None provided.

• Responsible Party: Merck Sharp & Dohme LLC
• ClinicalTrials.gov Identifier: NCT02576990
• Other Study ID Numbers: 3475-170; 2015-002406-37; MK-3475-170; KEYNOTE-170
• First Posted: Oct 15, 2015
• Last Update Posted: Nov 1, 2021
• Last Verified: Oct 1, 2021

• 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 Merck Sharp & Dohme LLC: Programmed Cell Death 1 (PD-1, PD1); Programmed Cell Death-Ligand 1 (PD-L1, PDL1); Programmed Cell Death-Ligand 2 (PD-L2, PDL2)
• Additional relevant MeSH terms: Lymphoma; Lymphoma, B-Cell; Syndrome; Pembrolizumab

Study Results

Participant Flow

Pre-assignment Detail	Of the 80 participants allocated in the study, 76 participants received at least one dose of study treatment.

Arm/Group Title	Pembrolizumab: Relapsed or Refractory Primary Mediastinal Large B-cell Lymphoma (rrPMBCL)	Pembrolizumab: Relapsed or Refractory Richter Syndrome (rrRS)
Arm/Group Description	Pembrolizumab 200 mg every 3 weeks (Q3W), intravenous infusion (IV) on Day 1 of each 3-week cycle for up to 35 administrations (approximately 2 years).	Pembrolizumab 200 mg Q3W, IV on Day 1 of each 3-week cycle for up to 35 administrations (approximately 2 years).
Period Title: Overall Study
STARTED	56	24
Treated	53	23
COMPLETED	0	0
NOT COMPLETED	56	24

Baseline Characteristics

Arm/Group Title	Pembrolizumab: Relapsed or Refractory Primary Mediastinal Large B-cell Lymphoma (rrPMBCL)	Pembrolizumab: Relapsed or Refractory Richter Syndrome (rrRS)	Total
Arm/Group Description	Pembrolizumab 200 mg every 3 weeks (Q3W), intravenous infusion (IV) on Day 1 of each 3-week cycle for up to 35 administrations (approximately 2 years).	Pembrolizumab 200 mg Q3W, IV on Day 1 of each 3-week cycle for up to 35 administrations (approximately 2 years).	Total of all reporting groups
Overall Participants	56	24	80
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	35.0 (10.4)	67.2 (11.0)	44.7 (18.2)
Sex: Female, Male (Count of Participants)
Female	30 53.6%	7 29.2%	37 46.3%
Male	26 46.4%	17 70.8%	43 53.8%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	4 7.1%	1 4.2%	5 6.3%
Not Hispanic or Latino	37 66.1%	21 87.5%	58 72.5%
Unknown or Not Reported	15 26.8%	2 8.3%	17 21.3%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	1 1.8%	0 0%	1 1.3%
White	51 91.1%	24 100%	75 93.8%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	4 7.1%	0 0%	4 5%

Outcome Measures

1. Primary Outcome

Title	Objective Response Rate (ORR) Based on International Working Group (IWG) Response Assessment Criteria Per Independent Central Review
Description	The ORR was assessed by independent central review utilizing the International Working Group [IWG] response assessment criteria per Cheson 2007 of pembrolizumab in participants with rrPMBCL. For participants with rrRS, IWG criteria with special considerations for RS was used for progression. The ORR was defined as the percentage of participants who had a response (complete response, CR or partial response, PR) prior to disease progression. CR is the disappearance of all evidence of disease and PR is the regression of measurable disease and no new sites. Participants with missing data were considered non-responders. In the rrPMBCL cohort, an exact binomial test was conducted versus a fixed historical control rate. For the rrPMBCL cohort, the ORR was estimated as well as a 95% 2-sided exact confidence interval (CI) using the Clopper-Pearson method whereas the rrRS cohort was estimated with a 90% 2-sided CI.
Time Frame	Up to approximately 27 months (Database Cutoff: 28MAY2019)

Outcome Measure Data

Analysis Population Description

The analysis population included all participants who received at least one dose of study medication (pembrolizumab).

Arm/Group Title	Pembrolizumab: Relapsed or Refractory Primary Mediastinal Large B-cell Lymphoma (rrPMBCL)	Pembrolizumab: Relapsed or Refractory Richter Syndrome (rrRS)
Arm/Group Description	Pembrolizumab 200 mg every 3 weeks (Q3W), intravenous infusion (IV) on Day 1 of each 3-week cycle for up to 35 administrations (approximately 2 years).	Pembrolizumab 200 mg Q3W, IV on Day 1 of each 3-week cycle for up to 35 administrations (approximately 2 years).
Measure Participants	53	23
Number (95% Confidence Interval) [Percentage of participants]	45.3 80.9%	13.0 54.2%

2. Secondary Outcome

Title	ORR Based on IWG Response Assessment Criteria by Investigator Assessment
Description	The ORR was assessed by Investigator assessment utilizing the IWG response assessment criteria per Cheson 2007 of pembrolizumab in participants with rrPMBCL. For participants with rrRS, IWG criteria with special considerations for RS was used for progression. The ORR was defined as the percentage of participants who had a response (CR or PR) prior to disease progression. CR is the disappearance of all evidence of disease and PR is the regression of measurable disease and no new sites. Participants with missing data were considered non-responders. In the rrPMBCL cohort, an exact binomial test was conducted versus a fixed historical control rate.
Time Frame	Up to approximately 27 months (Database Cutoff Date: 28MAY2019)

Outcome Measure Data

Analysis Population Description

The analysis population included all participants who received at least one dose of study medication (pembrolizumab).

Arm/Group Title	Pembrolizumab: Relapsed or Refractory Primary Mediastinal Large B-cell Lymphoma (rrPMBCL)	Pembrolizumab: Relapsed or Refractory Richter Syndrome (rrRS)
Arm/Group Description	Pembrolizumab 200 mg every 3 weeks (Q3W), intravenous infusion (IV) on Day 1 of each 3-week cycle for up to 35 administrations (approximately 2 years).	Pembrolizumab 200 mg Q3W, IV on Day 1 of each 3-week cycle for up to 35 administrations (approximately 2 years).
Measure Participants	53	23
Number (90% Confidence Interval) [Percentage of participants]	41.5 74.1%	4.3 17.9%

3. Secondary Outcome

Title	Progression Free Survival (PFS) Based on IWG Response Assessment Criteria by Independent Central Review
Description	PFS was defined as the time from first dose to the first documented progressive disease (PD) or death due to any cause, whichever occurs first. PD is the appearance of any new lesion or increase by ≥ 50% of previously involved site from nadir. Calculated from the product-limit (Kaplan-Meier) method for censored data.
Time Frame	Up to approximately 27 months (Database Cutoff Date: 28MAY2019)

Outcome Measure Data

Analysis Population Description

The analysis population included all participants who received at least one dose of study medication (pembrolizumab).

Arm/Group Title	Pembrolizumab: Relapsed or Refractory Primary Mediastinal Large B-cell Lymphoma (rrPMBCL)	Pembrolizumab: Relapsed or Refractory Richter Syndrome (rrRS)
Arm/Group Description	Pembrolizumab 200 mg every 3 weeks (Q3W), intravenous infusion (IV) on Day 1 of each 3-week cycle for up to 35 administrations (approximately 2 years).	Pembrolizumab 200 mg Q3W, IV on Day 1 of each 3-week cycle for up to 35 administrations (approximately 2 years).
Measure Participants	53	23
Median (95% Confidence Interval) [Months]	5.5	1.6

4. Secondary Outcome

Title	Progression Free Survival (PFS) Based on IWG Response Assessment Criteria by Investigator Assessment
Description	PFS was defined as the time from the first dose to the first documented PD or death due to any cause, whichever occurs first. PD is the appearance of any new lesion or increase by ≥ 50% of previously involved site from nadir. Calculated from the product-limit (Kaplan-Meier) method for censored data.
Time Frame	Up to approximately 27 months (Database Cutoff Date: 28MAY2019)

Outcome Measure Data

Analysis Population Description

The analysis population included all participants who received at least one dose of study medication (pembrolizumab).

Arm/Group Title	Pembrolizumab: Relapsed or Refractory Primary Mediastinal Large B-cell Lymphoma (rrPMBCL)	Pembrolizumab: Relapsed or Refractory Richter Syndrome (rrRS)
Arm/Group Description	Pembrolizumab 200 mg every 3 weeks (Q3W), intravenous infusion (IV) on Day 1 of each 3-week cycle for up to 35 administrations (approximately 2 years).	Pembrolizumab 200 mg Q3W, IV on Day 1 of each 3-week cycle for up to 35 administrations (approximately 2 years).
Measure Participants	53	23
Median (95% Confidence Interval) [Months]	4.3	1.8

5. Secondary Outcome

Title	Duration of Response (DOR) Based on IWG Response Assessment Criteria by Independent Central Review in Participants With Responses
Description	The DOR was defined, only for the subgroup of participants who achieved a CR or PR by independent central review, as the time from start of the first documentation of objective tumor response (CR or PR) to the first documentation of PD or to death due to any cause, whichever comes first. CR is the disappearance of all evidence of disease and PR is the regression of measurable disease and no new sites. PD is the appearance any new lesion or increase by ≥ 50% of previously involved site from nadir. The analysis consisted of Kaplan-Meier estimates. DOR data was censored on the date of the last disease assessment documenting absence of PD for participants who did not have tumor progression and were still on study at the time of an analysis, were given antitumor treatment other than the study treatment, or were removed from study prior to documentation of tumor progression.
Time Frame	Up to approximately 27 months (Database Cutoff Date: 28MAY2019)

Outcome Measure Data

Analysis Population Description

The analysis population included all participants who received at least one dose of study medication (pembrolizumab) and who achieved a CR or PR by independent central review, as the time from start of the first documentation of objective tumor response (CR or PR).

Arm/Group Title	Pembrolizumab: Relapsed or Refractory Primary Mediastinal Large B-cell Lymphoma (rrPMBCL)	Pembrolizumab: Relapsed or Refractory Richter Syndrome (rrRS)
Arm/Group Description	Pembrolizumab 200 mg every 3 weeks (Q3W), intravenous infusion (IV) on Day 1 of each 3-week cycle for up to 35 administrations (approximately 2 years).	Pembrolizumab 200 mg Q3W, IV on Day 1 of each 3-week cycle for up to 35 administrations (approximately 2 years).
Measure Participants	24	3
Median (95% Confidence Interval) [Months]	NA	4.5

6. Secondary Outcome

Title	Duration of Response (DOR) Based on IWG Response Assessment Criteria by Investigator Assessment in Participants With Responses
Description	The DOR was defined, only for the subgroup of participants who achieved a CR or PR by investigator assessment, as the time from start of the first documentation of objective tumor response (CR or PR) to the first documentation of PD or to death due to any cause, whichever comes first. CR is the disappearance of all evidence of disease and PR is the regression of measurable disease and no new sites. PD is the appearance any new lesion or increase by ≥ 50% of previously involved site from nadir. The analysis consisted of Kaplan-Meier estimates. DOR data was censored on the date of the last disease assessment documenting absence of PD for participants who did not have tumor progression and were still on study at the time of an analysis, were given antitumor treatment other than the study treatment, or were removed from study prior to documentation of tumor progression.
Time Frame	Up to approximately 27 months (Database Cutoff Date: 28MAY2019)

Outcome Measure Data

Analysis Population Description

The analysis population included all participants who received at least one dose of study medication (pembrolizumab) and who achieved a CR or PR by investigator assessment, as the time from start of the first documentation of objective tumor response (CR or PR).

Arm/Group Title	Pembrolizumab: Relapsed or Refractory Primary Mediastinal Large B-cell Lymphoma (rrPMBCL)	Pembrolizumab: Relapsed or Refractory Richter Syndrome (rrRS)
Arm/Group Description	Pembrolizumab 200 mg every 3 weeks (Q3W), intravenous infusion (IV) on Day 1 of each 3-week cycle for up to 35 administrations (approximately 2 years).	Pembrolizumab 200 mg Q3W, IV on Day 1 of each 3-week cycle for up to 35 administrations (approximately 2 years).
Measure Participants	24	1
Median (95% Confidence Interval) [Months]	NA	NA

7. Secondary Outcome

Title	Disease Control Rate (DCR) Based on IWG Response Assessment Criteria by Independent Central Review
Description	The DCR was defined as the percentage of participants in the analysis population who have achieved a CR, PR or stable disease (SD) response prior to PD. CR is the disappearance of all evidence of disease and PR is the regression of measurable disease and no new sites. SD is the failure to attain CR/PR or PD. PD is the appearance any new lesion or increase by ≥ 50% of previously involved site from nadir. Participants with missing data were considered non-responders.
Time Frame	Up to approximately 27 months (Database Cutoff Date: 28MAY2019)

Outcome Measure Data

Analysis Population Description

The analysis population included all participants who received at least one dose of study medication (pembrolizumab).

Arm/Group Title	Pembrolizumab: Relapsed or Refractory Primary Mediastinal Large B-cell Lymphoma (rrPMBCL)	Pembrolizumab: Relapsed or Refractory Richter Syndrome (rrRS)
Arm/Group Description	Pembrolizumab 200 mg every 3 weeks (Q3W), intravenous infusion (IV) on Day 1 of each 3-week cycle for up to 35 administrations (approximately 2 years).	Pembrolizumab 200 mg Q3W, IV on Day 1 of each 3-week cycle for up to 35 administrations (approximately 2 years).
Measure Participants	53	23
Number (90% Confidence Interval) [Percentage of participants]	54.7 97.7%	17.4 72.5%

8. Secondary Outcome

Title	Disease Control Rate (DCR) Based on IWG Response Assessment Criteria by Investigator Assessment
Description	The DCR was defined as the percentage of participants in the analysis population who have achieved a CR, PR or SD response prior to PD. CR is the disappearance of all evidence of disease and PR is the regression of measurable disease and no new sites. SD is the failure to attain CR/PR or PD. PD is the appearance any new lesion or increase by ≥ 50% of previously involved site from nadir. Participants with missing data were considered non-responders.
Time Frame	Up to approximately 27 months (Database Cutoff Date: 28MAY2019)

Outcome Measure Data

Analysis Population Description

The analysis population included all participants who received at least one dose of study medication (pembrolizumab).

Arm/Group Title	Pembrolizumab: Relapsed or Refractory Primary Mediastinal Large B-cell Lymphoma (rrPMBCL)	Pembrolizumab: Relapsed or Refractory Richter Syndrome (rrRS)
Arm/Group Description	Pembrolizumab 200 mg every 3 weeks (Q3W), intravenous infusion (IV) on Day 1 of each 3-week cycle for up to 35 administrations (approximately 2 years).	Pembrolizumab 200 mg Q3W, IV on Day 1 of each 3-week cycle for up to 35 administrations (approximately 2 years).
Measure Participants	53	23
Number (90% Confidence Interval) [Percentage of participants]	52.8 94.3%	26.1 108.8%

9. Secondary Outcome

Title	Overall Survival (OS)
Description	OS was defined as the time from the first dose to death due to any cause. OS is presented from product limit (Kaplan-Meier) method for censored data (censored at the last assessment).
Time Frame	Up to approximately 27 months (Database Cutoff Date: 28MAY2019)

Outcome Measure Data

Analysis Population Description

The analysis population included all participants who received at least one dose of study medication (pembrolizumab).

Arm/Group Title	Pembrolizumab: Relapsed or Refractory Primary Mediastinal Large B-cell Lymphoma (rrPMBCL)	Pembrolizumab: Relapsed or Refractory Richter Syndrome (rrRS)
Arm/Group Description	Pembrolizumab 200 mg every 3 weeks (Q3W), intravenous infusion (IV) on Day 1 of each 3-week cycle for up to 35 administrations (approximately 2 years).	Pembrolizumab 200 mg Q3W, IV on Day 1 of each 3-week cycle for up to 35 administrations (approximately 2 years).
Measure Participants	53	23
Median (95% Confidence Interval) [Months]	22.3	3.8

10. Secondary Outcome

Title	Number of Participants Who Experienced an Adverse Event (AE)
Description	An adverse event (AE) is defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it is considered related to the medical treatment or procedure, that occurs during the course of the study. The number of participants who experienced an AE were reported.
Time Frame	Up to approximately 30 months (Up to 90 days after last dose of study treatment) (Database Cutoff Date: 28MAY2019)

Outcome Measure Data

Analysis Population Description

The analysis population included all participants who received at least one dose of study medication (pembrolizumab).

Arm/Group Title	Pembrolizumab: Relapsed or Refractory Primary Mediastinal Large B-cell Lymphoma (rrPMBCL)	Pembrolizumab: Relapsed or Refractory Richter Syndrome (rrRS)
Arm/Group Description	Pembrolizumab 200 mg every 3 weeks (Q3W), intravenous infusion (IV) on Day 1 of each 3-week cycle for up to 35 administrations (approximately 2 years).	Pembrolizumab 200 mg Q3W, IV on Day 1 of each 3-week cycle for up to 35 administrations (approximately 2 years).
Measure Participants	53	23
Count of Participants [Participants]	50 89.3%	23 95.8%

11. Secondary Outcome

Title	Number of Participants Who Discontinued Study Drug Due to an AE
Description	An AE is defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it is considered related to the medical treatment or procedure, that occurs during the course of the study. The number of participants who discontinued study drug due to an AE were reported.
Time Frame	Up to approximately 27 months (Database Cutoff Date: 28MAY2019)

Outcome Measure Data

Analysis Population Description

The analysis population included all participants who received at least one dose of study medication (pembrolizumab).

Arm/Group Title	Pembrolizumab: Relapsed or Refractory Primary Mediastinal Large B-cell Lymphoma (rrPMBCL)	Pembrolizumab: Relapsed or Refractory Richter Syndrome (rrRS)
Arm/Group Description	Pembrolizumab 200 mg every 3 weeks (Q3W), intravenous infusion (IV) on Day 1 of each 3-week cycle for up to 35 administrations (approximately 2 years).	Pembrolizumab 200 mg Q3W, IV on Day 1 of each 3-week cycle for up to 35 administrations (approximately 2 years).
Measure Participants	53	23
Count of Participants [Participants]	6 10.7%	4 16.7%

Adverse Events

Time Frame	Serious adverse events (AEs), non-serious AEs and all-cause mortality was collected up to approximately 56 months through end of trial (EOT) data cut-off date 23 Oct 2020.
Adverse Event Reporting Description	All-cause mortality was reported on all allocated participants. Serious and non-serious AEs were reported among participants who received at least one dose of study treatment. Per protocol, disease progression of cancer was not considered an AE unless related to study drug. Thus, MedDRA preferred terms "Neoplasm progression", "Malignant neoplasm progression" and "Disease progression" unrelated to study drug were excluded.
Arm/Group Title	Pembrolizumab: Relapsed or Refractory Primary Mediastinal Large B-cell Lymphoma (rrPMBCL)		Pembrolizumab: Relapsed or Refractory Richter Syndrome (rrRS)
Arm/Group Description	Pembrolizumab 200 mg every 3 weeks (Q3W), intravenous infusion (IV) on Day 1 of each 3-week cycle for up to 35 administrations (approximately 2 years).		Pembrolizumab 200 mg Q3W, IV on Day 1 of each 3-week cycle for up to 35 administrations (approximately 2 years).
All Cause Mortality
	Pembrolizumab: Relapsed or Refractory Primary Mediastinal Large B-cell Lymphoma (rrPMBCL)		Pembrolizumab: Relapsed or Refractory Richter Syndrome (rrRS)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	30/56 (53.6%)		19/24 (79.2%)
Serious Adverse Events
	Pembrolizumab: Relapsed or Refractory Primary Mediastinal Large B-cell Lymphoma (rrPMBCL)		Pembrolizumab: Relapsed or Refractory Richter Syndrome (rrRS)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	14/53 (26.4%)		15/23 (65.2%)
Blood and lymphatic system disorders
Autoimmune haemolytic anaemia	0/53 (0%)	0	1/23 (4.3%)	1
Febrile neutropenia	1/53 (1.9%)	1	3/23 (13%)	4
Neutropenia	0/53 (0%)	0	1/23 (4.3%)	1
Thrombocytopenia	0/53 (0%)	0	1/23 (4.3%)	1
Cardiac disorders
Cardiac tamponade	1/53 (1.9%)	1	0/23 (0%)	0
Myocardial infarction	1/53 (1.9%)	1	0/23 (0%)	0
Pericardial effusion	1/53 (1.9%)	1	0/23 (0%)	0
Pericarditis	1/53 (1.9%)	1	0/23 (0%)	0
Supraventricular tachycardia	1/53 (1.9%)	2	0/23 (0%)	0
Tachycardia	1/53 (1.9%)	1	0/23 (0%)	0
Endocrine disorders
Hypercalcaemia of malignancy	0/53 (0%)	0	1/23 (4.3%)	1
Hyperthyroidism	0/53 (0%)	0	1/23 (4.3%)	1
Gastrointestinal disorders
Diarrhoea	1/53 (1.9%)	1	0/23 (0%)	0
Gastric perforation	1/53 (1.9%)	1	0/23 (0%)	0
General disorders
Death	0/53 (0%)	0	1/23 (4.3%)	1
General physical health deterioration	0/53 (0%)	0	1/23 (4.3%)	1
Pyrexia	1/53 (1.9%)	1	0/23 (0%)	0
Hepatobiliary disorders
Cholecystitis	0/53 (0%)	0	1/23 (4.3%)	1
Infections and infestations
Aspergillus infection	1/53 (1.9%)	1	0/23 (0%)	0
Clostridium difficile infection	1/53 (1.9%)	1	0/23 (0%)	0
Lower respiratory tract infection	0/53 (0%)	0	1/23 (4.3%)	1
Pneumonia	1/53 (1.9%)	1	0/23 (0%)	0
Sepsis	0/53 (0%)	0	1/23 (4.3%)	1
Septic shock	0/53 (0%)	0	1/23 (4.3%)	1
Staphylococcal infection	0/53 (0%)	0	1/23 (4.3%)	1
Staphylococcal sepsis	0/53 (0%)	0	1/23 (4.3%)	1
Injury, poisoning and procedural complications
Subdural haematoma	0/53 (0%)	0	1/23 (4.3%)	1
Investigations
Aspartate aminotransferase increased	1/53 (1.9%)	1	0/23 (0%)	0
Hepatic enzyme increased	1/53 (1.9%)	1	0/23 (0%)	0
Metabolism and nutrition disorders
Hypercalcaemia	0/53 (0%)	0	2/23 (8.7%)	2
Renal and urinary disorders
Acute kidney injury	1/53 (1.9%)	1	1/23 (4.3%)	1
Urinary tract obstruction	0/53 (0%)	0	1/23 (4.3%)	1
Respiratory, thoracic and mediastinal disorders
Dyspnoea	1/53 (1.9%)	1	0/23 (0%)	0
Pleural effusion	1/53 (1.9%)	1	1/23 (4.3%)	1
Pneumonia aspiration	0/53 (0%)	0	1/23 (4.3%)	1
Pneumonitis	1/53 (1.9%)	2	1/23 (4.3%)	1
Skin and subcutaneous tissue disorders
Rash	0/53 (0%)	0	1/23 (4.3%)	2
Vascular disorders
Hypotension	0/53 (0%)	0	1/23 (4.3%)	1
Venous thrombosis	1/53 (1.9%)	1	0/23 (0%)	0
Other (Not Including Serious) Adverse Events
	Pembrolizumab: Relapsed or Refractory Primary Mediastinal Large B-cell Lymphoma (rrPMBCL)		Pembrolizumab: Relapsed or Refractory Richter Syndrome (rrRS)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	46/53 (86.8%)		23/23 (100%)
Blood and lymphatic system disorders
Anaemia	6/53 (11.3%)	6	7/23 (30.4%)	9
Leukopenia	4/53 (7.5%)	5	2/23 (8.7%)	2
Lymph node pain	0/53 (0%)	0	2/23 (8.7%)	2
Neutropenia	15/53 (28.3%)	29	2/23 (8.7%)	2
Thrombocytopenia	2/53 (3.8%)	3	3/23 (13%)	3
Endocrine disorders
Hypothyroidism	4/53 (7.5%)	4	2/23 (8.7%)	2
Gastrointestinal disorders
Abdominal pain	5/53 (9.4%)	5	3/23 (13%)	3
Constipation	4/53 (7.5%)	4	3/23 (13%)	3
Diarrhoea	7/53 (13.2%)	9	5/23 (21.7%)	5
Nausea	6/53 (11.3%)	8	6/23 (26.1%)	7
Stomatitis	0/53 (0%)	0	2/23 (8.7%)	2
Vomiting	5/53 (9.4%)	5	2/23 (8.7%)	2
General disorders
Asthenia	7/53 (13.2%)	10	2/23 (8.7%)	2
Chest pain	4/53 (7.5%)	4	0/23 (0%)	0
Chills	0/53 (0%)	0	3/23 (13%)	3
Fatigue	6/53 (11.3%)	7	8/23 (34.8%)	8
Pyrexia	15/53 (28.3%)	25	3/23 (13%)	4
Infections and infestations
Bronchitis	3/53 (5.7%)	3	0/23 (0%)	0
Herpes zoster	3/53 (5.7%)	3	1/23 (4.3%)	1
Nasopharyngitis	8/53 (15.1%)	10	0/23 (0%)	0
Pharyngitis	3/53 (5.7%)	3	0/23 (0%)	0
Rhinitis	5/53 (9.4%)	6	0/23 (0%)	0
Upper respiratory tract infection	4/53 (7.5%)	5	0/23 (0%)	0
Urinary tract infection	1/53 (1.9%)	1	2/23 (8.7%)	2
Vulvovaginal mycotic infection	4/53 (7.5%)	5	0/23 (0%)	0
Investigations
Aspartate aminotransferase increased	1/53 (1.9%)	2	2/23 (8.7%)	2
Blood alkaline phosphatase increased	1/53 (1.9%)	1	2/23 (8.7%)	2
Blood bilirubin increased	0/53 (0%)	0	2/23 (8.7%)	2
Blood creatinine increased	0/53 (0%)	0	3/23 (13%)	3
Metabolism and nutrition disorders
Decreased appetite	2/53 (3.8%)	2	3/23 (13%)	3
Hyperglycaemia	4/53 (7.5%)	5	4/23 (17.4%)	4
Hyperkalaemia	0/53 (0%)	0	3/23 (13%)	3
Hypokalaemia	2/53 (3.8%)	2	2/23 (8.7%)	2
Hyponatraemia	2/53 (3.8%)	2	2/23 (8.7%)	2
Hypophosphataemia	1/53 (1.9%)	1	2/23 (8.7%)	2
Musculoskeletal and connective tissue disorders
Arthralgia	6/53 (11.3%)	7	0/23 (0%)	0
Back pain	5/53 (9.4%)	5	2/23 (8.7%)	2
Myalgia	3/53 (5.7%)	4	0/23 (0%)	0
Pain in extremity	3/53 (5.7%)	3	1/23 (4.3%)	1
Nervous system disorders
Dizziness	3/53 (5.7%)	3	0/23 (0%)	0
Headache	6/53 (11.3%)	11	1/23 (4.3%)	1
Hypoaesthesia	0/53 (0%)	0	2/23 (8.7%)	2
Neuropathy peripheral	1/53 (1.9%)	1	2/23 (8.7%)	2
Somnolence	2/53 (3.8%)	3	2/23 (8.7%)	2
Psychiatric disorders
Insomnia	1/53 (1.9%)	1	2/23 (8.7%)	2
Respiratory, thoracic and mediastinal disorders
Cough	10/53 (18.9%)	15	2/23 (8.7%)	2
Dyspnoea	10/53 (18.9%)	11	2/23 (8.7%)	2
Oropharyngeal pain	3/53 (5.7%)	4	0/23 (0%)	0
Productive cough	4/53 (7.5%)	4	0/23 (0%)	0
Skin and subcutaneous tissue disorders
Dry skin	3/53 (5.7%)	3	0/23 (0%)	0
Pruritus	4/53 (7.5%)	6	1/23 (4.3%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The Sponsor must have the opportunity to review all proposed abstracts, manuscripts or presentations regarding this trial 45 days prior to submission for publication/presentation. Any information identified by the Sponsor as confidential must be deleted prior to submission; this confidentiality does not include efficacy and safety results. Sponsor review can be expedited to meet publication timelines.