Safety and Efficacy Study of PDR001 in Patients With Recurrent or Metastatic Nasopharyngeal Carcinoma

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02605967
• Collaborator: (none)
• Enrollment: 122
• Locations: 18
• Arms: 2
• Actual Duration (Months): 58
• Patients Per Site: 6.8
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The purpose of this randomized controlled Phase II study is to assess the efficacy of PDR001 versus investigator's choice of chemotherapy in patients with advanced nasopharyngeal carcinoma (NPC).

By blocking the interaction between PD-1 and its ligands PD-L1 and PD-L2, PDR001 leads to the activation of a T-cell mediated antitumor immune response.

Condition or Disease	Intervention/Treatment	Phase
Nasopharyngeal Carcinoma	Drug: Spartalizumab; Drug: Investigator choice of chemotherapy	Phase 2

Detailed Description

This was an open-label, multi-center, randomized, and controlled Phase II study to evaluate the efficacy and safety of spartalizumab versus investigator's choice of treatment in subjects with moderately differentiated/undifferentiated locally advanced recurrent or metastatic NPC who progressed on or after first-line treatment.

Participants who met the inclusion/exclusion criteria were randomized in a 2:1 ratio to either investigational arm (spartalizumab) or control arm (commonly used chemotherapy as per investigator's choice). Participants treated with spartalizumab could continue treatment until confirmed progressive disease as per immune-related response criteria (irRC). Participants in the chemotherapy arm were allowed to crossover to spartalizumab if they had radiological progression as per Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v1.1) documented by an independent central review and the Investigator believed this was the best treatment option for the patient.

Study Design

• Study Type: Interventional
• Actual Enrollment: 122 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II, Open-label, Randomized Controlled Study of PDR001 in Patients With Moderately Differentiated/Undifferentiated Locally Advanced Recurrent or Metastatic Nasopharyngeal Carcinoma Who Progressed on Standard Treatment
• Actual Study Start Date: Apr 20, 2016
• Actual Primary Completion Date: Nov 5, 2019
• Actual Study Completion Date: Feb 19, 2021

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Spartalizumab 400 mg Q4W anti-PD1 humanized monoclonal antibody. Participants treated with spartalizumab who remained on spartalizumab	Drug: Spartalizumab; Spartalizumab was administered via intravenous infusion at a dose of 400 mg every 4 weeks (Q4W). Spartalizumab is a humanized anti-PD-1 IgG4 antibody which blocks the binding of PD1 to its ligands PD-L1 and PD-L2.; Other Names: PDR001
Active Comparator: Chemotherapy commonly used chemotherapy as per investigator's choice	Drug: Investigator choice of chemotherapy; Commonly used chemotherapy as per investigator's choice. The dose and route of administration was the one described in each drug's label.

Outcome Measures

Primary Outcome Measures

1. Progression-free Survival (PFS) as Per RECIST v 1.1 Using Central Assessment - Number of Participants With Progression or Death [From randomization up to maximum 3.3 years]

   PFS is the time from the date of randomization to the date of event defined as the first documented confirmed progression or death due to any cause. If a patient has not had an event, progression-free survival is censored at the date of last adequate tumor assessment. Tumor response was based on central review of tumor scan and the assessment criteria was Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). Progressive disease is at least a 20% increase in the sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline. Number of participants in each category (progression, death, censored) is reported in this record.

2. Progression-free Survival (PFS) as Per RECIST v 1.1 Using Central Assessment - Median PFS [From randomization up to maximum 3.3 years]

   PFS is the time from the date of randomization to the date of event defined as the first documented confirmed progression or death due to any cause. If a patient has not had an event, progression-free survival is censored at the date of last adequate tumor assessment. Tumor response was based on central review of tumor scan and the assessment criteria was Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). Progressive disease is at least a 20% increase in the sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline.

Secondary Outcome Measures

1. Overall Survival (OS) [From randomization up to maximum 4.8 years.]

   Overall survival (OS) is defined as the time from date of randomization to date of death due to any cause. If a patient is not known to have died, survival is censored at the date of last known date the patient was alive.

2. Overall Response Rate (ORR) as Per RECIST v 1.1 [From randomization up to maximum 3.3 years]

   ORR is defined as the percentage of participants with a best overall response of Complete Response (CR) or Partial Response (PR). Tumor response was based on central review of overall lesion response according to RECIST 1.1. For RECIST v1.1, CR=Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to < 10 mm; PR= At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.

3. Duration of Response (DOR) as Per RECIST v 1.1 [From randomization up to maximum 3.3 years]

   DOR only applies to subjects for whom best overall response is complete response (CR) or partial response (PR) based on central review of overall lesion response according to RECIST 1.1. DOR is defined as the time between the date of first documented response (confirmed CR or confirmed PR) and the date of first documented disease progression or death due to underlying cancer. If a patient not had an event, duration was censored at the date of last adequate tumor assessment.

4. Time to Progression (TTP) as Per RECIST v 1.1 [From randomization up to maximum 3.3 years]

   TTP is defined as time from date of randomization to the date of event defined as the first documented progression or death due to underlying cancer. If a subject did not had an event, TTP was censored at the date of last adequate tumor assessment. Tumor response was based on central review of tumor scan and the assessment criteria was RECIST v1.1. Progressive disease is at least a 20% increase in the sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline.

5. Immune-related Progression-free Survival (irPFS) as Per irRC [From randomization up to maximum 3.3 years]

   irPFS is the time from the date of randomization to the date of event defined as the first documented progression or death due to any cause. If a patient has not had an event, progression-free survival is censored at the date of last adequate tumor assessment. Tumor response was based on central review of tumor scan and the assessment criteria was immune-related Response Criteria (irRC). Immune-related progressive disease is at least a 20% increase in the sum of diameters of all measured target lesions including new measurable lesions.

6. Maximum Observed Serum Concentration (Cmax) of Spartalizumab [pre-dose, 1, 24, 168, 336 and 672 hours post spartalizumab dose on Cycle 1 and Cycle 3. The duration of one cycle was 28 days.]

   Pharmacokinetic (PK) parameters were calculated based on spartalizumab serum concentrations by using non-compartmental methods. Cmax is defined as the maximum (peak) observed serum concentration following a dose.

7. Time to Reach Maximum Serum Concentration (Tmax) of Spartalizumab [pre-dose, 1, 24, 168, 336 and 672 hours post spartalizumab dose on Cycle 1 and Cycle 3. The duration of one cycle was 28 days.]

   Pharmacokinetic (PK) parameters were calculated based on spartalizumab serum concentrations by using non-compartmental methods. Tmax is defined as the time to reach maximum (peak) serum concentration following a dose. Actual recorded sampling times were considered for the calculations.

8. Area Under the Serum Concentration-time Curve From Time Zero to the End of the Dosing Interval Tau (AUCtau) of Spartalizumab [pre-dose, 1, 24, 168, 336 and 672 hours post spartalizumab dose on Cycle 1 and Cycle 3. The duration of one cycle was 28 days.]

   Pharmacokinetic (PK) parameters were calculated based on spartalizumab serum concentrations by using non-compartmental methods. The linear trapezoidal method was used for AUC calculation. The duration of the dosing interval (tau) was 28 days.

9. Area Under the Serum Concentration-time Curve From Time Zero to Infinity (AUCinf) of Spartalizumab [pre-dose, 1, 24, 168, 336 and 672 hours post spartalizumab dose on Cycle 1 and Cycle 3. The duration of one cycle was 28 days.]

   Pharmacokinetic (PK) parameters were calculated based on spartalizumab serum concentrations by using non-compartmental methods. The linear trapezoidal method was used for AUC calculation. The extrapolation of AUC to infinity could be calculated if the percentage of area extrapolated was less than 20% and the regression analysis of the terminal serum elimination phase met a pre-defined criteria of goodness of fit.

10. Accumulation Ratio (Racc) of Spartalizumab [pre-dose, 1, 24, 168, 336 and 672 hours post spartalizumab dose on Cycle 1 and Cycle 3. The duration of one cycle was 28 days.]

    Pharmacokinetic (PK) parameters were calculated based on spartalizumab serum concentrations by using non-compartmental methods. Racc was calculated as the ratio between AUCtau Cycle 3 and AUCtau Cycle 1.

11. Terminal Elimination Half-life (T1/2) of Spartalizumab [pre-dose, 1, 24, 168, 336 and 672 hours post spartalizumab dose on Cycle 1 and Cycle 3. The duration of one cycle was 28 days.]

    Pharmacokinetic (PK) parameters were calculated based on spartalizumab serum concentrations by using non-compartmental methods. Elimination half-life (T1/2) values were calculated as 0.693/terminal elimination rate constant.

12. Number of Participants With Anti-spartalizumab Antibodies [Baseline (pre-dose on Cycle 1 Day 1) and post-baseline (assessed throughout the treatment up to maximum 655 days).]

    Validated immunoassays were used for screening and confirmation of the presence of anti-spartalizumab antibodies (ADA, anti-drug antibodies) in serum. Number of participants with each ADA status is reported in this record.

13. PD-L1 Percent Positive Tumor [Baseline (screening), Cycle 3 Day 1. The duration of one cycle was 28 days.]

    The expression of programmed cell death-ligand 1 (PD-L1) was measured in tumor samples by immunohistochemical methods. This record summarizes the PD-L1 positivity percentage in tumor samples.

14. Percent Marker Area for CD8 Expression in Tumor Samples [Baseline (screening), Cycle 3 Day 1. The duration of one cycle was 28 days.]

    The expression of CD8 was measured in tumor samples by immunohistochemical methods. This record summarizes the percent marker area for CD8 expression in tumor samples.

15. TIL Count in Tumor Samples [Baseline (screening), Cycle 3 Day 1. The duration of one cycle was 28 days.]

    The count of tumor-infiltrating lymphocytes (TILs) was measured in baseline (screening) and post-baseline paired tumor samples by immunohistochemical methods. This record summarizes the TIL count in tumor samples.

16. Fold Change From Baseline in IFN-gamma Levels in Plasma [Baseline (pre-dose on Cycle 1 Day 1), Cycle 1 Day 15, Cycle 2 Day 15 and end of treatment (assessed up to maximum 4 years). The duration of one cycle was 28 days.]

    The levels of interferon-gamma (IFN-gamma) were measured in plasma samples by immunoassay methods. This record summarizes the fold change from baseline in IFN-gamma levels in plasma.

17. Fold Change From Baseline in IL-6 Levels in Plasma [Baseline (pre-dose on Cycle 1 Day 1), Cycle 1 Day 15, Cycle 2 Day 15 and end of treatment (assessed up to maximum 4 years). The duration of one cycle was 28 days.]

    The levels of interleukin-6 (IL-6) were measured in plasma samples by immunoassay methods. This record summarizes the fold change from baseline in IL-6 levels in plasma.

18. Fold Change From Baseline in TNF-alfa Levels in Plasma [Baseline (pre-dose on Cycle 1 Day 1), Cycle 1 Day 15, Cycle 2 Day 15 and end of treatment (assessed up to maximum 4 years). The duration of one cycle was 28 days.]

    The levels of tumor necrosis factor-alpha (TNF-alfa) were measured in plasma samples by immunoassay methods. This record summarizes the fold change from baseline in TNF-alfa levels in plasma.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Histologically documented non-keratinizing locally advanced recurrent or metastatic NPC.

• Must be resistant to platinum-based chemotherapy (defined as progression on or after platinum-based chemotherapy given in the recurrent/metastatic setting).

• May have received at least 1 prior therapy for recurrent or metastatic disease, up to 2 prior systemic therapies.

• An archival tumor specimen or newly obtained tumor sample may be submitted at screening/baseline (a fresh tumor sample is preferred), unless agreed differently between Novartis and the Investigator.

• At least 1 measurable lesion (as per RECIST v1.1) progressing or new since last anti-tumor therapy.

• Prior treated brain or meningeal metastases must be without MRI evidence of progression for at least 8 weeks and off systemic steroids for at least 2 weeks prior to screening/baseline.

• Patient must be willing to undergo testing for human immunodeficiency virus (HIV) if not tested within the past 6 months. If HIV+ positive, patient will be eligible if: his/ her CD4+ count ≥ 300/μL; his/her viral load is undetectable; he/she is currently receiving highly active antiretroviral therapy (HAART).

Exclusion Criteria:

• History of severe hypersensitivity reactions to other mAbs

• Active autoimmune disease or a documented history of autoimmune disease, except vitiligo or resolved asthma/atopy that is treated with broncho-dilators.

• Active HBV or HCV infections requiring therapy.

• Prior PD-1- or PD-L1-directed therapy or any therapeutic cancer vaccine.

• Patients receiving systemic treatment with any immunosuppressive medication.

• Use of any vaccines against infectious diseases (e.g. varicella, pneumococcus) within 4 weeks of initiation of study treatment.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Northwest Georgia Oncology Center NWGA Onc - Carrollton	Marietta	Georgia	United States	30060
2	Karmanos Cancer Institute	Detroit	Michigan	United States	48201
3	NYU Laura and Isaac Perlmutter Cancer Center Laura & Isaac Perlmutter Ctr	New York	New York	United States	10016
4	Virginia Cancer Specialists	Fairfax	Virginia	United States	22031
5	Novartis Investigative Site	Guangzhou		China	510060
6	Novartis Investigative Site	Nice Cedex 2	Alpes Maritimes	France	06189
7	Novartis Investigative Site	Villejuif Cedex	Villejuif	France	94800
8	Novartis Investigative Site	Hong Kong		Hong Kong
9	Novartis Investigative Site	Kowloon		Hong Kong
10	Novartis Investigative Site	Tuen Mun		Hong Kong
11	Novartis Investigative Site	Singapore		Singapore	169610
12	Novartis Investigative Site	Tainan	Taiwan ROC	Taiwan	70403
13	Novartis Investigative Site	Kaohsiung City		Taiwan	83301
14	Novartis Investigative Site	Taipei		Taiwan	10002
15	Novartis Investigative Site	Taoyuan		Taiwan	33305
16	Novartis Investigative Site	Songkhla	Hat Yai	Thailand	90110
17	Novartis Investigative Site	Bangkok		Thailand	10330
18	Novartis Investigative Site	Chiang Mai		Thailand	50200

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

• Study Protocol - Jun 24, 2019
• Statistical Analysis Plan - Mar 23, 2021

More Information

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT02605967
• Other Study ID Numbers: CPDR001X2201; 2015-000454-38
• First Posted: Nov 17, 2015
• Last Update Posted: Feb 10, 2022
• Last Verified: Jan 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 Novartis Pharmaceuticals: PDR001; nasopharyngeal cancer; moderately differentiated/undifferentiated; locally advanced; recurrent or metastatic NPC; after first- line platinum-based therapy
• Additional relevant MeSH terms: Carcinoma; Nasopharyngeal Carcinoma; Spartalizumab

Study Results

Participant Flow

Recruitment Details	Participants took part in 19 investigative sites in 7 countries.
Pre-assignment Detail	The screening period began once patients had signed the study informed consent. All screening evaluations were performed as closely as possible to the beginning of treatment and never more than 4 weeks before the beginning of the study treatment. After screening, the treatment period started on Cycle 1 Day 1.

Arm/Group Title	Spartalizumab 400 mg Q4W	Chemotherapy
Arm/Group Description	anti-PD1 humanized monoclonal antibody. Participants treated with spartalizumab who remained on spartalizumab	Commonly used chemotherapy as per investigator's choice
Period Title: Overall Study
STARTED	82	40
Safety Set	82	39
Crossover to Spartalizumab	0	27
COMPLETED	0	0
NOT COMPLETED	82	40

Baseline Characteristics

Arm/Group Title	Spartalizumab 400 mg Q4W	Chemotherapy	Total
Arm/Group Description	anti-PD1 humanized monoclonal antibody. Participants treated with spartalizumab who remained on spartalizumab	Commonly used chemotherapy as per investigator's choice	Total of all reporting groups
Overall Participants	82	40	122
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	51.1 (11.54)	50.5 (12.32)	50.9 (11.75)
Sex: Female, Male (Count of Participants)
Female	14 17.1%	7 17.5%	21 17.2%
Male	68 82.9%	33 82.5%	101 82.8%
Race/Ethnicity, Customized (Count of Participants)
Caucasian	12 14.6%	2 5%	14 11.5%
Black	0 0%	1 2.5%	1 0.8%
Asian	70 85.4%	37 92.5%	107 87.7%

Outcome Measures

1. Primary Outcome

Title	Progression-free Survival (PFS) as Per RECIST v 1.1 Using Central Assessment - Number of Participants With Progression or Death
Description	PFS is the time from the date of randomization to the date of event defined as the first documented confirmed progression or death due to any cause. If a patient has not had an event, progression-free survival is censored at the date of last adequate tumor assessment. Tumor response was based on central review of tumor scan and the assessment criteria was Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). Progressive disease is at least a 20% increase in the sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline. Number of participants in each category (progression, death, censored) is reported in this record.
Time Frame	From randomization up to maximum 3.3 years

Outcome Measure Data

Analysis Population Description

All participants to whom study treatment was assigned by randomization.

Arm/Group Title	Spartalizumab 400 mg Q4W	Chemotherapy
Arm/Group Description	anti-PD1 humanized monoclonal antibody. Participants treated with spartalizumab who remained on spartalizumab	Commonly used chemotherapy as per investigator's choice
Measure Participants	82	40
number of progression	62 75.6%	32 80%
number of deaths	3 3.7%	1 2.5%
number of censored	17 20.7%	7 17.5%

2. Primary Outcome

Title	Progression-free Survival (PFS) as Per RECIST v 1.1 Using Central Assessment - Median PFS
Description	PFS is the time from the date of randomization to the date of event defined as the first documented confirmed progression or death due to any cause. If a patient has not had an event, progression-free survival is censored at the date of last adequate tumor assessment. Tumor response was based on central review of tumor scan and the assessment criteria was Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). Progressive disease is at least a 20% increase in the sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline.
Time Frame	From randomization up to maximum 3.3 years

Outcome Measure Data

Analysis Population Description

All participants to whom study treatment was assigned by randomization.

Arm/Group Title	Spartalizumab 400 mg Q4W	Chemotherapy
Arm/Group Description	anti-PD1 humanized monoclonal antibody. Participants treated with spartalizumab who remained on spartalizumab	Commonly used chemotherapy as per investigator's choice
Measure Participants	82	40
Median (95% Confidence Interval) [months]	1.9	5.6

3. Secondary Outcome

Title	Overall Survival (OS)
Description	Overall survival (OS) is defined as the time from date of randomization to date of death due to any cause. If a patient is not known to have died, survival is censored at the date of last known date the patient was alive.
Time Frame	From randomization up to maximum 4.8 years.

Outcome Measure Data

Analysis Population Description

All participants to whom study treatment was assigned by randomization.

Arm/Group Title	Spartalizumab 400 mg Q4W	Chemotherapy
Arm/Group Description	anti-PD1 humanized monoclonal antibody. Participants treated with spartalizumab who remained on spartalizumab	Commonly used chemotherapy as per investigator's choice
Measure Participants	82	40
Median (95% Confidence Interval) [months]	20.1	16.0

4. Secondary Outcome

Title	Overall Response Rate (ORR) as Per RECIST v 1.1
Description	ORR is defined as the percentage of participants with a best overall response of Complete Response (CR) or Partial Response (PR). Tumor response was based on central review of overall lesion response according to RECIST 1.1. For RECIST v1.1, CR=Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to < 10 mm; PR= At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.
Time Frame	From randomization up to maximum 3.3 years

Outcome Measure Data

Analysis Population Description

All participants to whom study treatment was assigned by randomization.

Arm/Group Title	Spartalizumab 400 mg Q4W	Chemotherapy
Arm/Group Description	anti-PD1 humanized monoclonal antibody. Participants treated with spartalizumab who remained on spartalizumab	Commonly used chemotherapy as per investigator's choice
Measure Participants	82	40
Count of Participants [Participants]	15 18.3%	13 32.5%

5. Secondary Outcome

Title	Duration of Response (DOR) as Per RECIST v 1.1
Description	DOR only applies to subjects for whom best overall response is complete response (CR) or partial response (PR) based on central review of overall lesion response according to RECIST 1.1. DOR is defined as the time between the date of first documented response (confirmed CR or confirmed PR) and the date of first documented disease progression or death due to underlying cancer. If a patient not had an event, duration was censored at the date of last adequate tumor assessment.
Time Frame	From randomization up to maximum 3.3 years

Outcome Measure Data

Analysis Population Description

All participants for whom best overall response is complete response (CR) or partial response (PR) as per RECIST 1.1 based on central review.

Arm/Group Title	Spartalizumab 400 mg Q4W	Chemotherapy
Arm/Group Description	anti-PD1 humanized monoclonal antibody. Participants treated with spartalizumab who remained on spartalizumab	Commonly used chemotherapy as per investigator's choice
Measure Participants	15	13
Median (95% Confidence Interval) [months]	10.2	5.7

6. Secondary Outcome

Title	Time to Progression (TTP) as Per RECIST v 1.1
Description	TTP is defined as time from date of randomization to the date of event defined as the first documented progression or death due to underlying cancer. If a subject did not had an event, TTP was censored at the date of last adequate tumor assessment. Tumor response was based on central review of tumor scan and the assessment criteria was RECIST v1.1. Progressive disease is at least a 20% increase in the sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline.
Time Frame	From randomization up to maximum 3.3 years

Outcome Measure Data

Analysis Population Description

All participants to whom study treatment was assigned by randomization.

Arm/Group Title	Spartalizumab 400 mg Q4W	Chemotherapy
Arm/Group Description	anti-PD1 humanized monoclonal antibody. Participants treated with spartalizumab who remained on spartalizumab	Commonly used chemotherapy as per investigator's choice
Measure Participants	82	40
Median (95% Confidence Interval) [months]	1.9	5.6

7. Secondary Outcome

Title	Immune-related Progression-free Survival (irPFS) as Per irRC
Description	irPFS is the time from the date of randomization to the date of event defined as the first documented progression or death due to any cause. If a patient has not had an event, progression-free survival is censored at the date of last adequate tumor assessment. Tumor response was based on central review of tumor scan and the assessment criteria was immune-related Response Criteria (irRC). Immune-related progressive disease is at least a 20% increase in the sum of diameters of all measured target lesions including new measurable lesions.
Time Frame	From randomization up to maximum 3.3 years

Outcome Measure Data

Analysis Population Description

All participants to whom study treatment was assigned by randomization to spartalizumab. For the chemotherapy arm, tumor scans for efficacy assessment as per irRC were not planned.

Arm/Group Title	Spartalizumab 400 mg Q4W	Chemotherapy
Arm/Group Description	anti-PD1 humanized monoclonal antibody. Participants treated with spartalizumab who remained on spartalizumab	Commonly used chemotherapy as per investigator's choice
Measure Participants	82	0
Median (95% Confidence Interval) [months]	1.9

8. Secondary Outcome

Title	Maximum Observed Serum Concentration (Cmax) of Spartalizumab
Description	Pharmacokinetic (PK) parameters were calculated based on spartalizumab serum concentrations by using non-compartmental methods. Cmax is defined as the maximum (peak) observed serum concentration following a dose.
Time Frame	pre-dose, 1, 24, 168, 336 and 672 hours post spartalizumab dose on Cycle 1 and Cycle 3. The duration of one cycle was 28 days.

Outcome Measure Data

Analysis Population Description

All participants who had at least one dose of spartalizumab and had at least one evaluable concentration measurement of spartalizumab. PK samples were only collected in participants to whom spartalizumab was assigned by randomization.

Arm/Group Title	Spartalizumab 400 mg Q4W
Arm/Group Description	anti-PD1 humanized monoclonal antibody. Participants treated with spartalizumab who remained on spartalizumab
Measure Participants	82
Cycle 1	116 (21.9)
Cycle 3	149 (25.8)

9. Secondary Outcome

Title	Time to Reach Maximum Serum Concentration (Tmax) of Spartalizumab
Description	Pharmacokinetic (PK) parameters were calculated based on spartalizumab serum concentrations by using non-compartmental methods. Tmax is defined as the time to reach maximum (peak) serum concentration following a dose. Actual recorded sampling times were considered for the calculations.
Time Frame	pre-dose, 1, 24, 168, 336 and 672 hours post spartalizumab dose on Cycle 1 and Cycle 3. The duration of one cycle was 28 days.

Outcome Measure Data

Analysis Population Description

All participants who had at least one dose of spartalizumab and had at least one evaluable concentration measurement of spartalizumab. PK samples were only collected in participants to whom spartalizumab was assigned by randomization.

Arm/Group Title	Spartalizumab 400 mg Q4W
Arm/Group Description	anti-PD1 humanized monoclonal antibody. Participants treated with spartalizumab who remained on spartalizumab
Measure Participants	82
Cycle 1	1.57
Cycle 3	1.57

10. Secondary Outcome

Title	Area Under the Serum Concentration-time Curve From Time Zero to the End of the Dosing Interval Tau (AUCtau) of Spartalizumab
Description	Pharmacokinetic (PK) parameters were calculated based on spartalizumab serum concentrations by using non-compartmental methods. The linear trapezoidal method was used for AUC calculation. The duration of the dosing interval (tau) was 28 days.
Time Frame	pre-dose, 1, 24, 168, 336 and 672 hours post spartalizumab dose on Cycle 1 and Cycle 3. The duration of one cycle was 28 days.

Outcome Measure Data

Analysis Population Description

All participants who had at least one dose of spartalizumab and had at least one evaluable concentration measurement of spartalizumab. PK samples were only collected in participants to whom spartalizumab was assigned by randomization.

Arm/Group Title	Spartalizumab 400 mg Q4W
Arm/Group Description	anti-PD1 humanized monoclonal antibody. Participants treated with spartalizumab who remained on spartalizumab
Measure Participants	82
Cycle 1	1340 (25.8)
Cycle 3	2260 (30.6)

11. Secondary Outcome

Title	Area Under the Serum Concentration-time Curve From Time Zero to Infinity (AUCinf) of Spartalizumab
Description	Pharmacokinetic (PK) parameters were calculated based on spartalizumab serum concentrations by using non-compartmental methods. The linear trapezoidal method was used for AUC calculation. The extrapolation of AUC to infinity could be calculated if the percentage of area extrapolated was less than 20% and the regression analysis of the terminal serum elimination phase met a pre-defined criteria of goodness of fit.
Time Frame	pre-dose, 1, 24, 168, 336 and 672 hours post spartalizumab dose on Cycle 1 and Cycle 3. The duration of one cycle was 28 days.

Outcome Measure Data

Analysis Population Description

All participants who had at least one dose of spartalizumab and the extrapolation of AUC to infinity could be calculated as described in the description of the endpoint. PK samples were only collected in participants to whom spartalizumab was assigned by randomization.

Arm/Group Title	Spartalizumab 400 mg Q4W
Arm/Group Description	anti-PD1 humanized monoclonal antibody. Participants treated with spartalizumab who remained on spartalizumab
Measure Participants	7
Cycle 1	1180 (23.9)
Cycle 3	1090 (84.8)

12. Secondary Outcome

Title	Accumulation Ratio (Racc) of Spartalizumab
Description	Pharmacokinetic (PK) parameters were calculated based on spartalizumab serum concentrations by using non-compartmental methods. Racc was calculated as the ratio between AUCtau Cycle 3 and AUCtau Cycle 1.
Time Frame	pre-dose, 1, 24, 168, 336 and 672 hours post spartalizumab dose on Cycle 1 and Cycle 3. The duration of one cycle was 28 days.

Outcome Measure Data

Analysis Population Description

All participants who had at least one dose of spartalizumab and had at least one evaluable concentration measurement of spartalizumab. PK samples were only collected in participants to whom spartalizumab was assigned by randomization.

Arm/Group Title	Spartalizumab 400 mg Q4W
Arm/Group Description	anti-PD1 humanized monoclonal antibody. Participants treated with spartalizumab who remained on spartalizumab
Measure Participants	39
Geometric Mean (Geometric Coefficient of Variation) [ratio]	1.61 (19.6)

13. Secondary Outcome

Title	Terminal Elimination Half-life (T1/2) of Spartalizumab
Description	Pharmacokinetic (PK) parameters were calculated based on spartalizumab serum concentrations by using non-compartmental methods. Elimination half-life (T1/2) values were calculated as 0.693/terminal elimination rate constant.
Time Frame	pre-dose, 1, 24, 168, 336 and 672 hours post spartalizumab dose on Cycle 1 and Cycle 3. The duration of one cycle was 28 days.

Outcome Measure Data

Analysis Population Description

All participants who had at least one dose of spartalizumab and had at least one evaluable concentration measurement of spartalizumab. PK samples were only collected in participants to whom spartalizumab was assigned by randomization.

Arm/Group Title	Spartalizumab 400 mg Q4W
Arm/Group Description	anti-PD1 humanized monoclonal antibody. Participants treated with spartalizumab who remained on spartalizumab
Measure Participants	82
Cycle 1	20.1
Cycle 3	22.7

14. Secondary Outcome

Title	Number of Participants With Anti-spartalizumab Antibodies
Description	Validated immunoassays were used for screening and confirmation of the presence of anti-spartalizumab antibodies (ADA, anti-drug antibodies) in serum. Number of participants with each ADA status is reported in this record.
Time Frame	Baseline (pre-dose on Cycle 1 Day 1) and post-baseline (assessed throughout the treatment up to maximum 655 days).

Outcome Measure Data

Analysis Population Description

All participants who had at least one dose of spartalizumab and had a determinant baseline immunogenicity (IG) sample and at least one determinant post-baseline IG sample. A determinant IG sample is neither ADA-inconclusive nor unevaluable. IG samples were only collected in participants to whom spartalizumab was assigned by randomization.

Arm/Group Title	Spartalizumab 400 mg Q4W
Arm/Group Description	anti-PD1 humanized monoclonal antibody. Participants treated with spartalizumab who remained on spartalizumab
Measure Participants	72
ADA-negative at baseline	66 80.5%
ADA-positive at baseline	6 7.3%
ADA-negative at post-baseline	59 72%
ADA-positive at post-baseline (i.e. ADA incidence)	9 11%

15. Secondary Outcome

Title	PD-L1 Percent Positive Tumor
Description	The expression of programmed cell death-ligand 1 (PD-L1) was measured in tumor samples by immunohistochemical methods. This record summarizes the PD-L1 positivity percentage in tumor samples.
Time Frame	Baseline (screening), Cycle 3 Day 1. The duration of one cycle was 28 days.

Outcome Measure Data

Analysis Population Description

All participants to whom study treatment was assigned by randomization to spartalizumab and had a valid assessment for the outcome measure. Biomarker samples were not collected in participants randomized to chemotherapy.

Arm/Group Title	Spartalizumab 400 mg Q4W
Arm/Group Description	anti-PD1 humanized monoclonal antibody. Participants treated with spartalizumab who remained on spartalizumab
Measure Participants	78
Measure tumor samples	79
Baseline	20.00
Cycle 3 Day 1	90.00

16. Secondary Outcome

Title	Percent Marker Area for CD8 Expression in Tumor Samples
Description	The expression of CD8 was measured in tumor samples by immunohistochemical methods. This record summarizes the percent marker area for CD8 expression in tumor samples.
Time Frame	Baseline (screening), Cycle 3 Day 1. The duration of one cycle was 28 days.

Outcome Measure Data

Analysis Population Description

All participants to whom study treatment was assigned by randomization to spartalizumab and had a valid assessment for the outcome measure. Biomarker samples were not collected in participants randomized to chemotherapy.

Arm/Group Title	Spartalizumab 400 mg Q4W
Arm/Group Description	anti-PD1 humanized monoclonal antibody. Participants treated with spartalizumab who remained on spartalizumab
Measure Participants	78
Measure tumor samples	79
Baseline	4.23
Cycle 3 Day 1	2.22

17. Secondary Outcome

Title	TIL Count in Tumor Samples
Description	The count of tumor-infiltrating lymphocytes (TILs) was measured in baseline (screening) and post-baseline paired tumor samples by immunohistochemical methods. This record summarizes the TIL count in tumor samples.
Time Frame	Baseline (screening), Cycle 3 Day 1. The duration of one cycle was 28 days.

Outcome Measure Data

Analysis Population Description

All participants to whom study treatment was assigned by randomization to spartalizumab and had paired tumor biopsies. Biomarker samples were not collected in participants randomized to chemotherapy.

Arm/Group Title	Spartalizumab 400 mg Q4W
Arm/Group Description	anti-PD1 humanized monoclonal antibody. Participants treated with spartalizumab who remained on spartalizumab
Measure Participants	1
Baseline	10
Cycle 3 Day 1	15

18. Secondary Outcome

Title	Fold Change From Baseline in IFN-gamma Levels in Plasma
Description	The levels of interferon-gamma (IFN-gamma) were measured in plasma samples by immunoassay methods. This record summarizes the fold change from baseline in IFN-gamma levels in plasma.
Time Frame	Baseline (pre-dose on Cycle 1 Day 1), Cycle 1 Day 15, Cycle 2 Day 15 and end of treatment (assessed up to maximum 4 years). The duration of one cycle was 28 days.

Outcome Measure Data

Analysis Population Description

All participants to whom study treatment was assigned by randomization to spartalizumab. Biomarker samples were not collected in participants randomized to chemotherapy.

Arm/Group Title	Spartalizumab 400 mg Q4W
Arm/Group Description	anti-PD1 humanized monoclonal antibody. Participants treated with spartalizumab who remained on spartalizumab
Measure Participants	82
Cycle 1 Day 15	1.53
Cycle 2 Day 15	1.31
End of treatment	1.11

19. Secondary Outcome

Title	Fold Change From Baseline in IL-6 Levels in Plasma
Description	The levels of interleukin-6 (IL-6) were measured in plasma samples by immunoassay methods. This record summarizes the fold change from baseline in IL-6 levels in plasma.
Time Frame	Baseline (pre-dose on Cycle 1 Day 1), Cycle 1 Day 15, Cycle 2 Day 15 and end of treatment (assessed up to maximum 4 years). The duration of one cycle was 28 days.

Outcome Measure Data

Analysis Population Description

All participants to whom study treatment was assigned by randomization to spartalizumab. Biomarker samples were not collected in participants randomized to chemotherapy.

Arm/Group Title	Spartalizumab 400 mg Q4W
Arm/Group Description	anti-PD1 humanized monoclonal antibody. Participants treated with spartalizumab who remained on spartalizumab
Measure Participants	82
Cycle 1 Day 15	1.10
Cycle 2 Day 15	1.35
End of treatment	1.41

20. Secondary Outcome

Title	Fold Change From Baseline in TNF-alfa Levels in Plasma
Description	The levels of tumor necrosis factor-alpha (TNF-alfa) were measured in plasma samples by immunoassay methods. This record summarizes the fold change from baseline in TNF-alfa levels in plasma.
Time Frame	Baseline (pre-dose on Cycle 1 Day 1), Cycle 1 Day 15, Cycle 2 Day 15 and end of treatment (assessed up to maximum 4 years). The duration of one cycle was 28 days.

Outcome Measure Data

Analysis Population Description

All participants to whom study treatment was assigned by randomization to spartalizumab. Biomarker samples were not collected in participants randomized to chemotherapy.

Arm/Group Title	Spartalizumab 400 mg Q4W
Arm/Group Description	anti-PD1 humanized monoclonal antibody. Participants treated with spartalizumab who remained on spartalizumab
Measure Participants	82
Cycle 1 Day 15	1.32
Cycle 2 Day 15	1.39
End of treatment	1.67

21. Post-Hoc Outcome

Title	Progression-free Survival (PFS) as Per RECIST v 1.1 Using Central Assessment in Participants Who Crossed Over - Number of Participants With Progression or Death
Description	PFS is the time from the date of first dose of spartalizumab to the date of event defined as the first documented confirmed progression or death due to any cause. If a patient has not had an event, progression-free survival is censored at the date of last adequate tumor assessment. Tumor response was based on central review of tumor scan and the assessment criteria was Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). Progressive disease is at least a 20% increase in the sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline. Number of participants in each category (progression, death, censored) is reported in this record.
Time Frame	From first dose of spartalizumab up to maximum 0.6 years

Outcome Measure Data

Analysis Population Description

All participants who crossed over from chemotherapy to spartalizumab.

Arm/Group Title	Crossover to Spartalizumab
Arm/Group Description	Patients treated with chemotherapy who crossed over to spartalizumab
Measure Participants	27
number of progression	20 24.4%
number of deaths	5 6.1%
number of censored	2 2.4%

22. Post-Hoc Outcome

Title	Progression-free Survival (PFS) as Per RECIST v 1.1 Using Central Assessment in Participants Who Crossed Over - Median PFS
Description	PFS is the time from the date of first dose of spartalizumab to the date of event defined as the first documented confirmed progression or death due to any cause. If a patient has not had an event, progression-free survival is censored at the date of last adequate tumor assessment. Tumor response was based on central review of tumor scan and the assessment criteria was Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). Progressive disease is at least a 20% increase in the sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline.
Time Frame	From first dose of spartalizumab up to maximum 0.6 years

Outcome Measure Data

Analysis Population Description

All participants who crossed over from chemotherapy to spartalizumab.

Arm/Group Title	Crossover to Spartalizumab
Arm/Group Description	Patients treated with chemotherapy who crossed over to spartalizumab
Measure Participants	27
Median (95% Confidence Interval) [months]	1.7

23. Post-Hoc Outcome

Title	All Collected Deaths
Description	On-treatment deaths were collected from the start of treatment up to 30 days after study drug discontinuation, for a maximum duration of 4.0 years. Post-treatment deaths were collected after the on-treatment period (starting at day 31 after last dose of study treatment), up to 4.8 years. For the crossover patients, the deaths collected before crossing over are summarized in the chemotherapy arm and the deaths collected after the crossover are summarized in the crossover arm.
Time Frame	Up to 4.0 years (on-treatment deaths) and 4.8 years (all deaths).

Outcome Measure Data

Analysis Population Description

All participants to whom study treatment was assigned by randomization.

Arm/Group Title	Spartalizumab 400 mg Q4W	Chemotherapy	Crossover to Spartalizumab
Arm/Group Description	anti-PD1 humanized monoclonal antibody. Participants treated with spartalizumab who remained on spartalizumab	Commonly used chemotherapy as per investigator's choice	Patients treated with chemotherapy who crossed over to spartalizumab
Measure Participants	82	40	27
Total Deaths	48 58.5%	9 22.5%	19 15.6%
Deaths on-treatment	5 6.1%	3 7.5%	3 2.5%

Adverse Events

Time Frame	From first dose of study treatment up to 30 days after last dose (maximum 4.0 years).
Adverse Event Reporting Description	For the crossover patients, safety data collected before crossing over is summarized in the chemotherapy arm and safety data collected after the crossover is summarized in the crossover arm. The column 'all spartalizumab participants' summarizes the safety data of the 2 arms with spartalizumab dosing. AEs and mortality are assessed in the safety set that includes all patients who received at least 1 dose of study medication and had at least 1 valid post-screening/post-baseline safety assessment.
Arm/Group Title	Spartalizumab 400 mg Q4W		Chemotherapy		Crossover to Spartalizumab		All Spartalizumab Participants
Arm/Group Description	anti-PD1 humanized monoclonal antibody. Participants treated with spartalizumab who remained on spartalizumab		Commonly used chemotherapy as per investigator's choice		Patients treated with chemotherapy who crossed over to spartalizumab		All participants who received at least one dose of spartalizumab
All Cause Mortality
	Spartalizumab 400 mg Q4W		Chemotherapy		Crossover to Spartalizumab		All Spartalizumab Participants
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/82 (6.1%)		3/39 (7.7%)		3/27 (11.1%)		8/109 (7.3%)
Serious Adverse Events
	Spartalizumab 400 mg Q4W		Chemotherapy		Crossover to Spartalizumab		All Spartalizumab Participants
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	28/82 (34.1%)		15/39 (38.5%)		12/27 (44.4%)		40/109 (36.7%)
Blood and lymphatic system disorders
Anaemia	2/82 (2.4%)		1/39 (2.6%)		1/27 (3.7%)		3/109 (2.8%)
Febrile neutropenia	1/82 (1.2%)		4/39 (10.3%)		0/27 (0%)		1/109 (0.9%)
Neutropenia	0/82 (0%)		1/39 (2.6%)		0/27 (0%)		0/109 (0%)
Normocytic anaemia	0/82 (0%)		1/39 (2.6%)		0/27 (0%)		0/109 (0%)
Thrombocytopenia	0/82 (0%)		1/39 (2.6%)		0/27 (0%)		0/109 (0%)
Cardiac disorders
Angina pectoris	1/82 (1.2%)		0/39 (0%)		0/27 (0%)		1/109 (0.9%)
Myocardial infarction	0/82 (0%)		1/39 (2.6%)		0/27 (0%)		0/109 (0%)
Pericardial effusion	1/82 (1.2%)		0/39 (0%)		0/27 (0%)		1/109 (0.9%)
Eye disorders
Papilloedema	0/82 (0%)		1/39 (2.6%)		0/27 (0%)		0/109 (0%)
Gastrointestinal disorders
Abdominal pain	1/82 (1.2%)		0/39 (0%)		1/27 (3.7%)		2/109 (1.8%)
Abdominal pain upper	1/82 (1.2%)		0/39 (0%)		1/27 (3.7%)		2/109 (1.8%)
Ascites	1/82 (1.2%)		0/39 (0%)		0/27 (0%)		1/109 (0.9%)
Diarrhoea	0/82 (0%)		2/39 (5.1%)		0/27 (0%)		0/109 (0%)
Duodenal ulcer	1/82 (1.2%)		0/39 (0%)		0/27 (0%)		1/109 (0.9%)
Dysphagia	1/82 (1.2%)		1/39 (2.6%)		0/27 (0%)		1/109 (0.9%)
Stomatitis	0/82 (0%)		1/39 (2.6%)		0/27 (0%)		0/109 (0%)
Vomiting	1/82 (1.2%)		2/39 (5.1%)		1/27 (3.7%)		2/109 (1.8%)
General disorders
Asthenia	1/82 (1.2%)		1/39 (2.6%)		1/27 (3.7%)		2/109 (1.8%)
Fatigue	0/82 (0%)		1/39 (2.6%)		1/27 (3.7%)		1/109 (0.9%)
Generalised oedema	0/82 (0%)		0/39 (0%)		1/27 (3.7%)		1/109 (0.9%)
Oedema peripheral	0/82 (0%)		1/39 (2.6%)		0/27 (0%)		0/109 (0%)
Pain	0/82 (0%)		1/39 (2.6%)		0/27 (0%)		0/109 (0%)
Peripheral swelling	0/82 (0%)		0/39 (0%)		1/27 (3.7%)		1/109 (0.9%)
Pyrexia	3/82 (3.7%)		0/39 (0%)		1/27 (3.7%)		4/109 (3.7%)
Hepatobiliary disorders
Cholecystitis acute	0/82 (0%)		0/39 (0%)		1/27 (3.7%)		1/109 (0.9%)
Hepatocellular injury	1/82 (1.2%)		0/39 (0%)		0/27 (0%)		1/109 (0.9%)
Infections and infestations
Brain abscess	0/82 (0%)		1/39 (2.6%)		0/27 (0%)		0/109 (0%)
Conjunctivitis	0/82 (0%)		1/39 (2.6%)		0/27 (0%)		0/109 (0%)
Gastroenteritis	1/82 (1.2%)		1/39 (2.6%)		0/27 (0%)		1/109 (0.9%)
Lower respiratory tract infection	1/82 (1.2%)		0/39 (0%)		0/27 (0%)		1/109 (0.9%)
Pneumonia	1/82 (1.2%)		1/39 (2.6%)		1/27 (3.7%)		2/109 (1.8%)
Sepsis	2/82 (2.4%)		0/39 (0%)		1/27 (3.7%)		3/109 (2.8%)
Septic shock	0/82 (0%)		1/39 (2.6%)		0/27 (0%)		0/109 (0%)
Sinusitis	1/82 (1.2%)		0/39 (0%)		0/27 (0%)		1/109 (0.9%)
Injury, poisoning and procedural complications
Electrical burn	1/82 (1.2%)		0/39 (0%)		0/27 (0%)		1/109 (0.9%)
Investigations
Aspartate aminotransferase increased	2/82 (2.4%)		0/39 (0%)		0/27 (0%)		2/109 (1.8%)
Bilirubin conjugated increased	1/82 (1.2%)		0/39 (0%)		0/27 (0%)		1/109 (0.9%)
Blood bilirubin increased	1/82 (1.2%)		0/39 (0%)		0/27 (0%)		1/109 (0.9%)
Blood bilirubin unconjugated increased	1/82 (1.2%)		0/39 (0%)		0/27 (0%)		1/109 (0.9%)
Metabolism and nutrition disorders
Decreased appetite	0/82 (0%)		0/39 (0%)		1/27 (3.7%)		1/109 (0.9%)
Hypercalcaemia	0/82 (0%)		1/39 (2.6%)		1/27 (3.7%)		1/109 (0.9%)
Hyperkalaemia	0/82 (0%)		0/39 (0%)		1/27 (3.7%)		1/109 (0.9%)
Hypokalaemia	0/82 (0%)		2/39 (5.1%)		0/27 (0%)		0/109 (0%)
Hyponatraemia	2/82 (2.4%)		0/39 (0%)		1/27 (3.7%)		3/109 (2.8%)
Malnutrition	1/82 (1.2%)		0/39 (0%)		0/27 (0%)		1/109 (0.9%)
Musculoskeletal and connective tissue disorders
Arthralgia	0/82 (0%)		0/39 (0%)		1/27 (3.7%)		1/109 (0.9%)
Bone pain	2/82 (2.4%)		0/39 (0%)		0/27 (0%)		2/109 (1.8%)
Muscular weakness	0/82 (0%)		1/39 (2.6%)		0/27 (0%)		0/109 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumour associated fever	0/82 (0%)		1/39 (2.6%)		1/27 (3.7%)		1/109 (0.9%)
Nervous system disorders
Diplegia	1/82 (1.2%)		0/39 (0%)		0/27 (0%)		1/109 (0.9%)
Hemiparesis	1/82 (1.2%)		0/39 (0%)		0/27 (0%)		1/109 (0.9%)
Spinal cord compression	2/82 (2.4%)		1/39 (2.6%)		0/27 (0%)		2/109 (1.8%)
Renal and urinary disorders
Acute kidney injury	0/82 (0%)		0/39 (0%)		1/27 (3.7%)		1/109 (0.9%)
Urinary retention	1/82 (1.2%)		0/39 (0%)		0/27 (0%)		1/109 (0.9%)
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure	0/82 (0%)		1/39 (2.6%)		0/27 (0%)		0/109 (0%)
Dyspnoea	0/82 (0%)		1/39 (2.6%)		2/27 (7.4%)		2/109 (1.8%)
Epistaxis	1/82 (1.2%)		0/39 (0%)		0/27 (0%)		1/109 (0.9%)
Nasal congestion	1/82 (1.2%)		0/39 (0%)		0/27 (0%)		1/109 (0.9%)
Pleural effusion	1/82 (1.2%)		0/39 (0%)		0/27 (0%)		1/109 (0.9%)
Pneumonia aspiration	2/82 (2.4%)		0/39 (0%)		1/27 (3.7%)		3/109 (2.8%)
Pneumonitis	2/82 (2.4%)		0/39 (0%)		1/27 (3.7%)		3/109 (2.8%)
Pneumothorax	1/82 (1.2%)		0/39 (0%)		0/27 (0%)		1/109 (0.9%)
Skin and subcutaneous tissue disorders
Angioedema	1/82 (1.2%)		0/39 (0%)		0/27 (0%)		1/109 (0.9%)
Rash maculo-papular	1/82 (1.2%)		0/39 (0%)		0/27 (0%)		1/109 (0.9%)
Social circumstances
Miscarriage of partner	1/82 (1.2%)		0/39 (0%)		0/27 (0%)		1/109 (0.9%)
Other (Not Including Serious) Adverse Events
	Spartalizumab 400 mg Q4W		Chemotherapy		Crossover to Spartalizumab		All Spartalizumab Participants
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	76/82 (92.7%)		37/39 (94.9%)		25/27 (92.6%)		101/109 (92.7%)
Blood and lymphatic system disorders
Anaemia	19/82 (23.2%)		19/39 (48.7%)		6/27 (22.2%)		25/109 (22.9%)
Leukopenia	2/82 (2.4%)		3/39 (7.7%)		0/27 (0%)		2/109 (1.8%)
Lymphopenia	0/82 (0%)		2/39 (5.1%)		1/27 (3.7%)		1/109 (0.9%)
Neutropenia	1/82 (1.2%)		12/39 (30.8%)		0/27 (0%)		1/109 (0.9%)
Thrombocytopenia	1/82 (1.2%)		3/39 (7.7%)		0/27 (0%)		1/109 (0.9%)
Endocrine disorders
Hypothyroidism	10/82 (12.2%)		2/39 (5.1%)		3/27 (11.1%)		13/109 (11.9%)
Gastrointestinal disorders
Abdominal discomfort	0/82 (0%)		2/39 (5.1%)		1/27 (3.7%)		1/109 (0.9%)
Abdominal distension	5/82 (6.1%)		0/39 (0%)		1/27 (3.7%)		6/109 (5.5%)
Abdominal pain	5/82 (6.1%)		2/39 (5.1%)		4/27 (14.8%)		9/109 (8.3%)
Abdominal pain upper	8/82 (9.8%)		3/39 (7.7%)		3/27 (11.1%)		11/109 (10.1%)
Constipation	13/82 (15.9%)		7/39 (17.9%)		3/27 (11.1%)		16/109 (14.7%)
Diarrhoea	5/82 (6.1%)		5/39 (12.8%)		1/27 (3.7%)		6/109 (5.5%)
Dry mouth	3/82 (3.7%)		3/39 (7.7%)		1/27 (3.7%)		4/109 (3.7%)
Dyspepsia	0/82 (0%)		2/39 (5.1%)		1/27 (3.7%)		1/109 (0.9%)
Dysphagia	5/82 (6.1%)		1/39 (2.6%)		0/27 (0%)		5/109 (4.6%)
Mouth ulceration	0/82 (0%)		2/39 (5.1%)		0/27 (0%)		0/109 (0%)
Nausea	13/82 (15.9%)		8/39 (20.5%)		4/27 (14.8%)		17/109 (15.6%)
Oral pain	0/82 (0%)		2/39 (5.1%)		0/27 (0%)		0/109 (0%)
Stomatitis	6/82 (7.3%)		9/39 (23.1%)		0/27 (0%)		6/109 (5.5%)
Vomiting	14/82 (17.1%)		6/39 (15.4%)		7/27 (25.9%)		21/109 (19.3%)
General disorders
Asthenia	11/82 (13.4%)		2/39 (5.1%)		1/27 (3.7%)		12/109 (11%)
Fatigue	14/82 (17.1%)		15/39 (38.5%)		5/27 (18.5%)		19/109 (17.4%)
Malaise	6/82 (7.3%)		2/39 (5.1%)		1/27 (3.7%)		7/109 (6.4%)
Oedema peripheral	2/82 (2.4%)		5/39 (12.8%)		0/27 (0%)		2/109 (1.8%)
Peripheral swelling	0/82 (0%)		0/39 (0%)		2/27 (7.4%)		2/109 (1.8%)
Pyrexia	16/82 (19.5%)		3/39 (7.7%)		8/27 (29.6%)		24/109 (22%)
Swelling face	0/82 (0%)		3/39 (7.7%)		1/27 (3.7%)		1/109 (0.9%)
Infections and infestations
Herpes zoster	3/82 (3.7%)		2/39 (5.1%)		0/27 (0%)		3/109 (2.8%)
Nasopharyngitis	3/82 (3.7%)		2/39 (5.1%)		0/27 (0%)		3/109 (2.8%)
Pneumonia	3/82 (3.7%)		2/39 (5.1%)		0/27 (0%)		3/109 (2.8%)
Sinusitis	1/82 (1.2%)		2/39 (5.1%)		0/27 (0%)		1/109 (0.9%)
Upper respiratory tract infection	9/82 (11%)		2/39 (5.1%)		1/27 (3.7%)		10/109 (9.2%)
Urinary tract infection	1/82 (1.2%)		2/39 (5.1%)		0/27 (0%)		1/109 (0.9%)
Investigations
Alanine aminotransferase increased	7/82 (8.5%)		6/39 (15.4%)		1/27 (3.7%)		8/109 (7.3%)
Aspartate aminotransferase increased	15/82 (18.3%)		7/39 (17.9%)		2/27 (7.4%)		17/109 (15.6%)
Blood alkaline phosphatase increased	4/82 (4.9%)		1/39 (2.6%)		2/27 (7.4%)		6/109 (5.5%)
Blood creatinine increased	5/82 (6.1%)		2/39 (5.1%)		1/27 (3.7%)		6/109 (5.5%)
Blood thyroid stimulating hormone increased	6/82 (7.3%)		1/39 (2.6%)		0/27 (0%)		6/109 (5.5%)
Lymphocyte count decreased	3/82 (3.7%)		2/39 (5.1%)		1/27 (3.7%)		4/109 (3.7%)
Neutrophil count decreased	1/82 (1.2%)		2/39 (5.1%)		0/27 (0%)		1/109 (0.9%)
Platelet count decreased	1/82 (1.2%)		7/39 (17.9%)		2/27 (7.4%)		3/109 (2.8%)
Weight decreased	9/82 (11%)		5/39 (12.8%)		0/27 (0%)		9/109 (8.3%)
White blood cell count decreased	1/82 (1.2%)		8/39 (20.5%)		0/27 (0%)		1/109 (0.9%)
Metabolism and nutrition disorders
Decreased appetite	16/82 (19.5%)		9/39 (23.1%)		8/27 (29.6%)		24/109 (22%)
Dehydration	3/82 (3.7%)		2/39 (5.1%)		0/27 (0%)		3/109 (2.8%)
Hyperglycaemia	5/82 (6.1%)		1/39 (2.6%)		0/27 (0%)		5/109 (4.6%)
Hypoalbuminaemia	6/82 (7.3%)		2/39 (5.1%)		3/27 (11.1%)		9/109 (8.3%)
Hypokalaemia	5/82 (6.1%)		13/39 (33.3%)		4/27 (14.8%)		9/109 (8.3%)
Hypomagnesaemia	7/82 (8.5%)		6/39 (15.4%)		2/27 (7.4%)		9/109 (8.3%)
Hyponatraemia	14/82 (17.1%)		6/39 (15.4%)		4/27 (14.8%)		18/109 (16.5%)
Hypophosphataemia	0/82 (0%)		2/39 (5.1%)		1/27 (3.7%)		1/109 (0.9%)
Musculoskeletal and connective tissue disorders
Arthralgia	9/82 (11%)		2/39 (5.1%)		5/27 (18.5%)		14/109 (12.8%)
Back pain	9/82 (11%)		6/39 (15.4%)		4/27 (14.8%)		13/109 (11.9%)
Bone pain	4/82 (4.9%)		2/39 (5.1%)		1/27 (3.7%)		5/109 (4.6%)
Muscular weakness	2/82 (2.4%)		2/39 (5.1%)		0/27 (0%)		2/109 (1.8%)
Musculoskeletal chest pain	4/82 (4.9%)		3/39 (7.7%)		0/27 (0%)		4/109 (3.7%)
Myalgia	1/82 (1.2%)		3/39 (7.7%)		0/27 (0%)		1/109 (0.9%)
Nervous system disorders
Dizziness	5/82 (6.1%)		1/39 (2.6%)		3/27 (11.1%)		8/109 (7.3%)
Headache	12/82 (14.6%)		4/39 (10.3%)		1/27 (3.7%)		13/109 (11.9%)
Hypoaesthesia	4/82 (4.9%)		5/39 (12.8%)		2/27 (7.4%)		6/109 (5.5%)
Neuropathy peripheral	3/82 (3.7%)		5/39 (12.8%)		2/27 (7.4%)		5/109 (4.6%)
Peripheral sensory neuropathy	0/82 (0%)		4/39 (10.3%)		0/27 (0%)		0/109 (0%)
Psychiatric disorders
Insomnia	9/82 (11%)		3/39 (7.7%)		3/27 (11.1%)		12/109 (11%)
Renal and urinary disorders
Urinary retention	0/82 (0%)		0/39 (0%)		2/27 (7.4%)		2/109 (1.8%)
Respiratory, thoracic and mediastinal disorders
Cough	17/82 (20.7%)		12/39 (30.8%)		1/27 (3.7%)		18/109 (16.5%)
Dysphonia	4/82 (4.9%)		2/39 (5.1%)		0/27 (0%)		4/109 (3.7%)
Dyspnoea	12/82 (14.6%)		3/39 (7.7%)		3/27 (11.1%)		15/109 (13.8%)
Epistaxis	10/82 (12.2%)		3/39 (7.7%)		0/27 (0%)		10/109 (9.2%)
Nasal congestion	3/82 (3.7%)		2/39 (5.1%)		1/27 (3.7%)		4/109 (3.7%)
Pleural effusion	2/82 (2.4%)		0/39 (0%)		3/27 (11.1%)		5/109 (4.6%)
Productive cough	1/82 (1.2%)		2/39 (5.1%)		1/27 (3.7%)		2/109 (1.8%)
Rhinorrhoea	2/82 (2.4%)		3/39 (7.7%)		1/27 (3.7%)		3/109 (2.8%)
Skin and subcutaneous tissue disorders
Alopecia	0/82 (0%)		9/39 (23.1%)		0/27 (0%)		0/109 (0%)
Dry skin	5/82 (6.1%)		0/39 (0%)		2/27 (7.4%)		7/109 (6.4%)
Palmar-plantar erythrodysaesthesia syndrome	0/82 (0%)		6/39 (15.4%)		1/27 (3.7%)		1/109 (0.9%)
Pruritus	10/82 (12.2%)		3/39 (7.7%)		4/27 (14.8%)		14/109 (12.8%)
Rash	15/82 (18.3%)		6/39 (15.4%)		1/27 (3.7%)		16/109 (14.7%)
Urticaria	0/82 (0%)		2/39 (5.1%)		0/27 (0%)		0/109 (0%)
Vascular disorders
Hypertension	1/82 (1.2%)		2/39 (5.1%)		2/27 (7.4%)		3/109 (2.8%)

Limitations/Caveats

[Not Specified]

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Certain Agreements

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

The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (ie, data from all sites) in the clinical trial.