PembROlizuMab Immunotherapy Versus Standard Chemotherapy... | NCT02991482

ID	Type	Description	Link
2016-002062-31	EudraCT Number
3475-594	Other Identifier	Merck Sharp Dohme

Name	Class
Merck Sharp & Dohme LLC	INDUSTRY
Frontier Science Foundation, Hellas	OTHER

Description Module

Detailed Description

Mesothelioma is an aggressive malignancy usually affecting the surfaces of body coelomic cavities. It most commonly originates from the pleura with a propensity to the lower parietal pleura and costo-diaphragmatic recess, and is almost always caused by asbestos exposure, with a usual lag time of 30 years between exposure and presentation. Outcomes for most patients are invariably fatal, with median survival from presentation around 9-12 months in most series due to difficulties in achieving a complete microscopic surgical resection and tumour relative chemo-refractoriness. Whilst initially considered rare, due to the demand of asbestos of all varieties associated with industrialization following the Second World War, the background incidence of mesothelioma of 1/million has risen to 40/million in some countries. In the UK, where substantial asbestos exposure continued until the 1970s, the death rate is the highest in the world with a current epidemic of new cases, predicted to continue for another 5-10 years. Two main histological subtypes of mesothelioma are identified. The epitheliod subtype is the commonest, accounting for around 40% of cases, whilst the sarcomatoid subtype is observed in 20% of cases; the latter being typically aggressive and chemorefractory. Around 35% cases have features of both epitheliod and sarcomatoid subtypes and are termed biphasic subtype.

For patients with pleural mesothelioma, in whom surgery is not considered appropriate, systemic chemotherapy (platinum combined with pemetrexed) remains the international standard of care. Cisplatin/pemetrexed is associated with a response rate of 41% and confers an OS advantage of 3 months over cisplatin alone, and is the only licensed systemic therapy for mesothelioma in Europe. Despite this, the median survival is 9-12 months from most series in unresectable cases. At relapse, after platinum-based chemotherapy, no anti-cancer systemic therapies are licensed. Whilst several small phase II studies and retrospective series have suggested potential efficacy for chemotherapy with agents including carboplatin/gemcitabine, or vinorelbine, none thus far have demonstrated efficacy benefit in a randomised study, with median PFS rates reported of about 3 months for both gemcitabine and vinorelbine. There is therefore a huge unmet need for effective therapy for patients with relapsed pleural mesothelioma. The largest trial ever performed of systemic therapy in relapsed pleural mesothelioma in 661 patients documented the natural outcome of this group of relapsed mesothelioma patients, reporting a median OS of 27.1 weeks (6 months) and median PFS for 6.1 weeks (1.5 months) for placebo.

Programmed cell death-1 (PD-1) is a co-inhibitory molecule at the immunological synapse that acts as a major regulator of adaptive immunity, and is exploited by tumour cells to result in adaptive immune resistance (tolerance). This occurs when PD-1 binds to the ligands PD-L1 (B7H1) or PD-L2, which are expressed on many tumour types. High PD-L1 expression on tumours is associated with poorer outcomes. Mesothelioma has been shown to express PD-L1, with a small study identifying PDL1 expression in up to 40% of mesotheliomas. Moreover, immunologically-mediated inflammation is known to be a key driver for mesothelioma development via the Nalp3 imflammasome.

Pembrolizumab (MK-3475) is a potent and highly selective humanized monoclonal antibody (mAb) of the IgG4/kappa isotype designed to directly block the interaction between PD-1 and its ligands, PD-L1 and PD-L2.

There is a need to identify new ways for the systemic therapy of malignant mesothelioma and immune checkpoint inhibition is a promising way forward. Results from the proposed trial will contribute to overcoming tumour-specific immune suppression with immune checkpoint inhibition.

Label	Type	Description	Intervention Names
Pembrolizumab arm	Experimental	Pembrolizumab is administrated at 200 mg fixed dose i.v. on day 1 of every 3 week cycle for a maximum or 2 years (expected maximum of 36 doses), or until progression of disease determined according to RECIST 1.1 criteria or lack of tolerability, or until the patient declines further treatment.	Drug: Pembrolizumab
Standard chemotherapy arm	Active Comparator	Gemcitabine (i.v. 1000 mg/m2) or vinorelbine (i.v. 30 mg/m2, or p.o 60/80 mg/m2) chemotherapy will be chosen on a per patient basis and delivered according to local standards. Chemotherapy will be administered on days 1 and 8 of every 3-week cycle. A maximum number of treatment cycles is not mandated. Patients randomised to the control arm will be allowed to cross over to receive pembrolizumab at progression, if cross-over criteria are met. Pembrolizumab administration will follow the same schedule as for patients in the experimental arm, i.e. 200 mg fixed dose i.v. on day 1 of every 3-week cycle for a maximum of 2 years or until trial termination.	Drug: Gemcitabine Drug: Vinorelbine

Name	Type	Description	Arm Group Labels	Other Names
Pembrolizumab	Drug	Pembrolizumab (MK-3475) is a potent and highly selective humanised monoclonal antibody (mAb) of the IgG4/kappa isotype designed to directly block the interaction between PD-1 and its ligands, PD-L1 and PD-L2. This blockade enhances functional activity of the target lymphocytes to facilitate tumour regression and ultimately immune rejection.

Measure	Description	Time Frame
Progression Free Survival (PFS) as Assessed by Independent Radiological Review	To investigate whether treatment with pembrolizumab improves PFS, compared to standard, institutional choice chemotherapy, assessed according to RECIST 1.1 criteria based on independent radiological review; using Kaplan-Meier method and compared between the two treatment arms by a stratified log rank test.	Time from randomization of the first patient until database cutoff date for the primary PFS analysis (Sep 2017 - Feb 2019; approximately 1.5 years).

Measure	Description	Time Frame
Objective Response Rate by Independent Radiological Review	Defined as the best overall response (complete or partial response) across all assessment time-points from randomisation to end of trial treatment, determined by RECIST 1.1 criteria.	Time from randomization of the first patient until database cutoff date for the primary PFS analysis (Sep 2017 - Feb 2019; approximately 1.5 years).

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

Histologically confirmed malignant pleural mesothelioma (all subtypes are eligible)
Progressing after or on previous platinum based chemotherapy.
Availability of tumour tissue for translational research.
Female and male patients aged 18 years or over.
Eastern Cooperative Oncology Group (ECOG) performance status 0-1.
Life expectancy of at least 3 months.
Measurable or evaluable disease according to RECIST 1.1 criteria.
Adequate renal function
Creatinine 1.5 × Upper Limit of Normal (ULN) OR Calculated creatinine clearance 40 mL/min (using the Cockroft-Gault formula).
Adequate haematological function
Haemoglobin 90 g/L or 5.6 mmol/L
White Blood Cell (WBC) 1.0 × 109/L
Lymphocytes 0.5 g/L
Absolute neutrophils count (ANC) 1.5 × 109/L
Platelet count 100 × 109/L.
Adequate liver function
ALT and AST 2.5 × ULN. If the patient has liver metastases, ALT and AST must be ≤5 × ULN.
Women of childbearing potential, including women who had their last menstrual period in the last 2 years, must have a negative serum or urine pregnancy test within 35 days before randomisation (the test has to be repeated 72 hours before pembrolizumab treatment start).
Written informed consent must be signed and dated by the patient and the investigator prior to any trial-related intervention including the submission of mandatory biomaterial.

Exclusion Criteria:

Prior therapy with an anti-programmed cell death protein 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).
Prior therapy with gemcitabine or vinorelbine.
Known active central nervous system metastases and/or carcinomatous meningitis. Patients with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least 4 weeks prior to randomisation and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to randomisation. This exception does not include carcinomatous meningitis, which is excluded regardless of clinical stability.
Known or suspected hypersensitivity to pembrolizumab or any of its excipients.
Known unstable or unresolved surgical or chemotherapy-related toxicity that would compromise the patient's capacity to participate in the trial.
Previous allogeneic tissue/solid organ transplant.
Live vaccines within 30 days prior to first dose of pembrolizumab.
Regular intake of immune-modulating drugs (such as interferon, methotrexate).
History of (non-infectious) pneumonitis that required steroids, evidence of interstitial lung disease or active, non-infectious pneumonitis.
Active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (i.e. thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) or topical therapy (e.g., steroids) for psoriasis or eczema is not considered a form of systemic treatment.
Ongoing clinically serious infections requiring systemic antibiotic or antiviral, antimicrobial, or antifungal therapy.
Human immunodeficiency virus (HIV) infection.
Known active hepatitis B or hepatitis C.
Known history of active tuberculosis.
Patients with diagnosed immunodeficiency or receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to randomisation.
Patients with other serious diseases or clinical conditions, including but not limited to uncontrolled active infection and any other serious underlying medical condition that could affect the patient's capacity to participate in the trial.
Substance abuse, medical, psychological or social conditions that may interfere with the patient's participation in the trial or evaluation of the trial results.
Women who are pregnant or in the period of lactation.
Sexually active men and women of childbearing potential who are not willing to use an effective contraceptive method during the trial and up to 120 days following cessation of trial treatment.

Name	Affiliation	Role
Sanjay Popat, MD	Royal Marsden NHS Foundation Trust	Study Chair
Alessandra Curioni-Fontecedro, MD	University Hospital, Zürich	Study Chair

Facility	Status	City	State	ZIP	Country	Contacts
Hospital Teresa Herrera		A Coruña			Spain
ICO Hospitalet

PubMed Identifier	Type	Citation	Retractions
26712084	Background	Herbst RS, Baas P, Kim DW, Felip E, Perez-Gracia JL, Han JY, Molina J, Kim JH, Arvis CD, Ahn MJ, Majem M, Fidler MJ, de Castro G Jr, Garrido M, Lubiniecki GM, Shentu Y, Im E, Dolled-Filhart M, Garon EB. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet. 2016 Apr 9;387(10027):1540-1550. doi: 10.1016/S0140-6736(15)01281-7. Epub 2015 Dec 19.
16054941

ID	Title	Description
FG000	Pembrolizumab Arm	Pembrolizumab is administrated at 200 mg fixed dose i.v. on day 1 of every 3 week cycle for a maximum or 2 years (expected maximum of 36 doses), or until progression of disease determined according to RECIST 1.1 criteria or lack of tolerability, or until the patient declines further treatment. Pembrolizumab: Pembrolizumab (MK-3475) is a potent and highly selective humanised monoclonal antibody (mAb) of the IgG4/kappa isotype designed to directly block the interaction between PD-1 and its ligands, PD-L1 and PD-L2. This blockade enhances functional activity of the target lymphocytes to facilitate tumour regression and ultimately immune rejection.

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
Prot	Yes	No	No	Study Protocol	Oct 31, 2016	Jun 17, 2021

Baseline Measures

Title

Description

Population Description

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Denominator Units Selected

Denominators

Classes

Age, Continuous

Median

Full Range

years

Title

Denominators

Categories

Title	Measurements
	OG0002.5(2.1 to 4.2) OG0013.4(2.2 to 4.3)

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG001		Log Rank		0.76														Superiority

Secondary

Objective Response Rate by Independent Radiological Review

Defined as the best overall response (complete or partial response) across all assessment time-points from randomisation to end of trial treatment, determined by RECIST 1.1 criteria.

Posted

Number

95% Confidence Interval

percentage of participants

Time from randomization of the first patient until database cutoff date for the primary PFS analysis (Sep 2017 - Feb 2019; approximately 1.5 years).

ID	Title	Description
OG000	Pembrolizumab Arm	Pembrolizumab is administrated at 200 mg fixed dose i.v. on day 1 of every 3 week cycle for a maximum or 2 years (expected maximum of 36 doses), or until progression of disease determined according to RECIST 1.1 criteria or lack of tolerability, or until the patient declines further treatment. Pembrolizumab: Pembrolizumab (MK-3475) is a potent and highly selective humanised monoclonal antibody (mAb) of the IgG4/kappa isotype designed to directly block the interaction between PD-1 and its ligands, PD-L1 and PD-L2. This blockade enhances functional activity of the target lymphocytes to facilitate tumour regression and ultimately immune rejection.
OG001	Standard Chemotherapy Arm	Gemcitabine (i.v. 1000 mg/m2) or vinorelbine (i.v. 30 mg/m2, or p.o 60/80 mg/m2) chemotherapy will be chosen on a per patient basis and delivered according to local standards. Chemotherapy will be administered on days 1 and 8 of every 3-week cycle. A maximum number of treatment cycles is not mandated. Patients randomised to the control arm will be allowed to cross over to receive pembrolizumab at progression, if cross-over criteria are met. Pembrolizumab administration will follow the same schedule as for patients in the experimental arm, i.e. 200 mg fixed dose i.v. on day 1 of every 3-week cycle for a maximum of 2 years or until trial termination. Gemcitabine: Gemcitabine replaces one of the building blocks of nucleic acids, in this case cytidine, during DNA replication. The process arrests tumour growth, as new nucleosides cannot be attached to the "faulty" nucleoside, resulting in apoptosis (cellular "suicide"). Vinorelbine: Vinorelbine is a vinca alkaloid cytotoxic chemotherapy that is available in intravenous and oral preparations with EMA licenses in lung cancer and breast cancer. Vinorelbine blocks mitosis in phase G2-M, causing cell death in interphase or at the following mitosis.

Secondary

Overall Survival.

Defined as time from the date of randomisation until death from any cause. Censoring will occur at the last follow-up date.

Posted

Median

95% Confidence Interval

months

Time from randomization of the first patient until database cutoff date for the OS analysis (Sep 2017 - Aug 2019; approximately 2 years).

ID	Title	Description
OG000	Pembrolizumab Arm	Pembrolizumab is administrated at 200 mg fixed dose i.v. on day 1 of every 3 week cycle for a maximum or 2 years (expected maximum of 36 doses), or until progression of disease determined according to RECIST 1.1 criteria or lack of tolerability, or until the patient declines further treatment. Pembrolizumab: Pembrolizumab (MK-3475) is a potent and highly selective humanised monoclonal antibody (mAb) of the IgG4/kappa isotype designed to directly block the interaction between PD-1 and its ligands, PD-L1 and PD-L2. This blockade enhances functional activity of the target lymphocytes to facilitate tumour regression and ultimately immune rejection.
OG001	Standard Chemotherapy Arm	Gemcitabine (i.v. 1000 mg/m2) or vinorelbine (i.v. 30 mg/m2, or p.o 60/80 mg/m2) chemotherapy will be chosen on a per patient basis and delivered according to local standards. Chemotherapy will be administered on days 1 and 8 of every 3-week cycle. A maximum number of treatment cycles is not mandated. Patients randomised to the control arm will be allowed to cross over to receive pembrolizumab at progression, if cross-over criteria are met. Pembrolizumab administration will follow the same schedule as for patients in the experimental arm, i.e. 200 mg fixed dose i.v. on day 1 of every 3-week cycle for a maximum of 2 years or until trial termination. Gemcitabine: Gemcitabine replaces one of the building blocks of nucleic acids, in this case cytidine, during DNA replication. The process arrests tumour growth, as new nucleosides cannot be attached to the "faulty" nucleoside, resulting in apoptosis (cellular "suicide"). Vinorelbine: Vinorelbine is a vinca alkaloid cytotoxic chemotherapy that is available in intravenous and oral preparations with EMA licenses in lung cancer and breast cancer. Vinorelbine blocks mitosis in phase G2-M, causing cell death in interphase or at the following mitosis.

Secondary

Time to Treatment Failure.

Time from from randomisation to discontinuation of treatment for any reason, including progression of disease, treatment toxicity, refusal and death, by Kaplan Meier method. Censoring will occur at the last follow-up date.

Posted

Median

95% Confidence Interval

months

Time from randomization of the first patient until database cutoff date for the primary PFS analysis (Sep 2017 - Feb 2019; approximately 1.5 years).

ID	Title	Description
OG000	Pembrolizumab Arm	Pembrolizumab is administrated at 200 mg fixed dose i.v. on day 1 of every 3 week cycle for a maximum or 2 years (expected maximum of 36 doses), or until progression of disease determined according to RECIST 1.1 criteria or lack of tolerability, or until the patient declines further treatment. Pembrolizumab: Pembrolizumab (MK-3475) is a potent and highly selective humanised monoclonal antibody (mAb) of the IgG4/kappa isotype designed to directly block the interaction between PD-1 and its ligands, PD-L1 and PD-L2. This blockade enhances functional activity of the target lymphocytes to facilitate tumour regression and ultimately immune rejection.
OG001	Standard Chemotherapy Arm	Gemcitabine (i.v. 1000 mg/m2) or vinorelbine (i.v. 30 mg/m2, or p.o 60/80 mg/m2) chemotherapy will be chosen on a per patient basis and delivered according to local standards. Chemotherapy will be administered on days 1 and 8 of every 3-week cycle. A maximum number of treatment cycles is not mandated. Patients randomised to the control arm will be allowed to cross over to receive pembrolizumab at progression, if cross-over criteria are met. Pembrolizumab administration will follow the same schedule as for patients in the experimental arm, i.e. 200 mg fixed dose i.v. on day 1 of every 3-week cycle for a maximum of 2 years or until trial termination. Gemcitabine: Gemcitabine replaces one of the building blocks of nucleic acids, in this case cytidine, during DNA replication. The process arrests tumour growth, as new nucleosides cannot be attached to the "faulty" nucleoside, resulting in apoptosis (cellular "suicide"). Vinorelbine: Vinorelbine is a vinca alkaloid cytotoxic chemotherapy that is available in intravenous and oral preparations with EMA licenses in lung cancer and breast cancer. Vinorelbine blocks mitosis in phase G2-M, causing cell death in interphase or at the following mitosis.

Secondary

Percentage of Patients Experienced AEs/SAEs

The safety and tolerability of pembrolizumab treatment will be assessed through analysis of the worst grade of toxicity/adverse events according to CTCAE v4.0 criteria observed over the whole treatment period. Adverse events are collected from study treatment initiation to 30 days after treatment is ceased for any reason. Serious adverse events and events of clinical interest are collected within 90 days after last dose of trial treatment.

Safety evaluation was conducted in the as-treated (AT) population: all randomised patients that received at least one dose of trial treatment, with treatment assignments designed according to actual study treatment received.

Posted

Count of Participants

Participants

Time from randomization of the first patient until database cutoff date for the primary PFS analysis (Sep 2017 - Feb 2019; approximately 1.5 years).

ID	Title	Description
OG000	Pembrolizumab Arm	Pembrolizumab is administrated at 200 mg fixed dose i.v. on day 1 of every 3 week cycle for a maximum or 2 years (expected maximum of 36 doses), or until progression of disease determined according to RECIST 1.1 criteria or lack of tolerability, or until the patient declines further treatment. Pembrolizumab: Pembrolizumab (MK-3475) is a potent and highly selective humanised monoclonal antibody (mAb) of the IgG4/kappa isotype designed to directly block the interaction between PD-1 and its ligands, PD-L1 and PD-L2. This blockade enhances functional activity of the target lymphocytes to facilitate tumour regression and ultimately immune rejection.
OG001

Secondary

Progression Free Survival (PFS) Assessed by Investigator

Investigator assessed PFS, from the date of randomisation until documented progression or death, if progression is not documented. Censoring occurs at the last tumor assessment.

Posted

Median

95% Confidence Interval

months

Time from randomization of the first patient until database cutoff date for the primary PFS analysis (Sep 2017 - Feb 2019; approximately 1.5 years).

ID	Title	Description
OG000	Pembrolizumab Arm	Pembrolizumab is administrated at 200 mg fixed dose i.v. on day 1 of every 3 week cycle for a maximum or 2 years (expected maximum of 36 doses), or until progression of disease determined according to RECIST 1.1 criteria or lack of tolerability, or until the patient declines further treatment. Pembrolizumab: Pembrolizumab (MK-3475) is a potent and highly selective humanised monoclonal antibody (mAb) of the IgG4/kappa isotype designed to directly block the interaction between PD-1 and its ligands, PD-L1 and PD-L2. This blockade enhances functional activity of the target lymphocytes to facilitate tumour regression and ultimately immune rejection.
OG001	Standard Chemotherapy Arm	Gemcitabine (i.v. 1000 mg/m2) or vinorelbine (i.v. 30 mg/m2, or p.o 60/80 mg/m2) chemotherapy will be chosen on a per patient basis and delivered according to local standards. Chemotherapy will be administered on days 1 and 8 of every 3-week cycle. A maximum number of treatment cycles is not mandated. Patients randomised to the control arm will be allowed to cross over to receive pembrolizumab at progression, if cross-over criteria are met. Pembrolizumab administration will follow the same schedule as for patients in the experimental arm, i.e. 200 mg fixed dose i.v. on day 1 of every 3-week cycle for a maximum of 2 years or until trial termination. Gemcitabine: Gemcitabine replaces one of the building blocks of nucleic acids, in this case cytidine, during DNA replication. The process arrests tumour growth, as new nucleosides cannot be attached to the "faulty" nucleoside, resulting in apoptosis (cellular "suicide"). Vinorelbine: Vinorelbine is a vinca alkaloid cytotoxic chemotherapy that is available in intravenous and oral preparations with EMA licenses in lung cancer and breast cancer. Vinorelbine blocks mitosis in phase G2-M, causing cell death in interphase or at the following mitosis.

Serious Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Lung infection	Infections and infestations	CTCAE (4.0)	Systematic Assessment	EG0004 affected72 at risk EG0018 affected70 at risk
Dyspnea	Respiratory, thoracic and mediastinal disorders	CTCAE (4.0)	Systematic Assessment	EG0000 affected72 at risk EG0012 affected70 at risk
Febrile neutropenia	Blood and lymphatic system disorders	CTCAE (4.0)	Systematic Assessment	EG0000 affected72 at risk EG0015 affected70 at risk
Pneumonitis	Respiratory, thoracic and mediastinal disorders	CTCAE (4.0)	Systematic Assessment	EG0004 affected72 at risk EG0010 affected70 at risk
Bronchial infection	Infections and infestations	CTCAE (4.0)	Systematic Assessment	EG0002 affected72 at risk EG0011 affected70 at risk
Pain	General disorders	CTCAE (4.0)	Systematic Assessment	EG0000 affected72 at risk EG0011 affected70 at risk
Urinary tract infection	Infections and infestations	CTCAE (4.0)	Systematic Assessment	EG0001 affected72 at risk EG0011 affected70 at risk
Vomiting	Gastrointestinal disorders	CTCAE (4.0)	Systematic Assessment	EG0002 affected72 at risk EG0010 affected70 at risk
Constipation	Gastrointestinal disorders	CTCAE (4.0)	Systematic Assessment	EG0000 affected72 at risk EG0011 affected70 at risk
Colitis	Gastrointestinal disorders	CTCAE (4.0)	Systematic Assessment	EG0002 affected72 at risk EG0010 affected70 at risk
Acute kidney injury	Renal and urinary disorders	CTCAE (4.0)	Systematic Assessment	EG0002 affected72 at risk EG0010 affected70 at risk
Cardiac arrest	Cardiac disorders	CTCAE (4.0)	Systematic Assessment	EG0001 affected72 at risk EG0011 affected70 at risk
Adrenal insufficiency	Endocrine disorders	CTCAE (4.0)	Systematic Assessment	EG0001 affected72 at risk EG0010 affected70 at risk
Atrial fibrillation	Cardiac disorders	CTCAE (4.0)	Systematic Assessment	EG0001 affected72 at risk EG0010 affected70 at risk
Atrial flutter	Cardiac disorders	CTCAE (4.0)	Systematic Assessment	EG0001 affected72 at risk EG0010 affected70 at risk
Catheter related infection	Infections and infestations	CTCAE (4.0)	Systematic Assessment	EG0001 affected72 at risk EG0011 affected70 at risk
Confusion	Psychiatric disorders	CTCAE (4.0)	Systematic Assessment	EG0001 affected72 at risk EG0010 affected70 at risk
Cytokine release syndrome	Immune system disorders	CTCAE (4.0)	Systematic Assessment	EG0001 affected72 at risk EG0010 affected70 at risk
Diarrhea	Gastrointestinal disorders	CTCAE (4.0)	Systematic Assessment	EG0001 affected72 at risk EG0010 affected70 at risk
Heart failure	Cardiac disorders	CTCAE (4.0)	Systematic Assessment	EG0001 affected72 at risk EG0010 affected70 at risk
Hypercalcemia	Metabolism and nutrition disorders	CTCAE (4.0)	Systematic Assessment	EG0001 affected72 at risk EG0010 affected70 at risk
Hyperkalemia	Metabolism and nutrition disorders	CTCAE (4.0)	Systematic Assessment	EG0001 affected72 at risk EG0010 affected70 at risk
Hypokalemia	Metabolism and nutrition disorders	CTCAE (4.0)	Systematic Assessment	EG0000 affected72 at risk EG0011 affected70 at risk
Malaise	General disorders	CTCAE (4.0)	Systematic Assessment	EG0001 affected72 at risk EG0010 affected70 at risk
Myocardial infarction	Cardiac disorders	CTCAE (4.0)	Systematic Assessment	EG0000 affected72 at risk EG0011 affected70 at risk
Neutrophil count decreased	Investigations	CTCAE (4.0)	Systematic Assessment	EG0000 affected72 at risk EG0011 affected70 at risk
Thromboembolic event	Vascular disorders	CTCAE (4.0)	Systematic Assessment	EG0000 affected72 at risk EG0011 affected70 at risk
Otitis media	Infections and infestations	CTCAE (4.0)	Systematic Assessment	EG0001 affected72 at risk EG0010 affected70 at risk
Abdominal pain	Gastrointestinal disorders	CTCAE (4.0)	Systematic Assessment	EG0001 affected72 at risk EG0010 affected70 at risk
Hypophysitis	Immune system disorders	CTCAE (4.0)	Systematic Assessment	EG0001 affected72 at risk EG0010 affected70 at risk
Infection NOS	Infections and infestations	CTCAE (4.0)	Systematic Assessment	EG0000 affected72 at risk EG0011 affected70 at risk
Lower respiratory infection	Infections and infestations	CTCAE (4.0)	Systematic Assessment	EG0001 affected72 at risk EG0010 affected70 at risk
Non-neutropaenic infection	Infections and infestations	CTCAE (4.0)	Systematic Assessment	EG0000 affected72 at risk EG0011 affected70 at risk
Alkaline phosphatase increased	Investigations	CTCAE (4.0)	Systematic Assessment	EG0001 affected72 at risk EG0010 affected70 at risk
Syncope	Nervous system disorders	CTCAE (4.0)	Systematic Assessment	EG0001 affected72 at risk EG0010 affected70 at risk
Rash maculo-papular	Skin and subcutaneous tissue disorders	CTCAE (4.0)	Systematic Assessment	EG0001 affected72 at risk EG0010 affected70 at risk

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Fatigue	General disorders	CTCAE (4.0)	Systematic Assessment	EG00028 affected72 at risk EG00132 affected70 at risk
Dyspnea	Respiratory, thoracic and mediastinal disorders	CTCAE (4.0)	Systematic Assessment	EG00020 affected72 at risk EG00110 affected70 at risk
Pain	General disorders	CTCAE (4.0)	Systematic Assessment	EG00019 affected72 at risk EG00119 affected70 at risk
Constipation	Gastrointestinal disorders	CTCAE (4.0)	Systematic Assessment	EG00017 affected72 at risk EG00123 affected70 at risk
Nausea	Gastrointestinal disorders	CTCAE (4.0)	Systematic Assessment	EG00016 affected72 at risk EG00124 affected70 at risk
Diarrhea	Gastrointestinal disorders	CTCAE (4.0)	Systematic Assessment	EG00016 affected72 at risk EG00126 affected70 at risk
Anorexia	Metabolism and nutrition disorders	CTCAE (4.0)	Systematic Assessment	EG00012 affected72 at risk EG00121 affected70 at risk
Cough	Respiratory, thoracic and mediastinal disorders	CTCAE (4.0)	Systematic Assessment	EG00016 affected72 at risk EG0013 affected70 at risk
Rash maculo-papular	Skin and subcutaneous tissue disorders	CTCAE (4.0)	Systematic Assessment	EG00011 affected72 at risk EG0012 affected70 at risk
Vomiting	Gastrointestinal disorders	CTCAE (4.0)	Systematic Assessment	EG00010 affected72 at risk EG0018 affected70 at risk
Dry skin	Skin and subcutaneous tissue disorders	CTCAE (4.0)	Systematic Assessment	EG00011 affected72 at risk EG0013 affected70 at risk
Pruritus	Skin and subcutaneous tissue disorders	CTCAE (4.0)	Systematic Assessment	EG00010 affected72 at risk EG0013 affected70 at risk
Insomnia	Psychiatric disorders	CTCAE (4.0)	Systematic Assessment	EG0008 affected72 at risk EG0015 affected70 at risk
Lung infection	Infections and infestations	CTCAE (4.0)	Systematic Assessment	EG0006 affected72 at risk EG0012 affected70 at risk
Arthralgia	Musculoskeletal and connective tissue disorders	CTCAE (4.0)	Systematic Assessment	EG0007 affected72 at risk EG0012 affected70 at risk
Edema limbs	General disorders	CTCAE (4.0)	Systematic Assessment	EG0006 affected72 at risk EG0014 affected70 at risk
Mucositis oral	Gastrointestinal disorders	CTCAE (4.0)	Systematic Assessment	EG0005 affected72 at risk EG0019 affected70 at risk
Urinary tract infection	Infections and infestations	CTCAE (4.0)	Systematic Assessment	EG0005 affected72 at risk EG0012 affected70 at risk
Back pain	Musculoskeletal and connective tissue disorders	CTCAE (4.0)	Systematic Assessment	EG0005 affected72 at risk EG0013 affected70 at risk
Bronchial infection	Infections and infestations	CTCAE (4.0)	Systematic Assessment	EG0004 affected72 at risk EG0012 affected70 at risk
Flu like symptoms	General disorders	CTCAE (4.0)	Systematic Assessment	EG0005 affected72 at risk EG0012 affected70 at risk
GGT increased	Investigations	CTCAE (4.0)	Systematic Assessment	EG0005 affected72 at risk EG0011 affected70 at risk
Myalgia	Musculoskeletal and connective tissue disorders	CTCAE (4.0)	Systematic Assessment	EG0005 affected72 at risk EG0010 affected70 at risk
Weight loss	Investigations	CTCAE (4.0)	Systematic Assessment	EG0005 affected72 at risk EG0013 affected70 at risk
Alanine aminotransferase increased	Investigations	CTCAE (4.0)	Systematic Assessment	EG0004 affected72 at risk EG0014 affected70 at risk
Dry mouth	Gastrointestinal disorders	CTCAE (4.0)	Systematic Assessment	EG0003 affected72 at risk EG0014 affected70 at risk
Headache	Nervous system disorders	CTCAE (4.0)	Systematic Assessment	EG0004 affected72 at risk EG0016 affected70 at risk
Hypoalbuminemia	Metabolism and nutrition disorders	CTCAE (4.0)	Systematic Assessment	EG0004 affected72 at risk EG0012 affected70 at risk
Anemia	Blood and lymphatic system disorders	CTCAE (4.0)	Systematic Assessment	EG0003 affected72 at risk EG00111 affected70 at risk
Neutrophil count decreased	Investigations	CTCAE (4.0)	Systematic Assessment	EG0000 affected72 at risk EG00110 affected70 at risk
Abdominal pain	Gastrointestinal disorders	CTCAE (4.0)	Systematic Assessment	EG0002 affected72 at risk EG0018 affected70 at risk
Peripheral sensory neuropathy	Nervous system disorders	CTCAE (4.0)	Systematic Assessment	EG0001 affected72 at risk EG0014 affected70 at risk
Fever	General disorders	CTCAE (4.0)	Systematic Assessment	EG0002 affected72 at risk EG0015 affected70 at risk
Chest wall pain	Musculoskeletal and connective tissue disorders	CTCAE (4.0)	Systematic Assessment	EG0000 affected72 at risk EG0014 affected70 at risk
Depression	Psychiatric disorders	CTCAE (4.0)	Systematic Assessment	EG0003 affected72 at risk EG0014 affected70 at risk
Paresthesia	Nervous system disorders	CTCAE (4.0)	Systematic Assessment	EG0001 affected72 at risk EG0014 affected70 at risk
Oral thrush	Gastrointestinal disorders	CTCAE (4.0)	Systematic Assessment	EG0004 affected72 at risk EG0012 affected70 at risk

ID	Term
D006571	Heterocyclic Compounds
D003841	Deoxycytidine
D003562	Cytidine
D011741	Pyrimidine Nucleosides
D011743	Pyrimidines
D006573	Heterocyclic Compounds, 1-Ring
D014748	Vinca Alkaloids
D046948	Secologanin Tryptamine Alkaloids
D026121	Indole Alkaloids
D000470	Alkaloids
D007211	Indoles
D006574	Heterocyclic Compounds, 2-Ring
D000072471	Heterocyclic Compounds, Fused-Ring
D054836	Indolizidines
D007212	Indolizines

ID	Title	Description
BG000	Pembrolizumab Arm	Pembrolizumab is administrated at 200 mg fixed dose i.v. on day 1 of every 3 week cycle for a maximum or 2 years (expected maximum of 36 doses), or until progression of disease determined according to RECIST 1.1 criteria or lack of tolerability, or until the patient declines further treatment. Pembrolizumab: Pembrolizumab (MK-3475) is a potent and highly selective humanised monoclonal antibody (mAb) of the IgG4/kappa isotype designed to directly block the interaction between PD-1 and its ligands, PD-L1 and PD-L2. This blockade enhances functional activity of the target lymphocytes to facilitate tumour regression and ultimately immune rejection.
BG001	Standard Chemotherapy Arm	Gemcitabine (i.v. 1000 mg/m2) or vinorelbine (i.v. 30 mg/m2, or p.o 60/80 mg/m2) chemotherapy will be chosen on a per patient basis and delivered according to local standards. Chemotherapy will be administered on days 1 and 8 of every 3-week cycle. A maximum number of treatment cycles is not mandated. Patients randomised to the control arm will be allowed to cross over to receive pembrolizumab at progression, if cross-over criteria are met. Pembrolizumab administration will follow the same schedule as for patients in the experimental arm, i.e. 200 mg fixed dose i.v. on day 1 of every 3-week cycle for a maximum of 2 years or until trial termination. Gemcitabine: Gemcitabine replaces one of the building blocks of nucleic acids, in this case cytidine, during DNA replication. The process arrests tumour growth, as new nucleosides cannot be attached to the "faulty" nucleoside, resulting in apoptosis (cellular "suicide"). Vinorelbine: Vinorelbine is a vinca alkaloid cytotoxic chemotherapy that is available in intravenous and oral preparations with EMA licenses in lung cancer and breast cancer. Vinorelbine blocks mitosis in phase G2-M, causing cell death in interphase or at the following mitosis.
BG002	Total	Total of all reporting groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Pembrolizumab Arm	Pembrolizumab is administrated at 200 mg fixed dose i.v. on day 1 of every 3 week cycle for a maximum or 2 years (expected maximum of 36 doses), or until progression of disease determined according to RECIST 1.1 criteria or lack of tolerability, or until the patient declines further treatment. Pembrolizumab: Pembrolizumab (MK-3475) is a potent and highly selective humanised monoclonal antibody (mAb) of the IgG4/kappa isotype designed to directly block the interaction between PD-1 and its ligands, PD-L1 and PD-L2. This blockade enhances functional activity of the target lymphocytes to facilitate tumour regression and ultimately immune rejection.	48	73	25	72	70	72
EG001	Standard Chemotherapy Arm	Gemcitabine (i.v. 1000 mg/m2) or vinorelbine (i.v. 30 mg/m2, or p.o 60/80 mg/m2) chemotherapy will be chosen on a per patient basis and delivered according to local standards. Chemotherapy will be administered on days 1 and 8 of every 3-week cycle. A maximum number of treatment cycles is not mandated. Patients randomised to the control arm will be allowed to cross over to receive pembrolizumab at progression, if cross-over criteria are met. Pembrolizumab administration will follow the same schedule as for patients in the experimental arm, i.e. 200 mg fixed dose i.v. on day 1 of every 3-week cycle for a maximum of 2 years or until trial termination. Gemcitabine: Gemcitabine replaces one of the building blocks of nucleic acids, in this case cytidine, during DNA replication. The process arrests tumour growth, as new nucleosides cannot be attached to the "faulty" nucleoside, resulting in apoptosis (cellular "suicide"). Vinorelbine: Vinorelbine is a vinca alkaloid cytotoxic chemotherapy that is available in intravenous and oral preparations with EMA licenses in lung cancer and breast cancer. Vinorelbine blocks mitosis in phase G2-M, causing cell death in interphase or at the following mitosis.	44	71	20	70	65	70

ID	Term
C582435	pembrolizumab
D000093542	Gemcitabine
D000077235	Vinorelbine