A Study of the Combination of Necitumumab (LY3012211) and... | NCT02451930

ID	Type	Description
I4X-MC-JFCQ	Other Identifier	Eli Lilly and Company
2015-001291-22	EudraCT Number
KEYNOTE -099	Other Identifier	Merck

Name	Class
Merck Sharp & Dohme LLC	INDUSTRY

Label	Type	Description	Intervention Names
Necitumumab + Pembrolizumab	Experimental	Part A Cohort 1: 600 mg Necitumumab + 200 mg Pembrolizumab: Participants received 200 mg pembrolizumab absolute dose by intravenous (IV) infusion on Day 1 of 21 days cycles followed by 600 mg necitumumab absolute dose by IV infusion on Days 1 and 8 of 21 days cycles in participants with Stage IV NSCLC (all histologies). Part A Cohort 2, Part B and Part C: 800mg Necitumumab + 200mg Pembrolizumab: Participants received 200 mg pembrolizumab absolute dose by intravenous (IV) infusion on Day 1 of 21 days cycles followed by 800 mg necitumumab absolute dose by IV infusion on Days 1 and 8 of 21 days cycles in Part A cohort 2 participants with any histology, Part B and C participants with Stage IV NSCLC of squamous and nonsquamous histology. Part C were Japan participants. Part C were Japan participants.	Drug: Necitumumab Drug: Pembrolizumab

Name	Type	Description	Arm Group Labels	Other Names
Necitumumab	Drug	Administered IV	Necitumumab + Pembrolizumab	LY3012211

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Number of Participants With Dose Limiting Toxicities (DLTs) in Part A and Part C	A dose limiting toxicity (DLT) was defined as an adverse event (AE) during the first 21 days that was possibly related to the study drug and fulfilled any of the following criteria using the National Cancer Institute's (NCI) Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0: Grade 3 or 4 nonhematologic toxicity, Grade 4 nausea, vomiting, or diarrhea that persists more than 3 days despite maximal supportive intervention, Grade 3 thrombocytopenia with bleeding requiring transfusion, Grade 4 thrombocytopenia with or without bleeding, Grade 4 neutropenia that persists more than 5 days, Grade 3 or 4 neutropenia with fever, Grade ≥3 skin toxicity despite best supportive care with some exceptions, if a total at least 75% of the planned dose for both agents cannot be administered in the first cycle due to toxicity, prolonged delay (>2 weeks) in initiating cycle 2 due to treatment-related toxicity and Grade 5 toxicity.	Baseline through Cycle 1 (21 day cycles)
Percentage of Participants Who Achieve Best Overall Tumor Response of Complete Response (CR) or Partial Response (PR) (Objective Response Rates [ORR]) in Part A and Part B	ORR was the percentage of participants achieving a best overall response (BOR) of complete response (CR) or partial response (PR) as per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. CR defined as the disappearance of all target and non-target lesions and no appearance of new lesions. PR defined as at least a 30% decrease in the sum of the longest diameters (LD) of target lesions (taking as reference the baseline sum LD), no progression of non-target lesions, and no appearance of new lesions. Progressive disease (PD) is defined as at least a 20% increase in the sum of the diameters of target lesions, with reference being the smallest sum on study and an absolute increase of at least 5 mm, or unequivocal progression of non-target lesions, or 1 or more new lesions.	Baseline to Measured Progressive Disease or Start of New Anti-Cancer Therapy (Up To 16 Months)

Secondary Outcomes

Measure	Description	Time Frame
Percentage of Participants Who Achieve Best Overall Tumor Response of Complete Response (CR) or Partial Response (PR) (Objective Response Rates [ORR]) in Part A Cohort 2, Part B and Part C	ORR was the percentage of participants achieving a best overall response (BOR) of complete response (CR) or partial response (PR) as per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. CR defined as the disappearance of all target and non-target lesions and no appearance of new lesions. PR defined as at least a 30% decrease in the sum of the longest diameters (LD) of target lesions (taking as reference the baseline sum LD), no progression of non-target lesions, and no appearance of new lesions. PD is defined as at least a 20% increase in the sum of the diameters of target lesions, with reference being the smallest sum on study and an absolute increase of at least 5 mm, or unequivocal progression of non-target lesions, or 1 or more new lesions.

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

The participant has Stage IV NSCLC.
- Part A: NSCLC Stage IV (any type)
- Part B: NSCLC Stage IV (squamous and nonsquamous)
- Part C: NSCLC Stage IV in Japanese participants (squamous and nonsquamous)
The participant must have progressed after 1 platinum-based chemotherapy regimen for Stage IV NSCLC. Prior therapy with VEGF/VEGFR targeting agents is permitted. Prior neoadjuvant/adjuvant therapy is permitted. Prior treatment with EGFR-TKI and ALK inhibitors is mandatory in participants with NSCLC whose tumor has EGFR-activating mutations or ALK translocations, respectively.
Measurable disease at the time of study entry as defined by Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST 1.1).
The participant has evaluable tumor tissue available for biomarker analyses.
The participant has adequate organ function.
Eastern Cooperative Oncology Group performance status (ECOG PS) score of 0-1.

Exclusion Criteria:

The participant is currently enrolled in a clinical trial involving an investigational product or non-approved use of a drug or device.
Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2 monoclonal antibody.
Have a serious concomitant systemic disorder or significant cardiac disease.
The participant has undergone major surgery or received anti-cancer monoclonal antibody therapy in the 30-days prior to study enrollment.
The participant has undergone chest irradiation within 2 weeks prior to receiving study treatment.
The participant has brain metastases that are symptomatic.
The participant has a history of arterial thromboembolism event (ATE) or venous thromboembolism event (VTE) within 3 months prior to study enrollment. Participants with history of VTE beyond 3 months prior to study enrollment can be enrolled if they are appropriately treated with low molecular weight heparin.
The participant has a known allergy / history of hypersensitivity reaction to any of the treatment components, including any ingredient used in the formulation of necitumumab or pembrolizumab, or any other contraindication to one of the administered treatments.
The participant has a concurrent active malignancy. Previous history of malignancy is permitted, provided that the participant has been free of disease for ≥3 years, with the exception of adequately treated basal or squamous cell carcinoma of the skin, preinvasive carcinoma of the cervix, or any cancers that in the judgment of the investigator and sponsor may not affect the interpretation of results (for example, prostate, bladder).
History of interstitial lung disease, pneumonitis, autoimmune disease or syndrome that requires steroids or immunosuppressive agents.
The participant has active infection requiring systemic therapy, including active tuberculosis or known history of infection with the human immunodeficiency virus (HIV 1/2 antibodies), or hepatitis B (e.g., HBsAg reactive) and/or C virus (e.g., HCV RNA [qualitative] is detected).
The participant has an active autoimmune disease or a documented history of autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents.
The participant has received a live vaccine within 30 days prior to the first dose of trial treatment.

Name	Affiliation	Role
Call 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559 Mon - Fri 9 AM - 5 PM Eastern time (UTC/GMT - 5 hours, EST)	Eli Lilly and Company	Study Director

Facility	Status	City	State	ZIP	Country	Contacts
Florida Cancer Specialists		Fort Myers	Florida	33916	United States
Florida Cancer Specialists

Label	URL
Click here for more information about this study: A Study of the Combination of Necitumumab (LY3012211) and Pembrolizumab (MK3475) in Participants With NSCLC	View source

ID	Title	Description
FG000	Part A Cohort 1: 600 mg Neci + 200 mg Pembro	Participants received 200 mg pembrolizumab (pembro) absolute dose by intravenous (IV) infusion on Day1 of 21 days cycles followed by 600 mg necitumumab (Neci) absolute dose by IV infusion on Days 1 and 8 of 21 days cycles in participants with Stage IV NSCLC (all histologies).
FG001

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
Prot	Yes	No	No	Study Protocol	Sep 17, 2018	Sep 11, 2020

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Number of Participants With Dose Limiting Toxicities (DLTs) in Part A and Part C

A dose limiting toxicity (DLT) was defined as an adverse event (AE) during the first 21 days that was possibly related to the study drug and fulfilled any of the following criteria using the National Cancer Institute's (NCI) Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0: Grade 3 or 4 nonhematologic toxicity, Grade 4 nausea, vomiting, or diarrhea that persists more than 3 days despite maximal supportive intervention, Grade 3 thrombocytopenia with bleeding requiring transfusion, Grade 4 thrombocytopenia with or without bleeding, Grade 4 neutropenia that persists more than 5 days, Grade 3 or 4 neutropenia with fever, Grade ≥3 skin toxicity despite best supportive care with some exceptions, if a total at least 75% of the planned dose for both agents cannot be administered in the first cycle due to toxicity, prolonged delay (>2 weeks) in initiating cycle 2 due to treatment-related toxicity and Grade 5 toxicity.

All participants who received at least one dose of study drug in Part A and Part C.

Posted

Count of Participants

Participants

Baseline through Cycle 1 (21 day cycles)

ID	Title	Description
OG000	Part A Cohort 1: 600 mg Neci + 200 mg Pembro	Participants received 200 mg pembrolizumab (pembro) absolute dose by intravenous (IV) infusion on Day1 of 21 days cycles followed by 600 mg necitumumab (Neci) absolute dose by IV infusion on Days 1 and 8 of 21 days cycles in participants with Stage IV NSCLC (all histologies).
OG001	Part A Cohort 2: 800 mg Neci + 200 mg Pembro	Participants received 200 mg pembrolizumab absolute dose by intravenous (IV) infusion on Day 1 of 21 days cycles followed by 800 mg necitumumab absolute dose by IV infusion on Days 1 and 8 of 21 days cycles in participants with Stage IV NSCLC (all histologies).
OG002	Part C: 800 mg Neci + 200 mg Pembro	Participants received 200 mg pembrolizumab absolute dose by intravenous (IV) infusion on Day 1 of 21 days cycles followed by 800 mg necitumumab absolute dose by IV infusion on Days 1 and 8 of 21 days cycles in participants with Stage IV NSCLC of squamous and nonsquamous histology. Part C were Japan participants.

Units	Counts
Participants	OG0003 OG0016 OG0027

Title

Denominators

Categories

Title	Measurements
	OG0000 OG0010 OG0020

Primary

Percentage of Participants Who Achieve Best Overall Tumor Response of Complete Response (CR) or Partial Response (PR) (Objective Response Rates [ORR]) in Part A and Part B

ORR was the percentage of participants achieving a best overall response (BOR) of complete response (CR) or partial response (PR) as per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. CR defined as the disappearance of all target and non-target lesions and no appearance of new lesions. PR defined as at least a 30% decrease in the sum of the longest diameters (LD) of target lesions (taking as reference the baseline sum LD), no progression of non-target lesions, and no appearance of new lesions. Progressive disease (PD) is defined as at least a 20% increase in the sum of the diameters of target lesions, with reference being the smallest sum on study and an absolute increase of at least 5 mm, or unequivocal progression of non-target lesions, or 1 or more new lesions.

All participants who received at least one dose of study drug in Part A and Part B. Per protocol, participants in Part A cohort 2 who received the recommended necitumumab dose for Part B were also analyzed together with Part B.

Posted

Number

95% Confidence Interval

Percentage of Participants

Baseline to Measured Progressive Disease or Start of New Anti-Cancer Therapy (Up To 16 Months)

ID	Title	Description
OG000	Part A Cohort 1: 600 mg Neci + 200 mg Pembro	Participants received 200 mg pembrolizumab (pembro) absolute dose by intravenous (IV) infusion on Day1 of 21 days cycles followed by 600 mg necitumumab (Neci) absolute dose by IV infusion on Days 1 and 8 of 21 days cycles in participants with Stage IV NSCLC (all histologies).

Secondary

Percentage of Participants Who Achieve Best Overall Tumor Response of Complete Response (CR) or Partial Response (PR) (Objective Response Rates [ORR]) in Part A Cohort 2, Part B and Part C

ORR was the percentage of participants achieving a best overall response (BOR) of complete response (CR) or partial response (PR) as per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. CR defined as the disappearance of all target and non-target lesions and no appearance of new lesions. PR defined as at least a 30% decrease in the sum of the longest diameters (LD) of target lesions (taking as reference the baseline sum LD), no progression of non-target lesions, and no appearance of new lesions. PD is defined as at least a 20% increase in the sum of the diameters of target lesions, with reference being the smallest sum on study and an absolute increase of at least 5 mm, or unequivocal progression of non-target lesions, or 1 or more new lesions.

All participants who received at least one dose of study drug in Part A Cohort 2, Part B and Part C. Part C were Japan participants. Per protocol, participants in Part A cohort 2 who received the recommended necitumumab dose for Part B were also analyzed together with Part B.

Posted

Number

95% Confidence Interval

percentage of participants

Baseline to Measured Progressive Disease or Start of New Anti-Cancer Therapy (Up To 40 Months)

ID	Title	Description
OG000	Part A Cohort 2, Part B and Part C: 800 mg Neci + 200mg Pembro	Participants received 200 mg pembrolizumab absolute dose by intravenous (IV) infusion on Day 1 of 21 days cycles followed by 800 mg necitumumab absolute dose by IV infusion on Days 1 and 8 of 21 days cycles in Part A cohort 2 participants with any histology, Part B and C participants with Stage IV NSCLC of squamous and nonsquamous histology. Part C were Japan participants.

Secondary

Pharmacokinetics (PK): Minimum Concentration (Cmin) of Necitumumab in Part A, Part B and Part C

Pharmacokinetics (PK): Minimum Concentration (Cmin) of Necitumumab.

All participants who received at least one dose of study drug and had evaluable PK data in Part A, Part B and Part C.

Posted

Geometric Least Squares Mean

Geometric Coefficient of Variation

micrograms per milliliter (μg/mL)

Predose sample (within 1 hour before infusion) and postdose sample (within 10 min after infusion) on Day 1 at Cycles 1, 2, 4, 6, 8; 30 days post treatment discontinuation

ID	Title	Description
OG000	Part A Cohort 1: 600 mg Neci + 200 mg Pembro	Participants received 200 mg pembrolizumab (pembro) absolute dose by intravenous (IV) infusion on Day1 of 21 days cycles followed by 600 mg necitumumab (Neci) absolute dose by IV infusion on Days 1 and 8 of 21 days cycles in participants with Stage IV NSCLC (all histologies).
OG001	Part A Cohort 2: 800 mg Neci + 200 mg Pembro	Participants received 200 mg pembrolizumab absolute dose by intravenous (IV) infusion on Day 1 of 21 days cycles followed by 800 mg necitumumab absolute dose by IV infusion on Days 1 and 8 of 21 days cycles in participants with Stage IV NSCLC (all histologies).
OG002	Part B: 800mg Neci + 200mg Pembro

Secondary

Number of Participants With Anti-Necitumumab Antibodies in Part A, Part B and Part C

Result is considered as treatment emergent anti-necitumumab antibody positive if postbaseline titer = 4*baseline titer for baseline titer > 0 or if postbaseline titer >= 20 for samples with antibody not detected.

All participants who received at least one dose of study drug who had evaluable data in Part A, Part B and Part C.

Posted

Count of Participants

Participants

Predose Cycle 1 Day 1 through Predose Cycle 8 Day 1 (21 Day Cycles)

ID	Title	Description
OG000	Part A Cohort 1: 600mg Neci + 200mg Pembro	Participants received 200 mg pembrolizumab (pembro) absolute dose by intravenous (IV) infusion on Day1 of 21 days cycles followed by 600 mg necitumumab (Neci) absolute dose by IV infusion on Days 1 and 8 of 21 days cycles in participants with Stage IV NSCLC (all histologies).
OG001	Part A Cohort 2 and Part B: 800 mg Neci + 200 mg Pembro	Participants received 200 mg pembrolizumab absolute dose by intravenous (IV) infusion on Day 1 of 21 days cycles followed by 800 mg necitumumab absolute dose by IV infusion on Days 1 and 8 of 21 days cycles in Part B participants with Stage IV NSCLC of squamous and nonsquamous histology and Part A cohort 2 participants with all histologies.
OG002	Part C: 800 mg Neci + 200 mg Pembro

Secondary

Percentage of Participants With a Best Overall Response of Complete Response (CR), Partial Response (PR), and Stable Disease (SD) (Disease Control Rate [DCR]) in Part A Cohort 2 and Part B

Disease control rate (DCR) is the percentage of participants with a best overall response of CR, PR or SD as defined by RECIST v1.1. CR defined as the disappearance of all target and non-target lesions and no appearance of new lesions. PR defined as at least a 30% decrease in the sum of the longest diameters (LD) of target lesions (taking as reference the baseline sum LD), no progression of non-target lesions, and no appearance of new lesions. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters. PD is defined as at least a 20% increase in the sum of the diameters of target lesions, with reference being the smallest sum on study and an absolute increase of at least 5 mm, or unequivocal progression of non-target lesions, or 1 or more new lesions.

All participants who received at least one dose of study drug in Part A Cohort 2 and Part B. Per protocol, participants in Part A cohort 2 who received the recommended necitumumab dose for Part B were also analyzed together with Part B.

Posted

Number

percentage of participants

Baseline to Measured Progressive Disease or Start of New Anti-Cancer Therapy (Up To 16 Months)

ID	Title	Description
OG000	Part A Cohort 2, Part B: 800 mg Neci + 200 mg Pembro	Participants received 200 mg pembrolizumab absolute dose by intravenous (IV) infusion on Day 1 of 21 days cycles followed by 800 mg necitumumab absolute dose by IV infusion on Days 1 and 8 of 21 days cycles in Part B participants with Stage IV NSCLC of squamous and nonsquamous histology and Part A cohort 2 participants with all histologies.

Secondary

Duration of Response (DoR) in Part A Cohort 2 and Part B

DOR was defined only for responders (participants with confirmed CR or PR). It was measured from the date of first evidence of a confirmed CR or PR to the date of objective progression or the date of death due to any cause, whichever was earlier.

All participants who received at least one dose of study drug who had evaluable data in Part A Cohort 2 and Part B. 11 participants were censored. Per protocol, participants in Part A cohort 2 who received the recommended necitumumab dose for Part B were also analyzed together with Part B.

Posted

Median

95% Confidence Interval

months

Date of Complete Response (CR) or Partial Response (PR) to Date of Objective Disease Progression or Death Due to Any Cause (Up To 16 Months)

ID	Title	Description
OG000	Part A Cohort 2, Part B: 800 mg Neci + 200 mg Pembro	Participants received 200 mg pembrolizumab absolute dose by intravenous (IV) infusion on Day 1 of 21 days cycles followed by 800 mg necitumumab absolute dose by IV infusion on Days 1 and 8 of 21 days cycles in Part B participants with Stage IV NSCLC of squamous and nonsquamous histology and Part A cohort 2 participants with all histologies.

Units	Counts
Participants

Secondary

Progression Free Survival (PFS) in Part A Cohort 2 and Part B

PFS was defined as the time from the date of first dose of study drug until first observation of objective (radiographically documented) PD as defined by RECIST v1.1 or death from any cause, whichever comes first. PD is defined as at least a 20% increase in the sum of the diameters of target lesions, with reference being the smallest sum on study and an absolute increase of at least 5 mm, or unequivocal progression of non-target lesions, or 1 or more new lesions.

All participants who received at least one dose of study drug and who had evaluable data in Part A Cohort 2 and Part B. 21 participants were censored. Per protocol, participants in Part A cohort 2 who received the recommended necitumumab dose for Part B were also analyzed together with Part B.

Posted

Median

95% Confidence Interval

Months

Baseline to Measured Progressive Disease or Death Due to Any Cause (Up To 16 Months)

ID	Title	Description
OG000	Part A Cohort 2 and Part B: 800 mg Neci + 200 mg Pembro	Participants received 200 mg pembrolizumab absolute dose by intravenous (IV) infusion on Day 1 of 21 days cycles followed by 800 mg necitumumab absolute dose by IV infusion on Days 1 and 8 of 21 days cycles in Part B participants with Stage IV NSCLC of squamous and nonsquamous histology and Part A cohort 2 participants with all histologies.

Units	Counts

Secondary

Overall Survival (OS) in Part A Cohort 2, Part B

OS duration was measured from the date of first dose of study drug (necitumumab and/or pembrolizumab) to the date of death from any cause.

Posted

Median

95% Confidence Interval

months

Baseline to Death from Any Cause (Up To 16 Months)

ID	Title	Description
OG000	Part A Cohort 2, Part B: 800 mg Neci + 200 mg Pembro	Participants received 200 mg pembrolizumab absolute dose by intravenous (IV) infusion on Day 1 of 21 days cycles followed by 800 mg necitumumab absolute dose by IV infusion on Days 1 and 8 of 21 days cycles in Part B participants with Stage IV NSCLC of squamous and nonsquamous histology and Part A cohort 2 participants with all histologies.

Units	Counts
Participants	OG000

Serious Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Cardiac arrest	Cardiac disorders	MedDRA 22.0	Systematic Assessment	EG0000 events0 affected3 at risk EG0011 events1 affected68 at risk
Cardiac failure congestive	Cardiac disorders	MedDRA 22.0	Systematic Assessment	EG0000 events0 affected3 at risk EG0011 events1 affected68 at risk
Pericarditis	Cardiac disorders	MedDRA 22.0	Systematic Assessment	EG0000 events0 affected3 at risk EG0011 events1 affected68 at risk
Ventricular extrasystoles	Cardiac disorders	MedDRA 22.0	Systematic Assessment	EG0000 events0 affected3 at risk EG0011 events1 affected68 at risk
Hyperthyroidism	Endocrine disorders	MedDRA 22.0	Systematic Assessment	EG0000 events0 affected3 at risk EG0011 events1 affected68 at risk
Diarrhoea	Gastrointestinal disorders	MedDRA 22.0	Systematic Assessment	EG0000 events0 affected3 at risk EG0011 events1 affected68 at risk
Intestinal obstruction	Gastrointestinal disorders	MedDRA 22.0	Systematic Assessment	EG0000 events0 affected3 at risk EG0011 events1 affected68 at risk
Pancreatitis	Gastrointestinal disorders	MedDRA 22.0	Systematic Assessment	EG0000 events0 affected3 at risk EG0011 events1 affected68 at risk
Pancreatitis acute	Gastrointestinal disorders	MedDRA 22.0	Systematic Assessment	EG0001 events1 affected3 at risk EG0010 events0 affected68 at risk
Asthenia	General disorders	MedDRA 22.0	Systematic Assessment	EG0000 events0 affected3 at risk EG0012 events2 affected68 at risk
Pain	General disorders	MedDRA 22.0	Systematic Assessment	EG0000 events0 affected3 at risk EG0014 events2 affected68 at risk
Biliary tract disorder	Hepatobiliary disorders	MedDRA 22.0	Systematic Assessment	EG0000 events0 affected3 at risk EG0011 events1 affected68 at risk
Cholecystitis acute	Hepatobiliary disorders	MedDRA 22.0	Systematic Assessment	EG0000 events0 affected3 at risk EG0011 events1 affected68 at risk
Enterococcal sepsis	Infections and infestations	MedDRA 22.0	Systematic Assessment	EG0000 events0 affected3 at risk EG0011 events1 affected68 at risk
Folliculitis	Infections and infestations	MedDRA 22.0	Systematic Assessment	EG0000 events0 affected3 at risk EG0011 events1 affected68 at risk
Pneumonia bacterial	Infections and infestations	MedDRA 22.0	Systematic Assessment	EG0000 events0 affected3 at risk EG0011 events1 affected68 at risk
Respiratory tract infection	Infections and infestations	MedDRA 22.0	Systematic Assessment	EG0000 events0 affected3 at risk EG0013 events2 affected68 at risk
Urinary tract infection	Infections and infestations	MedDRA 22.0	Systematic Assessment	EG0000 events0 affected3 at risk EG0011 events1 affected68 at risk
Urosepsis	Infections and infestations	MedDRA 22.0	Systematic Assessment	EG0000 events0 affected3 at risk EG0011 events1 affected68 at risk
Lumbar spinal stenosis	Musculoskeletal and connective tissue disorders	MedDRA 22.0	Systematic Assessment	EG0000 events0 affected3 at risk EG0011 events1 affected68 at risk
Cancer pain	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA 22.0	Systematic Assessment	EG0000 events0 affected3 at risk EG0012 events1 affected68 at risk
Hepatocellular carcinoma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA 22.0	Systematic Assessment	EG0000 events0 affected3 at risk EG0011 events1 affected68 at risk
Malignant neoplasm progression	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA 22.0	Systematic Assessment	EG0000 events0 affected3 at risk EG0011 events1 affected68 at risk
Aphasia	Nervous system disorders	MedDRA 22.0	Systematic Assessment	EG0000 events0 affected3 at risk EG0011 events1 affected68 at risk
Encephalopathy	Nervous system disorders	MedDRA 22.0	Systematic Assessment	EG0000 events0 affected3 at risk EG0011 events1 affected68 at risk
Ischaemic stroke	Nervous system disorders	MedDRA 22.0	Systematic Assessment	EG0000 events0 affected3 at risk EG0011 events1 affected68 at risk
Peripheral sensory neuropathy	Nervous system disorders	MedDRA 22.0	Systematic Assessment	EG0000 events0 affected3 at risk EG0011 events1 affected68 at risk
Seizure	Nervous system disorders	MedDRA 22.0	Systematic Assessment	EG0000 events0 affected3 at risk EG0011 events1 affected68 at risk
Confusional state	Psychiatric disorders	MedDRA 22.0	Systematic Assessment	EG0000 events0 affected3 at risk EG0011 events1 affected68 at risk
Acute respiratory failure	Respiratory, thoracic and mediastinal disorders	MedDRA 22.0	Systematic Assessment	EG0000 events0 affected3 at risk EG0012 events2 affected68 at risk
Dyspnoea	Respiratory, thoracic and mediastinal disorders	MedDRA 22.0	Systematic Assessment	EG0000 events0 affected3 at risk EG0014 events4 affected68 at risk
Hypersensitivity pneumonitis	Respiratory, thoracic and mediastinal disorders	MedDRA 22.0	Systematic Assessment	EG0000 events0 affected3 at risk EG0011 events1 affected68 at risk
Pleural effusion	Respiratory, thoracic and mediastinal disorders	MedDRA 22.0	Systematic Assessment	EG0000 events0 affected3 at risk EG0011 events1 affected68 at risk
Pneumonitis	Respiratory, thoracic and mediastinal disorders	MedDRA 22.0	Systematic Assessment	EG0000 events0 affected3 at risk EG0011 events1 affected68 at risk
Pulmonary embolism	Respiratory, thoracic and mediastinal disorders	MedDRA 22.0	Systematic Assessment	EG0000 events0 affected3 at risk EG0013 events3 affected68 at risk
Fixed eruption	Skin and subcutaneous tissue disorders	MedDRA 22.0	Systematic Assessment	EG0000 events0 affected3 at risk EG0011 events1 affected68 at risk
Orthostatic hypotension	Vascular disorders	MedDRA 22.0	Systematic Assessment	EG0000 events0 affected3 at risk EG0011 events1 affected68 at risk
Venous thrombosis	Vascular disorders	MedDRA 22.0	Systematic Assessment	EG0000 events0 affected3 at risk EG0011 events1 affected68 at risk

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Anaemia	Blood and lymphatic system disorders	MedDRA 22.0	Systematic Assessment	EG0000 events0 affected3 at risk EG00111 events7 affected68 at risk
Hypothyroidism	Endocrine disorders	MedDRA 22.0	Systematic Assessment	EG0001 events1 affected3 at risk EG0017 events5 affected68 at risk
Dry eye	Eye disorders	MedDRA 22.0	Systematic Assessment	EG0001 events1 affected3 at risk EG0012 events2 affected68 at risk
Abdominal pain	Gastrointestinal disorders	MedDRA 22.0	Systematic Assessment	EG0000 events0 affected3 at risk EG0015 events5 affected68 at risk
Constipation	Gastrointestinal disorders	MedDRA 22.0	Systematic Assessment	EG0000 events0 affected3 at risk EG00116 events11 affected68 at risk
Diarrhoea	Gastrointestinal disorders	MedDRA 22.0	Systematic Assessment	EG0003 events1 affected3 at risk EG00123 events16 affected68 at risk
Nausea	Gastrointestinal disorders	MedDRA 22.0	Systematic Assessment	EG0001 events1 affected3 at risk EG00113 events7 affected68 at risk
Pancreatitis acute	Gastrointestinal disorders	MedDRA 22.0	Systematic Assessment	EG0001 events1 affected3 at risk EG0010 events0 affected68 at risk
Stomatitis	Gastrointestinal disorders	MedDRA 22.0	Systematic Assessment	EG0005 events2 affected3 at risk EG00126 events16 affected68 at risk
Vomiting	Gastrointestinal disorders	MedDRA 22.0	Systematic Assessment	EG0000 events0 affected3 at risk EG00117 events10 affected68 at risk
Asthenia	General disorders	MedDRA 22.0	Systematic Assessment	EG0001 events1 affected3 at risk EG00146 events22 affected68 at risk
Chills	General disorders	MedDRA 22.0	Systematic Assessment	EG0000 events0 affected3 at risk EG0015 events5 affected68 at risk
Fatigue	General disorders	MedDRA 22.0	Systematic Assessment	EG0003 events1 affected3 at risk EG00129 events21 affected68 at risk
Non-cardiac chest pain	General disorders	MedDRA 22.0	Systematic Assessment	EG0001 events1 affected3 at risk EG0013 events2 affected68 at risk
Oedema peripheral	General disorders	MedDRA 22.0	Systematic Assessment	EG0001 events1 affected3 at risk EG0016 events5 affected68 at risk
Pyrexia	General disorders	MedDRA 22.0	Systematic Assessment	EG0001 events1 affected3 at risk EG00121 events9 affected68 at risk
Xerosis	General disorders	MedDRA 22.0	Systematic Assessment	EG0000 events0 affected3 at risk EG00128 events8 affected68 at risk
Bronchitis	Infections and infestations	MedDRA 22.0	Systematic Assessment	EG0000 events0 affected3 at risk EG0015 events5 affected68 at risk
Conjunctivitis	Infections and infestations	MedDRA 22.0	Systematic Assessment	EG0000 events0 affected3 at risk EG00110 events8 affected68 at risk
Folliculitis	Infections and infestations	MedDRA 22.0	Systematic Assessment	EG0000 events0 affected3 at risk EG00110 events5 affected68 at risk
Paronychia	Infections and infestations	MedDRA 22.0	Systematic Assessment	EG0003 events2 affected3 at risk EG00118 events10 affected68 at risk
Pharyngitis	Infections and infestations	MedDRA 22.0	Systematic Assessment	EG0001 events1 affected3 at risk EG0011 events1 affected68 at risk
Respiratory tract infection	Infections and infestations	MedDRA 22.0	Systematic Assessment	EG0000 events0 affected3 at risk EG0015 events4 affected68 at risk
Skin infection	Infections and infestations	MedDRA 22.0	Systematic Assessment	EG0001 events1 affected3 at risk EG00111 events7 affected68 at risk
Alanine aminotransferase increased	Investigations	MedDRA 22.0	Systematic Assessment	EG0000 events0 affected3 at risk EG00117 events11 affected68 at risk
Amylase increased	Investigations	MedDRA 22.0	Systematic Assessment	EG0000 events0 affected3 at risk EG00119 events4 affected68 at risk
Aspartate aminotransferase increased	Investigations	MedDRA 22.0	Systematic Assessment	EG0000 events0 affected3 at risk EG00121 events10 affected68 at risk
Blood alkaline phosphatase increased	Investigations	MedDRA 22.0	Systematic Assessment	EG0004 events1 affected3 at risk EG0019 events7 affected68 at risk
Blood creatine phosphokinase increased	Investigations	MedDRA 22.0	Systematic Assessment	EG0004 events1 affected3 at risk EG0014 events2 affected68 at risk
Gamma-glutamyltransferase increased	Investigations	MedDRA 22.0	Systematic Assessment	EG0000 events0 affected3 at risk EG0017 events6 affected68 at risk
International normalised ratio increased	Investigations	MedDRA 22.0	Systematic Assessment	EG0003 events1 affected3 at risk EG0012 events2 affected68 at risk
Lipase increased	Investigations	MedDRA 22.0	Systematic Assessment	EG0000 events0 affected3 at risk EG00122 events4 affected68 at risk
Weight decreased	Investigations	MedDRA 22.0	Systematic Assessment	EG0000 events0 affected3 at risk EG0018 events5 affected68 at risk
Decreased appetite	Metabolism and nutrition disorders	MedDRA 22.0	Systematic Assessment	EG0000 events0 affected3 at risk EG00126 events20 affected68 at risk
Hypoalbuminaemia	Metabolism and nutrition disorders	MedDRA 22.0	Systematic Assessment	EG0001 events1 affected3 at risk EG00114 events5 affected68 at risk
Hypocalcaemia	Metabolism and nutrition disorders	MedDRA 22.0	Systematic Assessment	EG0001 events1 affected3 at risk EG0011 events1 affected68 at risk
Hypokalaemia	Metabolism and nutrition disorders	MedDRA 22.0	Systematic Assessment	EG0000 events0 affected3 at risk EG00113 events7 affected68 at risk
Hypomagnesaemia	Metabolism and nutrition disorders	MedDRA 22.0	Systematic Assessment	EG00012 events2 affected3 at risk EG00162 events24 affected68 at risk
Hypophosphataemia	Metabolism and nutrition disorders	MedDRA 22.0	Systematic Assessment	EG0003 events1 affected3 at risk EG00122 events9 affected68 at risk
Arthralgia	Musculoskeletal and connective tissue disorders	MedDRA 22.0	Systematic Assessment	EG0003 events2 affected3 at risk EG00114 events12 affected68 at risk
Back pain	Musculoskeletal and connective tissue disorders	MedDRA 22.0	Systematic Assessment	EG0000 events0 affected3 at risk EG0017 events7 affected68 at risk
Dizziness	Nervous system disorders	MedDRA 22.0	Systematic Assessment	EG0000 events0 affected3 at risk EG0018 events8 affected68 at risk
Dysgeusia	Nervous system disorders	MedDRA 22.0	Systematic Assessment	EG0001 events1 affected3 at risk EG0012 events2 affected68 at risk
Headache	Nervous system disorders	MedDRA 22.0	Systematic Assessment	EG0001 events1 affected3 at risk EG00116 events14 affected68 at risk
Paraesthesia	Nervous system disorders	MedDRA 22.0	Systematic Assessment	EG0000 events0 affected3 at risk EG0016 events4 affected68 at risk
Insomnia	Psychiatric disorders	MedDRA 22.0	Systematic Assessment	EG0000 events0 affected3 at risk EG00111 events7 affected68 at risk
Haematuria	Renal and urinary disorders	MedDRA 22.0	Systematic Assessment	EG0001 events1 affected3 at risk EG0015 events3 affected68 at risk
Proteinuria	Renal and urinary disorders	MedDRA 22.0	Systematic Assessment	EG0000 events0 affected3 at risk EG0014 events4 affected68 at risk
Menorrhagia	Reproductive system and breast disorders	MedDRA 22.0	Systematic Assessment	EG0000 events0 affected1 at risk EG0012 events1 affected19 at risk
Cough	Respiratory, thoracic and mediastinal disorders	MedDRA 22.0	Systematic Assessment	EG0001 events1 affected3 at risk EG00120 events11 affected68 at risk
Dysphonia	Respiratory, thoracic and mediastinal disorders	MedDRA 22.0	Systematic Assessment	EG0000 events0 affected3 at risk EG0015 events4 affected68 at risk
Dyspnoea	Respiratory, thoracic and mediastinal disorders	MedDRA 22.0	Systematic Assessment	EG0001 events1 affected3 at risk EG00117 events12 affected68 at risk
Epistaxis	Respiratory, thoracic and mediastinal disorders	MedDRA 22.0	Systematic Assessment	EG0000 events0 affected3 at risk EG0014 events4 affected68 at risk
Dermatitis acneiform	Skin and subcutaneous tissue disorders	MedDRA 22.0	Systematic Assessment	EG0007 events3 affected3 at risk EG00196 events46 affected68 at risk
Dry skin	Skin and subcutaneous tissue disorders	MedDRA 22.0	Systematic Assessment	EG0002 events2 affected3 at risk EG00136 events26 affected68 at risk
Hirsutism	Skin and subcutaneous tissue disorders	MedDRA 22.0	Systematic Assessment	EG0000 events0 affected1 at risk EG0014 events2 affected19 at risk
Pruritus	Skin and subcutaneous tissue disorders	MedDRA 22.0	Systematic Assessment	EG0001 events1 affected3 at risk EG00136 events15 affected68 at risk
Rash maculo-papular	Skin and subcutaneous tissue disorders	MedDRA 22.0	Systematic Assessment	EG0000 events0 affected3 at risk EG00115 events4 affected68 at risk
Skin fissures	Skin and subcutaneous tissue disorders	MedDRA 22.0	Systematic Assessment	EG0000 events0 affected3 at risk EG00133 events11 affected68 at risk
Skin ulcer	Skin and subcutaneous tissue disorders	MedDRA 22.0	Systematic Assessment	EG0003 events1 affected3 at risk EG0011 events1 affected68 at risk

ID	Term
D002283	Carcinoma, Bronchogenic
D001984	Bronchial Neoplasms
D008175	Lung Neoplasms
D012142	Respiratory Tract Neoplasms
D013899	Thoracic Neoplasms
D009371	Neoplasms by Site
D009369	Neoplasms
D008171	Lung Diseases
D012140	Respiratory Tract Diseases

ID	Title	Description
BG000	Part A Cohort 1: 600 mg Neci + 200 mg Pembro	Participants received 200 mg pembrolizumab (pembro) absolute dose by intravenous (IV) infusion on Day1 of 21 days cycles followed by 600 mg necitumumab (Neci) absolute dose by IV infusion on Days 1 and 8 of 21 days cycles in participants with Stage IV NSCLC (all histologies).
BG001	Part A Cohort 2 and Part B: 800 mg Neci + 200 mg Pembro	Participants received 200 mg pembrolizumab absolute dose by intravenous (IV) infusion on Day 1 of 21 days cycles followed by 800 mg necitumumab absolute dose by IV infusion on Days 1 and 8 of 21 days cycles in participants with Stage IV NSCLC of squamous and nonsquamous histology.
BG002	Part C: 800 mg Neci + 200 mg Pembro	Participants received 200 mg pembrolizumab absolute dose by intravenous (IV) infusion on Day 1 of 21 days cycles followed by 800 mg necitumumab absolute dose by IV infusion on Days 1 and 8 of 21 days cycles in participants with Stage IV NSCLC of squamous and nonsquamous histology. Part C were Japan participants.
BG003	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	Part A Cohort 1: 600 mg Neci + 200 mg Pembro	Participants received 200 mg pembrolizumab (pembro) absolute dose by intravenous (IV) infusion on Day 1 of 21 days cycles followed by 600 mg necitumumab (Neci) absolute dose by IV infusion on Days 1 and 8 of 21 days cycles in participants with Stage IV NSCLC (all histologies).	0	3	1	3	3	3
EG001	Part A Cohort 2, Part B and Part C: 800mg Neci + 200mg Pembro	Participants received 200 mg pembrolizumab absolute dose by intravenous (IV) infusion on Day 1 of 21 days cycles followed by 800 mg necitumumab absolute dose by IV infusion on Days 1 and 8 of 21 days cycles in Part B and C participants with Stage IV NSCLC of squamous and nonsquamous histology and Part A cohort 2 participants with any histology. Part C were Japan participants.	23	68	30	68	66	68