A Study of the Combination of Necitumumab (LY3012211) and Pembrolizumab (MK3475) in Participants With NSCLC

• Sponsor: Eli Lilly and Company (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02451930
• Collaborator: Merck Sharp & Dohme LLC (Industry)
• Enrollment: 71
• Locations: 16
• Arm: 1
• Actual Duration (Months): 48.4
• Patients Per Site: 4.4
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The main purpose of this study is to evaluate the safety and efficacy of the combination of necitumumab with pembrolizumab in participants with stage IV non-small cell lung cancer (NSCLC).

Condition or Disease	Intervention/Treatment	Phase
Stage IV Non-Small Cell Lung Cancer	Drug: Necitumumab; Drug: Pembrolizumab	Phase 1

Study Design

• Study Type: Interventional
• Actual Enrollment: 71 participants
• Allocation: N/A
• Intervention Model: Sequential Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open-Label, Multicenter, Phase 1b Study With an Expansion Cohort to Evaluate Safety and Efficacy of the Combination of Necitumumab With Pembrolizumab in Patients With Stage IV Non-Small Cell Lung Cancer
• Actual Study Start Date: Sep 4, 2015
• Actual Primary Completion Date: Jan 26, 2017
• Actual Study Completion Date: Sep 17, 2019

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Necitumumab + Pembrolizumab 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; Administered IV; Other Names: LY3012211 ; Drug: Pembrolizumab; Administered IV; Other Names: MK3475

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Dose Limiting Toxicities (DLTs) in Part A and Part C [Baseline through Cycle 1 (21 day cycles)]

   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.

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

   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.

Secondary Outcome Measures

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

   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.

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

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

3. Number of Participants With Anti-Necitumumab Antibodies in Part A, Part B and Part C [Predose Cycle 1 Day 1 through Predose Cycle 8 Day 1 (21 Day Cycles)]

   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.

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

   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.

5. Duration of Response (DoR) in Part A Cohort 2 and Part B [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)]

   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.

6. Progression Free Survival (PFS) in Part A Cohort 2 and Part B [Baseline to Measured Progressive Disease or Death Due to Any Cause (Up To 16 Months)]

   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.

7. Overall Survival (OS) in Part A Cohort 2, Part B [Baseline to Death from Any Cause (Up To 16 Months)]

   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.

Eligibility Criteria

Criteria

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

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Florida Cancer Specialists	Fort Myers	Florida	United States	33916
2	Florida Cancer Specialists	Saint Petersburg	Florida	United States	33705
3	Tennessee Oncology PLLC	Nashville	Tennessee	United States	37203
4	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Lille		France	59037
5	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Lyon Cedex 08		France	69373
6	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Paris		France	75015
7	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Saint Herblain Cedex		France	44805
8	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Strasbourg Cedex		France	67091
9	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Villejuif Cedex		France	94805
10	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician	Chuo-Ku		Japan	104-0045
11	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician	Sunto-Gun		Japan	411-8777
12	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Badajoz		Spain	06080
13	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Barcelona		Spain	08907
14	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Madrid		Spain	28034
15	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Madrid		Spain	28040
16	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Valencia		Spain	46026

Sponsors and Collaborators

• Eli Lilly and Company
• Merck Sharp & Dohme LLC

Investigators

• Study Director: 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 Documents (Full-Text)

• Study Protocol - Sep 17, 2018
• Statistical Analysis Plan - Dec 14, 2016

More Information

Additional Information:

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

Publications

None provided.

• Responsible Party: Eli Lilly and Company
• ClinicalTrials.gov Identifier: NCT02451930
• Other Study ID Numbers: 15568; I4X-MC-JFCQ; 2015-001291-22; KEYNOTE -099
• First Posted: May 22, 2015
• Last Update Posted: Oct 5, 2020
• Last Verified: Oct 1, 2019

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Additional relevant MeSH terms: Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Pembrolizumab; Necitumumab

Study Results

Participant Flow

Pre-assignment Detail	Per protocol, participants in Part A Cohort 2 who received the recommended necitumumab dose for Part B were also analyzed together with Part B.

Arm/Group Title	Part A Cohort 1: 600 mg Neci + 200 mg Pembro	Part A Cohort 2, Part B and Part C: 800mg Neci + 200mg Pembro
Arm/Group Description	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).	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.
Period Title: Overall Study
STARTED	3	68
Received at Least One Dose of Study Drug	3	68
Part A Cohort 2 Participants	0	6
Part B Participants	0	55
Part C Participants	0	7
COMPLETED	1	38
NOT COMPLETED	2	30

Baseline Characteristics

Arm/Group Title	Part A Cohort 1: 600 mg Neci + 200 mg Pembro	Part A Cohort 2 and Part B: 800 mg Neci + 200 mg Pembro	Part C: 800 mg Neci + 200 mg Pembro	Total
Arm/Group Description	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).	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.	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.	Total of all reporting groups
Overall Participants	3	61	7	71
Age (years) [Mean (Standard Deviation) ]
Part A and B	67.0 (7.21)	63.13 (9.82)	NA (NA)	63.31 (9.73)
Part C	NA (NA)	NA (NA)	64.14 (8.55)	64.14 (8.55)
Sex: Female, Male (Count of Participants)
Female	1 33.3%	17 27.9%	2 28.6%	20 28.2%
Male	2 66.7%	44 72.1%	5 71.4%	51 71.8%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	1 1.6%	0 0%	1 1.4%
Not Hispanic or Latino	1 33.3%	21 34.4%	0 0%	22 31%
Unknown or Not Reported	2 66.7%	39 63.9%	7 100%	48 67.6%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	7 100%	7 9.9%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%
Black or African American	0 0%	1 1.6%	0 0%	1 1.4%
White	3 100%	47 77%	0 0%	50 70.4%
More than one race	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	13 21.3%	0 0%	13 18.3%
Region of Enrollment (Count of Participants)
United States	0 0%	7 11.5%	0 0%	7 9.9%
Japan	0 0%	0 0%	7 100%	7 9.9%
France	2 66.7%	40 65.6%	0 0%	42 59.2%
Spain	1 33.3%	14 23%	0 0%	15 21.1%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Dose Limiting Toxicities (DLTs) in Part A and Part C
Description	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.
Time Frame	Baseline through Cycle 1 (21 day cycles)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Part A Cohort 1: 600 mg Neci + 200 mg Pembro	Part A Cohort 2: 800 mg Neci + 200 mg Pembro	Part C: 800 mg Neci + 200 mg Pembro
Arm/Group Description	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).	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).	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.
Measure Participants	3	6	7
Count of Participants [Participants]	0 0%	0 0%	0 0%

2. Primary Outcome

Title	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
Description	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.
Time Frame	Baseline to Measured Progressive Disease or Start of New Anti-Cancer Therapy (Up To 16 Months)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Part A Cohort 1: 600 mg Neci + 200 mg Pembro	Part A Cohort 2, Part B: 800 mg Neci + 200 mg Pembro
Arm/Group Description	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).	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.
Measure Participants	3	61
Number (95% Confidence Interval) [Percentage of Participants]	66.7 2223.3%	21.3 34.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Part A Cohort 1: 600 mg Neci + 200 mg Pembro, Part A Cohort 2: 800 mg Neci + 200 mg Pembro
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.4491
	Comments
	Method	Fisher Exact
	Comments

3. Secondary Outcome

Title	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
Description	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.
Time Frame	Baseline to Measured Progressive Disease or Start of New Anti-Cancer Therapy (Up To 40 Months)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Part A Cohort 2, Part B and Part C: 800 mg Neci + 200mg Pembro
Arm/Group Description	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.
Measure Participants	68
Number (95% Confidence Interval) [percentage of participants]	25.0 833.3%

4. Secondary Outcome

Title	Pharmacokinetics (PK): Minimum Concentration (Cmin) of Necitumumab in Part A, Part B and Part C
Description	Pharmacokinetics (PK): Minimum Concentration (Cmin) of Necitumumab.
Time Frame	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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Part A Cohort 1: 600 mg Neci + 200 mg Pembro	Part A Cohort 2: 800 mg Neci + 200 mg Pembro	Part B: 800mg Neci + 200mg Pembro	Part C: 800mg Neci + 200mg Pembro
Arm/Group Description	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).	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).	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.	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 Japanese participants.
Measure Participants	3	6	44	7
Pre-Dose Cycle 2	50.4 (54.7)	70 (49.7)	58.2 (56)	90.4 (18.4)
Pre-Dose Cycle 4	79.2 (32.5)	148 (32.1)	101 (48)	136 (9.51)
Pre-Dose Cycle 6	89.5 (24.7)	195 (12.2)	114 (58.3)	114 (66.5)
Pre-Dose Cycle 8	98.5 (3.73)	155 (33)	91 (62.7)	209 (18.7)
End-of-Infusion Cycle 1	152 (32.1)	269 (15.6)	226 (24.6)	281 (26)
End-of-Infusion Cycle 2	194 (29)	352 (25.3)	273 (36.8)	391 (25.4)
End-of-Infusion Cycle 4	246 (28.7)	353 (45.3)	315 (45.4)	428 (5.18)
End-of-Infusion Cycle 6	234 (26.3)	396 (8.53)	312 (42.1)	406 (12.9)
End-of-Infusion Cycle 8	291 (20.8)	526 (8.49)	295 (46.4)	507 (7.95)

5. Secondary Outcome

Title	Number of Participants With Anti-Necitumumab Antibodies in Part A, Part B and Part C
Description	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.
Time Frame	Predose Cycle 1 Day 1 through Predose Cycle 8 Day 1 (21 Day Cycles)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Part A Cohort 1: 600mg Neci + 200mg Pembro	Part A Cohort 2 and Part B: 800 mg Neci + 200 mg Pembro	Part C: 800 mg Neci + 200 mg Pembro
Arm/Group Description	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).	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.	Participants received 200 mg pembrolizumab absolute dose by intravenous (IV) infusion on Day 1 every 21 days followed by 800 mg necitumumab absolute dose by IV infusion on Days 1 and 8 of 21-day cycles in participants with Stage IV NSCLC of squamous and nonsquamous histology. Part C were Japan participants.
Measure Participants	3	61	7
Count of Participants [Participants]	0 0%	2 3.3%	0 0%

6. Secondary Outcome

Title	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
Description	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.
Time Frame	Baseline to Measured Progressive Disease or Start of New Anti-Cancer Therapy (Up To 16 Months)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Part A Cohort 2, Part B: 800 mg Neci + 200 mg Pembro
Arm/Group Description	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.
Measure Participants	61
Number [percentage of participants]	62.3 2076.7%

7. Secondary Outcome

Title	Duration of Response (DoR) in Part A Cohort 2 and Part B
Description	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.
Time Frame	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)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Part A Cohort 2, Part B: 800 mg Neci + 200 mg Pembro
Arm/Group Description	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.
Measure Participants	4
Median (95% Confidence Interval) [months]	10.94

8. Secondary Outcome

Title	Progression Free Survival (PFS) in Part A Cohort 2 and Part B
Description	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.
Time Frame	Baseline to Measured Progressive Disease or Death Due to Any Cause (Up To 16 Months)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Part A Cohort 2 and Part B: 800 mg Neci + 200 mg Pembro
Arm/Group Description	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.
Measure Participants	40
Median (95% Confidence Interval) [Months]	3.98

9. Secondary Outcome

Title	Overall Survival (OS) in Part A Cohort 2, Part B
Description	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.
Time Frame	Baseline to Death from Any Cause (Up To 16 Months)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Part A Cohort 2, Part B: 800 mg Neci + 200 mg Pembro
Arm/Group Description	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.
Measure Participants	61
Median (95% Confidence Interval) [months]	NA

Adverse Events

Time Frame	Baseline Up to 49 Months
Adverse Event Reporting Description	All participants who received at least one dose of study drug. Gender specific events only occurring in male or female participants have had the number of participants At risk adjusted accordingly. Per protocol, participants in Part A Cohort 2 who received the recommended necitumumab dose for Part B were also analyzed together with Part B.
Arm/Group Title	Part A Cohort 1: 600 mg Neci + 200 mg Pembro		Part A Cohort 2, Part B and Part C: 800mg Neci + 200mg Pembro
Arm/Group Description	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).		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.
All Cause Mortality
	Part A Cohort 1: 600 mg Neci + 200 mg Pembro		Part A Cohort 2, Part B and Part C: 800mg Neci + 200mg Pembro
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/3 (0%)		23/68 (33.8%)
Serious Adverse Events
	Part A Cohort 1: 600 mg Neci + 200 mg Pembro		Part A Cohort 2, Part B and Part C: 800mg Neci + 200mg Pembro
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/3 (33.3%)		30/68 (44.1%)
Cardiac disorders
Cardiac arrest	0/3 (0%)	0	1/68 (1.5%)	1
Cardiac failure congestive	0/3 (0%)	0	1/68 (1.5%)	1
Pericarditis	0/3 (0%)	0	1/68 (1.5%)	1
Ventricular extrasystoles	0/3 (0%)	0	1/68 (1.5%)	1
Endocrine disorders
Hyperthyroidism	0/3 (0%)	0	1/68 (1.5%)	1
Gastrointestinal disorders
Diarrhoea	0/3 (0%)	0	1/68 (1.5%)	1
Intestinal obstruction	0/3 (0%)	0	1/68 (1.5%)	1
Pancreatitis	0/3 (0%)	0	1/68 (1.5%)	1
Pancreatitis acute	1/3 (33.3%)	1	0/68 (0%)	0
General disorders
Asthenia	0/3 (0%)	0	2/68 (2.9%)	2
Pain	0/3 (0%)	0	2/68 (2.9%)	4
Hepatobiliary disorders
Biliary tract disorder	0/3 (0%)	0	1/68 (1.5%)	1
Cholecystitis acute	0/3 (0%)	0	1/68 (1.5%)	1
Infections and infestations
Enterococcal sepsis	0/3 (0%)	0	1/68 (1.5%)	1
Folliculitis	0/3 (0%)	0	1/68 (1.5%)	1
Pneumonia bacterial	0/3 (0%)	0	1/68 (1.5%)	1
Respiratory tract infection	0/3 (0%)	0	2/68 (2.9%)	3
Urinary tract infection	0/3 (0%)	0	1/68 (1.5%)	1
Urosepsis	0/3 (0%)	0	1/68 (1.5%)	1
Musculoskeletal and connective tissue disorders
Lumbar spinal stenosis	0/3 (0%)	0	1/68 (1.5%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cancer pain	0/3 (0%)	0	1/68 (1.5%)	2
Hepatocellular carcinoma	0/3 (0%)	0	1/68 (1.5%)	1
Malignant neoplasm progression	0/3 (0%)	0	1/68 (1.5%)	1
Nervous system disorders
Aphasia	0/3 (0%)	0	1/68 (1.5%)	1
Encephalopathy	0/3 (0%)	0	1/68 (1.5%)	1
Ischaemic stroke	0/3 (0%)	0	1/68 (1.5%)	1
Peripheral sensory neuropathy	0/3 (0%)	0	1/68 (1.5%)	1
Seizure	0/3 (0%)	0	1/68 (1.5%)	1
Psychiatric disorders
Confusional state	0/3 (0%)	0	1/68 (1.5%)	1
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure	0/3 (0%)	0	2/68 (2.9%)	2
Dyspnoea	0/3 (0%)	0	4/68 (5.9%)	4
Hypersensitivity pneumonitis	0/3 (0%)	0	1/68 (1.5%)	1
Pleural effusion	0/3 (0%)	0	1/68 (1.5%)	1
Pneumonitis	0/3 (0%)	0	1/68 (1.5%)	1
Pulmonary embolism	0/3 (0%)	0	3/68 (4.4%)	3
Skin and subcutaneous tissue disorders
Fixed eruption	0/3 (0%)	0	1/68 (1.5%)	1
Vascular disorders
Orthostatic hypotension	0/3 (0%)	0	1/68 (1.5%)	1
Venous thrombosis	0/3 (0%)	0	1/68 (1.5%)	1
Other (Not Including Serious) Adverse Events
	Part A Cohort 1: 600 mg Neci + 200 mg Pembro		Part A Cohort 2, Part B and Part C: 800mg Neci + 200mg Pembro
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/3 (100%)		66/68 (97.1%)
Blood and lymphatic system disorders
Anaemia	0/3 (0%)	0	7/68 (10.3%)	11
Endocrine disorders
Hypothyroidism	1/3 (33.3%)	1	5/68 (7.4%)	7
Eye disorders
Dry eye	1/3 (33.3%)	1	2/68 (2.9%)	2
Gastrointestinal disorders
Abdominal pain	0/3 (0%)	0	5/68 (7.4%)	5
Constipation	0/3 (0%)	0	11/68 (16.2%)	16
Diarrhoea	1/3 (33.3%)	3	16/68 (23.5%)	23
Nausea	1/3 (33.3%)	1	7/68 (10.3%)	13
Pancreatitis acute	1/3 (33.3%)	1	0/68 (0%)	0
Stomatitis	2/3 (66.7%)	5	16/68 (23.5%)	26
Vomiting	0/3 (0%)	0	10/68 (14.7%)	17
General disorders
Asthenia	1/3 (33.3%)	1	22/68 (32.4%)	46
Chills	0/3 (0%)	0	5/68 (7.4%)	5
Fatigue	1/3 (33.3%)	3	21/68 (30.9%)	29
Non-cardiac chest pain	1/3 (33.3%)	1	2/68 (2.9%)	3
Oedema peripheral	1/3 (33.3%)	1	5/68 (7.4%)	6
Pyrexia	1/3 (33.3%)	1	9/68 (13.2%)	21
Xerosis	0/3 (0%)	0	8/68 (11.8%)	28
Infections and infestations
Bronchitis	0/3 (0%)	0	5/68 (7.4%)	5
Conjunctivitis	0/3 (0%)	0	8/68 (11.8%)	10
Folliculitis	0/3 (0%)	0	5/68 (7.4%)	10
Paronychia	2/3 (66.7%)	3	10/68 (14.7%)	18
Pharyngitis	1/3 (33.3%)	1	1/68 (1.5%)	1
Respiratory tract infection	0/3 (0%)	0	4/68 (5.9%)	5
Skin infection	1/3 (33.3%)	1	7/68 (10.3%)	11
Investigations
Alanine aminotransferase increased	0/3 (0%)	0	11/68 (16.2%)	17
Amylase increased	0/3 (0%)	0	4/68 (5.9%)	19
Aspartate aminotransferase increased	0/3 (0%)	0	10/68 (14.7%)	21
Blood alkaline phosphatase increased	1/3 (33.3%)	4	7/68 (10.3%)	9
Blood creatine phosphokinase increased	1/3 (33.3%)	4	2/68 (2.9%)	4
Gamma-glutamyltransferase increased	0/3 (0%)	0	6/68 (8.8%)	7
International normalised ratio increased	1/3 (33.3%)	3	2/68 (2.9%)	2
Lipase increased	0/3 (0%)	0	4/68 (5.9%)	22
Weight decreased	0/3 (0%)	0	5/68 (7.4%)	8
Metabolism and nutrition disorders
Decreased appetite	0/3 (0%)	0	20/68 (29.4%)	26
Hypoalbuminaemia	1/3 (33.3%)	1	5/68 (7.4%)	14
Hypocalcaemia	1/3 (33.3%)	1	1/68 (1.5%)	1
Hypokalaemia	0/3 (0%)	0	7/68 (10.3%)	13
Hypomagnesaemia	2/3 (66.7%)	12	24/68 (35.3%)	62
Hypophosphataemia	1/3 (33.3%)	3	9/68 (13.2%)	22
Musculoskeletal and connective tissue disorders
Arthralgia	2/3 (66.7%)	3	12/68 (17.6%)	14
Back pain	0/3 (0%)	0	7/68 (10.3%)	7
Nervous system disorders
Dizziness	0/3 (0%)	0	8/68 (11.8%)	8
Dysgeusia	1/3 (33.3%)	1	2/68 (2.9%)	2
Headache	1/3 (33.3%)	1	14/68 (20.6%)	16
Paraesthesia	0/3 (0%)	0	4/68 (5.9%)	6
Psychiatric disorders
Insomnia	0/3 (0%)	0	7/68 (10.3%)	11
Renal and urinary disorders
Haematuria	1/3 (33.3%)	1	3/68 (4.4%)	5
Proteinuria	0/3 (0%)	0	4/68 (5.9%)	4
Reproductive system and breast disorders
Menorrhagia	0/1 (0%)	0	1/19 (5.3%)	2
Respiratory, thoracic and mediastinal disorders
Cough	1/3 (33.3%)	1	11/68 (16.2%)	20
Dysphonia	0/3 (0%)	0	4/68 (5.9%)	5
Dyspnoea	1/3 (33.3%)	1	12/68 (17.6%)	17
Epistaxis	0/3 (0%)	0	4/68 (5.9%)	4
Skin and subcutaneous tissue disorders
Dermatitis acneiform	3/3 (100%)	7	46/68 (67.6%)	96
Dry skin	2/3 (66.7%)	2	26/68 (38.2%)	36
Hirsutism	0/1 (0%)	0	2/19 (10.5%)	4
Pruritus	1/3 (33.3%)	1	15/68 (22.1%)	36
Rash maculo-papular	0/3 (0%)	0	4/68 (5.9%)	15
Skin fissures	0/3 (0%)	0	11/68 (16.2%)	33
Skin ulcer	1/3 (33.3%)	3	1/68 (1.5%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.