Biomarkers of Response to Pembrolizumab Combined With Chemotherapy in Non-Small Cell Lung Cancer (KEYNOTE-782, MK-3475-782)

NCT03664024 | Completed Phase 2 Results FDA Drug

• 3 other identifiers: 3475-782MK-3475-7822018-002598-22
• Study Type: interventional
• Target: 118
• Locations: 5 countries
• Sites: 15

Brief Summary

Participants with Stage IV nonsquamous non-small cell lung cancer (NSCLC) without prior systemic treatment will be treated with standard of care pembrolizumab combined with platinum-doublet chemotherapy for 4 cycles, then pembrolizumab plus pemetrexed maintenance for up to 31 additional cycles. The platinum doublet would be pemetrexed plus the investigator's choice of either cisplatin or carboplatin. The primary objective is to evaluate if total baseline tumor mutation burden (TMB) in cell-free circulating tumor deoxyribonucleic acid (ctDNA) is predictive of objective response per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) by the investigator by estimating the level of association.

Conditions

Non-Small Cell Lung Cancer

Keywords

Programmed Cell Death-1 (PD1, PD-1); Programmed Cell Death 1 Ligand 1 (PDL1, PD-L1); Programmed Cell Death 1 Ligand 2 (PDL2, PD-L2); Carcinoma, Non-Small-Cell Lung; Adenocarcinoma

Outcome Measures

Primary Outcomes (2)

• Objective Response Rate

  Objective response rate is the proportion of participants who have a confirmed complete response (CR) or partial response (PR). Objective response rate is assessed by investigator review according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Participants with missing data are considered non-responders. The percentage of participants with an ORR is presented.

  Up to ~25 months

• Tumor Mutation Burden (TMB) in Cell-free Circulating Tumor Deoxyribonucleic Acid (ctDNA)

  Cell-free ctDNA allows the exploration of tumor features from blood samples. TMB is a measure of mutational load in tumor cells and expressed as the number of somatic mutations per megabase (mut/MB) of DNA. The mean TMB in cell-free ctDNA of participants is presented.

  Baseline (Day 1)

Secondary Outcomes (4)

• Progression Free Survival (PFS)

  Up to ~36 months

• Overall Survival (OS)

  Up to ~36 months

• Percentage of Participants Who Experienced One or More Adverse Events (AEs)

  Up to ~31 months

• Percentage of Participants Discontinuing Study Intervention Due to an AE.

  Up to ~28 months

Study Arms (1)

Pembrolizumab Standard of Care

EXPERIMENTAL

Participants will receive standard of care pembrolizumab combined with platinum-doublet chemotherapy for 4 cycles, then pembrolizumab plus pemetrexed maintenance for up to 31 additional cycles. The platinum doublet would be pemetrexed plus the investigator's choice of either cisplatin or carboplatin.

Drug: Pembrolizumab; Drug: Pemetrexed; Drug: Carboplatin; Drug: Cisplatin

Interventions

Pembrolizumab DRUG

Pembrolizumab, 200 mg, Day 1 of each 21-day cycle (Q3W), intravenous infusion (IV), standard of care in most countries

Pembrolizumab Standard of Care

Pemetrexed DRUG

Pemetrexed, 500 mg/m\^2 infusion, standard of care, Q3W, IV

Pembrolizumab Standard of Care

Carboplatin DRUG

Carboplatin AUC 5 mg/mL/min, IV infusion, Day 1 of each 21-day cycle for 4 cycles (Cycles 1 - 4). Investigator's choice of either cisplatin or carboplatin.

Pembrolizumab Standard of Care

Cisplatin DRUG

Cisplatin, 75 mg/m\^2, IV infusion, Day 1 of each 21-day cycle for 4 cycles (Cycles 1 - 4). Investigator's choice of either cisplatin or carboplatin.

Pembrolizumab Standard of Care

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Has a histologically-confirmed or cytologically-confirmed diagnosis of stage IV (M1a, M1b, or M1c \[AJCC 8th edition\]) nonsquamous NSCLC.
• Have confirmation that epidermal growth factor receptor- (EGFR-), anaplastic lymphoma kinase- (ALK-), c-ros oncogene 1 (ROS1), or B isoform of rapidly accelerated fibrosarcoma (BRAF) directed therapy is not indicated as primary therapy. Documentation of the absence of tumor activating EGFR mutations, BRAF mutations, ALK gene rearrangements, and ROS1 gene rearrangements is required.
• Has measurable disease based on RECIST 1.1 as determined by the local site investigator/radiology assessment. Target lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.
• Has not received prior systemic treatment for their advanced/metastatic NSCLC. Participants who received adjuvant or neoadjuvant therapy are eligible if the adjuvant/neoadjuvant therapy was completed at least 12 months prior to the development of metastatic disease.
• Have provided sufficient evaluable Stage IV, archival, solid tumor tissue sample or newly obtained core or excisional biopsy of a tumor lesion (that was not previously irradiated) for biomarker analysis (Fine Needle Aspiration \[FNA\] samples will not be accepted). Formalin-fixed, paraffin embedded (FFPE) tissue blocks are preferred to slides. Newly obtained biopsies are preferred to archived tissue.
• Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 within 10 days prior to the first dose of study treatment.
• A male participant must agree to use contraception through the end of treatment and for at least 120 days, and refrain from donating sperm during this period.
• A female participant is eligible to participate if she is not pregnant, not breastfeeding, and if participant is a woman of childbearing potential (WOCBP), agrees to follow the contraceptive guidance as provided in the protocol through the end of treatment.
• Has adequate organ function.
• Has provided blood for cell-free ctDNA analysis that has been received and determined to be of sufficient quality and quantity by the designated laboratory for the primary endpoint.

You may not qualify if:

• Has predominantly squamous cell histology NSCLC. Mixed tumors will be categorized by the predominant cell type.
• Has small cell elements present in NSCLC tumor.
• A WOCBP who has a positive urine pregnancy test within 72 hours prior to treatment allocation.
• Has clinically active diverticulitis, intra-abdominal abscess, gastrointestinal (GI) obstruction, peritoneal carcinomatosis.
• Has a known history of prior malignancy except if the participant has undergone potentially curative therapy with no evidence of that disease recurrence for 2 years since initiation of that therapy.
• Has symptomatic ascites or pleural effusion. A participant who is clinically stable following treatment for these conditions (including therapeutic thoraco- or paracentesis) is eligible.
• If participant received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting study intervention.
• Has received prior radiotherapy within 2 weeks of start of study intervention. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (≤2 weeks of radiotherapy) to non-central nervous system disease.
• Has received prior therapy with a multiple programmed cell death 1 (PD-1)/ (PD-1) receptor/programmed cell death ligand 1 (PD-L1) receptor inhibitor.
• Is expected to require any other form of antineoplastic therapy while on study (including maintenance therapy with another agent for NSCLC, radiation therapy, and/or surgical resection).
• Has received a live vaccine within 30 days prior to treatment.
• Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients or to another monoclonal antibody.
• Has a known sensitivity to any component of cisplatin, carboplatin or pemetrexed.
• Has active autoimmune disease that has required systemic treatment in past 2 years (i.e., with use of disease-modifying agents, corticosteroids, or immunosuppressive drugs).
• Is on chronic systemic steroids. Participants with asthma that require intermittent use of bronchodilators, inhaled steroids, or local steroid injections would not be excluded from the study.

Sponsors & Collaborators

• Merck Sharp & Dohme LLC: lead

Study Sites (15)

University Of Colorado ( Site 0908)

Aurora, Colorado, 80045, United States

Location

Harry & Jeanette Weinberg Cancer Institute ( Site 0901)

Baltimore, Maryland, 21237, United States

Location

Henry Ford Health System ( Site 0903)

Detroit, Michigan, 48202, United States

Location

Kingston General Hospital ( Site 0800)

Kingston, Ontario, K7L 2V7, Canada

Location

CISSS de la Monteregie-Centre ( Site 0801)

Greenfield Park, Quebec, J4V 2H1, Canada

Location

Orszagos Koranyi TBC es Pulmonologiai Intezet ( Site 0400)

Budapest, 1121, Hungary

Location

Petz Aladar Megyei Oktato Korhaz ( Site 0402)

Győr, 9024, Hungary

Location

Jasz Nagykun Szolnok Megyei Hetenyi Geza Korhaz Rendelointezet ( Site 0401)

Szolnok, 5000, Hungary

Location

Meir Medical Center ( Site 0501)

Kfar Saba, 4428164, Israel

Location

Chaim Sheba Medical Center ( Site 0500)

Ramat Gan, 5262000, Israel

Location

Hospital Universitario Insular de Gran Canaria ( Site 0700)

Las Palmas de Gran Canaria, Gran Canaria, 35001, Spain

Location

Hospital Puerta de Hierro ( Site 0702)

Majadahonda, Madrid, 28222, Spain

Location

H.U. Vall de Hebron ( Site 0701)

Barcelona, 08035, Spain

Location

Hospital General Universitario 12 de Octubre ( Site 0703)

Madrid, 28041, Spain

Location

Hospital Universitario Central de Asturias ( Site 0704)

Oviedo, 33011, Spain

Location

Related Publications (1)

• Bar J, Esteban E, Rodriguez-Abreu D, Aix SP, Szalai Z, Felip E, Gottfried M, Provencio M, Robinson A, Fulop A, Rao SB, Camidge DR, Speranza G, Townson SM, Kobie J, Ayers M, Dettman EJ, Hunkapiller N, McDaniel R, Jung B, Burkhardt D, Mauntz R, Csoszi T. Blood tumor mutational burden and response to pembrolizumab plus chemotherapy in non-small cell lung cancer: KEYNOTE-782. Lung Cancer. 2024 Apr;190:107506. doi: 10.1016/j.lungcan.2024.107506. Epub 2024 Feb 17.

  PMID: 38422883 RESULT

MeSH Terms

Conditions

Carcinoma, Non-Small-Cell Lung; Parkinson Disease 4, Autosomal Dominant Lewy Body; Adenocarcinoma

Interventions

pembrolizumab; Pemetrexed; Carboplatin; Cisplatin

Condition Hierarchy (Ancestors)

Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type

Intervention Hierarchy (Ancestors)

Guanine; Hypoxanthines; Purinones; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Glutamates; Amino Acids, Acidic; Amino Acids; Amino Acids, Peptides, and Proteins; Amino Acids, Dicarboxylic; Coordination Complexes; Organic Chemicals; Chlorine Compounds; Inorganic Chemicals; Nitrogen Compounds; Platinum Compounds

Results Point of Contact

• Title: Senior Vice President, Global Clinical Development
• Organization: Merck Sharp and Dohme LLC

ClinicalTrialsDisclosure@merck.com

1-800-672-6372

Study Officials

• Medical Director

  Merck Sharp & Dohme LLC

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 7, 2018
• First Posted: September 10, 2018
• Study Start: October 30, 2018
• Primary Completion: November 5, 2021
• Study Completion: November 5, 2021
• Last Updated: August 22, 2024
• Results First Posted: November 14, 2022

Record last verified: 2024-07

Data Sharing

• IPD Sharing: Will share

Locations

ES (5); CA (2); HU (3); IL (2); US (3)