A Study Evaluating the Efficacy and Safety of Divarasib and Pembrolizumab Versus Pembrolizumab and Pemetrexed and Carboplatin or Cisplatin in Participants With Previously Untreated, KRAS G12C-Mutated, Advanced or Metastatic Non-Squamous Non-Small Cell Lung Cancer

Official title

A Phase III, Randomized, Open-Label Study Evaluating the Efficacy and Safety of Divarasib and Pembrolizumab Versus Pembrolizumab and Pemetrexed and Carboplatin or Cisplatin in Patients With Previously Untreated, KRAS G12C-Mutated, Advanced or Metastatic Non-Squamous Non-Small Cell Lung Cancer

Overview

The purpose of this study is to evaluate the efficacy and safety of divarasib and pembrolizumab compared with pembrolizumab and pemetrexed and carboplatin or cisplatin, for the first-line treatment of adult participants with KRAS G12C-mutated, advanced or metastatic non squamous non-small cell lung cancer (NSCLC).

Interventions

• Drug Divarasib
  Divarasib will be administered orally QD
• Drug Pembrolizumab
  Pembrolizumab will be administered via IV infusion Q3W
• Drug Pemetrexed
  Pemetrexed will be administered via IV infusion Q3W
• Drug Carboplatin
  Carboplatin will be administered via IV infusion Q3W
• Drug Cisplatin
  Cisplatin will be administered via IV infusion Q3W

Primary outcome measures

• Progression-Free Survival (PFS) [Time frame: Up to approximately 5 years]
• Overall Survival (OS) [Time frame: Up to approximately 5 years]

Secondary outcome measures (9)

• Objective Response [Time frame: Up to approximately 5 years]
• Change from Baseline on the European Organisation for Research and Treatment of Cancer Quality-of-Life Questionnaire-Supplemental Lung Cancer Module (EORTC QLQ-LC13) Cough Scale [Time frame: Baseline up to Cycle 5 Day 1 (each cycle is 21 days)]
• Change from Baseline on the EORTC Quality of Life Questionnaire (QLQ-C30) Dyspnea Item and Physical Functioning Scale [Time frame: Baseline up to Cycle 5 Day 1 (each cycle is 21 days)]
• Duration of Response (DOR) [Time frame: Up to approximately 5 years]
• Percentage of Participants with Adverse Events (AEs) [Time frame: Up to approximately 5 years]
• Number of Participants Reporting Presence, Frequency, Severity, and/or Degree of Interference with Daily Function of Symptomatic Treatment Toxicities Assessed by NCI Patient-Reported Outcomes Common Terminology Criteria for Adverse Events (PRO-CTCAE) [Time frame: Up to approximately 5 years]
• Change from Baseline in the Severity of Selected Symptomatic Treatment Toxicities as Assessed Through use of the NCI PRO-CTCAE [Time frame: Up to approximately 5 years]
• Frequency of Participants' Response of the Degree they are Troubled with Treatment Symptoms, as Assessed Through use of the single-item EORTC Item List (IL46) [Time frame: Up to approximately 5 years]
• Change from Baseline on the EORTC QLQ-C30 and QLQ-LC13 Functional and Global Health Status Score/Quality of Life Score (GHS/QoL) [Time frame: Up to approximately 5 years]

Eligibility criteria

Inclusion criteria

• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• Histologically or cytologically confirmed diagnosis of advanced or metastatic non squamous NSCLC that is not eligible for curative surgery and/or definitive chemoradiotherapy
• Measurable disease, as defined by RECIST v1.1
• No prior systemic treatment for advanced or metastatic NSCLC
• Documentation of the presence of a KRAS G12C mutation
• Documentation of known PD-L1 expression status in tumor tissue
• Availability of a representative tumor specimen
• Adequate end-organ function
• Eligible to receive a platinum-based chemotherapy regimen

Exclusion Criteria Related to NSCLC:

• Known concomitant second oncogenic driver with available targeted treatment
• Symptomatic, untreated, or actively progressing central nervous system (CNS) metastases
• Spinal cord compression not definitively treated with surgery and/or radiation or previously diagnosed and treated spinal cord compression without evidence that disease has been clinically stable for >=2 weeks prior to randomization
• History of leptomeningeal disease
• Uncontrolled tumor-related pain
• Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (once a month or more frequently)

Exclusion Criteria Related to Current or Prior Treatments:

• Any anti-cancer systemic therapy, including hormonal therapy, within 21 days prior to randomization, or is expected to require any other form of antineoplastic therapy while in the study
• Radiation therapy including palliative RT to bone metastases within 2 weeks prior to randomization and RT to the lung >30Gy within 6 months prior to randomization
• Prior treatment with KRAS G12C inhibitors or pan-KRAS/RAS inhibitors
• Treatment with systemic immunosuppressive or immunostimulatory medications, including CD137 agonists and immune checkpoint inhibitors
• Current treatment with medications that are well known to prolong the QT interval
• Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to randomization
• Prior allogeneic stem cell or solid organ transplantation

Exclusion Criteria Related to General Health:

• History of malignancy other than NSCLC within 5 years prior to screening, with the exception of malignancies with a negligible risk of metastasis or death (e.g., 5-year overall survival \[OS\] rate >90%), such as adequately treated carcinoma in situ of the cervix, non melanoma skin carcinoma, localized prostate cancer, ductal breast carcinoma in situ, or Stage I uterine cancer
• Individuals with chronic diarrhea, short bowel syndrome or significant upper gastrointestinal surgery including gastric resection, a history of inflammatory bowel disease (e.g., Crohn's disease or ulcerative colitis) or any active bowel inflammation (including diverticulitis), malabsorption syndrome, conditions that would interfere with enteral absorption
• History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on the screening chest computed tomography scan
• Significant cardiovascular disease within 3 months prior to screening

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 55 centers

• Alaska Oncology and Hematology — Anchorage
• City of Hope - Phoenix — Goodyear
• Community Cancer Institute (CCI) — Clovis
• Marin Cancer Care Inc — Greenbrae
• UCLA Oncology Center — Los Angeles
• Hoag Memorial Hospital — Newport Beach
• Palo Alto Medical Foundation Research Center — Palo Alto
• Sutter Institute for Medical Research — Roseville
• … and 47 more centers

Germany · 23 centers

Center list to be confirmed — check the primary protocol.

Japan · 20 centers

Center list to be confirmed — check the primary protocol.

Spain · 15 centers

Center list to be confirmed — check the primary protocol.

France · 14 centers

Center list to be confirmed — check the primary protocol.

Italy · 14 centers

Center list to be confirmed — check the primary protocol.

United Kingdom · 11 centers

Center list to be confirmed — check the primary protocol.

Poland · 10 centers

Center list to be confirmed — check the primary protocol.

Canada · 9 centers

Center list to be confirmed — check the primary protocol.

China · 9 centers

Center list to be confirmed — check the primary protocol.

Australia · 8 centers

• Kinghorn Cancer Centre — Darlinghurst
• Liverpool Hospital — Liverpool
• Calvary Mater Newcastle — Waratah
• Sunshine Coast University Hospital — Birtinya
• Royal Hobart Hospital — Hobart
• Monash Health — Clayton
• Austin Health — Heidelberg
• Peter Maccallum Cancer Centre — Melbourne

Belgium · 8 centers

• AZORG Campus Aalst-Moorselbaan — Aalst
• UZ Brussel — Brussels
• Cliniques Universitaires St-Luc — Brussels
• Jessa Zkh (Campus Virga Jesse) — Hasselt
• UZ Leuven Gasthuisberg — Leuven
• CHU de Liège (Sart Tilman) — Liège
• CHU HELORA - Hôpital de Mons - Site Kennedy — Mons
• AZ Delta (Campus Rumbeke) — Roeselare

Brazil · 7 centers

• Crio - Centro Regional Integrado de Oncologia — Fortaleza
• Centro Integrado de Oncologia de Curitiba — Curitiba
• Liga Norte Riograndense Contra O Câncer — Natal
• Irmandade Da Santa Casa de Misericordia de Porto Alegre — Porto Alegre
• … and 3 more centers

Greece · 7 centers

Center list to be confirmed — check the primary protocol.

Netherlands · 7 centers

Center list to be confirmed — check the primary protocol.

Taiwan · 7 centers

Center list to be confirmed — check the primary protocol.

South Korea · 6 centers

Center list to be confirmed — check the primary protocol.

Argentina · 5 centers

• Hospital Aleman de Buenos Aires — Buenos Aires
• Hospital Italiano — Buenos Aires
• Hospital Britanico — Ciudad Autonoma Buenos Aires
• Centro Oncologico Korben — Ciudad Autonoma Buenos Aires
• Clinica Adventista Belgrano — Ciudad Autonoma Buenos Aires

Denmark · 5 centers

Center list to be confirmed — check the primary protocol.

Hong Kong · 4 centers

Center list to be confirmed — check the primary protocol.

Hungary · 4 centers

Center list to be confirmed — check the primary protocol.

Ireland · 4 centers

Center list to be confirmed — check the primary protocol.

Portugal · 4 centers

Center list to be confirmed — check the primary protocol.

Switzerland · 4 centers

Center list to be confirmed — check the primary protocol.

Mexico · 2 centers

Center list to be confirmed — check the primary protocol.

New Zealand · 2 centers

Center list to be confirmed — check the primary protocol.

Singapore · 2 centers

Center list to be confirmed — check the primary protocol.

South Africa · 2 centers

Center list to be confirmed — check the primary protocol.

Identifiers

NCT: NCT06793215 · CO45042

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗