Trial: A Study Evaluating the Efficacy and Saf…

Trial Details

Sponsor: Hoffmann-La Roche (industry)

Phase: 3

Start date: Sept. 23, 2024

Planned enrollment: 320

Trial ID: NCT06497556

More trial details at ClinicalTrials.gov

Show Summary from Sponsor

Investigational Drug AI Analysis

Show for: Divarasib (RG 6330)

Overview

Divarasib (GDC-6036; also known as RG6330, RO7435846) is an oral, covalent KRAS G12C inhibitor in clinical development by Genentech/Roche for KRAS G12C–mutant solid tumors. As of October 7, 2025, divarasib remains investigational and is being studied in Phase I/II programs across tumor types. (drugs.ncats.io)

Mechanism of action

Divarasib binds irreversibly to the switch II pocket of KRAS G12C in its inactive GDP-bound state, locking KRAS in an inactive conformation and suppressing downstream MAPK signaling. Preclinical and translational reports describe high potency and selectivity versus wild-type KRAS. (nejm.org)

Efficacy

Single-agent (Phase I, dose-escalation/expansion; NCT04449874)
Across KRAS G12C–mutant solid tumors (n=137), investigator-assessed confirmed response rate (cRR) was:
- NSCLC: 53.4% (95% CI, 39.9–66.7); median PFS 13.1 months (95% CI, 8.8–NE). At the 400 mg dose, cRR 56.4% and median PFS 13.7 months. (nejm.org)
- Colorectal cancer (CRC): cRR 29.1% (95% CI, 17.6–42.9); median PFS 5.6 months (95% CI, 4.1–8.2). (nejm.org)
Long-term follow-up updates reported in KRAS G12C–mutant NSCLC:
- cRR 55.6% (95% CI, 42.5–68.1); median duration of response 18.0 months (95% CI, 11.1–24.9); median PFS 13.8 months overall and 15.3 months at 400 mg. (pubmed.ncbi.nlm.nih.gov)
Congress update (ESMO 2024) at 400 mg dose showed:
- NSCLC: ORR 59.1%, median PFS 15.3 months; CRC: ORR 33.3%, median PFS 6.9 months; other solid tumors: ORR 33.3%, median PFS 7.1 months. (oncologypro.esmo.org)
Combination therapy: Divarasib + cetuximab in KRAS G12C–mutant CRC (Phase 1b arm of NCT04449874)
In KRAS G12C inhibitor–naive patients (n=24), ORR 62.5% (95% CI, 40.6–81.2); median PFS 8.1 months (95% CI, 5.5–12.3); median DOR 6.9 months. Results published in Nature Medicine (2024). (pubmed.ncbi.nlm.nih.gov)
Earlier AACR 2023 abstract reported encouraging activity for the combination in CRC; details align with the subsequent Nature Medicine publication. (aacrjournals.org)
Additional combinations under evaluation within NCT04449874 include SHP2 inhibition (migoprotafib/GDC-1971), anti-EGFR (cetuximab), anti-VEGF (bevacizumab), EGFR TKI (erlotinib), PD-L1 blockade (atezolizumab), and PI3Kα inhibition (inavolisib); early clinical activity of divarasib + SHP2 inhibitor has been presented in NSCLC. (mycancergenome.org)

Safety

Single-agent (Phase I, NCT04449874; NEJM 2023):
No dose-limiting toxicities or treatment-related deaths were reported.
Treatment-related AEs occurred in 93%; grade 3 in 11% and grade 4 in 1%.
Dose reductions in 14% and discontinuations in 3%, most commonly for gastrointestinal events (nausea, vomiting, diarrhea) and liver enzyme elevations. (nejm.org)
Long-term follow-up in NSCLC showed safety consistent with earlier reports over ≥1 year of therapy. (pubmed.ncbi.nlm.nih.gov)
Divarasib + cetuximab (CRC Phase 1b) had a safety profile consistent with the single agents; divarasib dose reductions in 13.8% and no treatment withdrawals due to adverse events in the reported cohort. (pubmed.ncbi.nlm.nih.gov)

HealthScout AI Analysis

Goal: Evaluate whether divarasib improves efficacy and maintains acceptable safety compared with locally approved KRAS G12C inhibitors (sotorasib or adagrasib) in previously treated KRAS G12C-mutant advanced or metastatic non-small cell lung cancer.

Patients: Adults with unequivocally confirmed metastatic or locally advanced NSCLC harboring a KRAS G12C mutation, ECOG 0–1, life expectancy ≥12 weeks, measurable disease by RECIST v1.1, and progression after 1–3 prior systemic therapies in the advanced/metastatic setting. Key exclusions include prior KRAS G12C or pan-KRAS/RAS inhibitors, active or untreated CNS metastases, leptomeningeal disease, mixed SCLC or LCNEC histology, significant uncontrolled effusions, unresolved ≥Grade 2 toxicities, recent serious infections, and known second oncogenic drivers.

Design: Multicenter, randomized, open-label, active-controlled Phase III study comparing divarasib versus physician’s choice of sotorasib (QD) or adagrasib (BID). Blinded independent central review is used for radiographic endpoints. Planned enrollment is approximately 320 participants.

Treatments: Divarasib, an oral, covalent KRAS G12C inhibitor (GDC-6036/RG6330) that selectively and irreversibly locks KRAS G12C in its inactive GDP-bound state, inhibiting downstream oncogenic signaling. Preclinical data suggest substantially higher potency and selectivity versus first-generation KRAS G12C inhibitors. In a Phase 1 study across KRAS G12C–mutated tumors, NSCLC cohorts at the 400 mg dose showed an objective response rate around 56% and median PFS approximately 13–15 months with a generally manageable GI-predominant safety profile and low discontinuation rates. Comparator arm uses standard-of-care KRAS G12C inhibitors: sotorasib (oral QD) or adagrasib (oral BID).

Outcomes: Primary endpoint is progression-free survival by blinded independent central review per RECIST v1.1. Key secondary endpoints include overall survival, objective response rate, duration of response, safety and adverse events, and patient-reported outcomes encompassing symptom burden and quality of life (EORTC QLQ-C30 and QLQ-LC13, PRO-CTCAE, and IL46), including time to confirmed deterioration in dyspnea, cough, chest pain, physical/role functioning, and global health status/quality of life. Assessment duration is up to approximately 4 years.

Burden on patient: Overall burden is moderate to low for a Phase III oral therapy study. Treatment is outpatient with oral agents and no mandated intensive pharmacokinetic sampling typical of early-phase trials. Requirements include provision of archival tumor tissue (or unstained slides) for biomarker confirmation, regular clinic visits for safety labs and toxicity monitoring, and periodic imaging per RECIST with central review, which aligns with standard oncology practice. Patients with CNS involvement must have treated/stable disease, potentially adding baseline CNS imaging if indicated. Patient-reported outcome instruments will be administered at scheduled visits, adding brief questionnaires. No invasive on-treatment biopsies are specified; thus, incremental burden beyond standard-of-care follow-up and imaging is limited, primarily involving adherence to oral dosing and scheduled assessments over a long follow-up period.

Last updated: Oct 2025

Eligibility

Show Criteria

Inclusion Criteria:

* Unequivocal histologically or cytologically confirmed diagnosis of metastatic or locally advanced NSCLC not amenable to treatment with surgical resection or combined chemoradiation

* Disease progression during or after treatment with at least one prior systemic therapy but no more than three lines of prior systemic therapy in the advanced or metastatic setting

* Measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1

* Documentation of the presence of a KRAS G12C mutation

* Availability of a representative formalin-fixed, paraffin-embedded (FFPE) tumor specimen in a paraffin block (preferred) or 10-15 (15 preferred) unstained, freshly cut, serial slides with an associated pathology report

* Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

* Life expectancy of \>= 12 weeks

Exclusion Criteria:

* Known hypersensitivity to any of the components of divarasib, or sotorasib or adagrasib

* Malabsorption syndrome or other condition that would interfere with enteral absorption

* Known concomitant second oncogenic driver

* Mixed small-cell lung cancer or large cell neuroendocrine histology

* Known and untreated, or active central nervous system (CNS) metastases

* Leptomeningeal disease or carcinomatous meningitis

* Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures biweekly or more frequently

* Any infection that, in the opinion of the investigator, could impact patient safety, or treatment with therapeutic oral or IV antibiotics within 14 days prior to Day 1 of Cycle 1

* Prior treatment with any KRAS G12C inhibitor or pan-KRAS/RAS inhibitor

* More than 30 Gy of radiotherapy to the lung within 6 months of randomization

* Uncontrolled tumor-related pain

* Unresolved toxicities from prior anticancer therapy

* History of malignancy within 5 years prior to screening, with the exception of the cancer under investigation in this study and malignancies with a negligible risk of metastasis or death (e.g., 5-year OS rate \>90%), such as adequately treated carcinoma in situ of the cervix, nonmelanoma skin carcinoma, localized prostate cancer, ductal carcinoma in situ, or Stage I uterine cancer

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Banner Health MD Anderson AZ

Phoenix, Arizona, 85006, United States

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Gilbert, Arizona, 85234, United States

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University of Arkansas For Medical Sciences

Little Rock, Arkansas, 72205, United States

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Community Clinical Trials

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Los Angeles Cancer Network

Los Angeles, California, 90017-4803, United States

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Los Angeles, California, 90095, United States

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Colorado Springs, Colorado, 80909, United States

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Bay Pines, Florida, 33744, United States

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Fort Myers, Florida, 33901, United States

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St. Petersburg, Florida, 33705, United States

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Miami, Florida, 33136, United States

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Savannah, Georgia, 31405, United States

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University Cancer & Blood Center, LLC

Athens, Georgia, 30607, United States

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Chicago, Illinois, 60612-3244, United States

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Chicago, Illinois, 60637, United States

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Muncie, Indiana, 47303, United States

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Waukee, Iowa, 50263, United States

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Lexington, Kentucky, 40503, United States

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Norton Cancer Institute- Poplar

Louisville, Kentucky, 40217, United States

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VA Shreveport Healthcare System

Shreveport, Louisiana, 71101, United States

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New England Cancer Specialists

Scarborough, Maine, 04074, United States

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Boston, Massachusetts, 02215, United States

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Boston, Massachusetts, 02215, United States

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Foxborough, Massachusetts, 02035, United States

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Methuen, Massachusetts, 01844, United States

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Cancer and Hematology Centers of Western Michigan

Grand Rapids, Michigan, 49503, United States

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Henry Ford Health System;Clinical Trials Office

Detroit, Michigan, 48202, United States

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University of Michigan

Ann Arbor, Michigan, 48109-0934, United States

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Nebraska Methodist Estabrook Cancer Center

Omaha, Nebraska, 68114, United States

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Renown Regional Medical Center Hospital

Reno, Nevada, 89502, United States

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Columbia University Medical Center

New York, New York, 10032, United States

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Mount SInai Medical Center

New York, New York, 10029, United States

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New York Cancer & Blood Specialists

The Bronx, New York, 10469, United States

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New York Cancer & Blood Specialists - New Hyde Park

New Hyde Park, New York, 11042-1116, United States

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New York Cancer and Blood Specialists-Central Park Hematology & Oncology

New York, New York, 10028, United States

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North Shore Hematology Oncology Associates P.C. DBA New York Cancer and Blood Specialists

Shirley, New York, 11967, United States

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East Carolina University

Greenville, North Carolina, 27834, United States

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Firsthealth of The Carolinas

Pinehurst, North Carolina, 28374, United States

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University of North Carolina At Chapel Hill

Chapel Hill, North Carolina, 27514, United States

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Ohio State University Comprehensive Cancer Center

Columbus, Ohio, 43210, United States

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Taylor Cancer Research Center

Maumee, Ohio, 43537, United States

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Oncology Associates of Oregon, P.C

Eugene, Oregon, 97401, United States

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Portland, Oregon, 97239, United States

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Fox Chase Cancer Center

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Virginia Commonwealth University - Massey Cancer Center

Richmond, Virginia, 23298-0042, United States

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