Sponsor: Hoffmann-La Roche (industry)
Phase: 3
Start date: Sept. 23, 2024
Planned enrollment: 320
Divarasib (also known as RG6330 or GDC-6036) is an investigational oral inhibitor targeting the KRAS G12C mutation, a common oncogenic driver in various solid tumors. (nejm.org)
Divarasib is a covalent inhibitor that binds irreversibly to the cysteine residue in the KRAS G12C mutant protein, locking it in its inactive GDP-bound state. This action prevents downstream oncogenic signaling pathways, thereby inhibiting tumor cell proliferation and survival. (nejm.org)
In a phase 1 clinical trial involving 137 patients with KRAS G12C-mutated advanced solid tumors, divarasib demonstrated notable antitumor activity:
Non–Small-Cell Lung Cancer (NSCLC): Among 60 patients, the confirmed objective response rate (ORR) was 53.4%, with a median progression-free survival (PFS) of 13.1 months. (nejm.org)
Colorectal Cancer (CRC): Among 55 patients, the confirmed ORR was 29.1%, with a median PFS of 5.6 months. (nejm.org)
Other Solid Tumors: Partial responses were observed in 36% of 22 patients with various other solid tumors, including pancreatic adenocarcinoma and cholangiocarcinoma. (nejm.org)
Divarasib was generally well-tolerated, with no dose-limiting toxicities reported. Treatment-related adverse events (TRAEs) occurred in 93% of patients, mostly grade 1 or 2. The most common TRAEs included nausea (74%), diarrhea (61%), and vomiting (58%). Grade 3 TRAEs were observed in 11% of patients, with no treatment-related deaths reported. (nejm.org)
Last updated: Apr 2025
The Phase III clinical trial NCT06497556 is designed to assess the efficacy and safety of divarasib compared to sotorasib or adagrasib in patients with previously treated KRAS G12C-positive advanced or metastatic non-small cell lung cancer (NSCLC). The trial commenced in September 2024 and is projected to complete primary data collection by September 2026. As of August 2025, no results from this specific trial have been published. (fdaaa.trialstracker.net)
Phase I Study Findings
A Phase I study evaluated divarasib as a single agent in patients with KRAS G12C-mutated solid tumors. Among NSCLC patients, the study reported:
The safety profile was considered manageable, with 12% of patients experiencing grade 3 or 4 adverse events. (healio.com)
Phase Ib Study Findings
In a Phase Ib study, divarasib was combined with cetuximab, an anti-EGFR therapy, in patients with advanced or metastatic KRAS G12C-positive colorectal cancer. The results showed:
The combination therapy demonstrated a manageable safety profile, with no patients discontinuing treatment due to adverse events. (roche.com)
The ongoing Phase III trial aims to provide more definitive data on the efficacy and safety of divarasib compared to existing KRAS G12C inhibitors. Previous studies have shown promising results, suggesting that divarasib could offer a new treatment option for patients with KRAS G12C-mutated NSCLC. Oncologists and patients considering participation in the trial may find these earlier findings encouraging, though it is important to await the results of the current study for more conclusive evidence.
Last updated: Aug 2025
Goal: To compare the efficacy and safety of divarasib with locally approved KRAS G12C inhibitors (sotorasib or adagrasib) in patients with previously treated KRAS G12C-positive advanced or metastatic non-small cell lung cancer (NSCLC).
Patients: Adults with advanced or metastatic NSCLC harboring a KRAS G12C mutation, having experienced disease progression after one to three prior lines of systemic therapy. Patients must have an ECOG performance status of 0 or 1, measurable disease by RECIST v1.1, and available tumor tissue for biomarker analysis. Patients with active CNS metastases, prior exposure to KRAS G12C inhibitors, or certain other medical exclusions are not eligible.
Design: This is a randomized, open-label, multicenter Phase III trial. Participants are allocated to either investigational divarasib or approved KRAS G12C inhibitor (sotorasib or adagrasib) arms.
Treatments: The investigational treatment is divarasib, a highly selective oral KRAS G12C inhibitor designed to irreversibly bind and inactivate KRAS G12C. In phase 1 trials, divarasib has demonstrated potent anti-tumor activity in KRAS G12C-mutant NSCLC with an objective response rate of 56.4% and a median progression-free survival of up to 15.3 months, as well as manageable gastrointestinal side effects. The comparator arm includes either sotorasib or adagrasib, both approved oral KRAS G12C inhibitors, given at their standard dosing schedules.
Outcomes: The primary endpoint is progression-free survival (PFS) by blinded independent central review per RECIST v1.1. Key secondary endpoints include overall survival (OS), objective response rate, duration of response, patient-reported quality of life and symptom scales, and rates of adverse events, with assessments planned for up to approximately 4 years.
Burden on patient: The trial is expected to have a low to moderate burden on participants. Both divarasib and comparator agents are administered orally. Requirements include provision of archival or new tumor tissue (likely from prior biopsy), regular imaging and clinical visits (in line with standard oncology practice), and completion of quality of life questionnaires. There is no mention of intensive or frequent pharmacokinetic sampling or additional invasive procedures beyond what is standard for this patient population.
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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