Novel KRAS Inhibitor Leads to Durable Responses in Multiple Tumor Types

— More than half of patients with NSCLC, more than a third of those with CRC responded to divarasib

A computer rendering of the KRAS G12C mutation in non-small cell lung cancer

A new-generation KRAS G12C inhibitor induced responses in more than half of patients with previously treated non-small cell lung cancer (NSCLC) harboring the mutation, a subgroup analysis of a phase I trial showed.

In 58 patients with NSCLC and measurable disease, divarasib led to objective responses in 35 patients, including one complete response. The NSCLC subgroup had a median progression-free survival of 13.1 months. Additionally, 20 of 55 patients with KRAS-positive colorectal cancer (CRC) responded to the targeted agent. Objective responses also were observed in a small number of patients with other types of KRAS-mutant solid tumors.

Divarasib was associated with mostly low-grade gastrointestinal adverse events (AEs) that were manageable and reversible with supportive medications, reported Adrian Sacher, MD, of Princess Margaret Cancer Center and the University of Toronto, and coauthors in the New England Journal of Medicine.

"This study demonstrated in metastatic non-small cell lung cancer, colon cancer, and other solid tumors that divarasib had an impressive response rate, good durability in terms of progression-free survival, and also good tolerability," Sacher told MedPage Today. "Keeping in mind all the caveats with cross-trial comparison, divarasib did exhibit at least numerically the best response rate that we've seen thus far compared to the older KRAS G12C inhibitor."

"This study provides increasing evidence that perhaps not all KRAS G12C inhibitors are created equally, and that newer-generation inhibitors like divarasib are demonstrating really significant promise," he continued. "I think the field needs to look really carefully at each individual KRAS G12C inhibitor and its characteristics in order to decide which ones are probably optimal for monotherapy and ultimately as a foundation for combination therapy in non-small cell lung cancer, colon cancer, and others."

The results compared favorably with the supporting data that led to accelerated approval of sotorasib (Lumakras) and adagrasib (Krazati) for NSCLC harboring KRAS G12C mutations. In the CodeBreaK 100 trial, sotorasib produced objective responses in 37.1% of patients and a median response duration of 10.0 months. In the phase II, single-arm KRYSTAL-1 trial, adagrasib led to a response rate of 43% and an 8.5-month median duration of response.

Sacher and coauthors reported the findings of a phase I trial evaluating single-agent divarasib and in combination with other anticancer therapies in patients with advanced/metastatic solid tumors with a KRAS G12C mutation. The protocol excluded patients with prior exposure to a KRAS G12C inhibitor.

The primary objective was safety, and investigator-assessed antitumor activity was a key secondary objective. Data encompassed 137 patients, 60 with NSCLC, 55 with CRC, and 22 with other solid malignancies (including seven each with pancreatic adenocarcinoma and cholangiocarcinoma).

Grade ≥3 AEs occurred in 12% of all patients, the most common being diarrhea (4%) and increased aspartate aminotransferase (AST, 3%). No grade 5 (fatal) AEs occurred during follow-up. The most common AEs of any grade were nausea (74%), diarrhea (61%), vomiting (58%), fatigue (22%), decreased appetite (13%), and increased AST (10%).

Efficacy data for the 58 NSCLC patients with measurable disease showed that 2% had a complete response and 59% had a partial response. An additional 29% had stable disease as best response. In the 55-patient subgroup with CRC, divarasib led to a complete response in 2% and partial responses in 35%, while another 49% had stable disease. In the 22-patient subgroup with other solid tumors, eight (36%) had objective responses (three patients with pancreatic adenocarcinoma and one each with anal adenocarcinoma, cholangiocarcinoma, endometrial squamous-cell carcinoma, large-cell neuroendocrine carcinoma of the lung, and stomach adenocarcinoma).

Sacher said studies of divarasib in combination with other therapies are ongoing, including divarasib paired with cetuximab (Erbitux), bevacizumab (Avastin), erlotinib (Tarceva), and atezolizumab (Tecentriq), as well as other classes of anticancer therapies. As reported earlier this year, the combination of divarasib and cetuximab led to objective responses in more than 60% of a small group of patients with advanced/metastatic CRC.

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    Charles Bankhead is senior editor for oncology and also covers urology, dermatology, and ophthalmology. He joined MedPage Today in 2007. Follow


The study was supported by Genentech.

Sacher disclosed relationships with Amgen, AstraZeneca, Bristol Myers Squibb, CRISPR Therapeutics AG, Eli Lilly, Genentech, GlaxoSmithKline, Iovance, Merck, Pfizer, and Spectrum Pharmaceuticals.

Primary Source

New England Journal of Medicine

Source Reference: Sacher A, et al "Single-agent divarasib (GDC-6036) in solid tumors with a KRAS G12C mutation" N Engl J Med 2023; DOI: 10.1056/NEJMoa2303810.