Divarasib induces durable responses in KRAS-mutated solid tumors
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Key takeaways:
- Divarasib induced a 53.4% confirmed response rate among patients with non-small cell lung cancer.
- Twelve percent of patients experienced grade 3 or grade 4 adverse events.
Divarasib induced durable clinical responses among patients with KRAS G12C-positive solid tumors, according to study findings published in The New England Journal of Medicine.
Researchers reported particular benefit for patients with non-small cell lung cancer or colorectal cancer; however, researchers cautioned that larger randomized studies are necessary to confirm the findings.
“These data have generated significant hope that divarasib will continue to demonstrate excellent tolerability and efficacy in ongoing randomized clinical trials, as well as in combination studies with other agents,” Adrian Sacher, MD, thoracic oncologist and affiliate scientist at Princess Margaret Cancer Centre and assistant professor in the departments of medicine and immunology at University of Toronto, told Healio.
Background and methodology
Divarasib (GDC-6036, Genentech) is a covalent KRAS G12C inhibitor.
Sacher and colleagues conducted a phase 1 study to assess divarasib monotherapy for patients with advanced or metastatic solid tumors that harbored KRAS G12C mutations.
The analysis included 137 patients (NSCLC, n = 60; colorectal cancer, n = 55; other solid tumors, n = 22).
Patients received oral divarasib once daily at doses that ranged from 50 mg to 400 mg.
Researchers evaluated safety, pharmacokinetics, antitumor activity, and biomarkers of response and resistance.
Results
Analyses of patients with NSCLC showed a confirmed response rate of 53.4% (95% CI, 39.9-66.7) across all dose levels, with a median response duration of 14 months (95% CI, 8.3 to not reached) and median PFS of 13.1 months (95% CI, 8.8 to not estimated).
Among 39 patients who received a 400-mg dose, 56.4% (95% CI, 39.6-72.2) achieved confirmed response, with median PFS of 13.7 months (95% CI, 8.1 to not estimated).
Analyses of patients with colorectal cancer showed a confirmed response rate of 29.1% (95% CI, 17.6-42.9) across all dose levels, with a median response duration of 7.1 months (95% CI, 5.5-7.8) and median PFS of 5.6 months (95% CI, 4.1-8.2).
Among those who received a 400-mg dose, 35.9% (95% CI, 21.2-52.8) achieved confirmed response, with median PFS of 6.9 months (95% CI, 5.3-9.1).
Among patients with other solid tumors, eight patients (36%) achieved partial response. These included three patients with pancreatic adenocarcinoma and one patient each with anal adenocarcinoma, stomach adenocarcinoma, cholangiocarcinoma, endometrial squamous cell carcinoma and large-cell neuroendocrine carcinoma of the lung.
The majority (93%; n = 127) of evaluable patients experienced treatment-related adverse events. Fifteen (11%) developed grade 3 events and one (1%) experienced a grade 4 event.
Treatment-related adverse events prompted dose reduction for 19 patients (14%) and treatment discontinuation for four patients (3%).
Next steps
The findings suggest divarasib has promising antitumor activity with a manageable safety profile for this patient population, researchers concluded.
However, researchers acknowledged limitations. These included response assessment by investigators instead of blinded independent central review, as well as limited racial diversity in the cohort.
“Divarasib has demonstrated excellent tolerability as well as remarkable activity as monotherapy in KRAS G12C mutant metastatic NSCLC, colon cancer and other solid tumors,” Sacher told Healio. “It has great potential as a novel monotherapy [or] as the basis for novel combinations in KRAS G12C-mutant tumors.
“It will be important to evaluate divarasib in larger randomized trials, as well as to evaluate it in combination with other promising agents,” Sacher added. “These studies are ongoing and we look forward to their results.”
For more information:
Adrian Sacher, MD, can be reached at adrian.sacher@uhn.ca.
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