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22-09-2023 | Targeted Therapy | News

Novel KRAS inhibitor elicits ‘durable responses’ in KRAS G12C mutation-positive tumors

Author: Dr. Shreeya Nanda

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medwireNews: The novel KRAS inhibitor divarasib has shown promising antitumor activity and manageable toxicity as monotherapy in previously treated patients with advanced solid tumors harboring a KRAS G12C mutation, say researchers.

“Treatment with divarasib resulted in durable clinical responses across KRAS G12C–positive tumors, with mostly low-grade adverse events,” in the phase 1 GO42144 trial, they write in The New England Journal of Medicine.

The team adds that this makes “it a promising clinical candidate both as a single agent and in combination with other anticancer therapies,” and divarasib is being evaluated alongside agents such as atezolizumab, bevacizumab, and erlotinib in this current, ongoing study.

The present report focused on 137 patients with locally advanced or metastatic cancer who received oral divarasib – a covalent KRAS G12C inhibitor with high potency and selectivity – at doses ranging from 50–400 mg/day in 21-day cycles. Participants had disease that was resistant or intolerant to at least one available standard therapy or disease for which an investigational clinical trial is considered standard of care. They were aged a median of 65 years and 60 had non-small-cell lung cancer (NSCLC), while 55 had colorectal cancer (CRC) and 22 had other solid tumors.

There were no dose-limiting toxicities at any of the investigated doses, say Jayesh Desai (Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia) and colleagues.

They continue: “Divarasib was associated with mainly low-grade gastrointestinal adverse effects that were reversible and manageable with supportive medications including antidiarrheal and antiemetic agents.”

Grade 3 treatment-related adverse events (TRAEs) were experienced by 11% of patients and included five cases of diarrhea and four cases each of elevated alanine aminotransferase and aspartate aminotransferase. There was just one grade 4 TRAE, a case of anaphylactic reaction, and no grade 5 TRAEs.

Desai et al highlight that “dose reductions and discontinuation of treatment resulting from divarasib-related adverse events were infrequent,” at rates of 14% and 3%, respectively.

With regard to efficacy, a confirmed response among patients with measurable disease at baseline was achieved by 53.4% of 58 NSCLC patients and 29.1% of 55 CRC patients. Responses lasted for a median of 14.0 and 7.1 months, respectively, and the corresponding median progression-free survival (PFS) times were 13.1 and 5.6 months.

When just the participants who received the recommended phase 2 dose of 400 mg/day were considered, the confirmed response rate was 56.4% for the NSCLC group (n=39) and 35.9% for the CRC group (n=39). The median durations of response were a respective 11.9 and 7.7 months, while the median PFS durations were 13.7 and 6.9 months.

Just over a third (36%) of the participants with other solid tumors had a partial response, all of whom received the 400 mg/day dose. This included three patients with pancreatic adenocarcinoma and one patient each with anal adenocarcinoma, cholangiocarcinoma, endometrial squamous-cell carcinoma, large-cell neuroendocrine carcinoma of the lung, and stomach adenocarcinoma.

The investigators note that “divarasib appears to show numerically more responses and longer progression-free survival among patients with either NSCLC or colorectal cancer than those observed with existing single-agent KRAS G12C inhibitors.” But they stress that “conclusions drawn from cross-trial comparisons must be interpreted cautiously.”

Desai and team conclude: “Further assessment of divarasib in larger randomized studies is needed.”

medwireNews is an independent medical news service provided by Springer Healthcare Ltd. © 2023 Springer Healthcare Ltd, part of the Springer Nature Group

N Engl J Med 2023; 389: 710–721

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