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September 22, 2020
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Sotorasib shows anticancer activity in KRAS G12C-mutated NSCLC

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Sotorasib demonstrated encouraging anticancer activity among patients with heavily pretreated advanced non-small cell lung cancer who harbor KRAS G12C mutations, according to phase 1 study results presented at ESMO Virtual Congress 2020.

“Despite the discovery of the KRAS oncogene almost 4 decades ago, there is no approved therapy targeting this,” David S. Hong, MD, deputy chair of the department of investigational cancer therapeutics at The University of Texas MD Anderson Cancer Center, said during a presentation of the findings, published simultaneously in The New England Journal of Medicine. “KRAS G12C is found in approximately 13% of NSCLC, 3% to 5% of colorectal cancer and 1% to 3% of other solid tumors.”

Sotorasib demonstrated encouraging anticancer activity among patients with heavily pretreated advanced non-small cell lung cancer who harbor KRAS G12C mutations.
Sotorasib demonstrated encouraging anticancer activity among patients with heavily pretreated advanced non-small cell lung cancer who harbor KRAS G12C mutations.

Sotorasib (AMG 510, Amgen) — a highly selective, first-in-class KRAS G12C inhibitor — showed anticancer activity and acceptable safety in previous studies of patients with KRAS G12C-mutant solid tumors.

David S. Hong, MD
David S. Hong

In the current multicenter, open-label study, Hong and colleagues assigned 59 patients with advanced KRAS G12C-mutated NSCLC (median age, 68 years; range, 49-83; 59.3% women) to sotorasib dose-escalation and dose-expansion cohorts. Most patients (74.6%) had two or more prior lines of therapy.

Patients received sotorasib at once-daily doses of 180 mg (n = 3), 360 mg (n = 16), 720 mg (n = 6) or 960 mg (n = 34).

Safety served as the primary endpoint.

Objective response rate, duration of response, PFS, disease control rate and stable disease served as secondary endpoints.

Median follow-up was 11.7 months (range, 4.8-21.2). At that time, 14 patients remained on treatment; 45 had discontinued sotorasib due to disease progression (n = 35), death (n = 5), patient request (n = 4) or adverse events (n = 1).

Thirty-seven patients (62.7%) experienced grade 3 or higher adverse events, including 18.6% of patients with grade 3 or grade 4 treatment-related adverse events. However, no dose-limiting toxicities or treatment-related fatal adverse events occurred.

Among all patients, 19 achieved a confirmed partial response, 33 had stable disease and five had progressive disease (ORR = 32.2%; 95% CI, 20.6-45.6). Among the 34 patients who received the 960 mg dose, 12 achieved a confirmed partial response, 19 had stable disease and two had progressive disease (ORR = 35.3%; 95% CI, 19.8-53.5).

Researchers observed a slightly higher disease control rate in the 960 mg cohort vs. all patients (91.2% vs. 88.1%) and identified 960 mg as the recommended phase 2 dose.

Tumor reduction occurred across dose levels. Median duration of response was 10.9 months (range, 1.1-13.6) among the 19 patients who achieved confirmed partial response and 4 months (range, 1.4-10.9) among the 33 patients with stable disease.

Median PFS was 6.3 months (range, 0-14.9).

“Sotorasib now demonstrates clinical activity in NSCLC across a range of KRAS G12C mutations, PD-L1 expression levels, tumor mutational burden plasma levels and co-mutational profiles,” Hong said. “Additional [studies] evaluating sotorasib as monotherapy or in combination with other anticancer agents are currently underway.”

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