Real-world data shows sotoracil effective in KRAS-mutant NSCLC

Real-world patient data from June 2021 to February 2023 showed that in a cohort of 128 patients who received the KRAS inhibitor sotoracib (AMG510) for the treatment of KRAS G12C-mutated non-small cell lung cancer (NSCLC), progression-free survival (PFS) was similar to that seen in the phase 2 CodeBreaK100 trial. Furthermore, according to the latest data published in JTO Clinical and Research Reports, dose reduction does not equate to ineffective treatment. The currently approved daily dose of sotoracil is 960 mg.

The U.S. Food and Drug Administration (FDA) first approved sotoraxib for this type of lung cancer in May 2021, making it the first targeted therapy for this mutation-specific non-small cell lung cancer. After at least 1 course of treatment through its accelerated approval pathway, data based on CodeBreaK100 (NCT03600883) showed an objective response rate of 36%, a median duration of response of 10 months and a disease control rate (DCR) of 81%. The FDA has requested postmarketing efficacy data on a lower dose (240 mg instead of the approved 960 mg).

Patients included in this analysis (n=128) were retrospectively identified from the company's data warehouse; all were prescribed sotorasib by the VHA before March 1, 2023. Their median age was 72 years (range, 43-93 years), 90% of patients were male, 77% reported white/Caucasian race, 19% reported black/African American race, 95% reported non-Hispanic race, 69% were former smokers, adenocarcinoma was the most common histological diagnosis (91%), and stage IV disease was the most common disease stage at initiating sotoraxib (94%). The study's investigators cited the need for real-world data on the drug's safety and effectiveness as the reason they conducted this analysis.

92 patients were included in the response analysis, with an overall response rate (ORR) of 34%, a DCR of 71%, a median response time of 2.4 months, and a median response duration of 4 months. For the entire 128-patient cohort, the median treatment duration was 6.3 months, the median PFS was 6 months, and the median overall survival (OS) was 12 months. Seven patients also had active central nervous system disease when they started sotoracib, with one patient having a partial response to sotoracib, one patient having stable disease, and two patients experiencing disease progression.

Sixteen patients were treatment-naïve when they started sotoraxib. Their median PFS and OS were 6.6 months and 8.1 months, respectively. The most common reasons for lack of prior chemotherapy were anticipated intolerance (n=8), patient refusal (n=6), and receipt of systemic therapy for another malignancy (n=2). The main reasons for the lack of first-line therapy with immune checkpoint inhibitors (ICIs) were expected lack of efficacy (n=9), unknown (m=4), and patient refusal (n=2).

ConsideringSTK11 mutations, KEAP1 mutations, glomerular filtration rate >60 mL/min, and Eastern Cooperative Oncology Group performance status (ECOG PS) of 3 or higher were found on univariate analysis to be associated with reduced PFS; only PD-L1 tumor proportion score ≥50% was associated with improved PFS. Multivariable analysis found that only an ECOG PS of 3 or higher conferred a higher risk (HR, 4.2; 95% CI, 1.28-13.75).

Thirty-seven percent of patients required dose interruption or reduction, and those who received ICIs within 3 months of starting sotoraxib had higher rates of treatment interruption, reduction, or discontinuation. Of those who required a dose reduction, 62% took the most common lower dose of 480 mg; 27% continued on 240 mg and 11% took 720 mg.

Limitations of the authors' findings include their retrospective nature, which allowed them to only consider treatment-related toxicities that led to discontinuation, dose reduction, or discontinuation of sotoraxib. Therefore, they may have seen higher rates of all 3 diseases compared to clinical trial populations.