Treatment hope for KRAS-mutated advanced NSCLC
medwireNews: AMG 510, a novel KRAS inhibitor, has promising efficacy and tolerability in previously treated patients with locally advanced or metastatic non-small-cell lung cancer (NSCLC) carrying a KRAS G12C mutation, according to phase I trial findings.
Reporting the results at the IASLC World Conference on Lung Cancer 2019 in Barcelona, Spain, study author Ramaswamy Govindan (Washington University School of Medicine, St Louis, Missouri, USA) explained that KRAS G12C mutations occur in about 11% of patients with NSCLC, but there are currently no approved targeted treatment options for these individuals.
He added that AMG 510 is a first-in-class, irreversible inhibitor of KRAS G12C that is being tested in a phase I trial enrolling patients with various advanced solid tumors, all of whom were positive for the mutation and had progressed after prior standard treatment. Participants received the KRAS inhibitor orally at a daily dose of 180, 360, 720, or 960 mg in 3-week cycles.
Data from the first 10 NSCLC patients were reported earlier this year, and now, findings are presented for these and an additional 13 patients.
The objective response rate (ORR) across all 23 NSCLC patients was 48%, with all responders achieving a partial response. A further 48% had stable disease, giving a disease control rate (DCR) of 96%, and just one patient had progressive disease.
WATCH | Ramaswamy Govindan outlines the key findings of the NSCLC cohort of the phase I trial of AMG 510, and comments on the next steps for the research (5:34).
Among the 13 participants who received the recommended phase II dose of 960 mg/day, the ORR was 54%, and again all responses were partial. Forty-six percent of patients had stable disease and no patient progressed, which equated to a DCR of 100%.
Of note, eight of the 11 responders and eight of the 11 participants with stable disease were continuing study treatment at the time of data analysis.
AMG 510 also has “a favorable safety profile,” said Govindan, with no dose-limiting toxicities, no treatment-related serious or fatal adverse events (AEs), and no AEs leading to discontinuation reported.
Any-grade treatment-related AEs occurred in 35.3% of participants, with grade 3 events in 8.8% and no grade 4 events.
“These data continue to show encouraging anti-tumor activity with AMG 510, underscoring the potential to close the treatment gap for non-small cell lung cancer patients with previously treated KRAS G12C-mutated [disease],” said Govindan in a press statement.
Jon Zugazagoitia (Hospital Universitario 12 de Octubre, Madrid, Spain), who discussed the results, described the safety profile of the drug as “remarkable” and the efficacy as promising, although he cautioned that the data thus far “are based on a small number of evaluable patients enrolled in an early-phase clinical trial.”
The discussant also outlined some key unanswered questions, such as the durability of responses, the activity against central nervous system metastases, and whether synergistic combinations with immunotherapy and other targeted agents will be clinically feasible.
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