AMG 510 Highly Active in KRAS+ NSCLC

Ramaswamy Govindan, MD

The investigational KRAS inhibitor AMG 510 induced near-universal disease control in patients with advanced non—small cell lung cancer (NSCLC) with KRAS mutations, according to results from a small, first-in-human trial presented at the 2019 World Conference on Lung Cancer (WCLC).

Only 1 of 23 patients had progressive disease, as 11 patients treated with AMG 510 attained partial responses (PRs) and 11 others had stable disease (SD), resulting in a disease control rate of 96%. Among 13 patients treated with the recommended phase II dose, 7 had PRs for an objective response rate (ORR) of 54%, with 6 others achieving SD.

The early results suggested a favorable safety profile, as no dose-limiting or cumulative toxicity was observed, Ramaswamy Govindan, MD, of Washington University in St. Louis, reported at the WCLC.

“AMG 510 demonstrated early promising antitumor activity in patients with advanced non—small cell lung cancer harboring the KRAS G12C mutation,” Govindan said in conclusion. “Enrollment is ongoing for a phase I combination trial and a phase II trial of monotherapy.”

The KRAS G12C mutation occurs in about 13% of lung cancers and no approved therapy targets the mutation. AMG 510 is a first-in-class small-molecule inhibitor that specifically and irreversibly inhibits KRAS G12C. The mutation occurs in 3% of colorectal and appendiceal cancers and 1% to 3% of several other types of tumors.

Govindan reported findings from a phase I dose-escalation trial involving patients with locally advanced or metastatic solid tumors associated with KRAS G12C mutation, confirmed by molecular analysis of tumor samples. Patients had progressed during or after prior standard therapies, and those with active brain metastases were excluded. Initial data from the trial were previously reported at the 2019 ASCO Annual Meeting.

Investigators enrolled a total of 76 patients, including 34 with NSCLC. The NSCLC cohort comprised 19 patients treated during the dose-escalation phase (180 mg to 960 mg) and 15 treated in the expansion phase with the phase II dose of 960 mg. Four patients in the NSCLC cohort discontinued, none because of treatment-related issues.

The 34 patients had a median age of 67.5, and women accounted for a majority (n = 18) of enrollees. All but 3 patients had an ECOG performance status of 0 or 1, and all but 5 had received more than 2 prior lines of therapy (median of 3.5 prior systemic anticancer regimens and a range of 1-8).

Three-fourths of the patients had adverse events during the trial (any grade), and 12 (35.3%) patients had treatment-related adverse events (TRAEs), most of which were grade 1/2. No grade ≥4, serious, or fatal TRAEs occurred, and no patient discontinued the study because of a TRAE. The most common adverse events were diarrhea (n = 4) and nausea (n = 2), and grade 3 toxicity consisted of 2 cases of diarrhea and 1 case of anemia.

The efficacy data focused on 23 patients who had completed the first 6-week CT scan or had early progressive disease. Partial responses and SD occurred across the range of AMG 510 doses evaluated in the study, including all 13 patients treated with the phase II dose. The ORR was 48% in all 23 patients and 54% in the subgroup treated with the phase II dose, and the disease control rates were 96% and 100%, respectively.

Initial response occurred within about 5 weeks for 10 of the 11 patients who had objective responses. The median duration of treatment was 15.1 weeks in responding patients and 10.0 weeks in the 11 patients who had SD.

Following Govindan’s oral presentation, invited discussant Jon Zugazagoitia, MD, PhD, of Hospital 12 de Octubre in Madrid, reserved judgment on the efficacy of AMG 510, saying too few patients had been treated to draw conclusions. He also posed several questions for investigators to consider as clinical evaluation of AMG 510 progresses.

“How will the molecular diversity of KRAS influence AMG 510 efficacy?” Zugazagoitia asked. “What is the impact of co-occurring mutations? What is the impact of KRAS allelic imbalance?”

Govindan R, Fakih M, Price T, et al. Phase 1 study of safety, tolerability, PK and efficacy of AMG 510, a novel KRAS^G12C inhibitor, evaluated in NSCLC. Presented at: IASLC 20th World Conference on Lung Cancer; September 7-10, 2019; Barcelona, Spain. Abstract OA02.02.

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