Novel KRAS Inhibitor Shows Activity in Early Study of Advanced Non–Small Cell Lung Cancer

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The investigational KRAS inhibitor AMG 510 yielded clinical activity in patients with advanced non–small cell lung cancer (NSCLC), according to updated results of a small ongoing phase I trial reported at the 2019 International Association for the Study of Lung Cancer (IASLC) World Conference on Lung Cancer (WCLC).1 The novel agent targets KRAS, formerly considered an undruggable target.

In the overall phase I study population, 96% of patients had disease control, and about half had partial responses. In patients treated with the highest dose, the disease control rate was 100%.

KRAS GC12–mutant lung adenocarcinoma is one of the largest subsets of NSCLC potentially amenable to targeted therapies.
— Ramaswamy Govindan, MD

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“Lung cancer is increasingly seen as a disease of multiple subtypes. One of the most common is KRAS GC12, with is overactivated in about 13% of lung adenocarcinomas. This mutation is difficult to target. AMG 510 is one of the first-in-class small-molecule inhibitors that binds to this mutant protein, locking in anticancer activity. As it is a customized drug, fewer toxicities are expected,” said lead author Ramaswamy Govindan, MD, of Washington University School of Medicine, St. Louis.

KRAS GC12–mutant lung adenocarcinoma is one of the largest subsets of NSCLC potentially amenable to targeted therapies. I am pleased that we have a promising new oral therapy for this group of patients. These data continue to show encouraging antitumor activity with AMG 510, underscoring the potential to close the treatment gap for patients with previously treated KRAS GC12–mutated NSCLC,” Dr. Govindan said.

Study Details

The phase I study enrolled 76 patients, including 34 with locally advanced or metastatic NSCLC treated with previous standard therapy. The NSCLC cohort included 19 patients treated in the dose-escalation phase and 15 treated with the highest dose in the phase II dose-expansion phase. The study was designed to assess toxicity and efficacy, including objective response rate, duration of response, disease control rate, progression-free survival, and duration of stable disease. Patients were enrolled in four dose cohorts: 180 mg, 360 mg, 720 mg, and 960 mg. The phase II dose going forward is 960 mg.

The phase I study was initiated 1 year ago, and the first results were presented at the 2019 ASCO Annual Meeting.2 At the 2019 WCLC, Dr. Govindan presented updated results on the NSCLC cohort of 34 patients.

The median age of patients in the NSCLC cohort was 67.5 years, and there were 18 women and 16 men. Th median number of prior anticancer therapies was 3.5 (range, 1–8).

AMG 510 in Lung Cancer

  • The novel KRAS inhibitor AMG 510 exhibited 100% disease control in pretreated patients with advanced NSCLC treated at the highest dose level.
  • These preliminary data are encouraging for a target expressed in about 13% of NSCLCs, and further study is ongoing.

Efficacy was evaluable in 23 patients who had 6-week computed tomography or had evidence of progressive disease (1 patient). Eleven patients had partial responses, and 11 additional patients had stable disease, for a disease control rate of 96%. Of the 13 patients treated at the highest dose level, the disease control rate was 100% (54% partial response, 46% stable disease).

“There was no disease progression observed on the first lung scan in patients treated at the highest dose,” Dr. Govindan told listeners.

Of the 11 patients with a partial response, 8 were still on study at the time of Dr. Govindan’s presentation. “Partial responses occur fairly quickly, and many are still ongoing. Five patients have been in response for 6 months or more, and 1 patient, for 8 months,” he noted.

“This is clearly an encouraging set of data. We see responses at all dose levels. And, as expected, there were minimal toxicities,” Dr. Govindan added.


Of all 34 patients, 76% had adverse events of any grade that were mostly disease-related. Twelve patients (35.3%) reported treatment-related adverse events, mostly grades 1 and 2 nausea and vomiting. Three patients had grade 3 treatment-related adverse events (anemia and diarrhea). There were no dose-limiting toxicities and no drug discontinuations reported.

“This drug works the way it is intended to. The data are encouraging and quite striking. Early data suggest that responses are durable,” Dr. Govindan said.

Ongoing studies include a phase I study of combination therapy with AMG 510 and a phase II study of monotherapy. 

DISCLOSURE: Dr. Govindan has served as a consultant or advisor to AbbVie, Adaptimmune, AstraZeneca, Celgene, Ignyta, Inivata, Merck, Nektar, Pfizer, and Roche.


1. Govindan R, Fakih M, Price T, et al: Phase 1 study of safety, tolerability, PK, and efficacy of AMG 510, a novel KRASGC12 inhibitor, evaluated in NSCLC. 2019 World Conference on Lung Cancer. Abstract OA2.02. Presented September 8, 2019.

2. Fakih M, O’Neil B, Price TJ, et al: Phase 1 study evaluating the safety, tolerability, pharmacokinets, and efficacy of AMG 510, a novel small molecule KRASG12C inhibitor, in advanced solid tumors. 2019 ASCO Annual Meeting. Abstract 3003. Presented June 3, 2019.

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Alex A. Adjei, MD, PhD, of the Mayo Clinic, Rochester, Minnesota, also commented on this phase I study of AMG 510. “Although it is a little bit early to tell and the number of patients with non–small cell lung cancer treated is still small, AMG 510 is the first...