First-in-Class Inhibitor Induces Responses in KRAS G12C+ NSCLC

Half of patients with&nbsp;<em>KRAS</em> G12C&ndash;positive advanced non&ndash;small cell lung cancer achieved a response from treatment with the&nbsp;investigational KRAS G12C inhibitor, AMG 510, in a phase I study presented at the 2019 ASCO Annual Meeting.

Marwan Fakih, MD

Half of patients withKRASG12C—positive advanced non–small cell lung cancer (NSCLC) achieved a response from treatment with the investigational KRAS G12C inhibitor, AMG 510, in a phase I study presented at the 2019 ASCO Annual Meeting.

The study has thus far examined the first-in-class irreversible inhibitor of KRAS G12C in 35 patients with NSCLC (n =14), colorectal cancer (CRC; n = 19), and appendix cancer (n = 2). Among 10 evaluable patients with NSCLC, 5 patients had a partial response (PR), with 4 confirmed PRs. The best response was stable disease in the non-NSCLC population.

“AMG 510 has been safe and well tolerated at dose levels tested in 35 patients in dose exploration. Preliminary monotherapy antitumor activity inKRASG12C—positive NSCLC was observed,” said lead investigator Marwan Fakih, MD, City of Hope.

There are no approved targeted agents forKRASG12C, which Fakih explained is “found in approximately 13% of lung cancers, 3% of colorectal and appendix cancers, and 1% to 3% in other solid tumors.”

Fakih added that “AMG 510 is a novel, first-in-class, small molecule that specifically and irreversibly inhibits KRAS G12C by locking it in an inactive GDP-bound state.”

The ongoing first-in-human, multicenter, open-label phase I study (NCT03600883) is enrolling patients with locally advanced or metastaticKRASG12C—positive solid tumors previously treated with standard therapy. Patients with active brain metastases are ineligible.

Study dosing began by enrolling 2 to 4 patients in each of four dose cohorts: 180 mg, 360 mg, 720 mg, and 960 mg. After a dose was determined to be safe, additional patients could be added to the cohort. Treatment was administered orally once daily until disease progression, intolerance, or consent withdrawal. Dose escalation was allowed.

At the data cutoff date, 29 of 35 patients were evaluable, including 10 with NSCLC, 18 with CRC, and 1 with appendix cancer. Overall, 26 patients remained on trial and 9 patients had discontinued treatment, all due to progressive disease.

Across all 35 patients, the median age was 55 years (range, 33-77), 40% of patients were male, and 60% were female. Eighty-eight percent of patients were white. The ECOG performance status was 0 for 20% of patients, 1 for 77% of patients, and 2 for 3% of patients. All patients had received at least 2 lines of prior systemic therapy.

All 5 NSCLC patients who achieved a PR are still on treatment. Four other patients with NSCLC achieve stable disease. There were 14 patients with CRC or appendix cancer who achieved stable disease.

Among the NSCLC responders, the duration of treatment as of April 4, 2019, ranged from 7.3 to 27.4 weeks. The duration ranged from 8.4 to 25.1 weeks among patients with NSCLC who had stable disease. Among patients with CRC/appendix cancer, the treatment duration ranged from 7.3 to 24.0 weeks.

Fakih offered details of 2 of the NSCLC responders. The first was a 61-year-old woman diagnosed in August 2010 withKRASG12C—positive metastatic NSCLC. She received several therapies, including chemotherapy, radiation, and nivolumab (Opdivo). In September 2018, she initiated treatment with AMG 510 at 180 mg. She had a 34% reduction in tumor size and was still on trial as of the data cutoff, having been on treatment for 27.4 weeks.

The second patient was a 59-year-old male patient who was diagnosed withKRASG12C—positive NSCLC in December 2013. He received several treatments, including chemotherapy, erlotinib (Tarceva), nivolumab, dasatinib, and the targeted biologic M3541. He initiated treatment with AMG 510 at 360 mg in December 2018. The patient remained on treatment at the data cutoff, with a 67% reduction in tumor size. His treatment duration at the cutoff was 14.3 weeks.

Grade 1 treatment-emergent adverse events (TEAEs) included diarrhea (n = 3), decreased appetite (n = 2), nausea (n = 2), elevated creatine phosphokinase (n = 2), and 1 incidence each of elevated/change AST, elevated/change ALT, elevated ALP, dry mouth, flatulence, vomiting, fatigue, WBC decrease, pyrexia, arthralgia, and hot flush.

Grade 2 TEAEs included 1 incidence each of elevated/change AST, elevated/change ALT, elevated ALP, cheilitis, hyperkalemia, and proteinuria. There were 2 grade 3 AEs, anemia and diarrhea. There were no dose-limiting toxicities, grade 4 TEAEs, or serious TEAEs.


Fakih M, O'Neil B, Price TJ, et al. Phase 1 study evaluating the safety, tolerability, pharmacokinetics (PK), and efficacy of AMG 510, a novel small molecule KRASG12C inhibitor, in advanced solid tumors.J Clin Oncol.2019;37 (suppl; abstr 3003).