Clinically Meaningful Benefit in Advanced KRAS G12C+ NSCLC Is Seen With Sotorasib

Patients with advanced non–small cell lung cancer (NSCLC) harboring KRAS G12C mutations benefitted from therapy with sotorasib (formerly AMG 510), an inhibitor of KRAS G12C, which induced a 6.8-month median progression-free survival. These results from the CodeBreaK 100 trial (NCT03600883) were presented at the International Association for the Study of Lung Cancer 2020 World Conference on Lung Cancer Singapore.^1,2

The confirmed objective response rate (ORR) and a disease control rate were 37.1% and 80.6%, respectively, at a median follow-up of 12.2 months. The median duration of response was 10 months.

These data show that sotorasib is the first KRAS G12C inhibitor to show PFS in a phase 2 study, stated Amgen, the manufacturer of the agent.

“These results are encouraging and clinically meaningful for patients with advanced NSCLC harboring the KRAS G12C mutation,” said lead investigator Bob T. Li, MD, PhD, MPH, medical oncologist at Memorial Sloan Kettering Cancer Center. "These are patients who have progressive disease after standard treatment, so they need additional treatments, and the fact that we are seeing rapid tumor shrinkages and durable responses in these patients, is for me a step forward and a win for patients."

In December 2020, the FDA granted a breakthrough therapy designation to sotorasib for use as a potential treatment in patients with KRAS G12C–mutated locally advanced or metastatic NSCLC, as determined via an FDA-approved test, after at least 1 prior systemic treatment.

Sotorasib had been accepted into the FDA’s Real-Time Oncology Review Pilot Program, which is designed to create a more effective review process dedicated to making safe and effective therapies available to patients quickly.

A prior phase 1 study showed consistent data with sotorasib in 35 previously treated patients with KRAS G12C–mutated advanced NSCLC.³ Data showed a 50% response rate in these patients; among 10 evaluable patients with NSCLC, 5 patients had a partial response (PR), with 4 confirmed PRs.

In the phase 2 trial, patients were treated with oral sotorasib at 960 mg once daily.

Eighty-one percent of patients had progressed on prior platinum-based chemotherapy and PD-1/PD-L1 inhibitors; the remainder had progressed after having received 1 of these therapies. The data cutoff date was December 1, 2020.

Additional findings showed that more than 80% of patients achieved disease control, which included 3 complete responses and 43 PRs. The median best tumor shrinkage among all responders (n = 46) was 60%, and the median time to objective response was 1.4 months.

Results of exploratory analyses showed that the clinical activity to sotorasib was observed across a range of biomarker subgroups, including those with PD-L1–negative or –low status, and also those with STK11 mutations. STK11 mutations are generally linked with poorer outcomes in patients with NSCLC who previously received treatment with checkpoint inhibitors and chemotherapy.

Regarding safety, sotorasib showed a favorable benefit-risk profile. The majority of treatment-related adverse events (TRAEs) were of grades 1 or 2, and no treatment-related deaths occurred. Grade 3 TRAEs occurred in 25 (19.8%) patients and 1 patient (0.8%) reported a grade 4 TRAE. The most frequently reported all-grade TRAEs (any grade) were diarrhea (31.0%), nausea (19.0%), increased alanine aminotransferase (15.1%) and increased aspartate aminotransferase (15.1%). Treatment discontinuation rates due to TRAEs occurred in 7.1% of patients.

References:

1. Li BT, Skoulidis F, Falchook G, et al. CodeBreaK 100: Registrational Phase 2 Trial of Sotorasib in KRAS p.G12C Mutated Non-small Cell Lung Cancer. Presented at: International Association for the Study of Lung Cancer 2020 World Conference on Lung Cancer; January 28-31, 2021; virtual. Abstract PS01.07.

2. Amgen's investigational KRAS G12C inhibitor sotorasib demonstrated rapid, deep and durable responses in previously treated patients with advanced non-small cell lung cancer. Amgen. News release. January 28, 2021. Accessed January 28, 2021. https://prn.to/3px7knl

3. 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). doi: 10.1200/JCO.2019.37.15_suppl.3003