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Phase II CodeBreak 100 Validates Early Benefit for KRAS Inhibitor in NSCLC


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The phase II CodeBreak 100 trial has validated the power of KRAS inhibition with sotorasib (AMG 510) in patients with advanced non–small cell lung cancer (NSCLC). In a follow-up to phase I data, the phase II cohort of the study has now shown a durable response rate of 37.1%, a disease control rate of 80.6%, and a median progression-free survival of 6.8 months, according to results presented at the International Association for the Study of Lung Cancer 2020 World Conference on Lung Cancer Singapore, which was moved to a virtual format and held January 28–31, 2021, in light of the COVID-19 pandemic (Abstract PS01.07).

Sotorasib is a first-in-class small molecule that specifically and irreversibly inhibits KRAS p.G12C, a mutation that occurs in approximately 13% of cases of NSCLC.

Bob T. Li, MD, PhD, MPH

Bob T. Li, MD, PhD, MPH

“This is a historic milestone in lung cancer therapy. After 4 decades of scientific efforts in targeting KRAS, sotorasib has the potential to be the first targeted treatment option for this patient population with a high unmet need,” said Bob T. Li, MD, PhD, MPH, of Memorial Sloan Kettering Cancer Center, who presented the first registrational phase II data from CodeBreak 100.

Dr. Li noted that 81% of patients had some tumor shrinkage of any magnitude, and tumors shrank by an average of about 60%.

“This is suggestive of the depth of response to sotorasib,” he said.

Dean A. Fennell, MD, PhD, Professor and Chair of Thoracic Medical Oncology at the University of Leicester and University Hospitals of Leicester NHS Trust in the United Kingdom, commented at a press briefing, “It’s absolutely remarkable. The ‘un-druggability’ of KRAS has been something of a challenge for decades. To see results like this from Dr. Li is absolutely fabulous.”

About CodeBreak 100

The open-label phase I/II study enrolled 126 patients with advanced NSCLC and a centrally confirmed KRAS p.G12C mutation. Patients had shown disease progression after three or fewer lines of therapy, including agents targeting PD-1/PD-L1 and/or platinum-based combination chemotherapy, or targeted therapy if they harbored EGFR, ALK, or ROS1 alterations.  

Patients were treated with oral sotorasib at 960 mg daily and followed for a median of 12.2 months. Of the 124 patients, 46 patients had a confirmed response (3 complete responses), resulting in an objective response rate of 37.1% (95% confidence interval = 28.6%–46.2%); 80.6% achieved disease control. The median time to response was 1.4 months, and the median duration of response was 10 months. Treatment without disease progression was observed in 43% of responders, and median progression-free survival was 6.8 months, reported Dr. Li.

In the previously reported phase I cohort in the CodeBreak 100 trial, sotorasib was well tolerated and demonstrated a confirmed response rate of 32.2%, a median duration of response of 10.9 months, and a median progression-free survival of 6.3 months.

Treatment-related adverse events of any grade occurred in 88 patients (69.8%) and led to discontinuation in 9 (7.1%). Grade 3 treatment-related adverse events were reported in 25 (19.8%) patients, including alanine aminotransferase increase (6.3%), aspartate aminotransferase increase (5.6%), and diarrhea (4.0%). There were no treatment-related deaths.

Further clinical trials of sotorasib, either alone or in combination with other cancer drugs, are ongoing. The new drug application for sotorasib has been granted Breakthrough Therapy designation by the U.S. Food and Drug Administration.

Disclosure: For full disclosures of the study authors, visit wclc2020.iaslc.org/disclosures.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
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