Phase II CodeBreak 100 Validates Benefit of KRAS Inhibitor Sotorasib in Advanced Lung Cancer

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The registrational phase II CodeBreak 100 trial has validated the power of KRAS inhibition with sotorasib (AMG 510) in advanced non–small cell lung cancer (NSCLC).1 In a follow-up to the groundbreaking findings of the phase I trial, the phase II cohort 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. The results were presented at the International Association for the Study of Lung Cancer 2020 World Conference on Lung Cancer in Singapore, which was held in a virtual format in January 2021.

“This is a historic milestone in lung cancer therapy,” said Bob T. Li, MD, PhD, MPH, of Memorial Sloan Kettering Cancer Center, New York, who presented the first registrational phase II data from CodeBreak 100. “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.”

Bob T. Li, MD, PhD, MPH

Bob T. Li, MD, PhD, MPH

Despite its discovery nearly 40 years ago, KRAS—the most frequently mutated oncogene—has remained “undruggable,” lacking an approved targeted therapy. Sotorasib is a first-in-class small molecule that specifically and irreversibly inhibits KRAS p.G12C, which is responsible for approximately 13% of lung adenocarcinomas and is associated with poor patient outcomes. Sotorasib traps GDP-bound KRAS p.G12C in its inactive state, thus “shutting down” oncogenic signaling and tumorigenesis.

At a press briefing, Dean A. Fennell, PhD, FRCP, Professor and Chair of Thoracic Medical Oncology, University of Leicester and University Hospitals of Leicester NHS Trust in the United Kingdom (UK), commented that the findings were “absolutely remarkable.” He noted: “The undruggability of KRAS has been something of a challenge for decades. I’m quite proud to be in the same meeting where these data were presented.”

“The undruggability of KRAS has been something of a challenge for decades. I’m quite proud to be in the same meeting where these data were presented.”
— Dean A. Fennell, PhD, FRCP

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“In the UK, our center and others screen for KRAS routinely—but without any purpose really. I’d like to think that, based on this evidence, this will be a new stratified treatment option for us,” Dr. Fennell added.

About CodeBreak 100

The global open-label phase I/II CodeBreak 100 trial evaluated sotorasib administered orally at 960 mg/d to 126 patients with advanced NSCLC and a centrally confirmed KRAS p.G12C mutation. Patients had experienced disease progression after up to three lines of therapy, including platinum-based chemotherapy and/or agents targeting PD-1/PD-L1. More than 80% of patients had experienced disease progression on both chemotherapy and PD-1/PD-L1 inhibitors.

The primary endpoint was objective response by blinded independent central radiology review. Patients were followed for a median of 12.2 months.

Key Outcomes and Toxicity

Of 124 evaluable patients, 46 patients (37.1%) had a confirmed response, including 3 patients with a complete response; disease control was achieved by 80.6%. The median time to response was 1.4 months, and the median duration of response was 10 months. As of data cutoff, 43% of responders remained on treatment without disease progression, and the median progression-free survival was 6.8 months, Dr. Li reported.

“Some 81% of patients had some tumor shrinkage of any magnitude, and the median percentage of best tumor shrinkage among all responders was 60%. This is suggestive of the depth of response to sotorasib,” he added.

In the exploratory biomarker analysis, tumor response to sotorasib was observed across a range of biomarker subgroups, including patients with negative or low expression of PD-L1 and those with mutant STK11 and TP53. Responses to sotorasib were durable and rapid, as 72% of patients had responses observed at the first assessment in week 6.

The phase II results were consistent with those of the previously reported phase I cohort in the CodeBreak 100 trial, commented Dr. Li. In the phase I cohort, sotorasib produced confirmed responses in 32.2%, with a median duration of response of 10.9 months and a median progression-free survival of 6.3 months.2

Treatment-related adverse events of any grade occurred in 69.8% and led to treatment discontinuation in 7.1% and dose modification in 22.2%. Grade 3 treatment-related adverse events were reported in 19.8%, including alanine aminotransferase increase (6.3%), aspartate aminotransferase increase (5.6%), and diarrhea (4.0%). There were no treatment-related deaths.

Breakthrough Therapy designation for sotorasib has been granted by the U.S. Food and Drug Administration (FDA), and regulatory filings have been submitted to the FDA and European Medicines Agency. A confirmatory phase III trial, CodeBreak 200, is currently enrolling patients. 

DISCLOSURE: Dr. Li has served as a consultant or advisor to Guardant Health and Hengrui Therapeutics; has received institutional research funding from Amgen, AstraZeneca, Daiichi Sankyo, GRAIL, Guardant Health, Hengrui Therapeutics, Lilly, MORE Health, and Roche/Genentech; has institutional intellectual property rights from Karger Publishers and is an inventor on two institutional patents at MSK (US62/514,661 and US62/685,057); has been reimbursed for travel, accommodations, or other expenses by Jiangsu Hengrui Medicine and MORE Health; and has served as an uncompensated advisor to Amgen, AstraZeneca, Boehringer Ingelheim, Genentech, and Lilly. Dr. Fennell has received honoraria from Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Inventiva, Novocure, RS Oncology, and Targovax; has served as a consultant or advisor to Bristol Myers Squibb, Inventiva, Novocure, Roche, and Targovax; has participated in a speakers bureau for Boehringer Ingelheim and Bristol Myers Squibb; has received research funding from Astex Pharmaceuticals and Bayer; has received institutional research funding from Boehringer Ingelheim, Fuji Pharma, and lab21; and has been reimbursed for travel, accommodations, or other expenses by Bristol Myers Squibb and MSD Oncology.


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. 2020 World Conference on Lung Cancer. Abstract PS01.07. Presented January 30, 2021.

2. Hong DS, Fakih MG, Strickler JH, et al: KRAS G12C inhibition with sotorasib in advanced solid tumors. N Engl J Med 383:1207-1217, 2020.

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