Evidence continues to grow that KRAS, once considered an “undruggable” target, can be targeted successfully in non–small cell lung cancer. In a phase I trial, the KRASG12C inhibitor sotorasib elicited responses in about a third of patients with the disease and was generally well tolerated.

Evidence continues to grow that KRAS, once considered “undruggable,” can be targeted successfully in non–small cell lung cancer (NSCLC). In a phase I trial, the KRASG12C inhibitor sotorasib (AMG 510; Amgen) elicited responses in about a third of patients with the disease and was generally well tolerated. Findings were concurrently published and presented at the European Society for Medical Oncology (ESMO) Virtual Congress 2020, September 19–21 (N Engl J Med 2020;383:1207–17).

“Despite the discovery of the KRAS oncogene almost four decades ago, there is currently no approved therapy targeting KRAS,” said David Hong, MD, of The University of Texas MD Anderson Cancer Center in Houston, who presented the results. However, over the past 2 years, drugs that target KRASG12C—a mutation that occurs in about 13% of NSCLCs and 3% to 5% of colorectal cancers—have begun to show promise. One of these agents is sotorasib, a small-molecule inhibitor that works by irreversibly binding to KRAS, locking it in an inactive state.

In early clinical testing, sotorasib had a manageable safety profile and led to responses in several solid cancers—notably NSCLC. At ESMO, Hong presented updated results from 59 patients with locally advanced or metastatic NSCLC and KRASG12C mutations enrolled in the phase I CodeBreak 100 trial. These patients had received a median of three prior therapies, and 90% were current or former smokers. The trial also included patients with colorectal, pancreatic, endometrial, and appendiceal cancers, and melanoma.

Nineteen patients with NSCLC responded to sotorasib, and 33 more experienced stable disease. Median progression-free survival was 6.3 months and median duration of response was 10.9 months. Overall, 66.1% of patients with NSCLC experienced treatment-related adverse events—most commonly diarrhea and elevated liver enzymes—and 18.6% of patients experienced grade 3 or 4 adverse events. “The overall trial showed really excellent safety—we didn' t find any [dose-limiting toxicities],” Hong said, adding that “many of the patients have been able to tolerate this [drug] for long periods of time.” Based on the safety and efficacy, researchers selected the highest dose, 960 mg, for phase II testing.


“The efficacy for smoking-related lung cancer, I think, continues to be impressive,” said Colin Lindsay, MD, PhD, of the University of Manchester in the UK, who provided commentary on the trial. He added that he was also struck by the drug' s activity: Even at doses of 180, 360, and 720 mg, patients experienced partial responses. The drug' s potency at lower doses may be important if it is combined with other agents, Hong said, and additive side effects necessitate dose reductions.

“The results of this trial are very encouraging, showing the first step in ‘drugging the undruggable,’” wrote Patricia LoRusso, DO, of Yale University School of Medicine in New Haven, CT, and Judith Sebolt-Leopold, PhD, of the University of Michigan Rogel Cancer Center in Ann Arbor, in an editorial (N Engl J Med 2020;383:1277–8). “Tumor responses were much better than those seen with the current standard of care for patients with similar disease profiles,” although there were no complete responses—perhaps because KRAS-mutant tumors often have multiple oncogenic drivers.

To address this possibility, “we are rapidly moving into combination trials,” Hong said, testing sotorasib with agents that inhibit EGFR, MEK, SHP2, PD-1/PD-L1, and other targets in the multiarm CodeBreak 101 trial.

Combination trials may also provide clues about resistance mechanisms. For example, CodeBreak 100 researchers reported that only 7.1% of patients with colorectal cancer responded to sotorasib. Recent preclinical research suggests that EGFR is a key resistance mechanism in the disease and that EGFR inhibitors may have a synergistic effect when combined with sotorasib—making this a compelling combination for clinical testing (Cancer Discov 2020;10:1129–39).

“There are a lot of exciting things to come … in the future,” Hong said. “I think the next couple years are going to keep me and a number of different investigators pretty busy.” –Catherine Caruso

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