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Adagrasib for Patients With Advanced KRAS G12C–Mutated NSCLC

Treatment with the KRAS G12C inhibitor adagrasib showed clinical activity in patients with advanced non–small cell lung cancer (NSCLC) harboring a KRAS G12C mutation, confirming its role as a therapeutic target. Results from the KRYSTAL-1 trial were reported at the European Lung Cancer Virtual Congress 2021 by Gregory J. Riely, MD, PhD.

“As we strive to identify the oncogenic driver in more and more of our patients with NSCLC, it becomes critical that we develop therapies that can target these identified oncogenic drivers,” said Dr. Riely, of Memorial Sloan Kettering Cancer Center. “KRAS mutations are the most frequent oncogenic driver that we see in patients with NSCLC, and we’ve known about KRAS-mutant NSCLC for 30 years. We are now, finally, seeing drugs that can target this subgroup of patients.”

KRYSTAL-1 Findings

The multicohort phase I/II KRYSTAL-1 study evaluated adagrasib, a selective inhibitor of KRAS G12C, in 79 patients with advanced or metastatic NSCLC harboring a KRAS G12C mutation. Most (92%) of the patients had previously been treated with chemotherapy and an anti–PD-1/PD-L1 therapy.

Results showed that nearly half (45%) of the 51 patients evaluable for clinical activity had a partial response to treatment with adagrasib, and 26 patients had stable disease.

“The 45% response rate is unprecedented activity in patients with KRAS G12C–mutant NSCLC,” commented Myung-Ju Ahn, MD, PhD, of Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. “A response of this magnitude could not be expected with other chemotherapy or immunotherapy in pretreated patients [with a KRAS mutation], suggesting that KRAS G12C is a therapeutic target.” She considered the finding is potentially practice-changing, although further studies are needed as long-term follow-up data are currently limited.

The results with adagrasib are comparable to those with another KRAS G12C inhibitor, sotorasib, reported earlier this year at the World Conference on Lung Cancer 2021.

“Finding another promising targeted agent against KRAS G12C–mutant NSCLC sheds light on the treatment of these patients who currently have unmet medical need,” said Dr. Ahn. KRAS G12C mutations occur in around 14% of patients with lung adenocarcinomas, the most common subtype of NSCLC, but there is currently no approved KRAS-targeting therapy.

Further data from KRYSTAL-1 showed an even greater response to adagrasib in the subpopulation of patients whose tumors had an STK11 mutation as well as a KRAS G12C mutation. STK11 mutations have been associated with inferior responses to immune checkpoint inhibitors in patients with NSCLC.

Dr. Riely noted, “Finding that the response rate was higher for patients with STK11 mutations suggests that this group of patients, who otherwise don’t benefit from checkpoint inhibitors, may have even better response to adagrasib.”

Future Therapeutic Role for Adagrasib

“Having more KRAS G12C inhibitors gives us additional opportunities to explore combinations of these inhibitors with other classes of agents, including immune checkpoint inhibitors, as well as other small-molecule MAP kinase inhibitor combinations,” said Dr. Riely.

“The current data really set up future trials to establish the role for adagrasib in patients with KRAS G12C–mutant NSCLC. They provide a particular opportunity to explore this drug’s activity in patients with KRAS G12C–mutant NSCLC that have been previously treated with platinum-based chemotherapies to potentially submit for regulatory approval.”

If approved, he suggested, “I think this would clearly set adagrasib as a preferred second-line therapy, compared with chemotherapy, for patients with KRAS mutant–NSCLC.”

“Given the low toxicity, adagrasib could potentially be combined with chemotherapy, immunotherapy, or other molecules to increase activity in patients with KRAS G12C–mutant NSCLC,” suggested Dr. Ahn.

From ASCO (American Society of Clinical Oncology, Inc.) - March 26, 2021


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