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Sotorasib Shows Clinically Meaningful Activity Among Patients With KRAS G12C–Mutated Advanced Pancreatic Cancer


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The KRAS G12C inhibitor sotorasib demonstrated clinically meaningful anticancer activity with an acceptable safety profile in heavily pretreated patients with KRAS G12C–mutated metastatic pancreatic cancer, according to a novel study published by Strickler et al in The New England Journal of Medicine.

Background

Mutations in KRAS have been known to drive abnormal cancer growth and are especially common in pancreatic cancers—occurring in about 90% of patients—while KRAS G12C mutations are present in 1% to 2% of cases.

Sotorasib—a small-molecule inhibitor capable of irreversibly binding the mutant KRAS G12C protein to lock it in an inactive state—was approved by the U.S. Food and Drug Administration (FDA) in 2021 for the treatment of KRAS G12C–mutated metastatic non–small cell lung cancer.

Study Methods and Results

The results of the phase I/II CodeBreaK 100 trial (ClinicalTrials.gov identifier NCT03600883), indicated an objective response rate of 21.1% and a median time-to-response of 1.5 months, with 84% of patients experiencing disease control. Median progression-free survival was 4 months and overall survival was 6.9 months.

“These are encouraging early data because they point toward establishing that KRAS [G12C] inhibitors can work in pancreatic cancers, which have been difficult to crack from a targeted therapy standpoint,” highlighted principal investigator David S. Hong, MD, Professor of Investigational Cancer Therapeutics in the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center. “We look forward to data from larger trials as we continue working to bring much-needed new therapies to these patients.”

In the novel study, the researchers enrolled 38 patients with metastatic pancreatic cancer who had a median of two prior lines of therapy. The participants had a median age of 65.5 years, 76.3% were male, and 55.3% had stage IV pancreatic cancer at their initial diagnoses.

All patients experienced treatment-emergent adverse events—including abdominal pain in 36.8% of patients, and diarrhea and nausea in 23.7% of patients—which were reported in 42.1% of patients, of which 15.8% were grade 3. The most frequently occurring grade 3 toxicities were diarrhea and fatigue, both present in 5.3% of the participants. No adverse events resulted in discontinuation of treatment.

Conclusions

Dr. Hong and his colleagues noted that these results may be a harbinger of success for other drugs in the pipeline targeting KRAS-mutated cancer that could potentially benefit far greater numbers of patients.

“It’s gratifying to see results like this, since targeting [KRAS-mutated cancer] seemed virtually impossible just a few years ago. Still, we must continue our research efforts to make progress against other common KRAS mutations found in pancreatic and other cancer types,” Dr. Hong emphasized, concluding that “Trials have recently begun on drugs targeting KRAS G12D, a much more common mutation in pancreatic cancer, as well as some pan-RAS therapies, which target multiple mutations.”

Disclosure: The research in this study was funded by Amgen and supported in part by the National Institutes of Health, the Cancer Prevention and Research Institute of Texas, and the Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy at The University of Texas MD Anderson Cancer Center. For full disclosures of the study authors, visit nejm.org.

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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