Potential Strategies to Fight KRAS Inhibitor Resistance in Lung Cancer Uncovered

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Two possible add-on drugs that could help fight resistance to KRAS inhibitors such as Amgen’s sotorasib (Lumakras) have been discovered, according to research presented at the 2021 Molecular Targets and Cancer Therapeutics conference.

The studies are both early stage—one Phase Ib testing afatinib and one testing an Aurora Kinase A (AURKA) inhibitor in preclinical tests—but show promising signs of being able to circumvent non-small cell lung cancer (NSCLC) resistance to sotorasib.

KRAS-mutated NSCLC comprise around 30% of all lung cancers and are difficult to treat. Sotorasib is the first therapy developed to target KRAS mutations in cancer and was approved by the FDA in May to treat NSCLC with a KRAS-G12C mutation.

“KRAS was considered an undruggable target until recently and the approval of the first direct KRAS-G12C inhibitor, sotorasib, by the U.S. Food and Drug Administration was a crucial milestone for targeted treatment of lung cancer,” commented the presenter of the afatinib study, David Gandara, professor at the UC Davis Comprehensive Cancer Center, in a press statement.

“While inhibitors of KRAS-G12C have been heralded as a significant breakthrough, resistance can develop rapidly through adaptive signaling mechanisms that lead to reactivation of mutant KRAS,” added the presenter of the AURKA inhibitor study Jong Woo Lee, a research scientist in medical oncology at Yale Cancer Center.

The afatinib Phase Ib study is part of CodeBreaK 101, a multi-arm master trial that is assessing a number of different anticancer agents in combination with sotorasib.

Overall, 33 patients with KRAS-G12C mutated NSCLC who had progressed on prior treatment, including KRAS-G12C inhibitors, were enrolled. In total, 10 received 20 mg afatinib/960 mg sotorasib and 23 pts received 30 mg afatinib/960 mg sotorasib over a period of 64 days.

The rate of disease control, those with complete or partial response, or stable disease, was 70% in the lower dose cohort and 74% in the higher dose cohort, respectively. Of five patients who had previously progressed on sotorasib alone, three had stable disease, one progressed and one withdrew to an adverse event. Serious adverse events occurred in 30% of each cohort, with diarrhea being the most common.

“The sotorasib/afatinib combination showed antitumor activity, including a high degree of disease control, in patients previously progressing on sotorasib alone, providing proof of principle for the rationale of combining HER family inhibitors with KRAS inhibitors,” said Gandara.

In the other study, AURKA inhibition in combination with either WEE1 or KRAS inhibition was assessed in a KRAS-mutated NSCLC cell line.

Lee and colleagues found that adding an investigational AURKA inhibitor to sotorasib seemed to increase cancer cell death in sotorasib-resistant cancer cells. Adding WEE1 inhibition to AURKA inhibition also seemed to increase cancer cell death.

“Our results suggest that AURKA activation may contribute to intrinsic and acquired resistance to sotorasib in KRAS-mutated lung cancer cells and that inhibition of AURKA may be a promising therapeutic approach in this setting,” said Lee.

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