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Expert Point of View: Rona Yaeger, MD


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Rona Yaeger, MD

Rona Yaeger, MD

Rona Yaeger, MD, Assistant Attending Physician at Memorial Sloan Kettering Cancer Center, New York, offered her thoughts on the findings of Morris et al for the combination regimen of encorafenib, cetuximab, and nivolumab in microsatellite-stable BRAF V600E–mutated metastatic colorectal cancer patients, as presented at the 2022 ASCO Gastrointestinal Cancers Symposium.

“Microsatellite-stable BRAF V600E metastatic colorectal cancer is usually an aggressive disease, and, while it is great that we now have matched targeted therapy with encorafenib plus cetuximab, we continue to look for ways to refine treatment, to expand activity and prolong response duration,” Dr. Yaeger said. “The data presented at ASCO GI by Dr. Morris for the new combination of encorafenib, cetuximab, and nivolumab show promising initial activity.”

Dr. Yaeger noted that a similar approach is being tested by investigators in the Corcoran lab at Massachusetts General Hospital, who are evaluating a regimen that includes the RAF inhibitor dabrafenib, the MEK inhibitor trametinib, and the PD-1 inhibitor spartalizumab.1 Early data suggest a response rate of about 35% in patients with microsatellite instability–high (MSI-H) plus microsatellite-stable metastatic colorectal cancer, she indicated.

“These studies are single-arm, single-center trials, but the early activity raises the question of whether targeted therapy sensitizes tumors to immune checkpoint inhibitors,” she said. Preclinical data suggest the modulation of ERK signaling may increase antigen expression and T-cell infiltration; however, in metastatic colorectal cancer, combining the MEK inhibitor cobimetinib with the PD-L1 inhibitor atezolizumab did not improve outcomes for microsatellite-stable disease in IMblaze370.2 “Thus, I think it’s unlikely that the effect of encorafenib and cetuximab on the microenvironment enhances sensitivity to nivolumab in microsatellite-stable colorectal cancer,” Dr. Yaeger maintained.

Instead, she posited that the direct tumor effect may create a vulnerability for immune checkpoint inhibition. The growth inhibition from targeted therapy in tumors with mutated BRAF V600E could create a strong selective pressure for new alterations that may overcome the drug inhibition of ERK signaling. Based on recent scientific data, it is possible that this promotes faulty DNA repair—a kind of temporary MSI-H state—to induce mutagenesis and survive drug therapy,3 Dr. Yaeger explained. 

DISCLOSURE: Dr. Yaeger has served as a consultant or advisor to Array BioPharma, Mirati Therapeutics, and Natera.

REFERENCES

1. Corcoran R, Giannakis M, Allen J, et al: Clinical efficacy of combined BRAF, MEK, and PD-1 inhibition in BRAF V600E colorectal cancer patients. Ann Oncol 31:S226-S227, 2020.

2. Eng C, Kim TW, Bendell J, et al: Atezolizumab with or without cobimetinib versus regorafenib in previously treated metastatic colorectal cancer (IMblaze370): A multicentre, open-label, phase 3, randomised, controlled trial. Lancet Oncol 20:849-861, 2019.

3. Russo M, Crisafulli G, Sogari A, et al: Adaptive mutability of colorectal cancers in response to targeted therapies. Science 366:1473-1480, 2019.


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