New molecule omaveloxolone counters checkpoint-inhibitor resistance in melanoma


Photo by Sapna Patel et al., via the European Socienty for Medical Oncology

Findings from an open-label, Phase 1b trial of a novel compound known as omaveloxolone suggest the molecule may be able to overcome checkpoint inhibitor resistance in patients with melanoma.

Published in Annals of Oncology (Dec. 1, 2017; 28(Issue suppl_11) and presented at the European Society for Medical Oncology (ESMO) Immuno Oncology Congress 2017, the paper investigated the safety and efficacy of the new compound in combination treatment with the checkpoint inhibitors ipilimumab or nivolumab. The study population included 30 patients with unresectable or metastatic melanoma. Seven of the patients were naive to checkpoint inhibitors and 23 had prior checkpoint inhibitor treatment.

“Checkpoint inhibitors are a standard of care immunotherapy for metastatic melanoma,” said lead author Dr. Sapna Patel, an assistant professor in the Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center in Houston, in a press release. “However, many patients do not respond because myeloid-derived suppressor cells (MDSCs), a type of inhibitory cell, are present in the tumour micro-environment.”

In earlier animal studies, omaveloxolone inhibited MDSCs and restored immune activity, Dr. Patel said.

“Myeloid-derived suppressor cells (MDSCs) produce reactive nitrogen radicals that alter the receptors on the surface of the tumour to hide it from cytotoxic lymphocytes that kill tumour cells. Omaveloxolone inhibits MDSC activity, suppresses reactive nitrogen radicals, and restores anti-tumour immune responses. Administering omaveloxolone with checkpoint inhibitors may improve the anti-tumour response of these immunotherapies.”

In the checkpoint inhibitor-naive patients, the overall response rate to the combination therapy was 57%. For patients with prior checkpoint inhibitor exposure, the response rate was 17%. Median time to response was 19 weeks, and there were no serious adverse events related to omaveloxolone. It was also well tolerated in combination with ipilimumab or nivolumab.

“Our findings suggest that omaveloxolone may overcome resistance to checkpoint inhibitors. Omaveloxolone in combination with checkpoint blockade had activity in both naive and checkpoint inhibitor refractory melanoma patients,” Dr. Patel said.

“This is one of the first studies to demonstrate a meaningful response rate in the checkpoint inhibitor refractory melanoma population. Further dose escalation and dose expansion studies are underway as well as translational tissue-based experiments to clarify the impact of this treatment combination.”

#Melanoma #Checkpointinhibitor #Ipilimumab #Nivolumab #UniversityofTexas #MDAndersonCancerCenter #DrSapnaPatel #Skincancer

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