Dr Moser on Treatment Considerations After Progression on Frontline PD-1 Inhibitors in Melanoma

"One of the challenges we have in melanoma is that the vast majority…of FDA-approved treatments that are still clinically relevant today are approved in the frontline setting. [Therefore, it’s hard to know what the best option is for [a patient in the] second-line. [However], based on retrospective data, it looks like the chance of [a patient] benefiting from a second-line checkpoint inhibitor–based combination depends on how well they responded in the first line."

Justin Moser, MD, a medical oncologist at HonorHealth and an associate clinical investigator at HonorHealth Research Institute, discussed therapeutic decision-making for patients with advanced melanoma who progress following initial treatment with checkpoint inhibitor–based combinations, such as nivolumab (Opdivo) plus ipilimumab (Yervoy) or nivolumab plus relatlimab-rmbw (Opdualag).

A major clinical challenge in this setting is that most FDA-approved regimens are indicated in the frontline setting, leaving limited guidance or prospective data to inform second-line strategies, Moser began. For patients without a BRAF mutation, the most accessible second-line options remain other checkpoint inhibitor combinations, Moser stated. However, the utility of these regimens is highly dependent on the patient’s initial response to immunotherapy, Moser stated.

Retrospective data suggest that patients who achieve a clinical benefit—such as partial response, complete response, or prolonged disease stability—before developing resistance to first-line checkpoint blockade have an approximately 30% to 33% chance of responding to a different checkpoint combination in the second-line setting, Moser stated. In these cases, re-challenging with another immunotherapy combination may be reasonable, particularly if the initial benefit was durable, Moser stated.

In contrast, for patients with primary resistance to frontline checkpoint inhibition—defined as no clinical benefit or early progression—the likelihood of response to a subsequent immunotherapy-based approach is low, likely under 10%, Moser stated. For these patients, non–checkpoint inhibitor–based strategies may be more appropriate, including clinical trial enrollment or other agents with alternative mechanisms of action, Moser stated.

Evaluating how a patient responded to their initial therapy is essential when determining appropriate next steps, Moser stated. He emphasized the need for prospective studies to better guide post–checkpoint inhibitor treatment, particularly for patients without actionable mutations, and underscored the importance of ongoing research to address resistance and expand second-line options for this population.

Although checkpoint inhibitors have transformed melanoma treatment, patients with dual checkpoint inhibitor–refractory disease are unlikely to benefit from additional checkpoint-based therapies, Moser stated. If patients responded to a prior checkpoint inhibitor and maintained benefit, re-challenge may be reasonable; otherwise, alternative strategies are needed, Moser asserted. Novel immune approaches, including cell therapies like tumor-infiltrating lymphocytes and investigational cytokines with improved delivery mechanisms, are showing early promise in phase 1 trials and may soon expand available options, Moser concluded.