Combination Immunotherapy Treatment for Patients With Metastatic Melanoma

Combination Immunotherapy Treatment for Patients With Metastatic Melanoma

In the following article, Nikhil I. Khushalani, MD, and Vernon K. Sondak, MD, answer a question posed by an attendee during a 2015 Best of ASCO® Meeting. Dr. Khushalani is a medical oncologist and associate member in the Department of Cutaneous Oncology at Moffitt Cancer Center, and Dr. Sondak is chair of the Department of Cutaneous Oncology and director of Surgical Education at Moffitt Cancer Center.

Dr. Nikhil I. Khushalani

Question: Are we putting the cart before the horse by adding dual immunotherapy agents in study designs when we haven’t defined and identified predictive markers to select patient populations to test immunotherapy modalities?

Answer: There has been dramatic progress in the treatment of unresectable metastatic melanoma since 2011, with major treatment paradigm changes brought about by seven different U.S. Food and Drug Administration drug approvals that have occurred during that time. Immune checkpoint inhibition with ipilimumab, nivolumab, or pembrolizumab can produce durable responses that may equate to cure in a subset of patients with metastatic melanoma.

Dr. Vernon K. Sondak Photo courtesy of Todd Buchanan

Whereas previous pessimistic views about melanoma therapeutics are being negated by rapid discovery, the enthusiasm for optimizing efficacy has far outpaced the development of biomarkers to predict response—and toxicity—from these agents. The response rate to single-agent anti–PD-1 therapy in ipilimumab-naive metastatic melanoma is 33% to 44% (complete response [CR] rate is 6% to 8%), with 1-year survival approximating 70%.1-3 Higher response rates and more CRs have been reported (Table) in peer-reviewed data from trials of combination immunotherapy (ipilimumab plus an anti–PD-1 agent, usually nivolumab).2,4,5

Many of the responses to combination treatment were ongoing at the time of reporting. However, the high rate of grade 3 and 4 toxicity is remarkably consistent across phase I, II, and III studies, and more than one-third of patients in the larger trials had to stop therapy because of adverse effects.2,5

It is not known whether the pattern of higher response to the combination immunotherapy translates into meaningful survival benefit over sequential single-agent therapy. Until final data are reported, we believe that combination immunotherapy as currently approved in the United States (nivolumab 1 mg/kg, followed by ipilimumab 3 mg/kg on the same day, every 3 weeks for 4 doses, then nivolumab 3 mg/kg every 2 weeks) should only be offered to carefully selected patients with bulky, symptomatic, or rapidly progressive disease. This “high-risk, high-reward” approach of combination immunotherapy is not applicable to all patients at this time. Obviously, this recommendation could change quickly depending on the mature survival results of ongoing trials involving ipilimumab, nivolumab, or pembrolizumab.

Biomarkers examining the phenotype and genotype are desperately needed in our quest to personalize immunotherapy in melanoma. Data on PD-L1 expression by immunohistochemistry, although intriguing, have been inconsistent and require improved standardization before they can be routinely used by clinicians to predict, for example, which patients might benefit from combination immunotherapy from the outset.

Investigation of the tumor microenvironment (inflammatory infiltrates), tumor genomics, blood and serum predictors (lymphocyte count, cytokine levels), and the gut microbiome are examples of active biomarker discovery research. Identification of clinically applicable predictive biomarkers for immunotherapy will likely prove more difficult and complex than the direct relationship between BRAF mutation status and the response to molecularly targeted drugs.

This elusiveness, however, should not hamper clinical progress. Rather, as we await more reliable and consistent biomarkers to personalize immunotherapy, we should continue efforts to identify more tolerable drug combinations without compromising efficacy and to improve efficacy without increasing toxicity through dose and schedule alterations.

We do not know right now if overall survival is improved by combining immunotherapy agents, so the cart here may be before the horse. But, if navigated carefully based on what we know so far, this may not be a bad ride for our patients.