CHICAGO – Immune checkpoint blockade, especially with a combination of agents having complementary mechanisms of action, has durable efficacy when used as initial therapy for advanced melanoma, according to an update of the CheckMate 067 trial.
The trial randomized 945 treatment-naive patients with unresectable stage III or IV melanoma evenly to double-blind treatment with nivolumab, an antibody to the cell surface receptor programmed death 1 (PD-1); ipilimumab, an antibody to the T-cell receptor cytotoxic T-lymphocyte–associated antigen 4 (CTLA4); or the combination.
Dr. Jedd D. Wolchock
Initial results, after a median follow-up of about 12.4 months, showed that the risk of progression-free survival events was 58% lower with the combination and 43% lower with nivolumab alone as compared with ipilimumab alone (N Engl J Med. 2015;373[1]:23-34).
The update, now with a median follow-up of 20.7 months, showed that these results held up, with respective 58% and 45% reductions in the risk of events, researchers reported at the annual meeting of the American Society of Clinical Oncology. The combination was also superior to nivolumab alone, netting a 24% lower risk of events. Additionally, no cumulative or new toxicities were seen.
“Based on available evidence, the combination of nivolumab and ipilimumab represents a means to improve outcomes versus nivolumab alone,” said first author Jedd D. Wolchok, MD, PhD, chief of the Melanoma & Immunotherapeutics Service at the Memorial Sloan Kettering Cancer Center in New York. “Additional insights will be gained with the emergence of overall survival data.”
Neither tumor expression of PD-L1, a ligand of PD-1, nor presence of a BRAF mutation was very helpful in identifying patients who would benefit to a greater extent from these therapies.
Dr. Marc S. Ernstoff
The findings add to evidence establishing the efficacy of combination immunotherapy in melanoma, according to invited discussant Marc S. Ernstoff, MD, professor and chair of the department of medicine at the Roswell Park Cancer Institute in Buffalo, N.Y. At the same time, the trial left unanswered questions such as what strategy should be used after progression on either or both agents, and what are the appropriate doses and durations of therapy. Also unclear is which type of therapy to use first line in patients with BRAF mutations, he added. “Whether you start with immunotherapy or targeted therapy in BRAF-mutated patients is still in equipoise, and I would encourage everyone here to participate in the ECOG 6134 trial looking at the randomization of immune checkpoint therapy versus targeted therapy in BRAF-mutated patients,” he said. “The biomarker studies are still provocative, and we still need a lot more data to be able to preselect patients who might benefit from either of these therapies.”
“One has to recognize that these agents are costly,” Dr. Ernstoff maintained, with the acquisition cost of the checkpoint inhibitors ranging from roughly $140,000 to $290,000 per year depending on the agent(s) used. This issue will also have to be addressed going forward.
“The future is very bright. There are now 76 trials listed in PDQ [Physician Data Query] of combination PD-1 therapies in melanoma alone,” he concluded. “Immunotherapy continues to capture our imagination.”
The updated intent-to-treat analyses of CheckMate 067 – conducted after all patients had at least 18 months of follow-up – showed that median progression-free survival, one of the trial’s primary endpoints, was now 11.5 months with the combination of nivolumab (Opdivo) and ipilimumab (Yervoy), 6.9 months with nivolumab alone, and 2.9 months with ipilimumab alone, Dr. Wolchok reported at the meeting.
The differences translated to significantly better outcomes with the combination (hazard ratio, 0.42) and with nivolumab (HR, 0.55) as compared with ipilimumab. Moreover, the combination was superior to nivolumab (HR, 0.76).
The overall response rate, the trial’s other primary endpoint, was 57.6% with the combination and 43.7% with nivolumab alone, both of which were superior to the 19.0% with ipilimumab alone.
“While the response rates have not changed, some partial responses have evolved into complete responses over time,” Dr. Wolchok noted.
Findings were similar when patients were stratified by BRAF mutational status. And in exploratory analyses, outcomes were numerically better with the combination than with nivolumab alone regardless of whether tumors had high or low PD-L1 expression.
Safety results were much the same as previously reported. The rate of grade 3 or 4 treatment-related adverse events was 56.5% with the combination, 19.8% with nivolumab monotherapy, and 27.0% with ipilimumab monotherapy. There were no treatment-related deaths with the combination and one with each of the monotherapies.
“There is no common signature adverse event with this combination,” Dr. Wolchok pointed out. “The majority of grade 3 or 4 adverse events resolved in all of the groups with the use of established algorithms. However, as observed in prior studies, most of the endocrine events did not resolve and required hormone replacement.”