August 2016, Vol. 5, No. 6
Combination Immunotherapy Makes Progress in Advanced Melanoma
Evidence is mounting that 2 immunotherapies are better than 1 as first-line treatment of advanced melanoma. A phase 3 study showed that nivolumab plus ipilimumab was superior to either agent alone, and a phase 1 study suggests that pembrolizumab can be safely and effectively combined as first-line treatment in this setting. Both studies were presented at the 2016 ASCO Annual Meeting.
Updated results of the phase 3 CheckMate 067 trial found that progression-free survival (PFS), response rate, and duration of response (DOR) were significantly better with the combination of nivolumab plus ipilimumab compared with either drug alone. In this study, nivolumab alone was also more effective than ipilimumab alone.
“Nivolumab plus ipilimumab continue to demonstrate superior clinical activity versus ipilimumab monotherapy, with greater efficacy than with either drug alone, regardless of PD-L1 [programmed death-1 (PD-1) ligand 1] expression or BRAF mutation status,” said first author Jedd Wolchok, MD, PhD, Memorial Sloan Kettering Cancer Center, New York City. The updated analysis showed a pattern similar to an earlier analysis of the trial at 9 months of follow-up, he added.
At 18 months, an intent-to-treat analysis demonstrated the following rates of PFS: 46% for the combination, 39% for nivolumab, and 14% for ipilimumab (P <.001 for both comparisons).
CheckMate 067 randomized 945 patients with untreated advanced melanoma to the combination, nivolumab alone, or ipilimumab alone, and patients were treated until disease progression. The study was powered to compare the combination versus ipilimumab alone, but not versus nivolumab alone.
Overall survival data were immature at the time of the meeting.
Overall response rate was significantly better for the combination as well as for nivolumab alone versus ipilimumab alone. “Response rates haven’t changed over time, but some partial responses became complete responses at a median follow-up of 20.7 months,” Dr Wolchok said.
Median DOR has not yet been reached for the combination arm versus 22 months for nivolumab alone and 14 months for ipilimumab alone.
In the updated analysis, the majority of adverse events were immune mediated, and a higher rate of grade 3/4 adverse events was reported for the combination.
The data show that patients who withdraw from treatment can develop a response. In fact, of the 40% who discontinued combination therapy due to treatment-related adverse events, 68% developed a response, and 50% had a response after discontinuing therapy.
“This is important to discuss in conversations with patients and families who want to discontinue therapy,” Dr Wolchok said.
Endocrine-related adverse events were treated with hormone replacement therapy, he noted.
Pembrolizumab plus Ipilimumab
The combination of pembrolizumab plus ipilimumab had manageable toxicity and strong antitumor activity in 153 patients with untreated advanced melanoma enrolled in an expansion cohort of the phase 1 KEYNOTE-029 study.
“The combination of standard-dose pembrolizumab combined with ipilimumab 1 mg/kg is tolerable. Seventy-two percent of patients were able to get all 4 ipilimumab doses, with no treatment-related deaths. Twenty-five percent of patients had grade 3/4 immune-mediated events. Overall response rate was 57%, and 78% of patients are progression-free at 6 months,” said first author Georgina Long, BSc, PhD, MBBS, Melanoma Institute of Australia, The University of Sydney, New South Wales, Australia.
At the time of data cutoff, 91% of responders retained their response, and 93% were alive.
Response to combination therapy was not dependent on PD-L1 status or lactate dehydrogenase level.
Immune-mediated adverse events of any grade were reported in 58%, and grade 3/4 events in 25%. Hypothyroidism, hyperthyroidism, and colitis, respectively, were reported in less than 10% of patients.
Of 145 immune-mediated events reported, 76% resolved with treatment (mainly corticosteroids); 81% of grade 3/4 immune-mediated adverse events resolved with treatment.
Comment on Studies
Discussant Marc S. Ernstoff, MD, Roswell Park Cancer Institute, Buffalo, NY, believes the future lies with combination therapy. He also saw little difference, if any, between pembrolizumab and nivolumab as the anti–PD-1 agent used in combination.
“Even though studies suggest that anti–PD-1 therapy is preferred as first-line immunotherapy over targeted therapy in advanced melanoma, the sequence of immunotherapy and targeted therapy remains to be established,” he said. He asked attendees to enroll their patients in ECOG 6134, which will evaluate the best sequence.
There are remaining questions, he continued, including whether ipilimumab is of benefit after failure on pembrolizumab or nivolumab.
“Also, we didn’t learn whether to continue treatment past disease progression. What is the optimal number of doses of ipilimumab?” he asked.
Finally, the cost of immunotherapy will also need to be addressed.
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