Studies Suggest Bright Future for Combination Immunotherapy in Advanced Melanoma, but Questions Remain

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Nivolumab plus ipilimumab continue to demonstrate superior clinical activity vs ipilimumab monotherapy, with greater efficacy than with either drug alone, regardless of PD-L1 expression or BRAF mutation status.
— Jedd Wolchok, MD, PhD

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Two studies presented at the 2016 ASCO Annual Meeting focused on the use of combination immunotherapy in the treatment of patients with advanced melanoma. Updated results from the phase III CheckMate 067 trial centered on the combination of nivolumab (Opdivo) plus ipilimu­mab (Yervoy) compared with each agent alone,1 and the expansion cohort of the phase I KEYNOTE-029 trial explored the combination of pembrolizumab (Keytruda) and ipilimumab.2

In the CheckMate 067 study, at a median follow-up of 20.7 months, median progression-free survival continues to be longer for the combination vs ipilimumab and for nivolumab vs ipilimumab (P < .001 for both comparisons). In an intent-to-treat analysis, median progression-free-survival was 11.5 months for the combination, 6.9 months for nivolumab, and 2.9 month for ipilimumab. Response rates and progression-free survival were higher with the combination or nivolumab alone in all subgroups analyzed, including those based on the level of PD-L1 (programmed cell death ligand 1) expression and BRAF-mutation status.

“Nivolumab plus ipilimumab continue to demonstrate superior clinical activity vs ipilimumab monotherapy, with greater efficacy than with either drug alone, regardless of PD-L1 expression or BRAF-mutation status,” said first author Jedd Wolchok, MD, PhD, of Memorial Sloan Kettering Cancer Center, New York. These results follow a similar pattern of data from this study presented at 9 months of follow-up, he added.

Details of CheckMate 067

CheckMate 067 randomized 945 patients with untreated advanced melanoma to the combination, nivolumab alone, or ipilimumab alone.1 Patients in all three arms of the study were treated until disease progression. Progression-free survival was reported at the first sign of disease progression. The study was not powered to compare the combination vs nivolumab alone, explained Dr. Wolchok. Overall survival data are still immature.

Update on Combination Immunotherapy in Melanoma

  • Longer follow-up of the CheckMate 067 trial showed that the combination of nivolumab plus ipilimumab is superior to either drug alone in advanced melanoma and that combination therapy is superior regardless of the level of PD-L1 expression and BRAF-mutation status.
  • It appears that response duration is deep, and patients will continue to respond.
  • The combination of pembrolizumab and ipilimumab also appears promising in the preliminary KEYNOTE-029 study.

The overall response rate was significantly better for the combination as well as for nivolumab alone vs ipilimumb alone. “Response rates haven’t changed over time, but some partial responses became complete responses at a median follow-up of 20.7 months,” he shared. The median duration of response has not yet been reached for the combination arm vs 22 months for nivolumab alone and 18 months for ipilimumab alone.

Adverse Events

Updated safety [of the combination] is consistent with previously reported results, Dr. Wolchok said. Grades 3 and 4 adverse events were more frequently reported with the combination therapy.

Close to 40% of patients in the combination therapy arm discontinued treatment due to adverse events, but 68% of those who discontinued treatment developed a response; 50% developed a response after discontinuing therapy. “This is important to discuss in conversations with patients and families who want to discontinue therapy,” Dr. Wolchok said.

“There was no common signature adverse event with the combination of nivolumab plus ipilimumab. As seen in prior studies, most of the endocrine events did not resolve and required hormone replacement therapy,” he added.

Details of KEYNOTE-029

In an expansion cohort of the KEYNOTE-029 phase I study, the combination of pembrolizumab plus ipilimumab had a manageable toxicity profile and robust antitumor activity in patients with advanced melanoma.2

The combination of standard-dose pembrolizumab combined with ipilimumab at 1 mg/kg is tolerable. The overall response rate was 57%, and 70% of patients are progression-free at 6 months.
— Georgina Long, MD, PhD

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“The combination of standard-dose pembrolizumab combined with ipilimumab at 1 mg/kg is tolerable. Seventy-two percent of patients were able to get all four ipilimumab doses, with no treatment-related deaths. Twenty-five percent of patients had grades 3/4 immune-mediated events. The overall response rate was 57%, and 70% of patients are progression-free at 6 months,” said first author Georgina Long, MD, PhD, of the Melanoma Institute of Australia, University of Sydney and Royal North Shore Hospital, New South Wales, Australia.

The rationale for this study is the established benefit of CTLA-4 (cytotoxic T-lymphocyte–associated protein 4) plus PD-1 (programmed cell death protein 1)/PD-L1 blockade in advanced melanoma, she explained.

After a run-in phase of this trial, the dose of pembrolizumab of 2 mg/kg every 3 weeks was found to be tolerable when combined with 4 doses of ipilimumab at 1 mg/kg. In the expansion phase of the trial, 153 patients were enrolled and treated. A total of 110 patients (72%) received all 4 planned doses of ipilimumab. Median follow-up was 10 months, and minimum follow-up was 6 months.

Outcomes and Toxicity

The overall response rate was 57% by independent central review, and 10% of these responses were complete responses. A total of 78% of patients achieved disease control (overall response plus stable disease). At the time of data cutoff, 98% of responders retained their response. In a subgroup analysis, all patients had robust responses, including patients who were PD-L1–negative and those with an elevated LDH (lactate dehydrogenase) level. At 6 months, 70% of all patients were progression-free, and median progression-free survival had not yet been reached. Ninety-three percent were alive at 6 months.

Immune-mediated adverse events of any grade were reported in 58% of patients, and grades 3/4 events were reported in 25%. “Colitis was seen in < 10% of patients, and diarrhea in 24%. This is less than what we expected from the results seen in trials of combined full-dose ipilimumab and reduced-dose anti–PD-1,” Dr. Long said. ■

Disclosure: Dr. Wolchok has been a consultant for, received research support from Bristol-Myers Squibb and Merck. Dr. Long has consulted for and received honoraria from Roche/Genentech, GlaxoSmithKline, Amgen, Bristol-Myers Squibb, Merck, Novartis, and Provectus. She also has received institutional travel expenses from Merck Sharp & Dohme and Roche/Genentech.


1. Wolchok JD, Chiarion-Sileni V, Gonzalez R, et al: Updated results from a phase III trial of nivolumab combined with ipilimumab in treatment-naive patients with advanced melanoma (CheckMate 067). 2016 ASCO Annual Meeting. Abstract 9505. Presented June 3, 2016.

2. Long GV, Atkinson V, Cebon JS, et al: Pembrolizumab plus ipilimumab for advanced melanoma: Results of the KEYNOTE-029 expansion cohort. 2016 ASCO Annual Meeting. Abstract 9506. Presented June 3, 2016.

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