CHICAGO – The combination of pembrolizumab, an antibody to the human cell surface receptor programmed death-1 (PD-1), and ipilimumab, an antibody to the human T-cell receptor cytotoxic T-lymphocyte-associated antigen 4 (CTLA4), is highly active against advanced melanoma and has acceptable safety, finds the KEYNOTE 029 trial’s expansion cohort.
The 153 patients in the cohort received a standard dose of pembrolizumab (2 mg/kg every 3 weeks) with a reduced dose of ipilimumab (1 mg/kg every 3 weeks for four doses) on the basis of earlier data showing substantial toxicity when a standard dose of ipilimumab was combined with other immune checkpoint inhibitors.
Results reported at the annual meeting of the American Society of Clinical Oncology showed that the overall response rate was 57%, and the disease control rate was 78%. Although 42% of patients experienced grade 3 or 4 treatment-related adverse events, most of these events resolved, and there were no treatment-related deaths.
“Pembrolizumab 2 mg/kg in combination with four doses of ipilimumab 1 mg/kg has a manageable toxicity profile and provides robust antitumor activity in patients with advanced melanoma,” concluded the investigators, who were led by Georgina Long, PhD, MBBS, chair of Melanoma Medical Oncology and Translational Research at the Melanoma Institute Australia and Royal North Shore Hospital, University of Sydney.
The response rate seen in KEYNOTE 029 was almost identical to that seen in the CheckMate 067 trial with the combination of nivolumab and standard-dose ipilimumab (3 mg/kg every 3 weeks for four doses), noted invited discussant Marc S. Ernstoff, MD, professor and chair of the department of medicine at the Roswell Park Cancer Institute in Buffalo, N.Y. It was also “remarkably comparable” to the 69% seen in the COMBI-d melanoma trial with the combination of dabrafenib (a BRAF inhibitor) and trametinib (an inhibitor of MEK MAPK/ERK kinase).
“There is a significant amount of grade 3 and 4 toxicity, but the dose of ipilimumab appeared to decrease this in the pembrolizumab-ipilimumab study compared to the nivolumab-ipilimumab study,” he noted. “There was a high percent of low-grade toxicities reported in all of these studies, and I would argue that as we are seeing patients survive longer, these low-grade toxicities are going to become more of an issue for us as oncologists to be able to deal with in terms of quality of life for patients surviving.”
There is good rationale for combining CTLA4 blockade and PD1 (or PD-L1) blockade in melanoma, Dr. Long maintained when introducing the research. “We know that CTLA inhibition at the priming phase in the periphery, at antigen presentation, is effective, as is PD-1 or PD-L1 [inhibition] at the effector phase down in the tumor bed,” she elaborated.
The patients with advanced melanoma enrolled in the expansion cohort could have received any number of prior therapies other than immune checkpoint inhibitors. However, in 87%, the study regimen was their first therapy.
At the time of data cutoff, 72% of patients had received all four planned doses of ipilimumab (Yervoy), and 56% were continuing on pembrolizumab (Keytruda).
The rates of any-grade and grade 3 or 4 treatment-related adverse events were 95% and 42%, respectively. The corresponding rates of immune-mediated adverse events were 58% and 25%.
The most common grade 3 or 4 treatment-related adverse events were lipase elevation (14%) and rash (3%). The former was asymptomatic and had no sequelae in the majority of cases, Dr. Long reported.
Hepatitis, colitis, and skin reactions were the most common grade 3 or 4 immune-mediated adverse events. The majority of immune-mediated adverse events were managed with systemic treatment, usually corticosteroids, and resolved.
When it came to efficacy, the overall response rate with the combination was similar across subgroups of patients stratified by PD-L1 status in the tumor and adjacent immune tissue, treatment history, baseline lactate dehydrogenase level, and BRAF mutational status.
Responses were ongoing in 98% of patients at data cutoff, with the duration of response ranging from about 6 weeks to 43 weeks, Dr. Long said. The disease control rate was 78%.
With a median follow-up of 10.0 months, median progression-free survival and overall survival were not yet reached. However, the 6-month rates of these outcomes were 70% and 93%, respectively.
Dr. Long disclosed that she is a consultant/adviser to Amgen, Bristol-Myers Squibb, Merck, Novartis, Provectus, and Roche, and that she has received honoraria from Bristol-Myers Squibb, Merck, and Novartis. The trial was supported by Merck.