Pembrolizumab Plus Reduced Ipilimumab Dose Active in Advanced Melanoma

The combination of standard-dose pembrolizumab with four reduced doses of ipilimumab followed by standard-dose pembrolizumab had a manageable safety profile and antitumor activity in patients with advanced melanoma, according to the results of the phase Ib KEYNOTE-029 study published in Lancet Oncology.

“These data suggest that treatment with a standard dose of anti–programmed death 1 (PD-1) therapy and a reduced dose of anti–cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) therapy is feasible and warrants further exploration,” wrote Georgina V. Long, BSc, PhD, MBBS, of Melanoma Institute Australia, University of Sydney, Mater Hospital, Sydney, and colleagues.

The US Food and Drug Administration has approved the anti–PD-1 therapy nivolumab 1 mg/kg plus ipilimumab 3 mg/kg for patients with advanced melanoma. This regimen has been shown to increase survival, delay progression, and increase the proportion of patients achieving an objective response compared with ipilimumab alone. However, these benefits came with increased toxicity, including a high proportion of grade 3/4 treatment-related adverse events.

According to Long and colleagues, these findings “raised the question of whether or not standard-dose anti–PD–1 combined with reduced-dose ipilimumab could show substantial clinical activity while avoiding severe toxicity.”  

The KEYNOTE-029 trial was designed to test standard-dose pembrolizumab plus reduced-dose ipilimumab. Patients had advanced melanoma, aged 18 and older, and had not received prior immune checkpoint inhibitor therapy. During the study, 153 patients were enrolled and treated with intravenous pembrolizumab 2 mg/kg plus intravenous ipilimumab 1 mg/kg every 3 weeks for four doses followed by intravenous pembrolizumab 2 mg/kg every 3 weeks for up to 2 years. Treatment was stopped for progression, intolerable toxicity, withdrawal of consent or at the investigator’s decision.

About three-quarters (72%) of patients received all four doses of pembrolizumab plus ipilimumab and 42% remained on pembrolizumab monotherapy.

About one-half (45%) of patients experienced a grade 3/4 treatment-related adverse events. No treatment-related deaths occurred, but 14% of patients discontinued therapy because of adverse events. Eight percent of patients discontinued ipilimumab only, and 9% discontinued pembrolizumab only.

Sixty percent of patients had an immune-mediated adverse event of any grade, and 27% had a grade 3/4 events. The most common immune-mediated events were hypothyroidism (16%) and hyperthyroidism (11%).

With a median follow-up of 17 months, 61% of patients achieved an objective response. The proportion of patient with an objective response was similar in those with PD-L1–positive or –negative tumors.

“The 61% of patients with an objective response to pembrolizumab plus ipilimumab in this study is higher than the proportion reported for anti–PD-1 monotherapy, which ranges from 20% to 45% depending on the number of previous treatments, and the 15% of patients with a complete response in this study is higher than most other estimates, which range from 2% to 15%, again depending on the number of previous treatments,” the researchers wrote.

The estimated 1-year progression-free survival was 69%, and the estimated 1-year overall survival was 89%.

In an editorial published with the article, Michael Postow, MD, of Memorial Sloan Kettering Cancer Center in New York, wrote: “Long and colleagues should be congratulated for the first trial of reduced-dose ipilimumab in combination with pembrolizumab, showing that the known dose-dependent toxicity of ipilimumab seems to extend to the combinatorial setting with anti–PD-1.”

Moving forward Postow said the field should complete trials testing various doses and schedules of combination reduced-dose ipilimumab with standard-dose pembrolizumab.

“Immunotherapy combinations blocking both CTLA-4 and PD-1 are the most developed combinations because studies targeting these checkpoints individually were the first to show clinical success,” Postow wrote. “Multiple other anti–PD-1 combinations are now being tested, and the principles that are learnt from refining of the combination of anti–CTLA-4 with anti–PD-1 immunotherapy will be instrumental to improve our understanding of how best to assess this growing list of promising additional combination strategies.”