Combining Ipilimumab and Nivolumab Shows Promise in Advanced Melanoma

Jedd D. Wolchok, MD, PhD

Combining the checkpoint antibodies ipilimumab (Yervoy) and nivolumab (formerly BMS-936558) led to deep tumor regression in approximately one-third of patients with advanced melanoma in an ongoing phase I study. Additionally, responses to the combination were quicker than those normally observed with immunotherapy. The data were presented Wednesday at an American Society of Clinical Oncology (ASCO) press conference held in advance of the 2013 ASCO Annual Meeting.

“The activity [in this study] appeared to be distinct from published data for nivolumab and ipilimumab monotherapy,” said Jedd D. Wolchok, MD, PhD, a medical oncologist at Memorial Sloan-Kettering Cancer Center in New York, who presented the research.

Ipilimumab was approved by the FDA in 2011 for metastatic melanoma, and clinical research has shown strong response rates for nivolumab in patients with the disease.

The two antibodies have similar mechanisms of action, in that they “both block pathways that are essentially molecular brakes which prevent T cells in the immune system from achieving a full and persistent state of activation,” said Wolchok.

Specifically, ipilimumab and nivolumab block the inhibitory checkpoints CTLA-4 and PD-1, respectively. “By blocking these braking pathways, [the two treatments] each result in immune activation in different ways,” said Wolchok.

The combination study was launched after preclinical animal studies demonstrated that using the treatments together proved more effective than monotherapy with either drug. In the trial, patients with nonresectable stage III or IV metastatic melanoma previously treated with three or fewer therapies were assigned to one of six treatment arms.

There were four concurrent and two sequenced cohorts. In the concurrent arms, patients received four doses of nivolumab (0.3-3 mg/kg) and ipilimumab (1-3 mg/kg) every 3 weeks, followed by nivolumab alone every 3 weeks for four doses. Every 3 months, there was one combination treatment administered at week 24. In the sequenced cohorts, patients previously treated with ipilimumab outside of the study received nivolumab alone (1 or 3 mg/kg) every 2 weeks.

At the press conference, Wolchok reported data on 86 evaluable patients from the six cohorts.

When data from the concurrent cohorts were combined, “Forty percent [of patients] had objective responses. If one broadens this to include patients who had slow responses, or stable findings on scans, then 65% of patients had the melanoma controlled with this combination. Ninety percent of the responding patients continued to respond as of February 2013,” said Wolchok.

In the largest concurrent group, patients received the FDA-approved dose of ipilimumab (3 mg/kg), along with 1 mg/kg of nivolumab (n = 17). In this cohort, the objective response rate (ORR) was 53% (95% CI, 28-77) and 41% of patients (n = 7) had ≥80% tumor reduction at week 12.

With patients in the largest sequenced cohort (n = 16), the ORR was 38% (95% CI, 15-65) and four patients had tumor reduction ≥80%.

Regarding the sequenced cohort results, Wolchok said, “The important [point] here is that there were responses noted. Even in patients who previously showed growth or progression of disease on ipilimumab. This indicates that even when one immunotherapy does not provide a response, patients can still respond to another immune modulator. This further supports the importance of studying combination therapy with medicines targeting distinct pathways.”

Toxicities with both the concurrent and the sequenced cohorts were manageable and generally reversible using protocols previously developed to address the side effects of each treatment individually.

Grade 3-4 side effects occurred in 53% of patients receiving concurrent treatment and 18% of patients in the sequenced cohorts. Elevation of liver or pancreatic enzymes were the most common side effects for both treatments. There have been no treatment-related deaths in the study.

Based on the results, a randomized phase III trial of the ipilimumab/nivolumab combination versus nivolumab alone versus ipilimumab alone in advanced melanoma is scheduled to start this year.

At the upcoming ASCO meeting, a separate biomarker analysis will be presented that explored how the ipilimumab/nivolumab combination may overcome factors that appear to inhibit patient response to monotherapy with either treatment.

Wolchok said that the combination is also being examined in patients with non—small cell lung cancer and renal cancer.

Wolchok JD, Kluger HM, Callahan MK, et al. Safety and clinical activity of nivolumab (anti-PD-1, BMS-936558, ONO-4538) in combination with ipilimumab in patients (pts) with advanced melanoma (MEL). J Clin Oncol. 2013;(suppl; abstr 9012).

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