Ipilimumab-Nivolumab Combination Produces Rapid, Durable Response in Melanoma

Jedd D. Wolchok, MD, PhD

Combination therapy with ipilimumab and the investigational PD-1 drug nivolumab led to durable tumor shrinkage in approximately half of patients with aggressive, advanced melanoma, according to results presented at ASCO 2013. The objective response rates (ORRs) in the combination trial were better than rates in monotherapy trials of each drug.

“The complete and near-complete response rates we’re seeing are unprecedented for an immunotherapy in melanoma,” said Jedd D. Wolchok, MD, PhD, a medical oncologist at Memorial Sloan-Kettering Cancer Center in New York City, who presented the research.

The drugs are both immune checkpoint inhibitors: Ipilimumab blocks CTLA-4 and nivolumab blocks PD-1. “By blocking these braking pathways, [the two treatments] each result in immune activation in different ways,” said Wolchok at an ASCO press conference to present the study results. Ipilimumab (Yervoy) was approved by the FDA in 2011 for metastatic melanoma. In murine models, the combined CTLA-4/PD-1 blockade showed enhanced antitumor activity.

In the phase I, dose-escalation trial, patients with nonresectable stage III or IV metastatic melanoma previously treated with up to three therapies were assigned to one of six treatment arms: 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 mg/kg or 3 mg/ kg) every 2 weeks.

At the press conference, Wolchok reported data on 86 evaluable patients from the six cohorts. Combined data for the concurrent treatment arms indicated an ORR of 40%. Patients receiving ipilimumab 3 mg/kg and nivolumab 1 mg/kg (n = 17) had an ORR of 53% (95% CI, 28-77). Ipilimumab monotherapy typically produces an ORR of 11%, and studies suggest that the ORR for nivolumab monotherapy is 41%, according to Wolchok.

In addition, 41% of patients (n = 7) in the highest-dosage concurrent group experienced tumor shrinkage of 80% or more at 12 weeks. Overall, one-third of patients in the concurrent treatment group had tumor reductions of 80% or better.

Responses to therapy in the concurrent group were also rapid, with 3 out of 4 patients experiencing tumor reduction within the first 3 months—a response that was faster than with ipilimumab monotherapy.

Sandra Swain, MD

Preliminary data for patients in the largest sequenced cohort (n = 16) indicated an ORR of 38% (95% CI, 15-65); 4 patients had a tumor reduction of 80% or higher at 8 weeks.

“Responses were noted even in patients [in the sequenced cohort] who previously showed growth or progression of disease on ipilimumab,” Wolchok said at the ASCO press conference. “This indicates that even when one immunotherapy does not provide a response, patients can still respond to another immune modulator.”

Toxicities with both the concurrent and the sequenced cohorts were manageable and generally reversible. Grade 3-4 adverse events 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.

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

“This is truly remarkable. This kind of response has not been seen with immunotherapy before,” said Sandra Swain, MD, president of ASCO, who commented on the study findings at the press conference. “This study is proof of principle that concurrent use of two immune checkpoint antibodies contains the treatment paradigm for advanced melanoma. It’s very exciting.”

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