Mario Sznol, MD
Phase I results presented in 2013 from a study combining ipilimumab with the anti-PD-1 antibody, nivolumab,1
showed a 40% objective response rate in 53 patients with advanced melanoma and a preliminary overall survival (OS) of 80%. During a June 2, 2014 press conference at the Annual Meeting of ASCO, long-term follow-up results were also encouraging, demonstrating nearly doubled median OS with the combination treatment compared with either agent alone.2
“The results are very significant for a small trial and very, very impressive,” said Mario Sznol, MD, professor of Medical Oncology at Yale University School of Medicine, New Haven, Connecticut, who presented the updated safety, survival, and clinical efficacy data of study cohorts 1 through 3. These three cohorts were administered the combination therapy every 3 weeks for 4 doses for an induction period of 12 weeks and then every 12 weeks for 8 doses.
The follow-up data confirmed that complete responses have increased in cohorts 1 through 3 from 5/52 patients to 9/53 patients. “I actually believe that is an underestimate because it is very hard to call a complete response these days with the sophistication of the CT scans, and probably the number of patients that had truly complete responses is even higher than that,” Sznol said. Tumor reduction of ≥80% was seen in 22 patients (42%), according to presented data. Durable objective responses are ongoing in 18/22 patients with the median duration of response not yet reached.
“In our experience these responses were just as active in patients with BRAF
-mutated and BRAF-wild–type disease,” Sznol said. Similar activity was observed regardless of PD-L1 status, according to study data, despite the fact that other studies of anti-PD-1 monotherapy have shown reduced activity in patients with tumors with low or negative PD-L1 expression. “It suggests that we are picking up activity in patients who might not have responded to anti-PD-1 alone,” Sznol said.
A preliminary ORR of 43% was also reported for a new cohort (cohort 8), which enrolled 41 patients using a phase II/III dosing regimen of nivolumab monotherapy 3 mg/kg every 2 weeks (following the initial combination induction dose) until disease progression. There was one drug-related death in this cohort from multi-organ failure as a result of colitis.
“There is no question that if you combine ipilimumab, which as you have heard has a fairly high incidence of toxicities with nivolumab that you are going to see increased toxicity. In fact, we did.” High-grade adverse events (AEs) increased from 53% of patients according to 2013 data to 62% of patients (58/94) as reported at ASCO 2014. A significant portion of these high-grade AEs were lab abnormalities.
“This raises some concerns,” said Sznol. “But many toxicities resemble those typically seen with ipilimumab monotherapy,” he said, adding that many of these are reversible with proactive management, education, and training. “It appears that the activity of the regimen would justify the increased rate of adverse events,” he said.
“The overall conclusion is that the concurrent therapy with nivolumab and ipilimumab produced, and this is a controversial work, we believe, an unprecedented 1- and 2-year overall survival rate of 85% and 79%,” said Sznol. “Of course these are small cohorts of patients and this [these results] needs to be verified in phase III trials which haven’t been completed.” He also noted that OS appeared higher in nivolumab dose cohorts ≥1 mg/kg and that substantial activity was observed in patients with PD-L1 low/negative disease.
Enrollment for the phase II and III trials have completed and are studying concurrent nivolumab + ipilimumab versus nivolumab versus ipilimumab; and concurrent nivolumab + ipilimumab vs ipilimumab monotherapy, respectively [NCT01844505 and NCT01927419). Nivolumab is not yet approved by the FDA for melanoma but is in phase III clinical trials.
“Anti CTLA-4 and anti-PD-1 single-agent therapies for metastatic melanoma have made significant contributions in recent years,” said moderator Steven O’Day, MD, from Beverly Hills Cancer Center, in an ASCO press release. “This study combines the two checkpoint inhibitors concurrently in efforts to improve clinical outcomes further. This update on the initial group of 53 patients treated with ipilimumab and nivolumab confirms continued excitement, with remarkable clinical benefit and longer survival than we’ve typically seen. Phase III trials will be necessary to determine the benefit of combination checkpoint therapy versus sequential single-agent therapy and delineate the price of additional toxicities,” O’Day said.