With a minimum of 28 months of follow-up, the median PFS was 11.7 months with the combination (95% CI, 8.9-21.9) versus 6.9 months with nivolumab and 2.9 months with ipilimumab. Additionally, the ORR with the combination, nivolumab, and ipilimumab were 58.9%, 44.6%, and 19%, respectively. These included a 17.2% complete response (CR) rate with nivolumab/ipilimumab, a 14.9% CR rate with nivolumab, and a 4.4% CR rate with ipilimumab. The partial response rate was 41.7% with nivolumab/ipilimumab, 29.7% with nivolumab, and 14.6% with ipilimumab.
The median duration of response was not reached in the nivolumab/ipilimumab arm, 31.1 months in the nivolumab arm, and 18.2 months in patients who received ipilimumab. At the initial 18-month database lock, the CR rates for nivolumab/ipilimumab, nivolumab, and ipilimumab were 12.1%, 9.8%, and 2.2%, respectively.
Regarding safety, Larkin said that with an additional 19 months of follow-up, safety was consistent with the initial findings. Grade 3/4 treatment-related adverse events (TRAEs) were reported in 58.5% of patients in the combination arm, 20.8% in the nivolumab arm, and 27.7% in the ipilimumab arm. All-grade TRAEs were reported in 95.8% of the nivolumab/ipilimumab patients, 86.3% in the nivolumab arm, and 86.2% in the ipilimumab arm. Thirty-one percent of patients in the combination arm had TRAEs that led to discontinuation of treatment, versus 7.7% and 14.1% in the nivolumab and ipilimumab arms, respectively.
Four treatment-related deaths were reported; 2 were included in the earlier reports. The 2 new deaths, both in the combination arm, were related to cardiomyopathy and liver necrosis and occurred more than 100 days following their last treatment.
“The safety profile of the combination is consistent with earlier experience with the majority of the AEs resolving in 3 to 4 weeks,” Larkin added. “Even in patients who discontinued the combination due to toxicity, an impressive survival benefit and responses over 70% were observed.”
The phase III findings coincide with earlier OS reports of the combination regimen; the phase II CheckMate-069 trial demonstrated a durable response rate of 61% and a 2-year OS rate of 64% in patients with advanced melanoma who were treated with nivolumab plus ipilimumab.2
“When used in combination, these drugs have a powerful antitumor effect in melanoma,” said program moderator Suzanne Topalian, MD, associate director, Bloomberg-Kimmel Institute for Cancer Immunotherapy, and professor of surgery and oncology at Johns Hopkins University School of Medicine. “This also carries with it an increased risk of toxicity. This combination is the first immunotherapy combination to be approved by the FDA. It reflects a very active area of research in immuno-oncology, with several hundred different clinical trials of various combinations ongoing.”
The FDA initially approved the combination of nivolumab and ipilimumab for patients with advanced melanoma for BRAF V600 wild-type disease, as well as those with unresectable or metastatic melanoma after treatment with ipilimumab or a BRAF inhibitor in October 2015. In January 2016, the agency expanded the combination’s indication to include patients with BRAF
V600 mutations, based on the CheckMate-067 findings that demonstrated superiority in PFS and ORR with nivolumab/ipilimumab versus ipilimumab alone.
“Considering all of the study findings, first-line nivolumab plus ipilimumab may represent a means to improve outcomes versus nivolumab,” Larkin concluded. “Although the data by PD-L1 expression are intriguing, the role of PD-L1 as a predictive biomarker is not fully understood, and the data are still immature. Therefore, decisions about the optimal first-line treatment choice should be made on an individual patient basis with all factors taken into consideration.”
<<< View more from the 2017 AACR Annual Meeting
- Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Overall survival results from a phase III trial of nivolumab combined with ipilimumab in treatment-naïve patients with advanced melanoma (CheckMate-067): press conference. In: Proceedings from the 2017 American Association for Cancer Research Annual Meeting; April 2 to 5, 2017; Washington DC. Abstract CT075.
- Postow MA, Chesney J, Pavlick AC, et al. Nivolumab and Ipilimumab versus Ipilimumab in Untreated Melanoma. N Engl J Med. 2015;372:2006-2017.