Adding Nivolumab to Frontline Ipilimumab Improves PFS by 60% in Melanoma

F. Stephen Hodi, MD

Frontline immunotherapy with nivolumab (Opdivo) plus ipilimumab (Yervoy) delayed disease progression by 60% compared with ipilimumab alone in patients with advanced melanoma, according to data from the phase II CheckMate-069 trial presented at the 2015 AACR Annual Meeting. The results, which were simultaneously published online in The New England Journal of Medicine, showed that the checkpoint inhibitor combination had an overall response rate (ORR) of 61% in a subgroup of BRAF V600 wild-type (WT) patients.

“These data are unprecedented in advanced melanoma, showing efficacy results that have not previously been observed with Immuno-Oncology agents,” F. Stephen Hodi, MD, lead study author and associate professor of Medicine at Dana-Farber Cancer Institute, said in a statement. “With the Opdivo plus Yervoy regimen, we observed much higher response rates which were sustained, as well as significant reduction in tumor burden than with Yervoy. These responses seen in CheckMate-069 demonstrate the potential of this regimen in patients with metastatic melanoma.”

The double-blind CheckMate-069 trial randomized 142 treatment-naïve patients with stage III/IV melanoma in a 2:1 ratio to 3 mg/kg of the CTLA-4 inhibitor ipilimumab plus 1 mg/kg of the anti—PD-1 agent nivolumab (n = 95) or placebo (n = 47) once every 3 weeks for four doses, followed by nivolumab at the same dose or placebo every 2 weeks until disease progression or unacceptable toxicity.

Median patient age was 65 years, two-thirds of patients were males, and all but two patients had an ECOG performance status of 0 or 1. Three percent of patients had a history of brain metastases.

Patient randomization was stratified by BRAF status, with the primary endpoint of the trial being ORR among BRAF WT patients. Secondary outcome measures included progression-free survival (PFS) in all patient cohorts, ORR in BRAF-positive patients, and safety.

Among BRAF WT patients (n = 109), PFS was not yet reached in the nivolumab/ipilimumab group (n = 72) versus 4.4 months in the ipilimumab arm (n = 37; HR = 0.40; 95% CI, 0.23-0.68; P <.001). Similar PFS data were observed among BRAF-positive patients (n = 33), at 8.5 versus 2.7 months in the combination (n = 23) and control (n = 10) arms, respectively (HR = 0.38; 95% CI, 0.15-1.00).

Forty-four BRAF WT patients (61%) receiving the checkpoint combination had objective responses, including complete responses (CRs) in 22% of patients (n = 16) and partial responses (PRs) in 39% (n = 28; odd ratio = 12.96; 95% CI, 3.91-54.49; P <.001). There were no CRs and four PRs with single-agent ipilimumab. Stable and progressive disease rates in WT patients for the combination versus monotherapy arms were 12% versus 35% and 14% versus 41%, respectively.

ORR in WT patients receiving the combination was independent of PD-L1 status; however, response rates with ipilimumab alone were higher in patients with PD-L1—positive tumors (18% vs 4%).

In BRAF-positive patients, ORR was 52% versus 10% with the two-drug regimen versus monotherapy. Responses in the dual-checkpoint arm included 5 CRs and 7 PRs, and 13% of patients had stable disease. Seventy percent of BRAF-positive patients in the control arm had progressive disease compared with 22% of patients receiving the combination.

Safety data were available for 140 patients. Rates of all-grade adverse events (AEs) were similar between the combination and monotherapy arms at 91% and 93%, respectively. Grade 3/4 AEs were 54% versus 24% in the dual checkpoint versus the control arm, leading to 36 and 6 discontinuations, respectively. Hodi noted that 68% of patients who discontinued combination therapy due to AEs continued to experience CRs or PRs.

The most common grade 3/4 AEs in patients receiving nivolumab/ipilimumab were colitis (17%), diarrhea (11%), elevated ALT (11%), increased lipase (9%), elevated AST (7%). There were three treatment-related deaths in the combination arm versus none with ipilimumab alone.

“In general, and as might be expected, side effects were more prevalent in patients who received the combination therapy,” said Hodi. “This is something that will have to be studied further. He added that the safety profile for the combination was as expected based on what was seen with phase I data, “with no real new safety signals.”

This was the second trial presented at AACR that showed an improvement over frontline ipilimumab in advanced melanoma. Data from the phae III KEYNOTE-006 study showed that the PD-1 inhibitor pembrolizumab (Keytruda) improved outcomes versus ipilimumab in treatment-naïve patients with melanoma.

At this point, of the three immunotherapies, only ipilimumab is approved by the FDA for use in the frontline setting. Hodi said there are ongoing trials that have been completed that should add further clarity in terms of the optimal use of these agents. One is a phase III study comparing nivolumab plus ipilimumab versus nivolumab alone or ipilimumab alone. The other is a sequencing study comparing nivolumab followed by ipilimumab versus ipilimumab followed by nivolumab.

In the meantime, Michael Giordano, senior vice president, head of development, Oncology, at Bristol-Myers Squibb, the developer of ipilimumab and nivolumab, shared his optimism about the progress of the two agents.

“The CheckMate-069 results reinforce our belief that the future lies in the combination of Immuno-Oncology agents, including Opdivo and Yervoy, that can leverage the immune system in order to offer cancer patients options with greater efficacy beyond current treatment approaches,” Giordano said in a statement. “Our strategy has always been to build upon the success achieved with Yervoy. In 2011, long-term survival for metastatic melanoma patients was unheard of, but the introduction of Yervoy has helped to make this a reality for some patients. Now we are building on this success with Opdivo, which was the first PD-1 inhibitor to demonstrate an improved survival benefit.”

Hodi FS, Postow MA, Chesney J, et al. Improved clinical response in patients with advanced melanoma treated with nivolumab combined with ipilimumab compared to ipilimumab alone. Presented at: 2015 AACR Annual Meeting; April 18-22; Philadelphia, PA. Abstract 4214.

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