Adding Opdivo to First-Line Yervoy Significantly Delays Progression in Melanoma

Frontline immunotherapy with Opdivo (nivolumab) plus Yervoy (ipilimumab) delayed disease progression by 60 percent compared with Yervoy alone in patients with advanced melanoma, according to data from the phase 2 CheckMate-069 trial presented at the 2015 American Association for Cancer Research 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 percent in a subgroup ofBRAF 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, 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 3/4 melanoma in a 2:1 ratio to 3 mg/kg of the CTLA-4 inhibitor Yervoy plus 1 mg/kg of the anti—PD-1 agent Opdivo (n = 95) or placebo (n = 47) once every three weeks for four doses, followed by Opdivo at the same dose or placebo every two 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 combo group versus 4.4 months in the Yervoy arm. Similar PFS data were observed among BRAF-positive patients, at 8.5 versus 2.7 months in the combination and control arms, respectively.

Forty-four BRAF WT patients receiving the checkpoint combination had objective responses, including complete responses (CRs) in 16 patients and partial responses (PRs) in 28. There were no CRs and four PRs with single-agent Yervoy. Stable and progressive disease rates in WT patients for the combination versus monotherapy arms were 12 percent versus 35 percent and 14 percent versus 41 percent, respectively.

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

In BRAF-positive patients, ORR was 52 percent versus 10 percent with the two-drug regimen versus monotherapy. Responses in the dual-checkpoint arm included 5 CRs and 7 PRs, and 13 percent of patients had stable disease. Seventy percent of BRAF-positive patients in the control arm had progressive disease compared with 22 percent 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 percent and 93 percent, respectively. Grade 3/4 AEs were 54 percent versus 24 percent in the dual checkpoint versus the control arm, leading to 36 and 6 discontinuations, respectively. Hodi noted that 68 percent 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 the combination were colitis, diarrhea, elevated ALT and increased lipase. There were three treatment-related deaths in the combination arm versus none with Yervoy 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 Yervoy in advanced melanoma. Data from the phase 3KEYNOTE-006 study showed that the PD-1 inhibitor Keytruda (pembrolizumab) improved outcomes versus Yervoy in treatment-naïve patients with melanoma.

At this point, of the three immunotherapies, only Yervoy is approved 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 3 study comparing Opdivo plus Yervoy versus Opdivo alone or Yervoy alone. The other is a sequencing study comparing Opdivo followed by Yervoy versus Yervoy followed by Opdivo.