Examining the Impact of Opdivo's Expanded Approval in Melanoma

The FDA granted an expanded approval to Opdivo (nivolumab) as a single agent and in combination with Yervoy (ipilimumab) on January 23 for the treatment of patients with melanoma who harbor BRAF V600 mutations. As a result of the expansion, Opdivo is now available as a frontline treatment for all patients with advanced melanoma, regardless of BRAF status.

The approval was based on the three-arm CheckMate-067 study, in which the dual checkpoint inhibitor combination reduced the risk of progression by 58 percent compared with Yervoy alone in patients with advanced melanoma. Single-agent Opdivo reduced the risk of progression by 43 percent versus Yervoy.

The trial randomized 945 patients with untreated unresectable or metastatic melanoma to receive Opdivo (316 patients), Yervoy (315 patients), or Opdivo plus Yervoy followed by Opdivo (314 patients).

In the monotherapy arms, Opdivo was administered at 3 mg/kg every two weeks and Yervoy was administered at 3 mg/kg every three weeks. In the combination arm, Opdivo at 1 mg/kg was administered with 3 mg/kg of Yervoy every three weeks for four doses followed by 3 mg/kg of Opdivo every two weeks.

Patients were stratified by M-stage, PD-L1 status, and BRAF mutation status. Approximately one-third of patients were BRAF-mutation positive. The coprimary endpoints were progression-free survival (PFS) and overall survival, with objective response rate, safety, and other measures as secondary endpoints.

At more than nine months of follow-up, the median PFS was 11.5 months for the combination, 6.9 months for Opdivo monotherapy, and 2.9 months for single-agent Yervoy. Outcomes were similar regardless of BRAF mutation status.

What impact will the expanded approval have on the patient population?

What is the current standard of care for patients with BRAF V600 mutated melanoma? Will this approval change that?

What are the biggest advantages of using Opdivo/Yervoy as a combination?

To better understand the implications of the expanded approval and the potential for Opdivo as both a single agent and as part of a combination regimen in advanced melanoma, CURE spoke to the CheckMate-067 lead investigator Jedd D. Wolchok, chief, Melanoma and Immunotherapeutics Service, Department of Medicine and Ludwig Center at Memorial Sloan Kettering Cancer Center.The approval brings the combination regimen to approximately twice as many patients on-label, now that the BRAF status is no longer considered.Fortunately, there are now numerous medications available for patients with metastatic melanoma harboring a BRAF V600 mutation. These include two different combinations of BRAF and MEK inhibitors, the Opdivo combination, monotherapy with each agent, and Keytruda (pembrolizumab) monotherapy.The combination of Opdivo plus Yervoy produces significantly longer progression-free survival compared with Yervoy alone. The phase 3 CheckMate-067 trial was not powered for a formal comparison of the combination with Opdivo alone; however, the hazard ratio for progression-free survival was 0.74 in favor of the combination.

Are there any concerning toxicities associated with the combination of Opdivo/Yervoy?

What is the best way for oncologists to determine which patients should receive single-agent Opdivo versus the combination with Yervoy?

What is the current role for PD-1/PD-L1 testing for patients in this space? What needs to be done to better understand the impact?

In general, immunotherapy yields durable responses and the initial data from this trial showed that median duration of response was not reached in any of the three groups — Yervoy, Opdivo, or the combination.The combination treatment results in a higher frequency of high-grade adverse events, compared with monotherapy. These are generally reversible with the exception of endocrinopathies, which may require long-term hormone replacement.

This is best accomplished through a thoughtful discussion of risks and benefits. In a subset analysis, patients whose tumors express lower levels of PD-L1 appear to gain the most with the combination compared with Opdivo alone.This testing can provide a nonbinary assessment of likelihood of response from PD-1 pathway blockade; however, we still need to learn more about the relative importance of expression on tumor cells versus infiltrating immune cells and the most appropriate definition of high/low/no expression.

How do you see the role of Opdivo continuing to evolve in melanoma? Is there potential for it to be used in earlier settings or in other combinations?

This testing is a first step in better stratification of likelihood of response. However, in my opinion, it is not yet optimal for determining if a patient with melanoma should or should not receive a specific therapy.It is certainly evolving. Clinical trials are currently exploring PD-1 blockade with Opdivo or Keytruda in the postsurgical adjuvant setting, and innovative combinations are being investigated in more advanced disease.

Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015;373:23-34.