Gino Kim In, MD

Initial results from CheckMate 067 demonstrated an improvement in PFS when using the combination of two checkpoint inhibitors, nivolumab (Opdivo, Bristol-Myers Squibb) — an anti–PD-1 therapy — and ipilimumab (Yervoy, Bristol-Myers Squibb), an anti–CTLA-4 drug, compared with ipilimumab alone. Based on these findings, the FDA granted accelerated approval for the combination. 

Larkin and colleagues now present follow-up data from CheckMate 067, which confirms the study’s earlier findings. The combination of nivolumab and ipilimumab significantly improved OS compared with ipilimumab alone. The 2-year OS rate of 64% with nivolumab and ipilimumab is particularly impressive and among the best from any melanoma treatment to date. In addition, rates of grade 3 to grade 4 toxicity did not change with longer follow-up. As such, these results validate the effectiveness of combination checkpoint blockade in metastatic melanoma.

However, there are questions that remain. Although the combination of nivolumab and ipilimumab appeared superior to nivolumab monotherapy, CheckMate 067 was not powered to exclusively compare these two arms. Longer follow-up may provide important clues, as a median OS advantage has not yet been demonstrated by the combination compared with nivolumab alone. Further, the combination led to significantly more grade 3 to grade 4 toxicity compared with nivolumab alone (58% vs. 21%), so it is particularly important that we select patients appropriately for each regimen.

Putative biomarkers may help personalize the use of immunotherapy regimens going forward. In the current study, BRAF status, PD-L1 expression and M stage did not impact outcomes. In, addition, there is an ongoing study evaluating the addition of nivolumab to ipilimumab as salvage after anti–PD-1 monotherapy (NCT02731729) that may further inform decisions as to the proper role and timing of combination therapy.

Although single-agent checkpoint inhibitors have previously been established as a standard systemic therapy for metastatic melanoma, this study supports the role for combination immunotherapy going forward. In addition to dual checkpoint blockade, targeting of other immune inhibitory (LAG3, TIM3) and stimulatory (OX40, 4-1BB, GITR) molecules is under active investigation.  Hopefully this is just the beginning and a sign of better things yet to come. 

Lynn Schuchter, MD

This represents a very important update to this ongoing clinical trial. Prior reports of this study and other clinical trials show that combination immunotherapy with nivolumab (Opdivo, Bristol-Myers Squibb) and ipilimumab (Yervoy, Bristol-Myers Squibb) is effective against advanced melanoma. There is good rational for combining these agents. The key is to ensure that we can manage the side effects associated with combination nivolumab and ipilimumab. The improvement in OS is encouraging, but I would still say these are early results in terms of OS impact. The combination looks to be more effective than single-agent nivolumab. However, the concern of the combination is that there is much greater toxicity. The survival difference between nivolumab alone or nivolumab plus ipilimumab is still small, so the take-home message for the practitioner is that decisions regarding the combination treatment need to be individualized. Combination therapy with ipilimumab and nivolumab is not be appropriate for every patient with metastatic melanoma. The results of this study also confirm single-agent ipilimumab is not the way to go for patients with metastatic melanoma.

If physicians choose to use nivolumab and ipilimumab, it is essential for patients to be well educated on the side effects associated with treatment. The whole team — nurse practitioner, nurses, physicians — need to provide education because early detection of the immune-based side effects is essential. The side effects are potentially life-threatening; care must be well coordinated with close attention to any new symptom.

Philip Friedlander, MD

There have been dramatic advances over the last 5 years in how we treat stage IV melanoma — from having no therapies with proven OS benefit to having multiple efficacious immunotherapies, like ipilimumab (Yervoy, Bristol-Myers Squibb), and PD-1 inhibitors, such as nivolumab (Opdivo, Bristol-Myers Squibb), which shows responses in approximately 40% of patients.

We clearly see that using a PD-1–based treatment has an OS benefit compared with ipilimumab alone. The price one pays for the combination therapy is the degree of severe side effects — various immune-mediated toxicities that can necessitate treatment with high doses of steroids or other immunosuppressives. When you use either nivolumab alone or with, 58% of patients experience severe side effects, and that is a limitation.

One of the biggest challenges still in the field of melanoma — and unfortunately this study does not completely address it — is whether to use the PD-1 inhibitor alone or the combination. This study wasn't designed for formal comparison of the combination therapy with nivolumab alone. Both appear to be good options but with different rates of efficacy and toxicity. Treatment selection should occur on an individualized basis.