Giving Best Shot First: Two ICIs Upfront for Advanced Melanoma

M. Alexander Otto and Zosia Chustecka

March 24, 2023

Immune checkpoint inhibitors (ICIs) have transformed the treatment of advanced melanoma, allowing some patients who respond to live for years. But there is still debate about how to best use these agents.

One important question is over the initial therapy: Should patients get two ICIs together upfront, even though the combination is more toxic and more expensive than ICI monotherapy first line?

A new study gives some hints. It looked at how patients with advanced melanoma who had progressed on ICI monotherapy fared when they were treated with two checkpoint inhibitors: the programmed cell death 1 (PD-1) blocker nivolumab and the lymphocyte activation gene 3 (LAG-3) inhibitor relatlimab, marketed together as Opdualag.

The study was published online on February 13 in the Journal of Clinical Oncology.

Across 518 patients with metastatic or unresectable melanoma who progressed on single-agent therapy, only 9%-12% responded to the dual ICI combination when given in second or later lines.

These objective responses are "clearly lower" than the 43% response rate that has been seen previously when the combination has been used upfront, points out Grant McArthur, MBBS, PhD, a melanoma specialist at the University of Melbourne in Australia, writing in an accompanying editorial.

In fact, the results led to US Food and Drug Administration approval for the combination as a first-line treatment for unresectable or metastatic melanoma in March 2022.

In the editorial, Grant writes that, overall, "it may be more prudent to deliver the most effective therapy" — dual treatment — "in the first line."

It is possible that delaying the addition of a second ICI could save some patients toxicity and reduce healthcare costs, he notes.

But there are no biomarkers at the moment to identify patients who can safely postpone combination therapy, and immunotherapy resistance developed during single-agent treatment probably carries over when two are used together in later lines.

For now, "it seems likely that giving our patients their best shot first will remain a strong consideration," McArthur concludes.

Study Details

The study was conducted by a team led by Paolo Antonio Ascierto, MD, a melanoma specialist at the Istituto Nazionale Tumori in Naples, Italy, and it was supported by Bristol-Myers Squibb, manufacturer of nivolumab and relatlimab.

The 518 patients in the study were split into two cohorts. Patients in the first cohort, which had 354 participants, had one prior line of treatment containing either nivolumab or pembrolizumab.

The second cohort, with 164 participants, had broader inclusion criteria: Treatment could include multiple prior lines of PD-1 or programmed death ligand 1 (PD-L1) regimens. Across both cohorts, more than half the participants had been on two or more prior lines of therapy, including anti–PD-(L)1, anti–CTLA-4, and BRAF/MEK inhibitors.

All patients received the nivolumab-relatlimab combination on progression.

The objective response rate (ORR) was 12% in the first cohort, with a median progression-free survival (PFS) of 2.1 months and a 6-month PFS of 29.1%. Median overall survival (OS) was 14.7 months.

In the second cohort, ORR was 9.2%, median PFS was 3.2 months, and 6-month PFS was 27.7%. Median OS was 17.1 months.

Responses were observed regardless of PD-L1 and LAG-3 expression, and these markers "may not be appropriate" for treatment selection, the investigators note.

Although the team cautions that "cross-trial comparisons should be made with caution because of differences in study design and median follow-up," they point out that other dual therapy options have shown better results when used in the second line.

For example, higher ORRs have been reported with lenvatinib and pembrolizumab, ipilimumab and nivolumab, and lifileucel, and higher rates of OS have been reported for the ipilimumab-nivolumab combination

However, the apparently better efficacy of the other options came at the cost of substantially higher grade 3/4 adverse events than were seen with the nivolumab-relatlimab combination, the team points out.

They report that the nivolumab-relatlimab combination had grade 3/4 treatment-related adverse event rates of 15% in the first cohort and 12.8% in the second. Across both groups, there was one case of grade 3 myocarditis and no treatment-related deaths.

This combination "had a manageable safety profile and demonstrated durable clinical activity" after single-agent PD-(L)1 progression, the investigators concluded.

This nivolumab-relatlimab combination is a "reasonable option" for advanced melanoma that progresses on single-agent PD-(L)1 therapy, commented Columbia University medical oncologist Gary Schwartz, MD.

The work was funded by Bristol-Myers Squibb, makers of both nivolumab and relatlimab. Four investigators are BMS employees, and many others reported ties to the company, including Ascierto who is an advisor and researcher for BMS. McArthur reported research funding from BMS and an unspecified "other relationship" with the company.

J Clin Oncol. Full text published online February 13, 2023; Editorial published online February 28, 2023

M. Alexander Otto is a physician assistant with a master's degree in medical science and a journalism degree from Newhouse. He is an award-winning medical journalist who worked for several major news outlets before joining Medscape. Alex is also an MIT Knight Science Journalism fellow. Email:

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