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ASCO 2021 | RELATIVITY-047: relatlimab, an anti-LAG-3 antibody + nivolumab in first-line advanced melanoma

Evan J. Lipson, MD, John Hopkins Medical Institute, Baltimore, MD, discusses findings of RELATIVITY-047 (NCT03470922), a global, randomized, double-blind Phase II/III study evaluating a novel immune checkpoint inhibitor combination of relatlimab, an anti-LAG3 antibody, plus nivolumab as a fixed-dose combination treatment in first-line advanced melanoma. First-line treatment with relatlimab and nivolumab demonstrated a significant improvement in progression-free survival when compared to nivolumab monotherapy in patients with advanced melanoma. The combination was well tolerated with a manageable safety profile and is the first Phase III study highlighting a benefit of dual inhibition of the LAG-3 and PD-1 pathways in any tumor type. This interview took place at the American Society of Clinical Oncology (ASCO) 2021 Virtual Meeting.

Transcript (edited for clarity)

I’d be delighted to discuss initial results from our study RELATIVITY-047, which is a global Phase III study that compares relatlimab with plus nivolumab, versus nivolumab alone for patients with previously untreated or unresectable metastatic melanoma. So as you know, over the past decade or so, drugs that target immune checkpoints like PD-1 have really dramatically improved survival rates and other outcomes for patients with a wide variety of cancers, including melanoma...

I’d be delighted to discuss initial results from our study RELATIVITY-047, which is a global Phase III study that compares relatlimab with plus nivolumab, versus nivolumab alone for patients with previously untreated or unresectable metastatic melanoma. So as you know, over the past decade or so, drugs that target immune checkpoints like PD-1 have really dramatically improved survival rates and other outcomes for patients with a wide variety of cancers, including melanoma. And so, to build on this success and to try to develop some novel regimens that are safe and effective, we combined relatlimab, which is sometimes called, “RELA,” for short, which blocks another immune checkpoint that’s called LAG-3, Lymphocyte-activation gene-3, with nivolumab “NIVO,” which blocks PD-1. And although these drugs work through distinct pathways, they have a common goal, of course, which is to unleash and attack by immune T cells against tumors, against malignancies of all kinds, in this case, melanoma.

We did some preliminary work in this space, both pre-clinically and clinically. And so the pre-clinical evidence demonstrated that these two approaches when used together can be synergistic. And then in fact, clinically we saw in earlier trials, when you gave RELA plus NIVO to patients with PD-1 refractory melanoma, we saw that the combination did in fact bring about anti-tumor immunity in some of those patients. So we had a good preclinical basis for this, and then some clinical evidence that it could be effective.

So RELATIVITY-047, the current study, is the first global randomized registrational trial comparing NIVO plus RELA to NIVO monotherapy. Our study patients all had previously untreated, unresectable, or metastatic melanoma and were randomized to either receive RELA plus NIVO, or NIVO monotherapy. I should say that the RELA plus NIVO, the two medications were combined in what’s called a fixed-dose combination, which means that the medicines were prepared in the same medication vial, and then administered as a single intravenous infusion in an effort to reduce the preparation and infusion times, and reduce the likelihood of administration errors.

The primary endpoint of the study was progression-free survival or PFS, and we defined that at the length of time between starting therapy in either tumor growth or patient death. I will say that the changes in tumor sizes seen on imaging in our study were assessed by a group of blinded independent radiologists. There were a couple of secondary endpoints, including overall survival objective response rate. Those outcomes at the moment are still in process, so the investigators in the study sponsor are both blinded to those outcomes.

So, in terms of the progression-free survival outcomes, the median PFS of patients that received the combination, the RELA plus NIVO, was 10.1 months, which is more than double that of the group that received NIVO alone, which was 4.6 months, and this correlated with a statistically significant improvement, meaning that the study met it’s primary endpoint. The hazard ratio on the trial was 0.75 with a P-value of 0.0055. It appeared on the survival curves that the PFS benefit occurred early in the course of therapy. So at about the 12 week mark, those two curves separate, and that was the time of the first on-treatment scan. And then the separation in those curves was sustained throughout the median follow-up of the study, which was about 13 months.

In terms of toxicity, the treatment-related adverse events that were associated with the combo, with RELA plus NIVO, were manageable, and they reflected the safety profile that we typically see with immune checkpoint inhibitors. I should say that the incidents of grade three/four toxicities, the severe toxicities that were treatment-related was higher with RELA plus NIVO than it was with NIVO alone, although these adverse events occurred at a lower rate than has been observed in other combination immunotherapy studies. The treatment-related AEs that led to discontinuation of trial therapy occurred in 14.6% of patients getting the dual therapy, and only about 6.7% of patients receiving NIVO alone, so a little higher in the combination group.

But in conclusion, the combination therapy administration of RELA plus NIVO together to this patient population; previously untreated, unresectable, or metastatic melanoma, led to a significant improvement in progression-free survival when compared with nivolumab alone. The safety profile was manageable. It does seem that the grade three or greater toxicity rate is lower than what we’ve seen with other immune checkpoint inhibitor combinations, and taken together, these findings demonstrate that RELA plus NIVO is a potential novel treatment option for this patient population. And importantly, this is the first Phase 3 study to validate inhibition of the LAG-3 immune checkpoint as a therapeutic strategy, not just for melanoma patients, but for patients with cancer generally, and I think this establishes the LAG-3 pathway as the third immune checkpoint pathway, really in history, after the CTLA-4 and PD-1 pathways for which a blockade has clinically benefited. So, we’re excited about the results of our study, and looking forward to maturing data in the coming months and years. And so, I thank you for your attention and for your interest in our trial.

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Disclosures

Evan J. Lipson, MD has received consulting or advisory roles from Bristol-Myers Squibb, Novartis, EMD Serono, Array BioPharma, Macrogenics, Merck, Sanofi/Regeneron, Genentech, and Odonate Therapeutics, as well as research funding from Bristol-Myers Squibb, Merck, and Sanofi/Regeneron.

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