Our study is called RELATIVITY-047 and it is a global phase III trial that compared relatlimab plus nivolumab versus nivolumab alone for patients with previously untreated unresectable or metastatic melanoma. The background is that over the last decade or so drugs that target immune checkpoints like PD-1 have dramatically improved survival rates for patients with a wide variety of cancers, including melanoma. In order to build on this success and to develop novel combination regimens that are both safe and effective we combine two medicines, relatlimab is the first, that’s often called RELA for short, and that blocks an immune checkpoint called LAG-3 which is a checkpoint that’s new on the scene although this study goes a long way towards validating it as an effective target in cancer. RELA in this study was combined with nivolumab, often called NIVO, which we know blocks PD-1. Although these two drugs work on distinct pathways – LAG-3 and PD-1 are distinct immune checkpoints – both of them have a common goal which is to unleash an attack by the immune T-cells against cancer.

So supporting this approach were both pre-clinical and clinical studies. The preclinical studies demonstrated synergy between blockade of both of these pathways. Clinically, and this was compelling, we saw that the administration of RELA plus NIVO, the combination, to patients with melanoma that had already progressed through anti-PD-1 alone led to tumour regressions. So we saw that the combo was effective in patients whose tumours that already progressed through, say, nivolumab by itself.

What was the methodology used in this study?

This was a global randomised registrational study. As I said, it compares RELA plus NIVO to NIVO monotherapy. Trial patients had previously untreated unresectable or metastatic melanoma and received either the combo or nivolumab by itself. I should say that the two drugs combined were in what’s called a fixed dose combination, abbreviated FDC. A fixed dose combination really just means that RELA and NIVO together were prepared in the same medication vial and then they were administered as a single intravenous infusion and it was done so in order to reduce preparation and infusion times and to minimise the risk of administration errors.

From a methodologic standpoint the study’s primary endpoint was progression free survival, or PFS as it’s known, which we measure as the length of time between starting therapy and either tumour growth or patient death. It’s important to note that on this study changes in tumour size that we saw on imaging were assessed by a group of independent blinded radiologists, so this was not an investigator assessed outcome, this was a blinded panel of radiologists. Secondary endpoints for the trial include overall survival and objective response rate although I should say that as of ASCO 2021 both the study sponsor and us, the trial investigators, remain blinded to those outcomes and that is part of the statistical design of the study.

What were your findings?

The median progression free survival on our study of patients who received RELA plus NIVO was 10.1 months and that was more than double that of the group that received NIVO by itself – the PFS there was 4.6 months. So this was a significant improvement and it also meant that the study met its primary endpoint, the PFS endpoint. The hazard ratio on the study was 0.75 with a p-value of 0.0055. What we saw was that the progression free survival benefit appeared relatively early in the course of therapy. If you look at the PFS curves you’ll see that they separate at the 12 week point which was at the time of the first on-treatment imaging. The separation of those curves is sustained throughout the median length of follow-up of the study which is approximately 13 months.

How can these results impact the future treatment of melanoma?

That is a great question, in order to answer that I need to discuss a little bit about toxicity which is, of course, a concern any time you’re combining immune checkpoint blockers. Generally the treatment related adverse events that were associated with the combination, with RELA plus NIVO, were manageable and they reflected, as you might imagine, the typical safety profile that we see with immune checkpoint inhibitors generally. The incidence of grade 3/4 treatment related adverse events was higher with RELA plus NIVO than it was with NIVO alone although it’s worth noting that the adverse events here occurred at a lower rate than has been observed with other immunotherapy combinations. So, for example, treatment related adverse events that led to discontinuation of trial therapy occurred in 14.6% of patients in the RELA plus NIVO group and only in 6.7% of patients receiving NIVO by itself.

So, in answer to your question about where this fits into treatment paradigms for patients with advanced melanoma, the take-home message here is that RELA plus NIVO administered to previously untreated unresectable or metastatic melanoma patients led to a significant improvement in progression free survival when compared with NIVO alone and the combination demonstrated a manageable safety profile. We saw a lower rate of serious toxicities that were related to therapy relative to other immune checkpoint inhibitor combinations. So if you take those two things together what we come away with is that RELA plus NIVO is potentially a novel treatment option, first line treatment option, for this patient population.

I should say too, importantly, that this is the first phase III study to validate inhibition of the LAG-3 immune checkpoint as a therapeutic strategy for patients with cancer. This goes quite a long way in establishing LAG-3 as a pathway that can be inhibited to provide clinical benefit to patients. This is the third immune checkpoint pathway in history, in fact, after CTLA-4 and PD-1 where we can demonstrate that blockade has clinical benefit.