ESMO 2021: Melanoma Highlights

Relatlimab (RELA) + nivolumab (NIVO) vs. NIVO in previously untreated metastatic or unresectable melanoma: Additional efficacy in RELATIVITY-047

While PD-1/L1s alone or in combination with CTLA-4 have been in use for melanoma since a decade, their use have exponentially increased with time. Oncologists are now eager to watch if new immune checkpoint inhibitors could also play a role in melanoma tumor cells. LAG-3 is a new targetable immune checkpoint that has garnered the interest of oncologists and companies alike. Various studies and clinical trials are ongoing to study LAG-3 inhibition in various oncology indications. Since the mechanism of action of LAG-3 inhibitors is to prevent the suppression of T-cells, which is the same as that of PD-1/L-1 and CTLA-4 inhibitors, the LAG-3 inhibitors are also expected to demonstrate good results. One such LAG-3 inhibitor is relatlimab, which is currently in phase II/III RELATIVITY-047 in combination with nivolumab (Opdivo), for the treatment of previously untreated metastatic or unresectable melanoma (Abstract #1036O). The trial had previously shown promising results and the drug combo is expected to be the next big thing in melanoma. The previous results have also indicated that it may be able to replace Yervoy as the duo has a higher safety advantage over Yervoy, with just a slight decrease in clinical benefit, as per the results presented during ASCO 2021. Based on these results, recently, the US FDA granted priority review to the combo and assigned a Prescription Drug User Fee Act (PDUFA) goal date of March 19, 2022.

In ESMO 2021, BMS presented additional efficacy results from the phase II/III RELATIVITY-047 trial. The patients in the trial were given relatlimab 160 mg + nivolumab 480 mg FDC or nivolumab monotherapy 480 mg, intravenously every 4 weeks. The primary endpoint was progression-free survival (PFS) and secondary endpoints were overall survival (OS) and objective response rate (ORR), while explanatory endpoints included treatment-free interval (TFI) and PFS2. The results demonstrated a longer TFI in the patients who received a combination of relatlimab and nivolumab as compared to nivolumab alone, with a median TFI of 3.22 months versus 1.41 months, respectively. Moreover, the risk of progression reduced following the next line of systemic therapy (PFS2), per investigator assessment, or death with the doublet when compared with nivolumab alone and the median PFS2 had not yet been reached in the drug combo arm, whereas it was 20.04 months with single agent nivolumab.

The safety profile of relatlimab and nivolumab combination was manageable and no unexpected safety signals were observed. Grade 3 or 4 TRAEs led to discontinuation in 8.5% of patients who received the doublet as compared to 3.1% of patients who received nivolumab.

Expert opinion- “Although we’ve seen significant advances in the treatment of melanoma since the introduction of immune checkpoint inhibitors, there continue to be patients who could benefit from a novel dual immunotherapy approach. Based on the results of the RELATIVITY-047 trial, we believe that the relatlimab and nivolumab fixed-dose combination has the potential to improve outcomes for patients with metastatic or unresectable melanoma. We look forward to potentially introducing the first LAG-3–blocking antibody, and Bristol Myers Squibb’s third distinct checkpoint inhibitor, to help patients in need.”

-         Expert Opinion

INSIGHTS- The melanoma market is a challenging space to navigate as there have been various therapies in the past that did not demonstrate clinical benefit despite being in the late-stage of their clinical development. Moreover, a handful of those trials could not reach the finishing line, such as Novartis’ spartalizumab (PDR001), in combination with dabrafenib and trametinib (COMBI-i), Idera Pharmaceuticals’ tilsotolimod in combination with ipilimumab (ILLUMINATE-301), as well as Roche’s atezolizumab and cobimetinib combination (IMspire170 trial). As per our analysis, the company’s idea of trying the novel combination of an anti-LAG-3 antibody with the already approved anti-PD-1 suggests its key strategy to enhance the immune response thereby improving the clinical outcomes in the patients who co-express these immune checkpoints on their tumor infiltrating lymphocytes (TILs) which are known to play a major role in tumor-mediated T-cell exhaustion. BMS’ strong contender Merck is also exploring its early phase anti-LAG-3 antibody, favezelimab (MK-4280) with its blockbuster checkpoint inhibitor, Keytruda in various solid and hematological malignancies. However, BMS leads the race as it has clinched the PDUFA date by the regulatory agency for the first-line setting of the indication, where, Merck may need to wait a bit longer to enter the space. Ass per Delveinsight’s analysis, relatlimab, if approved, could be a game changer not only for the millions of people fighting this disease, but also for the entire field of oncology and reckons good fortune for the combination in the global market in terms of revenue generation and market size.