Bristol Myers' Opdivo combo Opdualag scores FDA approval in melanoma, opens 3rd immune checkpoint drug class

Bristol Myers Squibb has established the third cancer checkpoint inhibitor class, going back to its immuno-oncology roots in melanoma with an FDA go-ahead.

The new drug, a LAG-3 antibody called relatlimab, has been approved in a fixed-dose combination with BMS’ PD-1 inhibitor Opdivo for the treatment of unresectable or metastatic melanoma. The combo will be sold under the brand name Opdualag.

With Friday’s approval, BMS now boasts three checkpoint inhibitors, including its CTLA-4 blocker Yervoy. All three drugs had their initial approvals in melanoma, and so did the duo immunotherapy cocktail of Opdivo and Yervoy.

LAG-3 is found on the surface of T cells and is linked with T-cell exhaustion and resistance to immunotherapies like PD-1 inhibitors, BMS’ chief medical officer, Samit Hirawat, M.D., explained in an interview ahead of the approval. Blocking LAG-3 with a drug like relatlimab could reactivate T cells and avoid resistance to PD-1 inhibition, he said.

The relatlimab-Opdivo combo is a key component in BMS’ plan to overcome the patent protection losses of three of its top-selling drugs—blood cancer therapy Revlimid, Pfizer-shared blood thinner Eliquis and Opdivo—within the decade. The company has projected the new pairing could reach over $4 billion sales in 2029.

Now, the question remains: How much of that revenue will come from cannibalizing Yervoy?

Opdualag earned a green light based on data showing it can double the time patients with previously untreated advanced melanoma can live without disease progression compared with Opdivo alone. In the phase 3 RELATIVITY-047 trial, patients on the fixed-dose combo registered a median progression-free survival of 10.1 months, versus 4.6 months for solo Opdivo.

An update a few days ago showed that Opdualag cut the risk of death by 20% over Opdivo, an improvement that narrowly missed statistical significance but was “clinically meaningful,” Georgina Long, an investigator of RELATIVITY-047 from the Melanoma Institute Australia, said at the March session of the ASCO Plenary Series.

Opdualag’s efficacy showing was slightly weaker than the Opdivo-Yervoy pairing, which demonstrated a median 11.5 months of progression-free survival in its own CheckMate-067 trial.

Cross-trial comparisons have various problems, but industry watchers constantly resort to them for commercial analysis anyway in lieu of a head-to-head study.

But relatlimab appears to boast a safety advantage over Yervoy. The incidence of treatment-related side effects of grades 3 or 4 was 55% for the Opdivo-Yervoy combo in CheckMate-067 and was 19% for Opdivo-and-relatlimab in RELATIVITY-047.

Some physicians may balk at the safety profile of Yervoy, BMS notes. The company hopes that another dual I-O option with less toxicity could convince doctors who’re currently treating melanoma patients with single-agent Opdivo to add relatlimab and reap the benefit of improved efficacy, Hirawat said. The BMS exec figures doctors who are already comfortable in managing Yervoy’s profile will continue using that doublet therapy.

Currently, about one-third of advanced melanoma patients are treated with PD-1 monotherapy, including Merck & Co.’s Keytruda, according to BMS. A third are getting Opdivo-plus-Yervoy, and the remaining third⁠— mainly with BRAF mutations⁠—use targeted therapies such as Novartis’ Tafinlar and Mekinist.

Opdualag is “likely to first take metastatic melanoma share from single-agent anti-PD1,” SVB Leerink analyst Daina Graybosch, Ph.D., wrote in a note Wednesday. Plus, the fixed-dose nature will also prevent physicians from substituting Keytruda for Opdivo in the new combo, she noted. But it will be harder for the new combo to erode share from the Opdivo-Yervoy doublet, she said, given doctor experience with the latter and its seemingly better efficacy.

First-line melanoma is just the first step BMS has planned for Opdualag. The phase 3 RELATIVITY-098 trial is assessing the Opdivo-plus-relatlimab cocktail versus Opdivo alone in postsurgery treatment of stages 3 to 4 melanoma in the adjuvant setting. The company will soon launch a registrational study for the new combo in second-line colorectal cancer, Hirawat said, and phase 2 studies are underway in non-small cell lung cancer and liver cancer.

The Opdualag approval comes on the heels of a high-profile failure for BMS in the melanoma space. Nektar Therapeutics’ long-acting interleukin-12 drug bempegaldesleukin, or bempeg, which BMS paid $1.85 billion upfront in 2018 to pair with Opdivo, bombed in a phase 3 trial in first-line melanoma. The drug, used in combination with Opdivo, failed to provide a benefit across tumor shrinkage, disease progression or patient survival, dealing a blow to BMS’ I-O ambition.

Editor's Note: The story has been updated to clarify that Opdualag is the brand name for the fixed-dose combination of Opdivo and relatlimab.