Bristol Myers Squibb’s Opdualag fails to meet primary endpoint in Phase 3 trial

Bristol Myers Squibb has announced that its Phase 3 RELATIVITY-098 clinical trial, designed to evaluate Opdualag (nivolumab and relatlimab-rmbw) for adjuvant melanoma treatment, failed to meet its primary endpoint of recurrence-free survival (RFS). The trial assessed whether the combination immunotherapy could prevent or delay cancer recurrence in patients with completely resected Stage III-IV melanoma, but the data showed no significant advantage over Opdivo (nivolumab) monotherapy.

The findings represent a setback for LAG-3 inhibition, which has been a promising but unproven approach in certain immunotherapy combinations. While Opdualag has demonstrated effectiveness in treating unresectable or metastatic melanoma, its performance in adjuvant melanoma treatment appears to be limited.

What is Opdualag and how does it work?

Opdualag is a first-in-class, fixed-dose combination therapy that pairs nivolumab, a PD-1 inhibitor, with relatlimab, a LAG-3-blocking antibody. This dual immunotherapy approach was designed to enhance T cell activity, helping the immune system target and destroy cancer cells more effectively.

Nivolumab works by blocking PD-1, a protein that helps tumors evade the immune system, while relatlimab targets LAG-3, another immune checkpoint that suppresses T cell activation. Preclinical studies suggested that combining these two mechanisms could produce a stronger anti-tumor response than PD-1 monotherapy alone.

In 2022, the U.S. Food and Drug Administration (FDA) approved Opdualag as the first combination therapy containing a LAG-3 inhibitor for unresectable or metastatic melanoma. However, its effectiveness in earlier-stage melanoma has remained uncertain, as shown by the RELATIVITY-098 trial results.

Why didn’t Opdualag improve recurrence-free survival in adjuvant melanoma?

The RELATIVITY-098 trial was a randomized, double-blind Phase 3 study comparing Opdualag to Opdivo after complete tumor removal. While previous research supported the theory that LAG-3 inhibition could boost T cell-mediated immunity, Bristol Myers Squibb’s data suggests that adjuvant melanoma treatment presents unique challenges.

Dr. Jeffrey Walch, vice president and global program lead for Opdualag at Bristol Myers Squibb, explained that the presence of antitumor T cells might be a critical factor in treatment success. Unlike metastatic melanoma, where the immune system is actively fighting tumors, completely resected melanoma may lack sufficient immune cell activation for Opdualag to work effectively. This raises questions about whether LAG-3 inhibition is viable in adjuvant settings, where tumor burden is significantly lower.

While the failure to improve recurrence-free survival is disappointing, Opdualag’s established role in first-line metastatic melanoma treatment remains unchanged.

What does this mean for Opdualag’s future in cancer treatment?

Despite the negative outcome, Bristol Myers Squibb remains committed to exploring Opdualag’s potential across various cancer types. The company is conducting ongoing clinical trials in non-small cell lung cancer and other solid tumors, where LAG-3 inhibition could still provide therapeutic benefits.

For now, Opdivo remains the standard of care for adjuvant melanoma treatment, particularly in patients 12 years and older with completely resected Stage IIB, IIC, III, or IV melanoma. Additionally, Bristol Myers Squibb has expanded its immunotherapy portfolio with Opdivo Qvantig (nivolumab + hyaluronidase-nvhy), a recently approved subcutaneous treatment option for adjuvant melanoma.

How will this impact the immunotherapy landscape?

The failure of LAG-3 inhibition in the adjuvant setting highlights the complexity of immune-based therapies. Experts in oncology believe that patient selection may be key to future success. Identifying biomarkers that predict T cell presence and immune activity could help determine which patients are most likely to benefit from dual checkpoint blockade therapies like Opdualag.

Additionally, some researchers suggest that combination approaches—including triple checkpoint blockade strategies—may offer better outcomes for certain patient populations. As the field of cancer immunotherapy continues to evolve, the role of LAG-3 inhibition will likely be refined based on further clinical data.

While the RELATIVITY-098 trial results are a setback, they provide valuable insights that could shape future melanoma treatment strategies. Bristol Myers Squibb has expressed gratitude to the patients, families, and investigators who participated in the study, emphasizing the ongoing commitment to advancing immunotherapy research.