Nivolumab/Relatlimab Does Not Meet RFS End Point in Stage III/IV Melanoma

The safety profile of nivolumab plus relatlimab in patients with stage III/IV melanoma was consistent with the known profiles for each individual agent.

The randomized, double-blind phase 3 RELATIVITY-098 trial (NCT05002569) evaluating nivolumab plus LAG-3–blocking antibody relatlimab-rmbw (Opdualag) as an adjuvant treatment in patients with completely resected stage III/IV melanoma did not meet its primary end point of recurrence-free survival (RFS), according to a news release from the drug’s developer, Bristol Myers Squibb.¹

The safety profile of nivolumab plus relatlimab in this patient population was consistent with the known profiles for each individual agent. According to the press release, nivolumab remains a standard of care in the adjuvant setting for adult and pediatric patients 12 years and older with completely resected stage IIB, stage IIC, stage III, or stage IV melanoma. Furthermore, nivolumab plus hyaluronidase-nvhy (Opdivo Qvantig) was approved as a subcutaneous treatment for all solid tumor indications, including for the adjuvant treatment of adult patients with completely resected stage IIB, stage IIC, stage III, or stage IV melanoma, in December 2024.²

Additionally, the FDA previously approved nivolumab plus relatlimab in patients with unresectable or metastatic melanoma in March 2022.³

“We are disappointed in the outcome of the RELATIVITY-098 trial and that LAG-3 inhibition in the adjuvant setting did not lead to the same improved efficacy outcomes seen in advanced melanoma,” Jeffrey Walch, MD, PhD, vice president and nivolumab and relatlimab global program lead at Bristol Myers Squibb, stated in the news release.¹ “Patients whose tumors are completely resected before treatment may not have sufficient antitumor T cells in place for [nivolumab plus relatlimab] to have its maximal effect. However, [nivolumab plus relatlimab] remains a standard of care in the first-line treatment of unresectable or metastatic melanoma, and we continue to explore its potential across tumor types, including in non–small cell lung cancer.”

Patients in the phase 3 RELATIVITY-098 trial were randomly assigned 1:1 to receive either nivolumab alone or nivolumab plus relatlimab as a fixed-dose combination.⁴

The primary end point was RFS. Secondary end points included distant metastasis-free survival, overall survival, progression-free survival, and incidence and severity of adverse events.

LAG-3 is a molecule found on the surface of multiple immune cell types, including CD4-positive, CD8-positive, and regulatory T cells, as well as natural killer cells. LAG-3 inhibits T cell function and reduces their activation and growth. Tumors are then able to grow unchecked due to T-cell dysfunction. By targeting both LAG-3 and PD-1, developers hypothesize that anti-tumor responses may be bolstered by the restoration of T-cell activity not observed in PD-1 inhibition alone.

Patients were eligible for enrollment if they were diagnosed with stage IIIA/B/C/D or stage IV melanoma by American Joint Committee on Cancer v8 criteria and had completely resected histologically confirmed melanoma with negative margins. Additionally, patients 18 years or older must have had an ECOG performance status score of 0 or 1, and patients 12 to 17 years must have had a Lansky/Karnofsky performance score of 80% or higher. Furthermore, complete resection must have occurred within 90 days prior to random assignment, all patients must have had disease-free status by complete physical examination within 14 days to random assignment, and tumor tissue must have been available for biomarker analysis.

Patients were excluded from trial enrollment if they had a history of ocular melanoma; untreated or unresected central nervous system or leptomeningeal metastases; or active, known, or suspected autoimmune disease. Furthermore, those with serious or uncontrolled medical disorders, prior immunotherapy treatment, severe acute respiratory syndrome coronavirus 2 infections within 4 weeks of screening, and a history of myocarditis were excluded from trial participation.

References

1. Bristol Myers Squibb provides update on phase 3 RELATIVITY-098 trial. News release. Bristol Myers Squibb. February 13, 2025. Accessed February 14, 2025. https://tinyurl.com/2e9mth87
2. FDA approves nivolumab and hyaluronidase-nvhy for subcutaneous injection. News release. FDA. December 27, 2024. Accessed February 14, 2025. https://tinyurl.com/42rfemr7
3. U.S. Food and Drug Administration approves first LAG-3-blocking antibody combination, Opdualag™ (nivolumab and relatlimab-rmbw), as treatment for patients with unresectable or metastatic melanoma. News release. Bristol Meyers Squibb. March 18, 2022. Accessed February 14, 2025. https://bit.ly/3DNa8a4
4. A study to assess adjuvant immunotherapy with nivolumab plus relatlimab versus nivolumab alone after complete resection of stage iii-iv melanoma (RELATIVITY-098). ClinicalTrials.gov. Updated January 20, 2025. Accessed February 14, 2025. https://tinyurl.com/4sh3vmck