FDA Approves Nivolumab and Relatlimab-Rmbw for Unresectable or Metastatic Melanoma
On March 18, 2022, the U.S. Food and Drug Administration (FDA) approved (https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-opdualag-unresectable-or-metastatic-melanoma) nivolumab and relatlimab-rmbw (Opdualag™) for adult and pediatric patients aged 12 years or older with unresectable or metastatic melanoma. Nivolumab and relatlimab-rmbw is a fixed-dose combination of the LAG-3–blocking antibody relatlimab and the programmed death receptor-1–blocking antibody nivolumab.
Efficacy was evaluated in a randomized, double-blinded trial (RELATIVITY-047; NCT03470922) of 714 patients with previously untreated metastatic or unresectable stage III or IV melanoma. The trial excluded patients with active autoimmune disease, medical conditions requiring systemic treatment with moderate or high-dose corticosteroids or immunosuppressive medications, uveal melanoma, and active or untreated brain or leptomeningeal metastases. Patients were randomized 1:1 to receive nivolumab 480 mg and relatlimab 160 mg via IV infusion every four weeks or nivolumab 480 mg via IV infusion every four weeks until they experienced disease progression or unacceptable toxicity.
The major efficacy outcome measure was progression-free survival (PFS) determined by blinded independent central review (BICR) using response evaluation criteria in solid tumors 1.1. The trial demonstrated a statistically significant improvement in PFS by BICR for nivolumab and relatlimab-rmbw compared to nivolumab (HR = 0.75; 95% confidence interval [CI] = 0.62, 0.92; p-value = 0.0055). Median PFS was 10.1 months (95% CI = 6.4, 15.7) in the nivolumab and relatlimab-rmbw arm and 4.6 months (95% CI = 3.4, 5.6) in the nivolumab arm. An additional efficacy outcome measure was overall survival (OS), which was not statistically significant (HR = 0.80; 95% CI = 0.64, 1.01) with median OS not reached (NR) in the nivolumab and relatlimab-rmbw arm (95% CI = 34.2, NR) and 34.1 months (95% CI = 25.2, NR) in the nivolumab arm.
The most common adverse reactions reported in 20% or more of patients were musculoskeletal pain, fatigue, rash, pruritus, and diarrhea. The most common laboratory abnormalities reported in 20% or more of patients were decreased hemoglobin, decreased lymphocytes, increased aspartate aminotransferase, increased alanine transaminase, and decreased sodium.
The recommended nivolumab and relatlimab-rmbw dose for adult and pediatric patients aged 12 years or older who weigh at least 40 kg is 480 mg nivolumab and 160 mg relatlimab administered via IV every four weeks until disease progression or unacceptable toxicity occurs. The recommended dose for pediatric patients aged 12 years or older who weigh less than 40 kg has not been established.
The review was conducted under Project Orbis (https://www.fda.gov/about-fda/oncology-center-excellence/project-orbis), an FDA Oncology Center of Excellence (OCE) initiative. Project Orbis provides a framework for concurrent submission and review of oncology drugs among international partners. For the review, FDA collaborated with the Australian Therapeutic Goods Administration and Switzerland’s Swissmedic. The application reviews may be ongoing at the other regulatory agencies.
The review used the Real-Time Oncology Review (https://www.fda.gov/about-fda/oncology-center-excellence/real-time-oncology-review) pilot program, which streamlined data submission prior to the filing of the entire clinical application, and Assessment Aid (https://www.fda.gov/about-fda/oncology-center-excellence/assessment-aid), a voluntary submission from the applicant to facilitate FDA’s assessment.
The application was granted priority review, fast track designation, and orphan drug designation. A description of FDA expedited programs is in the Guidance for Industry—Expedited Programs for Serious Conditions—Drugs and Biologics (https://www.fda.gov/regulatory-information/search-fda-guidance-documents/expedited-programs-serious-conditions-drugs-and-biologics).
Healthcare professionals should report all serious adverse events they suspect are associated with the use of any medicine and device to FDA’s MedWatch Reporting System (https://www.accessdata.fda.gov/scripts/medwatch/index.cfm) or by calling 800-FDA-1088.
For assistance with single-patient investigational new drug applications for oncology products, healthcare professionals may contact OCE’s Project Facilitate (mailto:OCE’s%20Project%20Facilitate) at 240-402-0004 or email OncProjectFacilitate@fda.hhs.gov (mailto:OncProjectFacilitate@fda.hhs.gov).