Author: [AUTHOR] Published on 4/8/2022 1:00:00 PM
FDA Approves OPDUALAG (nivolumab and relatlimab-rmbw) for the treatment of adult and pediatric patients 12 years of age or older with unresectable or metastatic melanoma
On March 18, 2022, the US Food and Drug Administration (FDA) approved OPDUALAG (nivolumab and relatlimab-rmbw) for the treatment of adult patients and pediatric patients 12 years of age or older who weigh at least 40 kg with unresectable or metastatic melanoma.
The approved recommended dosage of OPDUALAG for adult patients and pediatric patients 12 years of age or older who weigh at least 40 kg is 480 mg nivolumab and 160 mg relatlimab administered intravenously (IV) every 4 weeks until disease progression or unacceptable toxicity occurs. The recommended dosage for pediatric patients 12 years of age or older who weigh less than 40 kg has not been established.
Additional information regarding dosage and administration as well as warnings and precautions about immune-mediated adverse reactions, infusion-related reactions, complication of allogenic hematopoietic stem cell transplantation (HSCT), and embryo-fetal toxicity can be found in the full prescribing information linked below.
Mechanism of Action (MOA) and Pharmacokinetics (PK)
MOA: OPUALAG is a combination of nivolumab, a programmed death receptor-1 (PD-1) blocking antibody, and relatlimab, a lymphocyte activation gene-3 (LAG-3) blocking antibody.
General PK: The PK of relatlimab following the administration of nivolumab and relatlimab-rmbw were characterized in patients with cancer who received relatlimab 20 to 800 mg every 2 weeks (0.25 to 10 times the approved recommended dosage) or 160 to 1440 mg every 4 weeks (1 to 9 times the approved recommended dosage) either as a monotherapy or in combination with nivolumab dosages of 80 or 240 mg every 2 weeks or 480 mg every 4 weeks.
Steady-state concentrations of relatlimab were reached by 16 weeks with an every 4-week dosing regimen and the systemic accumulation was 1.9-fold. The average concentration (Cavg) of relatlimab after the first dose increased dose proportionally at doses ≥160 mg every 4 weeks.
Following the recommended dosage, the geometric mean [coefficient of variation (CV%)] maximum and average concentrations (Cmax and Cavg) of relatlimab at steady state were 62.2 (30%), and 28.8 (45%) μg/mL, respectively; and the mean Cmax and Cavg of nivolumab at steady state were 187 (33%) and 94.4 (43%) μg/mL, respectively.
In the RELATIVITY-047 trial, the nivolumab geometric mean minimum concentration (Cmin) at steady state in the OPDUALAG arm was comparable to the nivolumab arm.
Distribution: The geometric mean (CV%) volume of distribution at steady state of relatlimab is 6.6 L (20%) and 6.6 L (19%) of nivolumab.
Elimination: The geometric mean (CV%) clearance of relatlimab is 5.5 mL/h (41%) at steady state, 10% lower than after the first dose [6 mL/h (39%)]. Following nivolumab 480 mg and relatlimab 160 mg every 4 weeks administration, the geometric mean (CV%) effective half-life (t1/2) of relatlimab is 26.2 days (37%).
The geometric mean (CV%) clearance of nivolumab is 7.6 mL/h (40%) at steady state, 21% lower than after the first dose [9.6 mL/h (40%)] and the terminal t1/2 is 26.5 days (36%).
Immunogenicity: During the initial 24-month treatment period in RELATIVITY-047:
- the incidence of anti-nivolumab antibodies and neutralizing antibodies in the nivolumab and relatlimab-rmbw group was 3.8% (11/288) and 0.3% (1/288), respectively, which was similar to that observed in the nivolumab group: 5.9% (16/272) and 0.4% (1/272), respectively.
- the incidence of anti-relatlimab antibodies and neutralizing antibodies in the nivolumab and relatlimab-rmbw group was 5.6% (16/286) and 0.3% (1/286), respectively.
Because of the low incidence of anti-drug antibodies, the effect of these antibodies on the PK, pharmacodynamics, safety, or effectiveness of OPDUALAG is unknown.
Use in Specific Populations
The following factors had no clinically important effect on the clearance of nivolumab and relatlimab: age (17 to 92 years), sex, race (White, Asian, and Black/African American), mild or moderate renal impairment (eGFR 30 to 89 mL/min/1.73 m2), mild hepatic impairment (total bilirubin [TB] less than or equal to upper limit of normal [ULN] and AST greater than ULN or TB greater than 1 to 1.5 times ULN and any AST) or moderate hepatic impairment (TB greater than 1.5 to 3 times ULN and any AST). The effects of severe renal impairment, or severe hepatic impairment on the PK of nivolumab and relatlimab are unknown.
Pediatric patients: The exposures of nivolumab and relatlimab in pediatric patients 12 years of age or older who weigh at least 40 kg are expected to be in the range of exposures in adult patients at the recommended dosage.
Efficacy and Safety
Efficacy of OPDUALAG was investigated in RELATIVITY-047, a randomized (1:1), double-blinded trial in 714 patients with previously untreated metastatic or unresectable Stage III or IV melanoma. The major efficacy outcome measure was progression-free survival (PFS) determined by Blinded Independent Central Review (BICR) using Response Evaluation Criteria in Solid Tumors (RECIST v1.1). Additional efficacy outcome measures were overall survival (OS) and overall response rate (ORR) determined by BICR using RECIST v1.1. Additional information regarding efficacy trial can be found in the full prescribing information linked below.
The most common adverse reactions (≥20%) are musculoskeletal pain, fatigue, rash, pruritus, and diarrhea. The most common laboratory abnormalities (≥20%) are decreased hemoglobin, decreased lymphocytes, increased AST, increased ALT, and decreased sodium.
Full prescribing information is available at https://go.usa.gov/xzG9p.
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This communication was prepared by Office of Clinical Pharmacology, Office of Translational Sciences, CDER, FDA.
