Monica Holmber, PharmD, BCPS

The FDA has approved nivolumab and relatlimab-rmbw intravenous (IV) injection (Opdualag; Bristol Myers Squibb) to treat metastatic or unresectable melanoma in patients 12 years or older.

The incidence of melanoma has been increasing over the past 3 decades, with an estimated 99,780 new melanoma diagnoses and 7650 melanoma-related deaths expected to occur in the United States in 2022.

Nivolumab is a human IgG4 monoclonal programmed death receptor-1 (PD-1) blocking antibody. It binds to the PD-1 receptor, blocks the interaction with its ligands PD-L1 and PD-L2, and reduces PD-1 pathway-mediated inhibition of the immune response. Relatlimab is a human IgG4 monoclonal lymphocyte activation gene-3 (LAG-3) blocking antibody. By binding to the LAG-3 receptor, blocking the interaction with its ligands, and reducing LAG-3 pathway-mediated inhibition of the immune response, promotion of both cytokine secretion and T-cell proliferation occurs. Combination therapy with both nivolumab and relatlimab leads to increased T-cell activation compared with monotherapy with either agent alone. The half-life of nivolumab is 26.5 days, whereas relatlimab is 26.2 days.

The recommended dose of Opdualag for patients 12 years or older who weigh at least 40 kg is 480 mg of nivolumab and 160 mg of relatlimab IV every 4 weeks until the disease progresses or unacceptable toxicity occurs. It should be given as a 30-minute infusion through an IV line containing a nonpyrogenic, sterile, low-protein–binding in-line nylon, polyethersulfone, or polyvinylidene fluoride filter with a pore size of 0.2 μm to 1.2 μm. Other medications should not be coadministered through the same IV line.

The efficacy of Opdualag was evaluated in RELATIVITY-047 (NCT03470922),
a double-blind, randomized trial of 714 participants with previously untreated metastatic or unresectable stage 3 or 4 melanoma. Patients with active autoimmune disease, active or untreated brain or leptomeningeal metastases, medical conditions requiring systemic treatment with moderate- or high-dose corticosteroids or immunosuppressive medications, and uveal melanoma were excluded from the trial. Participants were randomized 1:1 to receive either nivolumab 480 mg IV every 4 weeks or Opdualag (nivolumab 480 mg and relatlimab 160 mg) IV every 4 weeks until their disease progressed or unacceptable toxicity occurred. Tumors were evaluated 12 weeks after randomization and every 8 weeks thereafter up to week 52, then every 12 weeks. The trial met its primary end point, which was progression-free survival. The median progression-free survival was 4.6 months for the nivolumab group and 10.1 months for the Opdualag group. Secondary end points were overall survival, which did not demonstrate a statically significant difference, and overall response rate.

Contraindications, Warnings, and Precautions

There are no contraindications to treatment with Opdualag. Immunemediated adverse reactions (IMARs), which may be severe or fatal, can occur in any organ system or tissue and at any time after starting or discontinuing treatment with LAG-3 and PD-1/ PD-L1 blocking antibodies. Patients should be monitored for early identification and management of IMARs. Occurrence of an IMAR may warrant either discontinuing or holding of Opdualag. Creatinine, liver enzymes, and thyroid function should be assessed at baseline and throughout treatment. Opdualag can cause severe infusion-related reactions. Fatal and other serious complications can occur in patients who receive allogeneic hematopoietic stem cell transplantation before or after being treated with a PD-1/PD-L1 blocking antibody. Because Opdualag can cause fetal harm, women of childbearing potential should use effective contraception during treatment. Opdualag should not be used during breastfeeding.

The most common adverse reactions are diarrhea, fatigue, musculoskeletal pain, pruritus, and rash. The most common laboratory abnormalities are decreased hemoglobin, lymphocytes, and sodium, increased alanine transaminase and aspartate transaminase.

, is a pharmacist in Phoenix, Arizona, and Pharmacy Times® contributor.

1. Opdualag.Prescribinginformation.Bristol Myers Squibb; 2022. Accessed April 1, 2022. https://packageinserts.bms.com/pi/pi_opdualag.pdf

2. 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. Bristol-Myers Squibb. News release. March 18, 2022. Accessed April 1, 2022. https://news.bms.com/news/corporate-financial/2022/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/default.aspx

Articles

Combination therapy with both nivolumab and relatlimab leads to increased T-cell activation compared with monotherapy with either agent alone.

Opdualag From Bristol Myers Squibb

The FDA approved an expanded indication for Isentress (raltegravir) to include the treatment of HIV-1 infection in children 2 years and older.

The FDA has expanded the indication of Merck’s Isentress (raltegravir) to include pediatric patients. The new approval indicates Isentress for use in combination with other antiretroviral agents for the treatment of HIV-1 infection in children 2 years and older who weigh at least 10 kg. A chewable tablet formulation (25 mg and scored 100 mg) was also approved.

Isentress first received FDA approval in 2007, but its use was limited to treatment-experienced adult patients with HIV-1. Its indication was expanded in 2009 to include treatment-naïve adult patients with HIV-1.

HIV-1 integrase is an encoded enzyme involved in viral replication. Isentress exerts its effect by inhibiting the catalytic activity of this enzyme, thus preventing the formation of the HIV-1 provirus. Without the provirus, the production of progeny virus cannot occur. As a result, the viral infection cannot be propagated.

Neither race nor gender affect the pharmacokinetics of Isentress.

Isentress is available as a 400-mg film-coated tablet, a 25-mg chewable tablet, and a 100-mg chewable tablet. The 400 mg film-coated tablet is not interchangeable with the 25- or 100-mg chewable tablet formulations.

Children 12 years and older should receive one 400-mg filmcoated Isentress tablet twice daily. Children aged 6 years to younger than 12 years who are at least 25 kg in weight should receive either one 400-mg film-coated Isentress tablet twice daily or a weight-based chewable tablet dose (Table), to a maximum dose of 300 mg twice daily. Children aged 6 years to younger than 12 years who weigh less than 25 kg should receive a weight-based chewable tablet to a maximum dose of 300 mg twice daily. Children aged 2 years to younger than 6 years who are at least 10 kg should receive a weight-based chewable tablet dose to a maximum dose of 300 mg twice daily.

The 400-mg film-coated tablet must be swallowed whole. Isentress can be given with or without food.

The approval for pediatric patients was based on data from a Phase I/II 24-week, open-label, multicenter trial that evaluated the pharmacokinetic profile, safety, tolerability, and efficacy of Isentress in HIV-1— infected children and adolescents with optimized background therapy. The study included 126 treatment-experienced HIV-1– infected children (aged 2-18 years), most of whom had previously used at least 1 nonnucloeoside reverse transcriptase inhibitor or 1 protease inhibitor.

Ninety-six patients used either the 400-mg film-coated tablet or the chewable tablet, given twice daily in combination with optimized background therapy. At baseline, the mean plasma HIV-1 RNA was 4.3 log 10 copies/mL, and the mean CD4 cell count was 481 cells/mm

. Ninety-seven percent of patients continued treatment for 24 weeks. At 24 weeks, 54% of these patients had a mean plasma HIV-1 RNA of less than 50 copies/ mL, and the mean CD4 cell count increased by 119 cells/mm3 from baseline.

There are no contraindications to treatment with Isentress.

Severe, potentially life-threatening and fatal skin reactions, including Stevens-Johnson syndrome, hypersensitivity reaction, and toxic epidermal necrolysis, have been reported. Discontinue treatment immediately if severe hypersensitivity, severe rash, or rash with systemic symptoms or liver aminotransaminase elevations occur. Patients should be monitored for immune reconstitution syndrome. Patients with phenylketonuria should be warned that the chewable tablets contain phenylalanine.

Concomitant administration of Isentress with strong inducers of UGT1A1 may result in decreased Isentress plasma concentrations. Isentress is Pregnancy Category C and should only be used if the potential benefit outweighs the potential risk. Isentress should not be used in patients who are breastfeeding. Creatine kinase elevations with reports of myopathy and rhabdomyolysis were noticed in patients using Isentress. Use cautiously in patients at risk for myopathy or rhabdomyolysis. Isentress should not be used in children younger than 2 years.

The most common adverse effects (≥2%) are insomnia, headache, nausea, and fatigue.

Dr. Holmberg is a pharmacist who resides in Phoenix, Arizona.

1. Isentress complete prescribing information. Available at http://www.merck.com/product/usa/pi_circulars/i/isentress/isentress_pi.pdf Accessed June 2012.

2. FDA Approves Merck’s ISENTRESS® (raltegravir) for Use in Children Ages Two Years and Older as Part of HIV-1 Combination Therapy. Available at http://www.isentress.com/isentress/hcp/documents/isentress_press_release.pdf 