Nivolumab Receives Two FDA Approvals in November

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Nivolumab (Opdivo) is a monoclonal antibody that binds to the programmed cell death protein 1 (PD-1) receptor and blocks its interaction with its ligands PD-L1 and PD-L2, releasing PD-1 pathway–mediated inhibition of the immune response. Late last month, the U.S. Food and Drug Administration (FDA) approved nivolumab as a single agent for the treatment of patients with BRAF V600 wild-type unresectable or metastatic melanoma. This followed the approval a day earlier on November 24 of nivolumab to treat patients with metastatic renal cell carcinoma who have received a prior antiangiogenic therapy.

Melanoma Indication

The approval of nivolumab for previously untreated BRAF wild-type advanced melanoma is based on data from the phase III CheckMate 066 trial. The trial included treatment-naive patients with unresectable or metastatic BRAF wild-type melanoma who were randomly assigned to receive nivolumab or dacarbazine. The primary endpoint of the trial was overall survival, and secondary endpoints were progression-free survival and objective response rate.

CheckMate 066

Nivolumab demonstrated superior overall survival vs chemotherapy in the first-line setting. Results were based on the analysis conducted on 47% of the total planned events for overall survival. The median overall survival was not reached for nivolumab and was 10.8 months (95% confidence interval [CI] = 9.3–12.1) in the dacarbazine arm (hazard ratio [HR] = 0.42, 95% CI = 0.30–0.60, P < .0001).

Median progression-free survival more than doubled with nivolumab: 5.1 months vs 2.2 months for patients treated with dacarbazine (HR = 0.43, 95% CI = 0.34–0.56, P < .0001). Objective response rate with nivolumab was 34% compared to 9% with dacarbazine. At the time of analysis, 88% of nivolumab-treated patients had ongoing responses, which included 43 patients with ongoing responses of 6 months or longer.

In the trial, serious adverse reactions occurred in 36% of patients receiving nivolumab. Grade 3 and 4 adverse reactions occurred in 41% of patients receiving nivolumab, the most frequent being gamma-glutamyl transferase increase (3.9%) and diarrhea (3.4%). Adverse reactions led to permanent discontinuation of nivolumab in 7% of patients and dose interruption in 26% of patients.

The most common adverse reactions in CheckMate 066 (> 20%) reported with nivolumab vs dacarbazine were fatigue (49% vs 39%), musculoskeletal pain (32% vs 25%), rash (28% vs 12%), and pruritus (23% vs 12%).

Advanced Kidney Cancer Indication

The FDA also approved nivolumab to treat patients with metastatic renal cell carcinoma who have received a prior antiangiogenic therapy. “[Nivolumab] provides an important therapy option for patients with renal cell carcinoma,” said Richard Pazdur, MD, Director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “It is one of few therapies that have demonstrated the ability to extend patients’ survival in treating this disease.” Temsirolimus (Torisel), approved in 2007, is the only other FDA-approved therapy that has demonstrated overall survival in renal cell cancer.

Clinical Trial

The safety and efficacy of nivolumab for this use were demonstrated in an open-label, randomized study of 821 patients with advanced renal cell carcinoma whose disease worsened during or after treatment with an antiangiogenic agent. Patients were treated with nivolumab or everolimus (Afinitor). Those treated with nivolumab lived an average of 25 months after starting treatment compared to 19.6 months in those treated with everolimus. This effect was observed regardless of the PD-L1 expression level of patients’ renal cell tumors. Additionally, 21.5% of those treated with nivolumab experienced a complete or partial shrinkage of their tumors, which lasted an average of 23 months, compared to 3.9% of those taking everolimus, lasting an average of 13.7 months.

Adverse Events

The most common side effects of nivolumab for this use are conditions relating to abnormal weakness or lack of energy, cough, nausea, rash, difficulty breathing, diarrhea, constipation, decreased appetite, back pain, and joint pain. Nivolumab also has the potential to cause serious immune-mediated side effects involving the lungs, colon, liver, kidneys, hormone-producing glands, and brain. ■