FDA Approves Nivolumab (Opdivo) for Advanced Melanoma

Roxanne Nelson

December 22, 2014

The US Food and Drug Administration (FDA) today granted accelerated approval to nivolumab (Opdivo, Bristol-Myers Squibb) for the treatment of advanced melanoma.

The indication is for patients with unresectable or metastatic melanoma and disease progression after treatment with ipilimumab (Yervoy, Bristol-Myers Squibb) and, for patients whose tumors are BRAF V600 mutation positive, a BRAF inhibitor.

The approval comes more than 3 months ahead of the scheduled date of March 30, 2015.

Nivolumab is a human programmed death receptor-1 (PD-1)–blocking antibody, and it became the first drug in this class to be approved worldwide when it was cleared in Japan in July 2011 for use in melanoma. However, it was beaten to approval in the United States by another PD-1 inhibitor, pembrolizumab (Keytruda, Merck). which was approved by the FDA in September 2014; this was also a priority review, and the approval came 2 months earlier than expected.

The product has shown unprecedented responses in melanoma, as well as several  other tumor types, and the data on this drug have dominated the news coming out of oncology meetings for the last 2 years.

"Nivolumab is the seventh new melanoma drug approved by the FDA since 2011," said Richard Pazdur, MD, director of the Office of Hematology and Oncology Products in the FDA's Center for Drug Evaluation and Research, in a statement. "The continued development and approval of novel therapies based on our increasing understanding of tumor immunology and molecular pathways are changing the treatment paradigm for serious and life-threatening diseases."

Other FDA-approved treatments for melanoma include ipilimumab (Yervoy, approved in 2011), peginterferon alfa-2b (2011), vemurafenib (Zelboraf, Genentech; 2011), dabrafenib (Tafinlar, GlaxoSmithKline; 2013), trametinib (Mekinist, GlaxoSmithKline; 2013), and pembrolizumab (2014).

"With this latest approval, we are continuing to build an arsenal of therapies for patients and their clinicians to use in the fight against deadly melanoma. Nivolumab's ability to engage a patient's immune system shows real potential to save the lives of late-stage melanoma patients who had little hope of survival just a few years ago," said Wendy Selig, president and chief executive officer of the Melanoma Research Alliance (MRA).

"Immunotherapy is a relatively new weapon in the anticancer arsenal and takes advantage of the power of the immune system to not just fight infection but also attack cancer," said Dr Louise M. Perkins, MRA chief science officer. "While traditional cancer treatment like chemotherapy kills cells that are reproducing quickly, immunotherapy drugs like anti-PD-1 agents take a completely different approach. Melanoma research is a case study for the success of anti-PD-1 agents, demonstrating how checkpoint blockade antibodies like nivolumab release the brakes and energize the immune system to great benefit in some patients."

"The approval of nivolumab is the latest in a string of advances…in the field," said Debra Black, MRA cofounder and chair of the Board. "When we started MRA 7 years ago, there was little hope for patients with advanced melanoma. Now we are in an amazing time of discovery and progress with new treatments that can save lives, not only for people with melanoma but also those with other diseases. Melanoma is really leading the way."

Only PD-1 Inhibitor With Phase 3 Data

Bristol-Myers Squibb points out in a press release that nivolumab is the only PD-1 inhibitor that has demonstrated efficacy in a phase 3 pivotal clinical trial (known as CheckMate-037), conducted in patients with advanced melanoma who had been previously treated with and progressed while receiving ipilimumab and, if BRAF mutation positive, a BRAF inhibitor.

The efficacy of nivolumab (administered as 3 mg/kg intravenously over 60 minutes every 2 weeks) was evaluated from a single-group, noncomparative planned interim analysis of the first 120 patients who received the drug and had a minimum of 6 months follow-up. The results show a 32% response rate (in 38 of 120 patients), of whom 3% of patients (4 of 120) achieved a complete response, and 28% (34 of 120) achieved a partial response. Responses were seen in both patients with and without BRAF mutation.

Among the 38 patients who responded to nivolumab, 33 patients (87%) had ongoing responses with durability of response ranging from 2.6 to 10 months, which included 13 patients with ongoing responses of 6 months or longer.

In this phase 3 trial, serious adverse reactions occurred in 41% of patients receiving nivolumab. Grade 3 and 4 adverse reactions occurred in 42% of patients, and the most frequent of these were abdominal pain, hyponatremia, increased aspartate aminotransferase, and increased lipase. The most common adverse reaction was rash (seen in 21% patients).

The company also notes that nivolumab is associated with immune-mediated pneumonitis, colitis, hepatitis, nephritis and renal dysfunction, hypothyroidism and hyperthyroidism, and embryofetal toxicity.

Potential as First-line Therapy

While the current indication for the drug is in patients with melanoma who have already tried other drugs, it has also shown promise in clinical trial as a first-line agent. Data from the international CheckMate 066 (and also CA209-066), which enrolled 418 treatment-naive patients treated for metastatic melanoma who did not have the BRAF mutation in their tumors, showed superior survival with nivolumab compared with chemotherapy. The 1-year survival rate was 72.9% with nivolumab vs 42.1% with chemotherapy (dacarbazine), with a hazard ratio of 0.42 (P < .0001).


This translated to a 58% reduction in the risk for death during treatment with nivolumab, noted the lead author, Georgina Long, MD, PhD, from the Melanoma Institute Australia at the University of Sydney, and represents "a potential new standard of care," in the first-line setting.

As of November 2014, when the data were published, the median overall survival duration had not yet been reached in the nivolumab group; it was 10.8 months with dacarbazine.

Median progression-free survival with nivolumab was 5.1 months vs 2.2 months with dacarbazine, and the overall response rate was 40.0% vs 13.9%, with complete responses seen in 7.5% vs 1.0% of patients, respectively.

"The safety profile of nivolumab is also considered "to be acceptable and manageable," according to the study authors, and the most common advents events reported with nivolumab were fatigue (20% of patients), pruritus (17%), nausea (17%), and diarrhea (16%). Immune-related adverse events affected the skin (37%), gastrointestinal tract (17%), hepatic endocrinopathies (2%), and pneumonitis (2%, all grade 1 or 2).

Early Christmas for BMS

Tim Turnham, executive director, Melanoma Research Foundation, points out that the early findings from research suggests that nivolumab may have the potential to generate exceptionally strong and long-lasting responses when combined with ipilimumab. There appears to be strong synergy between the two drugs, but there is also increased toxicity when the drugs are combined, making it important for both health care professionals and patients to be educated and vigilant in managing side effects," said Turnham in a statement.

"The growing use of combination therapies to treat melanoma signals an important shift in the treatment landscape, and charts important progress in making melanoma a chronic manageable disease," said Turnham.

The drug is predicted to be a blockbuster, according to some industry analysts. BioPharma Dive noted that nivolumab is expected to have sales of $658 million next year and $7.122 billion by 2020 — "and that was assuming that approval would not be granted until 2015."

BioPharma Dive previously projected it to be the biggest new drug launch in the United States in 2015, and one of the biggest launches worldwide this decade, "but Christmas seems to have come three days early for BMS," they wrote.


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