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FDA expands approval of Opdivo for advanced squamous NSCLC
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The FDA today expanded the existing indication of nivolumab to include patients with metastatic squamous non–small cell lung cancer with progression on or after platinum-based chemotherapy, according to a press release from the agency.
In December, the FDA granted accelerated approval to nivolumab (Opdivo, Bristol-Myers Squibb) for the treatment of patients with unresectable or metastatic melanoma who no longer responded to other drugs.
Nivolumab is designed to inhibit the PD-1 protein on cells that blocks the body’s immune system from attacking cancerous cells.
“The FDA worked proactively with the company to facilitate the early submission and review of this important clinical trial when results first became available in late December 2014,” Richard Pazdur, MD, director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, said in a press release. “This approval will provide patients and health care providers knowledge of the survival advantage associated with Opdivo and will help guide patient care and future lung cancer trials.”
Nivolumab’s efficacy in squamous NSCLC was established in a randomized trial of 272 participants, wherein 135 received nivolumab and 137 received docetaxel. On average, OS was 3.2 months longer for participants who received nivolumab vs. those who received docetaxel.
The safety and efficacy of nivolumab in squamous NSCLC was supported by a single-arm trial of 117 participants who had disease progression after platinum-based therapy and at least one additional systemic regimen. Of the cohort, 15% of participants experienced overall response rate, of whom 59% had response durations of 6 months or longer.
The most common adverse effects of nivolumab include fatigue, shortness of breath, musculoskeletal pain, decreased appetite, cough, nausea and constipation.
The most serious adverse effects of nivolumab are severe immune-mediated adverse effects involving healthy organs, including the lung, colon, liver, kidneys and hormone-producing glands.
Nivolumab was approved more than 3 months ahead of the prescription drug user fee goal date of June 22, the date the FDA was scheduled to complete its review of the application.
Perspective
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Scott Nicholas Gettinger, MD
The approval of nivolumab (Opdivo, Bristol-Myers Squibb) for advanced pretreated squamous cell carcinoma of the lung marks a new era in the treatment of non–small cell lung carcinoma. The decades of frustration with clinical trials evaluating immunotherapies for lung cancer have ended, with a growing enthusiasm around the potential of harnessing one’s own immune system to attack and control cancer.The decision by the FDA was reached after review of the CheckMate-017 trial, in which researchers randomly assigned 272 patients with advanced pretreated squamous cell NSCLC to nivolumab or docetaxel. The primary endpoint of survival was met, with a statistically significant improvement in median OS of 3.2 months (9.2 months vs. 6 months; HR = 0.59; P = .00025).
These results came on the heels of CheckMate-063, a phase 2 trial that evaluated nivolumab in patients with advanced squamous cell carcinoma of the lung who received two or more prior lines of therapy for advanced disease (Rizvi NA. Lancet Oncol. 2015;doi:10.1016/S1470-2045(15)
70054-9). That trial demonstrated a median OS of 8.2 months and 1-year survival rate of 41%.
Although the results of these two trials together are practice changing, the true potential of nivolumab has yet to be fully appreciated in these trials. That is, we expect a percentage of patients treated to achieve long-term survival, measured in years. Indeed, a prior trial of nivolumab with longer follow-up — which consisted of 129 patients with pretreated advanced NSCLC, more than 50% of whom received at least three prior lines of therapy for advanced lung cancer — demonstrated an unprecedented 3-year survival rate of 18% (Gettinger SN, et al. Poster 170. Presented at: Chicago Multidisciplinary Symposium in Thoracic Oncology; Oct. 30–Nov. 1, 2014; Chicago).
As nivolumab is introduced into the clinic, we will need to be aware of potential immune-mediated toxicities, including endocrinopathies (eg, hypothyroidism, hyperthyroidism, hypophysitis with adrenal insufficiency and diabetes), autoimmune neurological syndromes, colitis, hepatitis, nephritis and — of particular concern — pneumonitis, which occurred in 6% of patients on the CheckMate-063 trial (grade 3, n = 5; grade 2, n = 2). That said, experience with nivolumab to date has been favorable, and it has demonstrated a far better toxicity profile than chemotherapy.
Although nivolumab will extend survival on the order of years with good tolerance in some patients, the majority will progress through therapy. Efforts will now need to focus on determining which patients are most likely to respond to nivolumab, and identifying mechanisms of resistance that may be overcome with other therapies. Tumor evaluation will be essential to this goal, and such analyses are currently ongoing at several academic centers. Additional clinical investigation into combination strategies of nivolumab with chemotherapy, targeted therapy, radiation and other immunotherapies are already ongoing or planned.
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