Clinicians who have been treating patients with melanoma using immunotherapy are warning that autoimmune pneumonitis, sometimes with respiratory distress that necessitates intensive care, is "a rare but potentially serious toxic effect" associated with the new programmed cell death (PD) inhibitors.
Two such drugs are on the market: nivolumab (Opdivo, Bristol-Myers Squibb) for melanoma and non–small cell lung cancer and pembrolizumab (Keytruda, Merck Sharpe & Dohme) for melanoma. Both list pneumonitis as an adverse event in their product labels.
The clinicians, with first author Mizuki Nishino, MD, all from Dana Farber/Brigham and Woman's Hospital in Boston, Massachusetts, report three cases of immune-pneumonitis seen after treatment with nivolumab in a letter published in the July 16 issue of the New England Journal of Medicine.
"The clinical oncology community has rapidly expanding access to a variety of immunotherapeutic agents for the treatment of several types of cancers," write the authors. They report the three cases in some detail, with the hope that this knowledge will be useful to clinicians who have to manage patients who develop this adverse effect.
"We believe that the increased awareness of immune-related pneumonitis is the first step, among treating clinicians as well as among physicians in related specialties, including radiologists, pulmonologists, and pathologists," Dr Nishino told Medscape Medical News. "It is also important to recognize that the clinical course can be fulminant and rapidly progress, as in some of our cases. If a suspicion for pneumonitis is raised based on clinical or radiological findings, immediate attention and assessments are needed, and a multidisciplinary approach is encouraged."
In the three cases they describe, all occurring after treatment with nivolumab, chest computed tomography (CT) revealed a spectrum of findings typically seen in interstitial pneumonias, including ground-glass and reticular opacities.
Two of the three patients also had decreased lung volumes and effusions and were admitted to the intensive care unit and received intravenous antibiotics, glucocorticoids, and infliximab.
One of these patients required intubation, and his condition improved over the course of 10 weeks, but the other patient died 4 weeks after the diagnosis of pneumonitis.
The third patient discontinued nivolumab after the CT findings were noted, and the pneumonitis resolved after 2 weeks. This patient then restarted nivolumab (the discontinuation period had lasted 8 weeks). He completed the 2-year treatment period with 12 cycles and is participating in the follow-up period of the trial, the researchers report. He remains progression-free from melanoma, with no recurrent pneumonitis for 39 months, they note.
The median time to development of pneumonitis was 5 months (range, 0.3 weeks to 9.9 months). The median duration was 4.9 months (range, 1 week to 14.4 months).
Dr Nishino told Medscape Medical News that pneumonitis has also been reported in clinical trials. In two recent phase 3 trials of nivolumab in advanced melanomas, the incidence of pneumonitis was 1.5% (N Engl J Med. 2015;372:320-330) and 1.9% (Lancet Oncol. 2015;16:375-384). In a recent phase 2 trial of nivolumab, pneumonitis was recognized as one of the most common grade 3/4 immune-related adverse events, occurring in 5% (6 of 117) of the patients (any grade), including 4 patients with grade 3 pneumonitis (3%) (Lancet Oncol. 2015;16:257-265).
Also Seen With Ipilimumab
One of the three patients described by Dr Nishino and colleagues had received treatment with ipilimumab (Yervoy, Bristol-Myers Squibb) before going on to receive nivolumab. Ipilimumab is also an immune checkpoint blocker, but it acts through a different mechanism than that of the PD inhibitors. Pneumonitis has also been reported with ipilimumab therapy, Dr Nishino told Medscape Medical News. It was reported in a recent phase 2 Eastern Cooperative Oncology Group trial, where 7.5% (9 of 120) of the patients treated with ipilimumab monotherapy at a dose of 10 mg/kg developed pulmonary toxicity (JAMA. 2014;312:1744-1753). In addition, in a retrospective review study of patients with melanoma treated with ipilimumab, 5% (8 of 147) patients developed radiologically identified pneumonitis (Cancer Immunol Res. 2015 Jun 22).
"We believe that these reports indicate a growing recognition of ipilimumab-associated pneumonitis," Dr Nishino commented.
Already on Product Label
Pneumonitis is already known as an adverse effect of PD-inhibitor therapy and is listed on the product labeling for both nivolumab and pemvbrolizumab.
The product label for nivolumab notes that severe pneumonitis or interstitial lung disease, including fatal cases, has occurred with this drug. Across the clinical trial experience in 574 patients with solid tumors, fatal immune-mediated pneumonitis occurred in 0.9% (5 of 574) of patients receiving nivolumab. All 5 fatal cases occurred in a dose-finding study with nivolumab doses of 1 mg/kg (2 patients), 3 mg/kg (2 patients), and 10 mg/kg (1 patient).
The product label for pembrolizumab states that pneumonitis occurred in 12 (2.9%) of 411 patients with melanoma, including grade 2 or 3 cases in 8 (1.9%) and 1 (0.2%) patients, respectively, in a pivotal trial. The median time to development of pneumonitis was 5 months (range, 0.3 weeks to 9.9 months). The median duration was 4.9 months (range, 1 week to 14.4 months). Five of eight patients with grade 2 and the one patient with grade 3 pneumonitis required initial treatment with high-dose systemic corticosteroids (greater than or equal to 40 mg prednisone or equivalent per day) followed by a corticosteroid taper. The median initial dose of high-dose corticosteroid treatment was 63.4 mg of prednisone or equivalent per day, with a median duration of treatment of 3 days (range, 1 to 34 days), followed by a corticosteroid taper. Pneumonitis led to discontinuation of pembrolizumab in 3 (0.7%) patients. Pneumonitis completely resolved in seven of the nine patients with grade 2 or 3 pneumonitis.
The labels for both products recommend that clinicians monitor patients for signs and symptoms of pneumonitis and advise on the administration of corticosteroids in patients suspected of having pneumonitis.
The product labeling for both products also advises withholding PD-inhibitor therapy in patients who develop moderate (grade 2) pneumonitis, but advises permanent discontinuation of the drug in patients who develop severe (grade 3) or life-threatening (grade 4) pneumonitis.
Dr Nishino reports personal fees from Bristol-Myers Squibb, grants from Canon USA Inc, and grants from the National Institutes of Health (National Cancer Institute outside the submitted work. Other coauthors also report relationships with pharmaceutical companies.
N Engl J Med. 2015;373:288-290. Abstract
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