CHICAGO – The novel immunotherapy ipilimumab was active in combination with paclitaxel and carboplatin chemotherapy in first-line advanced lung cancer, but a phase II trial did not deliver the blockbuster results recently observed in metastatic melanoma.
Researchers randomized 204 patients with stage IIIb/IV recurrent or metastatic non–small cell lung cancer to three arms in the study. One group received ipilimumab 10 mg/kg every 3 weeks concurrent with the first four cycles of chemotherapy, another was given ipilimumab at the same dose in combination with cycles three through six of chemotherapy, and a control group received chemotherapy alone.
The trial’s primary end point of immune-related progression-free survival showed significant improvement from a median of 4.63 months with chemotherapy alone to 5.52 months with ipilimumab and concurrent chemotherapy (hazard ratio, 0.77; P =.09) and 5.68 months with ipilimumab and phased chemotherapy (HR, 0.68; P = .02). Of note, statistical significance was calculated using a one-side log-rank test with an alpha of 0.10 and not the standard 0.05.
When traditional modified World Health Organization criteria were used, ipilimumab significantly extended progression-free survival only in the phased arm from 4.21 months in the control group to 5.13 months (HR, 0.69; P = .02), lead author Dr. Thomas J. Lynch Jr. reported in a poster at the Chicago Multidisciplinary Thoracic Oncology Symposium. The secondary end point fell short at 4.11 months in the ipilimumab concurrent arm (HR, 0.88; P = .25)
There was a trend toward improved overall survival in favor of ipilimumab plus chemotherapy, but it did not reach statistical significance. Median survival times were 9.69 months for the ipilimumab concurrent arm (HR, 0.98; P = .47), 12.2 months for the phased arm (HR, 0.86; P = .23), and 8.28 months for the chemotherapy-alone arm, reported Dr. Lynch, director of Yale Cancer Center and physician-in-chief of the Smilow Cancer Hospital in New Haven, Conn.
At the American Society of Clinical Oncology (ASCO) meeting earlier this year ipilimumab became the first drug in 30 years to demonstrate a significant survival advantage in metastatic melanoma in a phase III trial. A biologics license application for that indication is before the Food and Drug Administration, which must respond by March 26. The Oncologic Drugs Advisory Committee is to discuss the application on Feb. 9.
Despite the relatively lackluster performance in lung cancer, Dr. Lynch described the phase II data as intriguing and said they provide justification for a phase III trial that is being planned.
"I thought for ages that immunotherapy was, I don’t want to say hokey, but was highly unlikely to make a difference in non–small cell lung cancer," he said during a press briefing at the meeting. "I thought it was good in renal cell and melanoma disease.
"I have really begun to come around on this, partly because of ipilimumab and partly because of the anti-PD-1 [programmed death–1] strategy. It really comes down to the whole principle of changing the paradigm of how we interact with the immune system."
Ipilimumab is a fully human monoclonal antibody that potentiates immune response by specifically inhibiting CTLA-4 (cytotoxic T-lymphocyte–associated antigen-4). Suppression of CTLA-4 can augment the immune system’s T-cell response in fighting disease.
Bristol-Myers Squibb, which is developing ipilimumab, is also evaluating the anti-PD-1 human monoclonal antibody MDX-1106 in various refractory or relapsed malignancies including non–small cell lung cancer.
Patients in the current trial were maintained on ipilimumab 10 mg/kg every 3 months after completion of chemotherapy until disease progression or development of undue toxicity. Grade 3 or higher diarrhea, which has been a concern among some patients receiving ipilimumab, was reported in 7% of the concurrent arm, 5% of the phased arm, and 3% of the chemotherapy-alone arm. One fatal toxic epidermal necrolysis occurred in the concurrent arm, Dr. Lynch reported at the symposium, cosponsored by ASCO, the American Society for Radiation Oncology, the International Association for the Study of Lung Cancer, and the University of Chicago.
The study was sponsored by Bristol-Myers Squibb. Dr. Lynch disclosed serving as a consultant or advisory board member for BMS. One of his coauthors is an employee of BMS, and others report financial relationships with BMS and other firms.