Ipilimumab (IPI), an anti-CTLA-4 antibody, has become a standard option in the management of advanced melanoma after demonstrating durable responses and improved overall survival (OS).1 In contrast to CTLA-4 antibodies, PD-1 and PD-L1 antibodies potentiate antitumor T-cell responses at a tumor-specific level.2 Sznol and colleagues conducted a large phase 1 study in which IPI and nivolumab (NIV), a PD-1 antibody, were administered concurrently to patients with advanced melanoma (ASCO 2014; LBA9003).
In this study, 94 patients with inoperable stage III or IV melanoma who had received up to 3 prior systemic therapies received concurrent treatment with IPI and NIV in various dose schemes. Approximately half (53%) of the patients who enrolled in this phase 1 trial had very advanced melanoma (stage M1c), and 55% had received no prior systemic treatments.
Dr Sznol stated that concurrent treatment with IPI + NIV produced an “unprecedented” median OS of approximately 3.5 years (40 months) for patients with advanced melanoma, based on long-term follow-up data on the 53 patients enrolled in the initial 4 concurrent dosing cohorts. Patients in these cohorts received IPI + NIV every 3 weeks for 4 cycles, followed by NIV alone every 3 weeks for 4 cycles. At week 24, patients who did not have disease progression or severe side effects could continue IPI + NIV every 12 weeks for 8 cycles. The median OS data were described as “nearly double” the OS findings in previous studies of either agent alone in advanced melanoma.
Among these 53 patients, 41% responded to concurrent IPI + NIV, with a complete remission rate of 17%. Tumor shrinkage was described as rapid and extensive; 42% of patients had a greater than 80% tumor reduction at week 36. Responses were also durable, with 18 of 22 responses (82%) ongoing at the time of analysis. Clinical responses were seen regardless of tumor BRAF mutation status or PD-L1 status, and across all dose levels.
Across all dosing cohorts in the phase 1 trial of concurrent IPI + NIV, the 1- and 2-year median OS rates were 85% and 79%, respectively, and the median OS was 40 months. In the cohort of patients receiving NIV at a dose of 1 mg/kg and IPI at a dose of 3 mg/kg, which is the approach being tested in an ongoing phase 2/3 trial, 1- and 2-year OS rates were 94% and 88%, respectively.
Rates of adverse events (AEs), including immune-related AEs, were higher than previously observed for either IPI or NIV used as single agents, but these were characterized as manageable and reversible in almost all melanoma patients.
Researchers continue to follow patients in all 8 cohorts of this phase 1 study, including a separate cohort of 41 patients who are receiving IPI + NIV every 3 weeks for 4 cycles, followed by NIV alone every 2 weeks for up to 2 years. A separate, ongoing phase 3 study comparing IPI + NIV with NIV and IPI alone, and a phase 2 randomized study comparing IPI + NIV to IPI alone, have completed accrual, but these findings have not yet been reported.
In a press release regarding the phase 1 study findings reported at ASCO 2014, Dr Sznol summarized his impressions of this immune checkpoint inhibitor combination regimen, “Just a few years ago, median survival for patients diagnosed with advanced melanoma was as little as a year or less, and only approximately 20% to 25% survived 2 years, so it’s truly remarkable that we’re seeing a median survival over 3 years in this trial. Even in the latest era of targeted and immunotherapy agents, the median survival is, on average, only about 16 to 18 months with any new treatment alone.”
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