Zurich, Switzerland—In previously treated patients with advanced melanoma, single-agent nivolumab demonstrated long-term survival that compares favorably with current standard-of-care agents, according to F. Stephen Hodi, Jr, MD, Director, Melanoma Center, Dana-Farber/Brigham and Women’s Cancer Center, Boston. The CA209-003 phase 1 clinical trial also showed that responses occurring early were durable even after the discontinuation of therapy, said Dr Hodi at the 2014 Society for Melanoma Research International Congress.
Investigators enrolled 107 patients with advanced melanoma who had received between 1 and 5 previous lines of systemic therapy. They received ≤96 weeks of nivolumab at doses between 0.1 mg/kg intravenously every 2 weeks and 10 mg/kg intravenously every 2 weeks. The study had safety and tolerability as its primary objectives, preliminary efficacy was a secondary objective, and the protocol was amended to collect overall survival (OS) and retreatment outcomes data.
The mean patient age was 61 years. Most (62%) patients had received ≥2 systemic therapy regimens, of which 65% were immunotherapies (but not CTLA-4 or programmed cell death [PD]-1 inhibitors). At baseline, visceral metastases were present in 78% of patients, and elevated lactate dehydrogenase levels were present in 36%. Dr Hodi emphasized that, with a median follow-up of 55 months, the follow-up in this study is longer than that of any other anti–PD-1 agent.
The overall response rate (ORR) for all doses was 32%, with a median response duration of 23 months. For the 3-mg/kg dose that was selected for phase 3 studies, the ORR was 41%, and the median duration of response was 22 months.
Dr Hodi also noted that 15 (44%) of the 34 patients with responses to nivolumab showed a response at week 8, the first tumor assessment. Among responders who discontinued therapy for reasons other than disease progression, the responses lasted ≥16 months in 21 patients, 14 of whom have ongoing responses.The OS rates with the 3-mg/kg dose (N = 17) at years 1 to 4 are 65%, 47%, 41%, and 35%, respectively, and for all cohorts, the responses are 63%, 48%, 42%, and 32%, respectively. “There is a suggestion of a plateau in the curve at this point…but further confirmation will obviously be needed in continued follow-up,” Dr Hodi noted.
The median OS is 17.3 months (95% confidence interval [CI], 12.5-37.8) for all cohorts and 20.3 months for the 3-mg/kg dose. The median progression-free survival was longest in the 3-mg/kg group (10 months; 95% CI, 2-16); the median OS in this cohort was 20 months.
Treatment with nivolumab was generally well-tolerated, and with all patients having ≥1 year of follow-up, no new safety signals have been observed. Treatment-related immune-mediated adverse events were reported in 58% of patients, with 5% of grades 3 to 4. Adverse reactions included skin (38%), gastrointestinal (19%), endocrinopathies (14%), and infusion reactions (6%). Dr Hodi noted that immune-mediated adverse events with potential immunologic etiologies require more frequent monitoring and/or unique interventions.
Concluding that long-term survival with nivolumab was comparable with current standard-of-care agents, Dr Hodi said that responses occurred early and were durable even after treatment discontinuation. As reported in earlier research, nivolumab was well-tolerated.
Dr Hodi noted that 3 ongoing phase 3 trials are evaluating nivolumab 3 mg/kg in patients with advanced melanoma.
An exploratory retreatment analysis was conducted among patients who entered the follow-up period with ongoing disease control (complete response, partial response, stable disease). Retreatment was permitted in these patients subsequent to confirmed disease progression at the same dose assigned for up to 3 years (including the initial treatment period). Prolonged response or stabilization of disease was observed among 5 patients who were retreated, with an increased adrenal mass successfully excised in 1 patient. “We need prospective analyses to evaluate the efficacy and safety of nivolumab retreatment,” Dr Hodi said.