A dose-escalation, cohort expansion study with nivolumab in patients with advanced melanoma aimed to observe its impact on overall survival, long-term safety, and response duration after treatment discontinuation. Results of the study were published online on March 3 in the Journal of Clinical Oncology. The results are seen as remarkable for patients with treatment-resistant, advanced/metastatic melanoma, with overall survival comparing favourably to literature studies of similar patient populations. Responses were durable and persisted after drug discontinuation with acceptable long-term safety.
PD-1 blockade in advanced melanoma
Programmed cell death 1 (PD-1) is an inhibitory receptor expressed by activated T cells that downmodulates effector functions and limits the generation of immune memory. PD-1 blockade can mediate tumour regression in a substantial proportion of patients with melanoma, but it is not known whether it is associated with extended survival or maintenance of response after treatment is discontinued, explained the authors in background of current study. The study lead-author is Dr Suzanne Topalian, professor of surgery and oncology, and director of the melanoma program at Johns Hopkins University School of Medicine.
In total, 107 patients with advanced melanoma enrolled in the study between 2008 and 2012. It is interesting that 62% of patients received two to five prior systemic therapies, 78% had visceral metastases, and 36% had increased lactate dehydrogenase levels.
Patients received nivolumab intravenously in an outpatient setting every two weeks for up to 96 weeks at 1, 3, or 10 mg/kg during dose escalation. After completion of dose escalation, each dose cohort was expanded and, after protocol amendment, additional patients were randomly assigned to receive doses of 0.1, 0.3, and 1.0 mg/kg.
The objective response rate was 31% in all patients, including rates of 35%, 28%, 31%, 41%, and 20% at doses of 0.1, 0.3, 1.0, 3, and 10 mg/kg. Although investigators observed responses at all doses, the highest response rate was in patients receiving 3 mg/kg, the dose now being tested in phase III trials.
Among 33 patients with objective tumour regressions (31% of studied population), the median response duration was 2 years. Seventeen patients discontinued therapy for reasons other than disease progression, and 12 (71%) of 17 maintained responses off-therapy for at least 16 weeks (range, 16 to 56+ weeks).
Among all patients, median progression-free survival was 3.7 months and median overall survival was 16.8 months, with 1- and 2-year survival rates of 62% and 43%, respectively.
Toxicity rates were similar to those reported previously; in an extended analysis of all 306 patients treated on this trial (including those with other cancer types), exposure-adjusted toxicity rates were not cumulative.
The most common adverse events of any grade were fatigue (32%), rash (23%), and diarrhoea (18%). Most common grade 3 or 4 treatment-related adverse events were lymphopenia (3%) and fatigue, diarrhoea, and abdominal pain (2% each). There were no drug-related deaths in patients with melanoma receiving nivolumab.
Treatment-related adverse events of any grade with potential immune-related causality occurred in 54% of patients, with the most common being skin disorders (36%), gastrointestinal events (18%), and endocrine. Grade 3 or 4 adverse events in this category occurred in 5% of patients.
The authors concluded that the overall survival following nivolumab compares favorably with that in literature for similar patient populations. Responses were durable and persisted after drug discontinuation. Long-term safety was acceptable.
Currently ongoing randomised clinical trials will further assess the impact of nivolumab therapy on overall survival in patients with metastatic melanoma.
Drs Suzanne Topalian and Mario Sznol contributed equally to this work.
Nivolumab is being developed and manufactured by Bristol-Myers Squibb, which provided funding for the trial along with Ono Pharmaceuticals Co., Ltd. Dr Topalian has served as an uncompensated consultant to Bristol-Myers Squibb and has received research support from the company.
Topalian S, Sznol M, McDermott, et al. Survival, Durable Tumor Remission, and Long-Term Safety in Patients With Advanced Melanoma Receiving Nivolumab. JCO 2014; Published online before print March 3. doi: 10.1200/JCO.2013.53.0105