NO SURVIVAL BENEFIT OF NIVOLUMAB IN IPILIMUMAB PRETREATED MELANOMA PATIENTS

As reported in the Journal of Clinical Oncology by Larkin et al, the phase III CheckMate 037 trial has shown no difference in overall survival with nivolumab (Opdivo) vs investigator’s choice of chemotherapy in ipilimumab (Yervoy)-refractory advanced melanoma. More chemotherapy patients never received study treatment and more received programmed cell death protein 1 (PD-1) inhibitors after assigned treatment. The finding of durable responses in the first 120 nivolumab patients enrolled in the trial supported the accelerated approval of nivolumab in this setting in December 2014.

Study Details

In the open-label trial, 405 patients with unresectable or metastatic melanoma from 90 sites in 14 countries were randomized 2:1 between December 2010 and January 2014 to receive nivolumab at 3 mg/kg every 2 weeks (n = 272) or investigator’s choice of dacarbazine or carboplatin plus paclitaxel (n = 133). Patients had to have progressed after treatment with ipilimumab or with ipilimumab and a BRAF inhibitor if they were BRAF V600–mutation positive. Chemotherapy consisted of dacarbazine at 1,000 mg/m2 every 3 weeks or carboplatin AUC = 6 plus paclitaxel at 175 mg/m2 every 3 weeks. Patients were treated until disease progression or unacceptable toxicity; nivolumab patients could continue to receive nivolumab beyond disease progression. The co-primary endpoints were objective response rate and overall survival.

Of patients randomized to receive nivolumab, 99% received study treatment. Of those patients randomized to receive chemotherapy, 77% received treatment, with 16 patients withdrawing consent and 13 not receiving treatment by patient request. More nivolumab patients had brain metastases (20% vs 14%) and elevated lactate dehydrogenase levels at baseline (52% vs 38%).

Overall Survival

At database lock in March 2016, median follow-up was approximately 2 years. Among all randomized patients, median overall survival was 15.7 months in the nivolumab group vs 14.4 months in the chemotherapy group (hazard ratio [HR] = 0.95, P = .716). Median progression-free survival was 3.1 months vs 3.7 months (HR = 1.0, 95.1% confidence interval [CI] = 0.78–1.436), reduced from medians of 4.7 vs 4.2 months in an earlier analysis. Overall response rates were 27% vs 10%, and median durations of response were 32 months vs 13 months.

Overall, more patients in the chemotherapy group received systemic therapy after assigned therapy (62% vs 40%) and more received anti–PD-1 or anti–programmed cell death ligand 1 treatment (41% vs 11%). In an analysis among patients who received study treatment that censored patients at the start of PD-1 inhibitor treatment after assigned therapy in the chemotherapy group, median overall survival was 16.4 months in the nivolumab group vs 11.8 months in the chemotherapy group (HR = 0.81, 95.54% CI = 0.59–1.11).

Adverse Events

Grade 3 or 4 treatment-related adverse events occurred in 14% of the nivolumab group vs 34% of the chemotherapy group. Treatment-related adverse events led to treatment discontinuation in 5% vs 11%. The most common treatment-related adverse events of any grade with a potential immunologic cause in the nivolumab group were skin (38%), gastrointestinal (18%), and hepatic (11%) adverse events.

The investigators concluded: “Nivolumab demonstrated higher, more durable responses but no difference in survival compared with [investigator’s choice chemotherapy]. [Overall survival] should be interpreted with caution, as it was likely impacted by an increased dropout rate before treatment, which led to crossover therapy in the [investigator’s choice chemotherapy] group, and by an increased proportion of patients in the nivolumab group with poor prognostic factors.”

The study was supported by Bristol-Myers Squibb.

James Larkin, PhD, FRCP, of the Royal Marsden NHS Foundation Trust, is the corresponding author of the Journal of Clinical Oncology article.