Nivolumab and pembrolizumab, both programmed cell death 1 (PD-1) receptor inhibitors, are well accepted as superior in efficacy to ipilimumab in patients with advanced melanoma, and do so with a much better safety profile.1 The CheckMate 066 study randomly assigned patients 1:1 to receive either nivolumab (3 mg/kg intravenously every 2 weeks plus dacarbazine-matched placebo intravenously every 3 weeks) or dacarbazine (1000 mg/m2 intravenously every 3 weeks plus nivolumab-matched placebo intravenously every 2 weeks).2 Of the 418 patients, 210 were in the nivolumab arm and 208 were in the dacarbazine arm. Patients were treated until progression or unacceptable toxic effects occurred but could be treated beyond initial progression.

A follow-up analysis of the CheckMate 066 study has confirmed nivolumab led to an improved 3-year overall survival compared to dacarbazine in patients with previously untreated BRAF wild-type advanced melanoma, with no new safety signals observed.1 In this post-hoc analysis, outcomes were assessed in patients who discontinued study treatment and received subsequent therapy, including nivolumab to subsequent therapy that included any ipilimumab (nivolumab to ipilimumab), dacarbazine to subsequent therapy that included any nivolumab (dacarbazine to nivolumab), and dacarbazine to subsequent therapy that included any ipilimumab (dacarbazine to ipilimumab).

“Nivolumab monotherapy is able to get a long-term benefit for about the half of advanced melanoma patients,” said corresponding author Paolo A. Ascierto, MD, the Instituto Nazionale Tumori Fondazione Pascale, Naples, Italy.

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In this analysis, “with 3 years of follow-up, nivolumab treatment resulted in improved overall survival (OS) compared with dacarbazine (median, 37.5 vs 11.2 months, respectively). Previously demonstrated improvements in progression-free survival and higher objective response rates with nivolumab vs dacarbazine, regardless of tumor PD-L1 expression, were maintained at the 3-year follow-up,” the study authors wrote. (The median OS had not been reached at the time of the initial report.)2

CheckMate 066 3-year Results

At a minimum follow-up of 38.4 months in the nivolumab group and 38.5 months in the dacarbazine group (database lock, June 22, 2017), the median overall survival was 37.5 months (95% confidence interval [CI], 25.5 months – not reached [NR]) with nivolumab and 11.2 months (95% CI, 9.6-13.0 months) with dacarbazine (hazard ratio [HR], 0.46; 95% CI, 0.36 – 0.59; P < .001). Three-year OS rates were 51.2% (95% CI, 44.1%-57.9%) and 21.6% (95% CI, 16.1%-27.6%) in the nivolumab and dacarbazine groups, respectively.

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As of the data cutoff, 63.8% (134 of 210) of patients in the nivolumab group had disease progression or had died compared with 82.7% (172 of 208) of patients in the dacarbazine group. The median progression-free survival was 5.1 months (95% CI, 3.5-12.2 months) in the nivolumab group and 2.2 months (95% CI, 2.1-2.5 months) in the dacarbazine group (hazard ratio, 0.42; 95% CI, 0.33-0.53; P < .001), with 3-year progression-free survival rates of 32.2% (95% CI, 25.6%-39.0%) and 2.9% (95% CI, 0.7%-8.1%), respectively.

A prespecified subgroup analysis analyzing outcomes based on PD-L1 tumor expression found similar results favoring nivolumab.

In patients with PD-L1 expression of at least 5%, the median OS was not reached (95%CI, 42.4-NR) in the nivolumab group and was 9.7 months (95% CI, 6.7-13.5 months) in the dacarbazine group; for those with PD-L1 expression less than 5%, the median overall survival with nivolumab was 28.2 months (95% CI, 18.2-38.5 months) and with dacarbazine was 11.6 months (95% CI, 9.3-13.0 months). Similarly, regardless of PD-L1 expression, patients in the nivolumab group had numerically longer progression-free survival compared with patients in the dacarbazine group.

Treatment-related grade 3/4 adverse events were reported in 15.0% (31 of 206) of nivolumab-treated patients and in 17.6% (36 of 205) of dacarbazine-treated patients, which led to treatment discontinuation in 4.9% (10 of 206) and 2.0% (4 of 205) of patients, respectively.