In the phase IIIb CheckMate 401 trial reported in the Journal of Clinical Oncology, Reinhard Dummer, MD, and colleagues described outcomes with first-line nivolumab/ipilimumab followed by nivolumab in a clinically diverse population of patients with unresectable stage III or IV melanoma, including patients with a poorer performance status, brain metastases, and different melanoma subtypes.

As stated by the investigators, “Although previous studies demonstrated clinical benefit with immunotherapy in patients with advanced melanoma, there is a paucity of data in patients with poor prognoses who are typically excluded from clinical trials. CheckMate 401 … evaluated the safety and efficacy of first-line nivolumab plus ipilimumab followed by nivolumab in clinically diverse patient populations with unresectable stage III [or] IV melanoma representative of real-life practice.”

Reinhard Dummer, MD

Study Details

In the European-Australian trial, 533 patients enrolled between December 2015 and August 2017 were to receive nivolumab at 1 mg/kg plus ipilimumab at 3 mg/kg once every 3 weeks for four doses, followed by nivolumab at 3 mg/kg (240 mg following protocol amendment) once every 2 weeks for up to 24 months. Among the patients, 68% (n = 365) had cutaneous melanoma; 20% had ocular/uveal (n = 64), mucosal (n = 32), or acral (n = 10) melanoma; 10% (n = 55) had an Eastern Cooperative Oncology Group (ECOG) performance status of 2 (including 37 with cutaneous melanoma); and 8% (n = 42) had brain metastases (5% previously treated, 3% untreated).

The primary outcome measure was incidence of grade ≥ 3 select treatment-related adverse events; these were defined as potentially immune-related pulmonary, gastrointestinal, skin, renal, hepatic, endocrine, infusion-related, or hypersensitivity events. Overall survival was a secondary outcome measure.

Adverse Events

Grade ≥ 3 select treatment-related adverse events among all patients included gastrointestinal events in 16%, hepatic events in 15%, endocrine events in 11%, skin events in 7%, renal events in 2%, and pulmonary events in 1%. Incidence rates were similar across patient subgroups. Gastrointestinal (14%) and hepatic (9%) events were the most common causes of treatment discontinuation due to select treatment-related adverse events. Grade 5 events occurred in two patients; one with acute kidney injury and one with colitis.

The most common any-grade treatment-related adverse events were diarrhea (35%), pruritus (25%), and fatigue (25%); grade 3 or 4 treatment-related adverse events occurred in 60% of patients, most commonly elevated lipase (8%), diarrhea (7%), and colitis (6%).

Overall Survival

Median follow-up for overall survival was 21.6 months. Overall survival at 24 months was 63% (95% confidence interval [CI] = 59%–68%) in the entire population. By melanoma subgroup, 24-month overall survival was 71% (95% CI = 66%–76%) in the cutaneous group, 36% (95% CI = 23%–48%) in the ocular/uveal group, 38% (95% CI = 21%–55%) in the mucosal group, and 47% (95% CI = 15%–74%) in the acral group. Overall survival at 24 months was 44% (95% CI = 27%–60%) among patients with cutaneous melanoma and a performance score of 2, and 71% (95% CI = 54%–82%) in the brain metastasis group.

The investigators concluded, “Nivolumab plus ipilimumab followed by nivolumab monotherapy was tolerable in patients with advanced melanoma and poor prognostic characteristics. Efficacy was similar between the all-treated population and patients with brain metastases. Reduced efficacy was observed in patients with [an] ECOG [performance status of] 2, ocular/uveal melanoma, and/or mucosal melanoma, highlighting the continued need for novel treatment options for these difficult-to-treat patients.”

Dr. Dummer, of University Hospital Zurich, Switzerland, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by Bristol Myers Squibb. For full disclosures of the study authors, visit ascopubs.org.