The benefit of nivolumab/ipilimumab plus single-agent nivolumab for unresectable advanced melanoma with poor prognostic characteristics was comparable in all-comers and patients with brain metastases.
Combination therapy with nivolumab (Opdivo) and ipilimumab (Yervoy) followed by nivolumab alone in the first line was tolerable across a clinically diverse patient population with advanced, unresectable melanoma with poor prognosis features, although the regimen was less effective among those with a higher ECOG performance status and certain disease subtypes, according to findings from the phase 3b CheckMate 401 (NCT02599402) trial published in Journal of Clinical Oncology.
Select any-grade treatment-related adverse effects (TRAEs) in the all-treated population included skin (56%), endocrine (43%), gastrointestinal (GI; 40%), hepatic (29%), renal (5%), and pulmonary (4%) toxicities. The most common grade 3 to 5 TRAEs were GI (16%), hepatic (15%), endocrine (11%), skin (7%), renal (2%), and pulmonary toxicities (1%). One patient with cutaneous melanoma had grade 5 acute kidney injury, and another with mucosal melanoma experienced grade 5 colitis.
The median time to any-grade TRAE onset occurred from 14 to 128 days and 31 to 76 days for grade 3 to 5 toxicities. Moreover, the median time to resolution for any-grade toxicities was 20 days to not reached (NR), and 23 days to NR for high-grade TRAEs.
In the all-treated population, the median overall survival (OS) was NR (95% CI, 33.9-NR). The OS rate was 63% (95% CI, 59%-68%) at 24 months, and the objective response rate (ORR) was 44% (95% CI, 40%-49%). This included a complete response (CR) rate of 11%. Additionally, the median duration of response (DOR) was NR.
The median OS was 11.0 months (95% CI, 4.4-NR) among patients with an ECOG performance status of 2 and cutaneous melanoma (n = 37), NR for those with brain metastases (n = 42), 15.3 months (95% CI, 10.4-21.4) for those with ocular or uveal melanoma (n = 64), 12.6 months (95% CI, 3.8-33.9) for those with mucosal melanoma (n = 32), and 20.8 months (95% CI, 1.2-NR) for those with acral melanoma (n = 10).
The 24-month OS rates among those who received the combination were 44% (95% CI, 27%-60%), 71% (95% CI, 66%-76%), 36% (95% CI, 23%-48%), 38% (95% CI, 21%-55%), and 47% (95% CI, 15%-74%) in each respective group.
The ORR for each respective group was 30%, 52%, 9%, 44%, and 30%, with corresponding CR rates of 3%, 17%, 2%, 9%, and 0%. The 24-month OS rates were 65% for patients younger than 75 years and 53% for those who were less than 75 years. Additionally, the corresponding values were 68% for those with BRAF-mutated disease and 65% for those with wild-type disease.
“Patients with relatively poor prognoses appeared to be at no greater risk of developing select TRAEs than the all-treated population,” the study authors wrote. “Although efficacy in the all-treated population and patients with brain metastases was similar, reduced efficacy was observed in patients with [an ECOG performance status of 2] and/or certain melanoma subtypes, such as ocular/uveal and mucosal melanoma, highlighting the continued need for novel treatment options for these patients.”
In the single-arm phase 3b CheckMate 401 trial, patients received 1 mg/kg of nivolumab plus 3 mg/kg of ipilimumab every 3 weeks for 4 doses prior to receiving additional doses of nivolumab alone at 240 mg once every 2 weeks for a maximum of 24 months.
The trial’s primary end point was incidence of grade 3 to 5 TRAEs per CTCAE v4.0 criteria. Secondary end points included time to select AE onset, OS, investigator-assessed ORR, PFS, and safety and tolerability.
Treatment-naïve adult patients needed to have histologically confirmed, measurable, unresectable stage III or IV melanoma and an ECOG performance status of no greater than 2 to enroll on the trial. Those with cutaneous, ocular or uveal, mucosal, or acral melanoma as well as asymptomatic brain metastases regardless of BRAF mutation status were also able to enroll.
Of 533 patients in the all-treated population who received at least 1 dose of the study regimen, 10% had an ECOG performance status of 2; 20% had ocular or uveal, mucosal, or acral melanoma; and 12% had other types of melanoma. Additionally, 44% had a lactate dehydrogenase level above the upper limit of normal, and 8% had brain metastases.
The median age in the all-treated population was 59.0 years (range, 20-84). Most patients were male (59%), from Europe (86%), had M1c disease without brain metastases (37%), and BRAF wild-type disease (55%). Nine percent of patients received prior systemic treatment in the adjuvant setting, and 61% had a PD-L1 expression lower than 1%.
Any-grade TRAEs occurred in 91% of patients, with the most common types including diarrhea (35%), pruritus (25%), and fatigue (25%). Moreover, grade 3/4 TRAEs occurred in 60% of patients, the most common of which included elevated lipase (8%), diarrhea (7%), and colitis (6%).
Investigators administered immunomodulatory agents to manage AEs in 86% of those in the all-treated population. Moreover, 14% and 9% of patients discontinued treatment due to GI and hepatic TRAEs, respectively. In the acral melanoma subgroup, 1 patient discontinued treatment due to Stevens-Johnson syndrome.
Investigators reported a total of 199 patient deaths in the all-treated population, 179 of which were due to melanoma. Investigators attributed 5 deaths to study drug toxicity and/or grade 5 TRAEs, which included 2 instances of myocarditis and 1 instance each of aplastic anemia, acute kidney injury, and colitis.
Dummer R, Corrie P, Gutzmer R, et al. First-line, fixed-duration nivolumab plus ipilimumab followed by nivolumab in clinically diverse patient populations with unresectable stage III or IV melanoma: CheckMate 401. J Clin Oncol. Published online June 12, 2023. doi:10.1200/JCO.22.02199