Adjuvant treatment with ipilimumab (Yervoy), when given at a 3-mg/kg dose, was found to improve overall survival (OS) compared with high-dose interferon alfa (HDI) in patients with high-risk melanoma, according to results of the phase III E1609 trial.
Results showed that the 3-mg/kg dose of ipilimumab led to a 22% reduction in the risk of death compared with HDI (HR, 0.78; 95.6% CI, 0.61-0.99; P
= .044). However, a 10-mg/kg dose of the CTLA-4 inhibitor was not found to be superior in efficacy and was also more toxic than HDI in this patient population.
“After the FDA approval of [3 mg/kg of ipilimumab] for patients with unresectable metastatic melanoma, based on significant improvement in OS and considering the relative toxicity, it became important to evaluate [this dose of ipilimumab] as adjuvant therapy,” the authors noted in the trial.
In the phase III E1609 trial, 1670 patients with resected cutaneous melanoma, determined as American Joint Committee on Cancer 7th edition stage IIIB, IIIC, M1a, or M1b, were randomized 1:1:1 to receive 3 mg/kg of ipilimumab (n = 523) or 10 mg/kg of ipilimumab (n = 511) or HDI (n = 636). The trial enrolled patients between May 2011 and August 2014.
To be eligible for enrollment, patients could not have received prior systemic adjuvant therapy. However, prior radiation therapy was permitted. Patients must have had an ECOG performance status of 0 or 1 and must have met screening laboratory test criteria. Those who had autoimmune disorders or conditions that required systemic corticosteroids, or other immunosuppressants, could not enroll on the trial.
Treatment with ipilimumab, at either 3 mg/kg or 10 mg/kg, was administered intravenously (IV) every 3 weeks for 4 doses as induction therapy, followed by the same dose every 12 weeks for ≤4 additional doses as maintenance therapy. HDI was administered IV at 20 million units/m2
of body surface area daily, 5 days per week, for 4 weeks as induction therapy, followed by 10 million units/m2
daily subcutaneously every other day, 3 days per week, for 48 weeks as maintenance therapy.
Treatment continued for ≤60 weeks with ipilimumab or for 52 weeks with HDI, or until unacceptable toxicity, disease progression, or withdrawal of consent. The primary endpoints were OS and relapse-free survival (RFS).
The data cutoff date was February 15, 2019, and the median follow-up was 57.4 months (range, 0.03-86.6). The primary endpoints were OS and relapse-free survival (RFS).
Additional results showed that the 5-year OS rate was 72% (95% CI, 68%-76%) with 3 mg/kg of ipilimumab and 67% (95% CI, 62%-72%) with HDI. Furthermore, the median RFS was 4.5 years for 3 mg/kg of ipilimumab compared with 2.5 years for HDI. Overall, there was a 15% reduction in the risk of relapse with the 3-mg/kg dose versus HDI (HR, 0.85; 99.4% CI, 0.66-1.09; P = .065).
In the 10-mg/kg dose of ipilimumab arm, the 5-year OS rate was 70% (95% CI, 65%-74%) in the compared with 65% (95% CI, 60%-70%) in the HDI arm. Additionally, the median RFS was 3.9 years (95% CI, 2.9–not reached) in this arm and 2.4 years (95% CI, 1.6-3.0) in the HDI arm.
Regarding safety, grade ≥3 adverse events (AEs) occurred in 38.6% of patients receiving 3 mg/kg of ipilimumab (95% CI, 34.3%-42.9%), 78.8% receiving HDI (95% CI, 75.1%-82.3%), and 57.9% receiving 10 mg/kg of ipilimumab (95% CI, 53.4%-62.2%). These AEs led to treatment discontinuation in 35% of the 3-mg/kg ipilimumab arm, 20% in the HDI arm, and 54% in the 10-mg/kg ipilimumab arm. Grade ≥3 AEs were significantly different between the 2 ipilimumab arms (P <.001).
Moreover, grade ≥3 immune-related toxicity in the ipilimumab arms were 28.5% (95% CI, 24.6%-32.6%) and 46.3% (95% CI, 41.9%-50.8%) in the 3-mg/kg and 10-mg/kg arms, respectively (P <.001). Fatal AEs, which were treatment related, occurred at the 3-mg/kg dose (n = 3), HDI (n = 2), and the 10-mg/kg dose (n = 8). There was a temporary suspension of treatment in the 10-mg/dose arm due to a series of fatal events.
“Immune-related AEs in the adjuvant setting may compromise therapeutic options in the event of recurrence. There were nonsignificant trends toward improvement in OS and RFS with [10 mg/kg of ipilimumab] versus HDI, which raises the question of whether increased toxicity with [10 mg/kg of ipilimumab] affected outcomes,” the authors stated. “The protocol had strict toxicity-specific criteria that mandated treatment delay for moderate immune-related AEs and discontinuation for more severe AEs.”
Tarhini AA, Lee SJ, Hodi FS, et al. Phase III study of adjuvant ipilimumab (3 or 10 mg/kg) versus high-dose interferon alfa-2b for resected high-risk melanoma: North American Intergroup E1609. J Clin Oncol. 2020;38(6):567-575. doi: 10.1200/JCO.19.01381.