Adjuvant Nivolumab Shows Potential RFS Benefit Over ipilimumab in Advanced Melanoma

Vicki Goodman, MD

Vicki Goodman, MD

In patients with advanced melanoma enrolled in the phase III CheckMate-238 trial, adjuvant nivolumab (Opdivo) extended recurrence-free survival (RFS) compared with adjuvant ipilimumab (Yervoy).

Bristol-Myers Squibb (BMS), the manufacturer of both checkpoint inhibitors, did not release any data, but reported that 3 mg/kg of nivolumab met its primary endpoint at a planned interim analysis by demonstrating superior RFS compared with 10 mg/kg of ipilimumab in patients with stage IIIb/c or stage IV melanoma who are at high risk for recurrence following complete surgical resection. Details will be presented at a future medical meeting.

“These topline results support the potential promise of Opdivo as a treatment option for patients with high-risk surgically resected melanoma,” Vicki Goodman, MD, development lead, melanoma and genitourinary cancers, BMS said in a press release. “There remains an unmet need for additional options as the majority of stage III and resected stage IV high-risk melanoma patients experience disease recurrence after surgery.”

Even with surgery and adjuvant treatment, 68% of patients with stage IIIb disease and 89% of those with IIIc disease will experience recurrence within 5 years.

In the ongoing double-blind CheckMate-238 study, 906 patients were randomized to receive either 3 mg/kg of nivolumab every 2 weeks or 10 mg/kg of ipilimumab every 3 weeks for 4 doses, then every 12 weeks for 1 year or until documented disease progression or unacceptable toxicity. The primary endpoint is RFS, defined as the time between randomization and the date of first recurrence or death.

Results from a phase I study published in 2015 (N = 33) showed that nivolumab plus a vaccine was active as adjuvant therapy in patients with resected stage IIIC and IV melanoma.1 Two patients had stage IIIc disease, while 31 patients had stage IV disease. Patients were assigned to nivolumab doses of 1 mg/kg, 3 mg/kg, or 10 mg/kg.

Maximum-tolerated dose had not been reached by the median follow-up of 32.1 months. Estimated median RFS was 47.1 months and median OS was not reached. Ten patients experienced relapse.

The most common treatment-related adverse events (AEs; >40%) were vaccine injection site reaction, fatigue, rash, pruritus, nausea, and arthralgia. Researchers observed 2 cases of grade 3 colitis, and 1 case each of grade 3 hypokalemia, rash, and enteritis.

Researchers noted increases in CTLA-4⁺/CD4⁺, CD25⁺Treg/CD4⁺, and tetramer specific CD8⁺T-cell populations with treatment (P<.05). Trends for lower baseline myeloid-derived suppressor cell and CD25⁺Treg/CD4⁺populations were seen in nonrelapsing patients, and researchers concluded that PD-L1 tumor status was not significantly associated with RFS.

The 10 mg/kg dose of ipilimumab in the adjuvant setting has been approved for patients with advanced melanoma in the United States since 2015. Phase III results from the international, double-blind EORTC 18071 trial, showed that adjuvant ipilimumab at a 10 mg/kg dose reduced the risk of recurrence by 25% versus placebo (HR, 0.75; 95% CI, 0.64-0.90;P<.002).²

The drug was approved at this 10 mg/kg dose, which is higher than the 3 mg/kg dose the FDA recommended in ipilimumab&rsquo;s initial approval for advanced melanoma.

The trial included 951 patients with stage III cutaneous melanoma who had adequate resection of lymph nodes. Patients were randomly assigned in a 1:1 ratio to receive ipilimumab at 10 mg/kg (IV) or placebo every 3 weeks for 4 doses, then every 3 months for up to 3 years. Patients in the ipilimumab arm received a median of 4 doses (range, 1-16), with 36% remaining on the drug for more than 6 months.

References:

1. Gibney, GT, Kudchadkar RR, DeConti RC, et al. Safety, correlative markers, and clinical results of adjuvant nivolumab in combination with vaccine in resected high-risk metastatic melanoma.Clin Cancer Res.2015 Feb 15; 21(4): 712-720.
2. Eggermont AM, Chiarion-Sileni V, Grob JJ et al. Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): a randomised, double-blind, phase 3 trial.Lancet Oncol.2015;16(5):522-530.