No Significant Benefit Demonstrated with Nivolumab/Ipilimumab Versus Nivolumab Alone in Advanced Melanoma

The combination of nivolumab (Opdivo) with ipilimumab (Yervoy) showed no statistically significant benefit in patients with stage IIIB/C/D or stage IV (no evidence of disease) melanoma compared with nivolumab alone in the phase III CheckMate 915 study, missing the co-primary endpoint of recurrence-free survival (RFS) in patients with <1% PD-L1 expression in their tumor cells, according to a press release from Bristol-Myers Squibb.¹

The phase III study randomized patients to nivolumab 240 mg intravenously every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks or nivolumab alone at 480 mg every 4 weeks to determine if the combination is more effective at delaying the return of cancer after a melanoma resection. The treatment is given for 1 year. In addition to the primary end point of RFS, the study is also evaluating overall survival (OS), and PD-L1 measured by immunoassay, as secondary end points.

The interventional study enrolled 1943 participants starting at age 12 who had a completely resected stage IIIB/C/D or stage IV melanoma and no prior treatment for melanoma. Patients were excluded if they had a history of uveal melanoma, had an active or suspected autoimmune disease, or had received prior treatment with interferon.

Nivolumab and ipilimumab were previously studied in the CheckMate 238 trial (NCT02388906), which primarily assessed RFS in patients who were at high risk for recurrence after complete resection of a stage IIIB/C or stage IV melanoma. CheckMate 238 was a phase III, double-blind study randomizing patients to nivolumab or ipilimumab. At 12 months follow up, patients receiving nivolumab had an RFS of 70.5% compared with 60.8% in the ipilimumab group (HR, 0.65; 95% CI, 0.51-0.83;P<.001).²

Grade 3 or 4 treatment-related adverse events occurred in 14.4% of CheckMate 238 participants in the nivolumab group and in 45.9% of those who received ipilimumab. A larger number of patients in the ipilimumab group (42.6%) discontinued treatment as a result of an adverse event versus the nivolumab group (9.7%). The study also had 2 deaths associated with adverse events directly related to treatment with ipilimumab.²

Nivolumab has multiple FDA-approved indications in melanoma, including, metastatic melanoma, unresectable melanoma. The drug is also indicated for treatment of patients with non—small cell lung cancer, small cell lung cancer, renal cell carcinoma, classical Hodgkin lymphoma, metastatic squamous cell carcinoma of the head and neck, advanced or metastatic urothelial carcinoma, hepatocellular carcinoma, and colorectal cancer in pediatric and adults patients with microsatellite instability&ndash;high disease or mismatch repair deficiency.

Ipilimumab also has indications for unresectable metastatic melanoma and cutaneous melanoma in the adjuvant setting.

Bristol-Myers Squibb also reported that the CheckMate 915 study will remain double-blinded and continue to assess for RFS in the study participants, based on the recommendation from the Data Monitoring Committee, which stated that the study should remain unchanged.

References

1. Bristol-Myers Squibb Announces Update on CheckMate -915 for Opdivo (nivolumab) Plus Yervoy (ipilimumab) Versus Opdivo Alone in Patients with Resected High-Risk Melanoma and PD-L1 <1% [press release]. Princeton, New Jersey; November 20, 2019. https://bit.ly/2qzEHg7. Accessed November 20, 2019.
2. Weber J, Mandala M, Del Vecchio M, et al; CheckMate 238 Collaborators. Adjuvant Nivolumab versus Ipilimumab in Resected Stage III or IV Melanoma.N Engl J Med. 2017;377:1824-1835. doi: 10.1056/NEJMoa1709030.