Long-Term Outcomes With Nivolumab Plus Ipilimumab or Nivolumab Alone Versus Ipilimumab in Patients With Advanced Melanoma

Abstract

PURPOSE In the phase III CheckMate 067 trial, durable clinical benefit was demonstrated previously with nivolumab plus ipilimumab and nivolumab alone versus ipilimumab. Here, we report 6.5-year efficacy and safety outcomes. PATIENTS AND METHODS Patients with previously untreated unresectable stage III or stage IV melanoma were randomly assigned 1:1:1 to receive nivolumab 1 mg/kg plus ipilimumab 3 mg/kg once every 3 weeks (four doses) followed by nivolumab 3 mg/kg once every 2 weeks (n = 314), nivolumab 3 mg/kg once every 2 weeks (n = 316), or ipilimumab 3 mg/kg once every 3 weeks (four doses; n = 315). Coprimary end points were progression-free survival and overall survival (OS) with nivolumab plus ipilimumab or nivolumab versus ipilimumab. Secondary end points included objective response rate, descriptive efficacy assessments of nivolumab plus ipilimumab versus nivolumab alone, and safety. Melanoma-specific survival (MSS; descriptive analysis), which excludes deaths unrelated to melanoma, was also evaluated. RESULTS Median OS (minimum follow-up, 6.5 years) was 72.1, 36.9, and 19.9 months in the combination, nivolumab, and ipilimumab groups, respectively. Median MSS was not reached, 58.7, and 21.9 months, respectively; 6.5-year OS rates were 57%, 43%, and 25% in patients with BRAF-mutant tumors and 46%, 42%, and 22% in those with BRAF–wild-type tumors, respectively. In patients who discontinued treatment, the median treatment-free interval was 27.6, 2.3, and 1.9 months, respectively. Since the 5-year analysis, no new safety signals were observed. CONCLUSION These 6.5-year CheckMate 067 results, which include the longest median OS in a phase III melanoma trial reported to date and the first report of MSS, showed durable, improved clinical outcomes with nivolumab plus ipilimumab or nivolumab versus ipilimumab in patients with advanced melanoma and, in descriptive analyses, with the combination over nivolumab monotherapy.

A decade of checkpoint blockade immunotherapy in melanoma: understanding the molecular basis for immune sensitivity and resistance

“…[15][16][17][18] ) (Table 1). Considering the different and potentially complementary effects of CTLA-4 and PD-1 blockade 94 , these therapies were subsequently tested in combination, demonstrating greater long-term efficacy than either agent alone in metastatic melanoma, with 49% of treated individuals remaining alive after 6.5 years (Table 1), albeit at the cost of greater toxicity 20 . Alternative regimens and/or dosages of anti-PD-1 + anti-CTLA-4 are currently being investigated to reduce toxicity 95 .…”

“…Overall, the clinical success with ICB in melanoma has confirmed the therapeutic impact of re-invigorating the immune system to effectively target this disease. However, even in the optimal scenarios with combination ICB, approximately half of patients do not derive long-lasting benefit 20 . This indicates the need for better predictive biomarkers of response and new rational targets for more effective combination treatments to overcome immune resistance.…”

Key Players of the Immunosuppressive Tumor Microenvironment and Emerging Therapeutic Strategies

“…As reviewed by Toor et al (2020) and Jiang et al (2019) , CTLA-4 and PD-1 are the most targeted inhibitory pathways involved in the immune escape by tumors. In patients with previously untreated unresectable stage III or IV melanomas, nivolumab plus ipilimumab demonstrated greater objective response rate (ORR), median overall survival (OS) and progression-free survival (PFS) than ipilimumab alone ( Wolchok et al, 2021 ). Similarly, in patients with ovarian cancer, nivolumab plus ipilimumab exhibited both increased ORR and PFS than nivolumab alone within 6 months of enrollment ( Zamarin et al, 2020 ).…”

Oxidative Stress Differentially Influences the Survival and Metabolism of Cells in the Melanoma Microenvironment

“…Skin cancer is one of the most common type of cancers, and malignant melanoma is its deadliest form [1,2]. Although the introduction of immune checkpoint inhibitors represents a great advancement in the treatment of melanoma and thus has improved patient prognosis, many patients do not respond to therapy-leaving them with limited treatment options [2][3][4][5][6][7]. Melanoma prognoses remain particularly poor in advanced metastatic disease and in mucosal forms [1,2,8].…”