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

Abstract

Purpose: Nivolumab (NIVO) + ipilimumab (IPI) combination and NIVO monotherapy have demonstrated durable clinical benefit in patients with unresectable/metastatic melanoma. This analysis describes long-term overall survival (OS) with the combination or monotherapy pooled across all major company-sponsored trials, as well as clinical factors associated with survival, in patients with immune checkpoint inhibitor (ICI) treatment-naïve unresectable/metastatic melanoma.

Methods: Data were pooled from six CheckMate studies in ICI treatment-naïve patients receiving NIVO + IPI (NIVO 1 mg/kg + IPI 3 mg/kg or NIVO 3 mg/kg + IPI 1 mg/kg) or NIVO monotherapy (3 mg/kg). OS was assessed for each treatment, as well as in select subgroups. Cox proportional multivariate analysis (MVA) and classification and regression tree (CART) analyses were performed within treatment arms.

Results: Median follow-up for OS was 45.0 months for patients treated with NIVO + IPI (n = 839) and 35.8 months for patients treated with NIVO (n = 536). OS was longer with NIVO + IPI versus NIVO monotherapy (hazard ratio, 0.78 [95% CI, 0.67 to 0.91]), with 6-year OS rates of 52% versus 41%, respectively. Consistent benefit was observed in BRAF-mutant and BRAF-wild-type patients and those with normal and elevated lactate dehydrogenase (LDH). Numerical difference in OS was also observed across PD-L1 expression levels, although more pronounced with no/low PD-L1 expression. Clinical factors associated with decreased survival in both the MVA and CART analyses were LDH > upper limit of normal with either treatment, age ≥65 years with NIVO + IPI, and the presence of liver metastases with NIVO monotherapy.

Conclusion: In this large, pooled nonrandomized retrospective analysis, we observed that NIVO + IPI provides longer OS than NIVO in patients with ICI treatment-naïve advanced melanoma and identifies clinical factors that appear to be associated with survival for each treatment, which may assist with treatment decision making.

Trial registration: ClinicalTrials.gov NCT02714218 NCT01721772 NCT01844505 NCT01024231 NCT00730639 NCT01927419.

FIG 1.

Patient flow. IPI, ipilimumab; NIVO, nivolumab.

FIG 2.

(A) OS and (B) MSS by investigator in all treated patients. HR, hazard ratio; IPI, ipilimumab; MSS, melanoma-specific survival; NIVO, nivolumab; NR, not reached; OS, overall survival.

FIG 3.

OS by study. (A) NIVO + IPI. (B) NIVO. IPI, ipilimumab; medF/U, median follow-up; mOS, median overall survival; NIVO, nivolumab; NR, not reached; OS, overall survival.

FIG 4.

OS by tumor PD-L1 and BRAF mutation status. (A) PD-L1 <1%. (B) PD-L1 ≥ 1%. (C) BRAF-mutant. (D) BRAF-wild-type. HR, hazard ratio; IPI, ipilimumab; mOS, median overall survival; NIVO, nivolumab; NR, not reached; OS, overall survival.

FIG 5.

OS CART analysis for (A) NIVO + ipilimumab and (B) NIVO monotherapy. CART, classification and regression tree; ECOG PS, Eastern Cooperative Oncology Group performance status; LDH, lactate dehydrogenase; M, metastasis; mets, metastases; mOS, median overall survival; NIVO, nivolumab; NR, not reached; OS, overall survival; ULN, upper limit of normal.