Abstract 2860: Improved clinical response in patients with advanced melanoma treated with nivolumab combined with ipilimumab compared to ipilimumab alone
Authors: Hodi F. Stephen , Postow Michael A. , Chesney Jason , Pavlick Anna C. , Robert Caroline , Grossmann Kenneth , McDermott David , Linette Gerald , Meyer Nicolas , Giguere Jeffrey , Agarwala Sanjiv S. , Shaheen Montaser , Ernstoff Marc S. , Minor David R. , Salama April , Taylor Matthew H. , Rollin Linda , Horak Christine , Gagnier Paul , Wolchok Jedd D. 
Published: August 2015

Abstract
Background: Blockade of the immune checkpoints PD-1 and CTLA-4 each results in improved overall survival in patients (pts) with metastatic melanoma using monotherapy. In a phase 1 dose-escalation study, dual inhibition of these pathways by nivolumab (NIVO) and ipilimumab (IPI) demonstrated encouraging antitumor activity.
Methods: Treatment-naïve pts with advanced melanoma were randomized (double-blind) 2:1 to IPI 3 mg/kg combined with either NIVO 1 mg/kg (NIVO+IPI combination group) or placebo (PBO; IPI alone group) every 3 weeks (Q3W) for 4 doses, followed by NIVO 3 mg/kg or PBO, respectively, Q2W until disease progression or unacceptable toxicity. Primary endpoint was investigator-assessed objective response rate (ORR) in BRAF wild-type (WT) pts. Secondary endpoints included progression-free survival (PFS), ORR in BRAF V600 mutation-positive (MT) pts, and safety.
Results: In BRAF WT pts, ORR was 60% (43/72) in the NIVO+IPI group vs 11% (4/37) in the IPI group (P&lt;0.0001); complete response reported in 12 (17%) and 0 pts, respectively. Median change in target lesions was 57% reduction for NIVO+IPI vs 4% increase for IPI alone. Median duration of response was not reached in either group. In BRAF WT pts, median PFS was 8.9 months for NIVO+IPI; 4.7 months for IPI (HR 0.40, 95% CI 0.22-0.71; P = 0.0012). Similar results for ORR and PFS favoring the combination were observed in BRAF MT pts (Table). A higher rate of drug-related grade 3-4 adverse events was observed in the NIVO+IPI group compared to IPI (Table), leading to more frequent discontinuation. Pts who discontinued NIVO+IPI due to study drug toxicity had a 67% response rate; most continue to respond. Immune-mediated AEs were manageable by standard treatment interventions, and the majority resolved with immune-modulating medication.
Conclusion: NIVO+IPI significantly improved ORR and PFS compared to IPI alone in treatment-naïve pts with advanced melanoma, and had a manageable safety profile.
Efficacy (evaluated in all randomized patients)BRAF WTBRAF WTBRAF MTNIVO+IPIIPINIVO+IPIIPIRandomized patients, N72372310ORR,% (95% CI)59.7 (47.5-71.1)a10.8 (3.0-25.4)a43.5 (23.2-65.5)0 (0-30.8)Best overall response, n (%)Complete response12 (16.7)04 (17.4)0Partial response31 (43.1)4 (10.8)6 (26.1)0Stable disease10 (13.9)12 (32.4)5 (21.7)2 (20.0)Progressive disease10 (13.9)16 (43.2)5 (21.7)7 (70.0)Median PFS, mo (95% CI)8.9 (7.0, NE)4.7 (2.8, 5.3)7.4 (2.8, NE)2.7 (0.99, 5.4)HR, (95% CI)0.40 (0.22-0.71) P = 0.00120.33 (0.1, 0.9)bSafety (evaluated in all treated patients)Patients reporting AE, n (%)NIVO+IPI (N = 94)IPI (N = 46)Any GradeGrade 3-4Any GradeGrade 3-4Treatment-related AEs86 (91.5)48 (51.1)42 (91.3)9 (19.6)aP&lt;0.0001; estimated odds ratio for objective response 12.23 (95% CI, 3.69-51.40)bDue to the small sample size in the BRAF MT subgroup, no P-value is provided NE = not estimable
Citation Format: F. Stephen Hodi, Michael A. Postow, Jason Chesney, Anna C. Pavlick, Caroline Robert, Kenneth Grossmann, David McDermott, Gerald Linette, Nicolas Meyer, Jeffrey Giguere, Sanjiv S. Agarwala, Montaser Shaheen, Marc S. Ernstoff, David R. Minor, April Salama, Matthew H. Taylor, Linda Rollin, Christine Horak, Paul Gagnier, Jedd D. Wolchok. Improved clinical response in patients with advanced melanoma treated with nivolumab combined with ipilimumab compared to ipilimumab alone. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2860. doi:10.1158/1538-7445.AM2015-2860