Abstract CT128: Association between tumor shrinkage and overall survival in advanced melanoma patients with nivolumab in combination with ipilimumab
Authors: Feng Yan , Gupta Manish , Agrawal Shruti , Roy Amit 
Published: August 2015

Abstract
Background: Immune checkpoint inhibitors enhance immunologic antitumor activity, and ongoing studies are exploring the potential of such agents to provide long-term overall survival (OS) benefits across several cancer types. We describe an exploratory analysis of the association between tumor shrinkage (TS) and OS in patients (pts) with melanoma receiving nivolumab in combination with ipilimumab, two immune checkpoint inhibitors that augment T-cell activity by blocking cytotoxic T-lymphocyte-associated protein 4 and programmed death-1 receptors, respectively.
Methods: The time-course of TS in pts with previously untreated advanced melanoma was described by a nonlinear mixed-effects tumor growth dynamics (TGDs) model, using data from three phase II ipilimumab monotherapy studies (CA184007/008/022, n = 351) and one phase Ib nivolumab monotherapy or nivolumab in combination with ipilimumab study CA209004 (n = 127). The relationship between TS following treatment with nivolumab in combination with ipilimumab and OS was determined by a multivariate Cox proportional-hazards model, using data from CA209004 (n = 127).
Results: The TGD model determined that there are two subpopulations of patients with respect to TGDs (fast tumor growth vs slow tumor growth), following treatment with nivolumab in combination with ipilimumab, or ipilimumab monotherapy. Higher nivolumab and ipilimumab exposures appear to be associated with faster TS in the slow tumor growth subpopulation. The risk of death decreased with increasing% TS and lower baseline lactate dehydrogenase (LDH) (hazard ratio [HR] coefficients and associated 95% confidence intervals [CIs] &lt;1.0). The HR (95% CI) in pts with 50% TS (corresponding to magnitude of modified WHO partial response) relative to 0% was 0.68 (0.57-0.82), and the HR (95% CI) in pts with 3-fold upper limit of normal (ULN) LDH compared to 1-fold ULN was 3.68 (1.60-8.46). The risk of death is also higher in pts with prior treatment, ECOG &gt;0, and BRAF wild-type (HR [95% CI] of 2.59 [1.22-5.49], 2.38 [1.14-4.98], and 2.49 [1.04-5.99], respectively).
Conclusions: In this exploratory retrospective analysis, the nonlinear mixed-effects TGD model adequately described the longitudinal tumor burden data, and an association was found between the extent of TS and OS in advanced melanoma pts receiving nivolumab in combination with ipilimumab. Measuring the extent and timing of TS may be useful in predicting the potential OS benefits of immune checkpoint inhibitors; however, this observation would need to be prospectively evaluated using data from a well-controlled study. Additional exploratory analyses are ongoing to assess correlates to OS benefit.
Citation Format: Yan Feng, Manish Gupta, Shruti Agrawal, Amit Roy. Association between tumor shrinkage and overall survival in advanced melanoma patients with nivolumab in combination with ipilimumab. [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 CT128. doi:10.1158/1538-7445.AM2015-CT128