Clinical Trials: Immunotherapy A Model of Overall Survival Predicts Treatment Outcomes with Atezolizumab versus Chemotherapy in Non–Small Cell Lung Cancer Based on Early Tumor Kinetics Laurent Claret 1 , Jin Y. Jin 2 , Charles Fert e 3 , Helen Winter 2 , Sandhya Girish 2 , Mark Stroh 2 , Pei He 4 , Marcus Ballinger 5 , Alan Sandler 5 , Amita Joshi 2 , Achim Rittmeyer 6 , David Gandara 7 , Jean-Charles Soria 3 , and Ren e Bruno 1 Abstract Purpose: Standard endpoints often poorly predict overall survival (OS) with immunotherapies. We investigated the pre- dictive performance of model-based tumor growth inhibition (TGI) metrics using data from atezolizumab clinical trials in patients with non–small cell lung cancer. Patients and Methods: OS benefit with atezolizumab versus docetaxel was observed in both POPLAR (phase II) and OAK (phase III), although progression-free survival was similar between arms. A multivariate model linking baseline patient characteristics and on-treatment tumor growth rate constant (KG), estimated using time profiles of sum of longest diameters (RECIST 1.1) to OS, was developed using POPLAR data. The model was evaluated to predict OAK outcome based on estimated KG at TGI data cutoffs ranging from 10 to 122 weeks. Results: In POPLAR, TGI profiles in both arms crossed at 25 weeks, with more shrinkage with docetaxel and slower KG with atezolizumab. A log-normal OS model, with albumin and num- ber of metastatic sites as independent prognostic factors and estimated KG, predicted OS HR in subpopulations of patients with varying baseline PD-L1 expression in both POPLAR and OAK: model-predicted OAK HR (95% prediction interval), 0.73 (0.63–0.85), versus 0.73 observed. The POPLAR OS model pre- dicted greater than 97% chance of success of OAK (significant OS HR, P < 0.05) from the 40-week data cutoff onward with 50% of the total number of tumor assessments when a successful study was predicted from 70 weeks onward based on observed OS. Conclusions: KG has potential as a model-based early end- point to inform decisions in cancer immunotherapy studies. Clin Cancer Res; 24(14); 3292–8. Ó2018 AACR. Introduction Atezolizumab is an engineered humanized immunoglobulin G1 monoclonal antibody that targets programmed death-ligand 1 (PD-L1) to block the interaction with its receptors programmed death-1 (PD-1) and B7.1, thereby restoring tumor-specific T-cell immunity (1–4). Targeting PD-L1 with atezolizumab may preserve immune homeostasis in normal tissue by leaving the programmed death-ligand 2 (PD-L2)/PD-1 interaction intact (5, 6). PD-L1 is expressed on tumor cells (TC) and tumor- infiltrating immune cells (IC) on a wide variety of cancers, and atezolizumab has demonstrated clinical efficacy against many different tumor types (4). Atezolizumab is approved in the United States for the treat- ment of metastatic urothelial carcinoma and metastatic non– small cell lung cancer (NSCLC). The open-label randomized controlled trials POPLAR (7) and OAK (8), comparing atezo- lizumab versus docetaxel, have been conducted in patients with advanced pretreated NSCLC. Both studies showed an overall survival (OS) benefit of atezolizumab compared with doce- taxel, whereas the objective response rate (ORR) and progres- sion-free survival (PFS) were similar between treatment groups. Increasing improvement in OS was associated with increasing PD-L1 expression (on TCs and tumor-infiltrating ICs) in POP- LAR with no benefit in patients with low or no expression (7). In OAK, OS was improved [median OS of 13.8 months (95% confidence interval, CI, 11.8–15.7) for atezolizumab versus 9.6 months (8.6–11.2) for docetaxel HR of 073 (95% CI, 062–087), P ¼ 00003] regardless of PD-L1 expression levels, whereas patients with high expression derived the greatest OS benefit (HR) (8). In addition, a nonrandomized phase II study, BIRCH (9), demonstrated responses with atezolizumab monotherapy in patients with PD-L1–selected advanced NSCLC across lines of therapy. 1 Clinical Pharmacology, Roche/Genentech, Marseille, France. 2 Clinical Pharma- cology, Roche/Genentech, South San Francisco, California. 3 Gustave Roussy, Villejuif, France. 4 Biostatistics, Roche/Genentech, South San Francisco, Califor- nia. 5 Clinical, Roche/Genentech, South San Francisco, California. 6 Lungenfachk- linik Immenhausen, Immenhausen, Germany. 7 University of California, Davis, Davis, California. Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/). Current address for C. Fert e and J.-C. Soria: AstraZeneca-MedImmune, Gaithers- burg, Maryland. Current address for M. Stroh: CytomX Therapeutics, South San Francisco, California. Corresponding Author: Ren e Bruno, Roche/Genentech, 84 Chemin des Grives, 13013 Marseille, France. Phone: 33-677-89-5298; Fax: 33-491-42-7397; E-mail: rene.bruno@roche.com doi: 10.1158/1078-0432.CCR-17-3662 Ó2018 American Association for Cancer Research. Clinical Cancer Research Clin Cancer Res; 24(14) July 15, 2018 3292 on May 23, 2020. © 2018 American Association for Cancer Research. clincancerres.aacrjournals.org Downloaded from Published OnlineFirst April 23, 2018; DOI: 10.1158/1078-0432.CCR-17-3662