Abstract 618: Application of clinical whole-exome sequencing as a predictor of clinical benefit of PD1/PDL1 blockade in a prospective study of advanced cancer patients
Authors: Wang Guan , Chen Cheng , Wei Jinwang , Wu Angela , Dai Chun , Xu Xiaoman , Cai Xin , Xu Qiang 
Published: August 2018

Abstract
Background: The effectiveness of PD1/PDL1 checkpoint blockade immunotherapy is influenced by several genetic factors, including microsatellite status, tumor mutation burden (TMB) and chromosomal status. Systemic understanding of why immunotherapy is effective may predict long lasting responses and resistance to immunotherapy.
Methods: Over 1,600 cancer patients from 72 hospitals across 20 provinces in China were recruited and the whole exome of tumor/blood samples of each patient were sequenced. We applied genomic checkpoint immunotherapy predict (GCIP) model that developed based on CWES data associated with histopathologic features to predict checkpoint immunotherapy effectiveness score (CIE score) for each patients. Clinical decision roadmap recommendations including targeted therapy and tumor immunotherapy were provided to each patient and their treating physician. Based on the latest follow-up results, 22 advanced cancer patients including 6 lung, 5 biliary system, 3 soft tissue sarcomas and 8 others tumor types received anti-PD1/PDL1 treatment following their physician's recommendations.
Results: Of these 22 prospective real-world enrolled patients, the disease control rate (DCR) was 72.7% and Objective response rate (ORR) was 40.9%, with four (18.1%) patients having a complete response (CR) by investigator assessment. Nine patients with TMB-high (3 CR, 4 PR and 2 PD) had better ORR and DCR than those with TMB-medium (77.7% vs. 14.2% and 77.7% vs. 70.0%). Interestingly, the highest TMB patient with primary resistance to anti-PD-1 therapy presented CDKN2A and IFN-α family somatic co-deletion at chromosome 9p21 segment which also be found by tumor biopsy from another patient with acquired resistant after an extraordinary 18-month response. Of 6 progressive disease (PD) patients, chromosomal arm-level aberrations have been identified in 4 patients and 5 somatic mutated genes (total 148) in histocompatibility complex class I (MHC-I) molecules have been detected in one patient with MSI-high. Notably, four patients with both the highest chromosomal stability and either the TMB-high, or Indel proportion high, but neither alone, exhibited the longest clinical benefit (CR lasts longer than 12 months). These findings would be the mechanisms of tumor escape from the host's immunity.
Conclusions: GCIP model can effectively predict checkpoint immunotherapy response, durable clinical benefit and genetic resistance features for most of the advanced cancer patients. Our findings demonstrate the importance of tumor genomic data, especially chromosomal status; those important clues may potentially overcome primary and acquired resistance to immunotherapy.
Citation Format: Guan Wang, Cheng Chen, Jinwang Wei, Angela Wu, Chun Dai, Xiaoman Xu, Xin Cai, Qiang Xu. Application of clinical whole-exome sequencing as a predictor of clinical benefit of PD1/PDL1 blockade in a prospective study of advanced cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 618.