The Impact of Molecular Subtype on Efficacy of Chemotherapy and Checkpoint Inhibition in Advanced Gastric Cancer
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Published OnlineFirst March 10, 2020; DOI: 10.1158/1078-0432.CCR-20-0075 CLINICAL CANCER RESEARCH | TRANSLATIONAL CANCER MECHANISMS AND THERAPY The Impact of Molecular Subtype on Efficacy of Chemotherapy and Checkpoint Inhibition in Advanced Gastric Cancer Yohei Kubota1,2, Akihito Kawazoe1, Akinori Sasaki1, Saori Mishima1, Kentaro Sawada1, Yoshiaki Nakamura1, Daisuke Kotani1, Yasutoshi Kuboki1, Hiroya Taniguchi1, Takashi Kojima1, Toshihiko Doi1, Takayuki Yoshino1, Genichiro Ishii2,3, Takeshi Kuwata3, and Kohei Shitara1 ABSTRACT ◥ Purpose: We evaluated the association between molecular sub- response rates (ORR) were 31%, 62%, 60%, and 49% in MMR-D, þ þ types of advanced gastric cancer (AGC) and the efficacy of standard EBV , HER2 , and all-negative subtypes, respectively. Multivariate chemotherapy or immune checkpoint inhibitors. analysis showed shorter PFS in MMR-D versus all-negative patients Experimental Design: Patients with AGC who received system- [HR, 1.97; 95% CIs, 1.09–3.53; P ¼ 0.022]. In second-line setting, ic chemotherapy from October 2015 to July 2018 with available there were no significant differences in efficacy. In 110 patients who molecular features were analyzed. We investigated the efficacy of received anti–PD-1 therapy, median PFS times were 13.0, 3.7, 1.6, standard first- (fluoropyrimidine þ platinum Æ trastuzumab) and and 1.9 months and the ORRs were 58%, 33%, 7%, and 13%, second-line (taxanes Æ ramucirumab) chemotherapy, and subse- respectively. Twelve patients with MMR-D received subsequent quent anti–PD-1 therapy in patients with four molecular subtypes: anti–PD-1 therapy and showed longer PFS compared with that in þ þ MMR-D (mismatch repair deficient), EBV , HER2 , and all 10 (83%) patients who received earlier-line chemotherapy. negative. Conclusions: MMR-D might result in shorter PFS with first-line þ Results: 410 patients were analyzed: MMR-D 5.9%, EBV 4.1%, chemotherapy for AGC. Subsequent anti–PD-1 therapy achieved þ HER2 13.7%, and all negative 76.3%. In 285 patients who received higher ORR and longer PFS than prior chemotherapy in most standard first-line chemotherapy, the median progression-free sur- patients with MMR-D, supporting the earlier use of immune vival (PFS) times were 4.2, 6.0, 7.5, and 7.6 months and the objective checkpoint inhibitors. Introduction combination and sequential regimen involving these agents was less than 15 months. Gastric cancer is the fifth most common type of cancer and the third The molecular characterization of gastric cancer has recently been leading cause of death from cancer globally (1). A combination of rapidly evolving. As shown in The Cancer Genome Atlas and The fluoropyrimidines and a platinum agent (with trastuzumab for HER2- Asian Cancer Research Group (15, 16), the microsatellite instability– positive cases) as first-line therapy is the standard treatment in high (MSI-H) subtype exhibits a greater number of mutations in patients with advanced gastric cancer (AGC; refs. 2–6). Second-line multiple genes and hypermethylation compared with other subtypes, therapy includes taxane agents with or without ramucirumab or which contributes to the enhanced expression of neoantigens irinotecan (7–12). In third-line or later therapy, two anti–PD-1 þ and subsequent high infiltration of CD8 T cells. Indeed, the FDA- inhibitors have been approved for AGC: pembrolizumab by the approved pembrolizumab for patients with MSI-H/mismatch repair- U.S. Food and Drug Administration (FDA) for PD-L1–positive deficient (MMR-D) solid tumors including AGC based on the durable tumors, and nivolumab in Asian countries, regardless of PD-L1 response shown in several trials (14, 17–19). Also, Epstein–Barr virus- status (13, 14). Despite the recent increase in treatment options, the (EBV)-positive status has been reported to be associated with a high median overall survival time of patients with AGC treated with a amplification rate of the CD274 gene (which encodes PD-L1) and the PDCD1LG2 gene (which encodes PD-L2; refs. 15, 16), as well as high expression of these immune checkpoints, which might lead to favor- 1Department of Gastroenterology and Gastrointestinal Oncology, National 2 able outcomes for AGC following the use of immune checkpoint Cancer Center Hospital East, Chiba, Japan. Courses of Advanced Clinical inhibitors (20). However, little is known about the association between Research of Cancer, Juntendo University Graduate School of Medicine, Tokyo, fi Japan. 3Department of Pathology and Clinical Laboratories, National Cancer molecular subtypes and the ef cacy of standard chemotherapy or the Center Hospital East, Chiba, Japan. relative efficacy of immune checkpoint inhibitors for AGC. Therefore, we investigated the efficacy of standard first- and second-line chemo- Note: Supplementary data for this article are available at Clinical Cancer þ therapy for various clinical molecular subtypes: MMR-D, EBV , Research Online (http://clincancerres.aacrjournals.org/). þ HER2 , and others (all negative). The impact of these subtypes on Y. Kubota and A. Kawazoe contributed equally to this article. the efficacy of subsequent anti–PD-1 therapy was also analyzed in this Corresponding Author: Kohei Shitara, Department of Gastroenterology study. and Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba 277-8577, Japan. Phone: 814-7133-1111; Fax: 814-7134-6865; E-mail: [email protected] Materials and Methods – Clin Cancer Res 2020;XX:XX XX Patients doi: 10.1158/1078-0432.CCR-20-0075 We performed a single-institute study to evaluate the efficacy of Ó2020 American Association for Cancer Research. standard first- (fluoropyrimidine þ platinum Æ trastuzumab) and AACRJournals.org | OF1 Downloaded from clincancerres.aacrjournals.org on September 28, 2021. © 2020 American Association for Cancer Research. Published OnlineFirst March 10, 2020; DOI: 10.1158/1078-0432.CCR-20-0075 Kubota et al. EBER Probe, Ventana) was performed to evaluate EBV status (23). All Translational Relevance specimens in this study were reviewed by T. Kuwata. Despite the recent increase in treatment options, the prognosis Genomic alterations were analyzed using Oncomine Comprehen- of patients with advanced gastric cancer (AGC) remains poor. sive Assay version 3 or Oncomine Cancer Research Panel (Thermo Recently, the molecular characterization of gastric cancer has been Fisher Scientific). TMB was defined as the number of nonsynonymous rapidly evolving, but little is known about the association between mutations, including indels, per megabase (mt/Mb) of genome exam- molecular subtypes and the efficacy of standard chemotherapy or ined in tumor tissue. the relative efficacy of immune checkpoint inhibitors for AGC. The aim of the present study was to analyze the efficacy of first- and Outcomes and statistical analysis second-line chemotherapy, and subsequent anti–PD-1 therapy on We evaluated the objective response rate (ORR), the disease þ þ the molecular subtypes (MMR-D, EBV , HER2 , and all-negative) control rate (DCR), and progression-free survival (PFS). Tumor of AGC. This article provides important data on the impact of these response was assessed in patients with measurable lesions using the subtypes on responses to first- or second-line standard chemo- Response Evaluation Criteria in Solid Tumors version 1.1. The ORR therapy and the relative efficacy of subsequent anti–PD-1 therapy was defined as the proportion of patients with the best overall for AGC, which data may support treatment optimization accord- response of complete response (CR) or partial response (PR). The ing to the molecular subtypes. DCR was defined as the proportion of patients with the best overall response of CR, PR, or stable disease. The PFS was defined as the interval from the start of treatment until disease progression or death from any cause or the last follow-up visit and estimated by the second-line (taxanes Æ ramucirumab) chemotherapy, and subse- Kaplan–Meier method. The x2 test or Fisher exact test was used to quent anti–PD-1 therapy in patients with AGC of four clinical compare baseline characteristics and response rates. PFS was also þ þ molecular subtypes: MMR-D, EBV ,HER2 , and others (all neg- compared between each molecular subtype using the Cox propor- ative). The eligibility criteria were as follows: (i) an Eastern Coop- tional hazards model and presented as an HR with 95% confidence erative Oncology Group performance status (ECOG PS) of 0–2; (ii) intervals (CIs). Confounders in the multivariate analyzes of PFS histologically proven, unresectable, locally advanced, or metastatic were prespecified according to previously reported prognostic gastric adenocarcinoma; (iii) adequate bone marrow, hepatic, and factors in AGC receiving standard chemotherapy (24–28); ECOG renal function; (iv) received systemic chemotherapy from October PS (1–2vs0),livermetastasis(yesvsno),peritonealmetastasis(yes 2015 to July 2018; and (v) with available molecular features (MMR/ vs no), number of metastatic sites (2 or more vs 1), prior gastrec- EBV/HER2 tests were all required, while PD-L1 expression or gene tomy (no vs yes), ALP [≥ upper limit normal (ULN) vs < ULN], alterations were not). Patients with recurrence within 6 months of histologic type (diffuse vs intestinal), and a measurable lesion (yes adjuvant chemotherapy were excluded from first-line analysis. All vs no). Statistical analyzes were performed using SPSS Statistics patients provided written informed consent for the biomarker software V22 (IBM). All tests were two-sided; P