Published OnlineFirst July 17, 2019; DOI: 10.1158/2159-8290.CD-19-0442 RESEARCH ARTICLE Tumor Genomic Profiling Guides Patients with Metastatic Gastric Cancer to Targeted Treatment: The VIKTORY Umbrella Trial Jeeyun Lee1, Seung Tae Kim1, Kyung Kim1, Hyuk Lee2, Iwanka Kozarewa3, Peter G.S. Mortimer4, Justin I. Odegaard5, Elizabeth A. Harrington3, Juyoung Lee1, Taehyang Lee1, Sung Yong Oh6, Jung-Hun Kang7, Jung Hoon Kim8, Youjin Kim9, Jun Ho Ji9, Young Saing Kim10, Kyoung Eun Lee11, Jinchul Kim1, Tae Sung Sohn12, Ji Yeong An12, Min-Gew Choi12, Jun Ho Lee12, Jae Moon Bae12, Sung Kim12, Jae J. Kim2, Yang Won Min2, Byung-Hoon Min2, Nayoung K.D. Kim13,4, Sally Luke3, Young Hwa Kim4, Jung Yong Hong1, Se Hoon Park1, Joon Oh Park1, Young Suk Park1, Ho Yeong Lim1, AmirAli Talasaz5, Simon J. Hollingsworth14, Kyoung-Mee Kim15, and Won Ki Kang1 Downloaded from cancerdiscovery.aacrjournals.org on October 2, 2021. © 2019 American Association for Cancer Research. Published OnlineFirst July 17, 2019; DOI: 10.1158/2159-8290.CD-19-0442 ABSTRACT The VIKTORY (targeted agent eValuation In gastric cancer basket KORea) trial was designed to classify patients with metastatic gastric cancer based on clinical sequencing and focused on eight different biomarker groups (RAS aberration, TP53 mutation, PIK3CA mutation/amplification, MET amplification, MET overexpression, all negative,TSC2 deficient, orRIC - TOR amplification) to assign patients to one of the 10 associated clinical trials in second-line (2L) treatment. Capivasertib (AKT inhibitor), savolitinib (MET inhibitor), selumetinib (MEK inhibitor), ada- vosertib (WEE1 inhibitor), and vistusertib (TORC inhibitor) were tested with or without chemotherapy. Seven hundred seventy-two patients with gastric cancer were enrolled, and sequencing was success- fully achieved in 715 patients (92.6%). When molecular screening was linked to seamless immediate access to parallel matched trials, 14.7% of patients received biomarker-assigned drug treatment. The biomarker-assigned treatment cohort had encouraging response rates and survival when compared with conventional 2L chemotherapy. Circulating tumor (ctDNA) analysis demonstrated good correlation between high MET copy number by ctDNA and response to savolitinib. SIGNIFICANCE: Prospective clinical sequencing revealed that baseline heterogeneity between tumor samples from different patients affected response to biomarker-selected therapies. VIKTORY is the first and largest platform study in gastric cancer and supports both the feasibility of tumor profiling and its clinical utility. INTRODUCTION It has been suggested by previous studies that this interpa- tient tumor molecular heterogeneity may affect the outcomes Recent advances in molecular analysis have revealed that of clinical trials, especially with molecularly targeted agents there are patient subsets with differing genomic alterations (4, 5). To deliver a more tailored approach for each patient, despite the same histologic diagnosis in gastric cancer (1–3). umbrella or platform clinical trials have been developed (6, 7), which assign treatment arms based on the molecular charac- teristics of the tumor. 1Division of Hematology-Oncology, Department of Medicine, Samsung Gastric cancer was the third leading cause of cancer- Medical Center, Sungkyunkwan University School of Medicine, Seoul, related mortality in 2018, causing 783,000 deaths world- 2 Korea. Division of Gastroenterology, Department of Medicine, Samsung wide (8). The prognosis of patients with metastatic gastric Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. 3Oncology Translational Sciences, IMED Biotech Unit, AstraZeneca, cancer remains extremely poor, with a median overall sur- Cambridge, United Kingdom. 4Clinical, Research and Early Development, vival (OS) of less than 12 months with cytotoxic chemo- Oncology R&D, AstraZeneca, Cambridge, United Kingdom. 5Guardant therapy (9, 10). In addition, gastric cancer is a disease with Health, Redwood, California. 6Dong-A University School of Medicine, significant molecular and histologic heterogeneity (1, 3, 7 Busan, Korea. Department of Internal Medicine, College of Medicine, 11), in which advancements based on “one-size-fits-all” Gyeongsang National University, Jinju, Korea. 8Department of Internal Medicine, Gyeongsang National University School of Medicine, Jinju, clinical trials have yielded only modest survival benefits. Korea. 9Division of Hematology-Oncology, Samsung Changwon Hospital, To identify optimal molecular targets and optimal bio- Sungkyunkwan University School of Medicine, Changwon, Korea. 10Depart- markers, we designed an umbrella trial for second-line ment of Internal Medicine, Gachon University Gil Medical Center, Incheon, (2L) treatment in metastatic gastric cancer based on tumor Republic of Korea. 11Division of Hematology-Oncology, Department of Internal Medicine, Ewha Womans University, Seoul, Korea. 12Department molecular profiling. We took advantage of an umbrella trial of Surgery, Samsung Medical Center, Sungkyunkwan University School design where patients of a single tumor type are directed of Medicine, Seoul, Korea. 13Samsung Genome Institute, Seoul, Korea. toward different arms of the study based on the tumor 14Oncology Business Unit, AstraZeneca, Cambridge, United Kingdom. molecular biomarkers relevant to one or more of the can- 15 Department of Pathology & Translational Genomics, Samsung Medical didate drugs (12). VIKTORY (targeted agent eValuation Center, Sungkyunkwan University School of Medicine, Seoul, Korea. In gastric cancer basket KORea, trial NCT#02299648) was Note: Supplementary data for this article are available at Cancer Discovery Online (http://cancerdiscovery.aacrjournals.org/). designed to classify patients with metastatic gastric cancer based on clinical sequencing and comprised eight different S.T. Kim, K. Kim, H. Lee, and I. Kozarewa contributed equally to this article. biomarker groups (RAS aberration, TP53 mutation, PIK3CA Corresponding Authors: Jeeyun Lee, Samsung Medical Center, Sungky- unkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul mutation/amplification, MET amplification, MET protein 06351, Korea. Phone: 822-3410-1779; Fax: 822-3410-1754; E-mail: overexpression, all negative, TSC2 deficient, orRICTOR [email protected]; Kyoung-Mee Kim, [email protected]; and Won Ki amplification) to assign patients to one of the 10 associ- Kang, [email protected] ated phase II clinical trials in 2L treatment. The study drugs Cancer Discov 2019;9:1–18 used were capivasertib (AKT inhibitor), savolitinib (MET doi: 10.1158/2159-8290.CD-19-0442 inhibitor), selumetinib (MEK inhibitor), adavosertib (WEE1 ©2019 American Association for Cancer Research. inhibitor), and vistusertib (TORC inhibitor). The umbrella OCTOBER 2019 CANCER DISCOVERY | OF2 Downloaded from cancerdiscovery.aacrjournals.org on October 2, 2021. © 2019 American Association for Cancer Research. Published OnlineFirst July 17, 2019; DOI: 10.1158/2159-8290.CD-19-0442 RESEARCH ARTICLE Lee et al. design was based on the preclinical evidence of known The primary tumor was located in the body (53.2%) or molecular alterations, the prevalence of molecular altera- antrum (37.7%) of the stomach in the majority of patients. tions, and the availability of the targeted agents for clinical All patients underwent 1L cytotoxic chemotherapy (>85% trials from AstraZeneca at the time of the study design. The with fluoropyrimidine/platinum regimen). In all, 460 of candidate molecular alterations for the umbrella trial at 715 patients (64.3%) were eligible for 2L therapies: 143 of the time of clinical trial design were molecular alterations 715 (20.6%) were assigned to one of the umbrella-associated in the p53, PIK3CA, MET, EGFR, FGFR2, RAS, and DDR parallel clinical trials in 2L (105 with Biomarker A–E or G; 38 pathways (3). Adavosertib is one of the most potent inhibi- with Biomarker F, unselected), whereas 317 patients received tors targeting WEE1 (13), which is a tyrosine kinase that conventional treatment or treatment via other clinical trials phosphorylates cyclin-dependent kinase 1 (CDK1, CDC2) (Figs. 1B and 2A). to inactivate the CDC2/cyclin B complex (14). Inhibition of WEE1 activity prevents the phosphorylation of CDC2 Tumor Genome Profiling and impairs the G2 DNA-damage checkpoint, leading to The tumor profiles of the 715 patients are shown in Sup- cancer-cell death. Preclinical studies have demonstrated plementary Fig. S1, and the detailed sequencing method is a very promising antitumor efficacyin vivo, especially in provided in the Supplementary Material. The prevalence combination with other cytotoxic chemotherapeutic agents of the predefined biomarkers was as follows (Fig. 2B): Bio- (15) including paclitaxel (16). Capivasertib is a selective marker A1: RAS mutation/amplification (81/715, 12.2%; pan-AKT inhibitor that inhibits the kinase activity of all KRAS 62/715, 8.7%; HRAS 6/715, 0.8%; NRAS 19/715, 2.7%); three AKT isoforms (AKT1–3; ref. 17). Preclinically, sensi- Biomarker A2: high or low MEK signature (49/107, 45.8%); tivity to capivasertib has been strongly correlated with the Biomarker B: TP53 mutation (321/715, 44.9%); Biomarker presence of PIK3CA mutations in gastric cancer models (18, C: PIK3CA mutation/amplification (54/715, 7.6%); Bio- 19). Savolitinib is a potent small-molecule reversible MET marker D: MET amplification (25/715, 3.5%); Biomarker E: kinase inhibitor that inhibits MET kinase at an IC50 of 4 MET overexpression by IHC 3+ (42/479, 8.8%); Biomarker