Biomarker analysis of the GATSBY study of trastuzumab emtansine versus a taxane in previously treated HER2-positive advanced gastric/gastroesophageal junction cancer
- 124 Downloads
Prespecified exploratory biomarker analyses of the phase II/III GATSBY study (NCT01641939) assessed whether patient subgroups experienced a survival benefit from trastuzumab emtansine (T-DM1) versus taxane therapy, and to advance understanding of HER2-positive advanced gastric/gastroesophageal junction cancer (AGC) disease biology.
Adults with HER2-positive AGC whose disease progressed during/after first-line therapy were enrolled and randomized to receive T-DM1 [Stage 1: 3.6 mg/kg q3w, 2.4 mg/kg qw, or taxane (docetaxel/paclitaxel); Stage 2: 2.4 mg/kg qw or taxane]. Primary efficacy endpoint was overall survival (OS). Prespecified exploratory biomarkers included HER2, HER3, PTEN, PIK3CA mutation status, FcγR, and cMET. Tumor samples from patients who received 2.4 mg/kg T-DM1 (n = 228) or taxane (n = 117) were included.
Median OS was longer in subgroups with HER2 immunohistochemistry (IHC) 3+ [9.5 versus 8.3 months for T-DM1 versus taxane; hazard ratio (HR) 0.99 (95% CI 0.68–1.43)] versus HER2 IHC 2+/in situ hybridization-positive [5.2 versus 9.2 months for T-DM1 versus taxane; HR 1.53 (95% CI 0.94–2.50)] tumors. Trends towards increased median OS were also observed in subgroups with > versus ≤ median HER2 mRNA expression, higher versus lower HER2 gene copy number, HER2 gene ratio and H score, and homogenous or nonfocal HER2 IHC staining. T-DM1 was not associated with superior OS versus taxane in any subgroup.
Patients with previously treated HER2-positive AGC with higher HER2 expression experienced a better treatment effect from T-DM1 than those with lower HER2 expression and may derive comparable survival benefits from T-DM1 and taxane therapy.
Clinical trials registration
KeywordsTrastuzumab emtansine Gastric cancer Gastroesophageal junction Biomarkers
We would like to acknowledge all patients and investigators participating in this trial and the central testing and biomarker laboratories (Targos Molecular Pathology GmbH, Kassel, Germany; Aros Applied Biotechnology A/S, Aarhus, Denmark; Genentech, Inc., BRM Operations Handling, South San Francisco, CA). We also gratefully acknowledge the contributions of Tina van Der Horst to all data analyses, and of Dr. Marjorie Green to the design and conduct of the study. Support for third-party writing assistance for this manuscript, furnished by Debbie Briggs, Ph.D., and Rachel Johnson, Ph.D., of Health Interactions, was provided by F. Hoffmann-La Roche Ltd, Basel, Switzerland.
Conception and design: MAS, PCT-P, SLH, JAA, M-LH-Y. Acquisition of data: MAS, Y-KK, PCT-P, EC, SLH, M-LH-Y. Analysis and interpretation of data: MAS, Y-KK, PCT-P, AO, EC, SLH, SH, M-LH-Y. Writing, review, and/or revision of the manuscript: MAS, Y-KK, PCT-P, AO, JAA, EC, M-LH-Y, SLH, SH. Administrative, technical, or material support (i.e., reporting or organizing data, constructing databases): Study supervision: MAS.
The sponsor of the GATSBY study was F. Hoffmann-La Roche Ltd, Basel, Switzerland. F. Hoffmann-La Roche Ltd was involved in the study design, the data interpretation, and the decision to submit for publication in conjunction with the authors.
Compliance with ethical standards
Disclosure of prior publication/presentation
This exploratory biomarker analysis has not been presented previously. Selected baseline data and univariate analyses have been published in the primary analysis: Thuss-Patience et al. .
Conflict of interest
Manish A. Shah has received research funding from Roche, Boston Biomedical, and Merck. Yoon-Koo Kang has acted in a consulting or advisory role for Novartis, Roche, BMS, Ono, Daehwa, and Blueprint and has received research funding from Daehwa. Peter C. Thuss-Patience has acted in a consulting or advisory role for Roche, Lilly, Pfizer, MSD, BMS, and Nordic and has received research funding (institutional support) from GSK and Novartis, and travel, accommodation, and expenses from Roche, Merck-KGaA, and TEVA. Atsushi Ohtsu has received research funding from BMS and a family member is employed by Celgene. Jaffer A. Ajani has received honoraria from BMS, Merck, Lilly, Taiho, and Astellas, has acted in a consulting or advisory role for Lilly, BMS, Insys, and AstraZeneca Medpace, and has received research funding from Merck, Delta-Fly, Gilead, Roche, and BMS. Eric Van Cutsem has acted in a consulting or advisory role for Bayer, Lilly, Roche, and Servier, and has received research funding (institutional support) from Amgen, Bayer, Boehringer, Lilly, Novartis, Roche, Sanofi, Celgene, Servier, Merck-KGaA, Merck, and Ipsen. Silke Hoersch is employed by KOEHLER eClinical and F. Hoffmann-La Roche. Marie-Laurence Harle-Yge is employed by F. Hoffmann-La Roche. Sanne Lysbet de Haas is employed by F. Hoffmann-La Roche.
Human rights statement
GATSBY was conducted in accordance with Good Clinical Practice and the Declaration of Helsinki. The protocol was approved at each site by the local ethics committee/institutional review board. All patients provided written informed consent.
- 1.Roche Registration Ltd. Herceptin® (trastuzumab). Summary of product characteristics. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000278/WC500074922.pdf. Accessed Sept 2018.
- 2.Waddell T, Verheij M, Allum W, Cunningham D, Cervantes A, Arnold D, et al. Gastric cancer: ESMO-ESSO-ESTRO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2013;24(Suppl. 6):vi57–63.Google Scholar
- 3.National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®): Gastric Cancer. Version 3. 2016. http://www.nccn.org/professionals/physician_gls/pdf/gastric.pdf. Accessed Aug 2016.
- 4.Bang YJ, Van Cutsem E, Feyereislova A, Chung HC, Shen L, Sawaki A, et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet. 2010;376:687–97.CrossRefGoogle Scholar
- 5.Yang Z, Guo L, Liu D, Sun L, Chen H, Deng Q, et al. Acquisition of resistance to trastuzumab in gastric cancer cells is associated with activation of IL-6/STAT3/Jagged-1/Notch positive feedback loop. Oncotarget. 2015;6:5072–87.Google Scholar
- 9.Wildiers H, Kim S, Gonzalez-Martin A, LoRusso PM, Ferrero J, Yu R, et al. Trastuzumab emtansine improves overall survival versus treatment of physician’s choice in patients with previously treated HER2-positive metastatic breast cancer: final overall survival results from the phase 3 TH3RESA study. Cancer Res. 2016;76:Abstract S5-05 (and associated oral presentation).CrossRefGoogle Scholar
- 12.Kim S, Wildiers H, Krop IE, Leung ACF, Trudeau C, Yu R, et al. Relationship between tumor biomarkers (BM) and efficacy in TH3RESA, a phase 3 study of trastuzumab emtansine (T-DM1) versus treatment of physician’s choice (TPC) in HER2-positive advanced breast cancer (BC) previously treated with trastuzumab and lapatinib. J Clin Oncol. 2014;32(20 May suppl.):Abstract 605.CrossRefGoogle Scholar
- 13.Thuss-Patience PC, Shah MA, Ohtsu A, Van Cutsem E, Ajani JA, Castro H, et al. Trastuzumab emtansine versus taxane use for previously treated HER2-positive locally advanced or metastatic gastric or gastro-oesophageal junction adenocarcinoma (GATSBY): an international randomised, open-label, adaptive, phase 2/3 study. Lancet Oncol. 2017;18:640–53.CrossRefGoogle Scholar
- 24.Loibl S, von Minckwitz G, Schneeweiss A, Paepke S, Lehmann A, Rezai M, et al. PIK3CA mutations are associated with lower rates of pathologic complete response to anti-human epidermal growth factor receptor 2 (her2) therapy in primary HER2-overexpressing breast cancer. J Clin Oncol. 2014;32:3212–20.CrossRefGoogle Scholar
- 26.McCarty KS Jr, Szabo E, Flowers JL, Cox EB, Leight GS, Miller L, et al. Use of a monoclonal anti-estrogen receptor antibody in the immunohistochemical evaluation of human tumors. Cancer Res. 1986;46:4244s-8s.Google Scholar
- 36.Peng Z, Zou J, Zhang X, Yang Y, Gao J, Li Y, et al. HER2 discordance between paired primary gastric cancer and metastasis: a meta-analysis. Chin J Cancer Res. 2015;27:163–71.Google Scholar
- 38.Esaki T, Makiyama A, Kashiwada T, Hosokawa A, Kawada J, Moriwaki T, et al. T-ACT (WJOG7112G): a randomized phase II study of weekly paclitaxel ± trastuzumab in patients with HER2-positive advanced gastric or gastro-esophageal junction cancer refractory to trastuzumab combined with fluoropyrimidine and platinum. J Clin Oncol. 2017;35(4 Suppl):TPS218.CrossRefGoogle Scholar