Data from Determinants of Survival with Combined HER2 and PD-1 Blockade in Metastatic Esophagogastric Cancer
Year: 2023
Type: other
Abstract: Purpose: We report updated clinical outcomes from a phase II study of pembrolizumab, trastuzumab, and chemotherapy (PTC) in metastatic esophagogastric cancer in conjunction with outcomes from an independent Memorial Sloan Kettering (MSK) cohort. Patients and Methods: The significance of pretreatment 89Zr-trastuzumab PET, plasma circulating tumor DNA (ctDNA) dynamics, and tumor HER2 expression and whole exome sequencing was evaluated to identify prognostic biomarkers and mechanisms of resistance in patients treated on-protocol with PTC. Additional prognostic features were evaluated using a multivariable Cox regression model of trastuzumab-treated MSK patients (n = 226). Single-cell RNA sequencing (scRNA-seq) data from MSK and Samsung were evaluated for mechanisms of therapy resistance. Results: 89Zr-trastuzumab PET, scRNA-seq, and serial ctDNA with CT imaging identified how pre-treatment intrapatient genomic heterogeneity contributes to inferior progression-free survival (PFS). We demonstrated that the presence of intensely avid lesions by 89Zr-trastuzumab PET declines in tumor-matched ctDNA by 3 weeks, and clearance of tumor-matched ctDNA by 9 weeks were minimally invasive biomarkers of durable PFS. Paired pre- and on-treatment scRNA-seq identified rapid clearance of HER2-expressing tumor clones with expansion of clones expressing a transcriptional resistance program, which was associated with MT1H, MT1E, MT2A, and MSMB expression. Among trastuzumab-treated patients at MSK, ERBB2 amplification was associated with improved PFS, while alterations in MYC and CDKN2A/B were associated with inferior PFS. Conclusions: These findings highlight the clinical relevance of identifying baseline intrapatient heterogeneity and serial ctDNA monitoring of HER2-positive esophagogastric cancer patients to identify early evidence of treatment resistance, which could guide proactive therapy escalation or deescalation.
Authors: Steven B. Maron, Walid Chatila, Henry Walch, Joanne F. Chou, Nicholas Ceglia, Ryan Ptashkin, Richard Kinh Gian Do, Viktoriya Paroder, Neeta Pandit-Taskar, Jason S. Lewis, Tiago Biachi De Castria, Shalom Sabwa, Fiona Socolow, Lara Feder, Jasmine Thomas, Isabell Schulze, Kwanghee Kim, Arijh Elzein, Viktoria Bojilova, Matthew Zatzman, Umesh Bhanot, Rebecca J. Nagy, Jeeyun Lee, Marc Simmons, Michal Segal, Geoffrey Yuyat Ku, David H. Ilson, Marinela Capanu, Jaclyn F. Hechtman, Taha Merghoub, Sohrab Shah, Nikolaus Schultz, David B. Solit, Yelena Y. Janjigian
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Funders: U.S. Department of Defense, Amgen, Bristol-Myers Squibb, Eli Lilly and Company, Pfizer, AstraZeneca, Memorial Sloan-Kettering Cancer Center, Society of Memorial Sloan Kettering, Robertson Foundation, Adaptive Biotechnologies, Cycle for Survival, Seagen, Natera, Daiichi-Sankyo, Basilea Pharmaceutica, Genentech, EMD Serono, Marie-Josée and Henry R. Kravis Center for Molecular Oncology, National Cancer Institute, Daiichi Sankyo Europe
OpenAlex ID: W4385456022