Synapse - Determinants of survival with combined HER2 and PD-1 blockade in metastatic esophagogastric cancer

Determinants of survival with combined HER2 and PD-1 blockade in metastatic esophagogastric cancer Journal Article

Authors:	Maron, S. B.; Chatila, W.; Walch, H.; Chou, J. F.; Ceglia, N.; Ptashkin, R.; Do, R. K. G.; Paroder, V.; Pandit-Taskar, N.; Lewis, J. S.; Biachi De Castria, T.; Sabwa, S.; Socolow, F.; Feder, L.; Thomas, J.; Schulze, I.; Kim, K.; Elzein, A.; Bojilova, V.; Zatzman, M.; Bhanot, U.; Nagy, R. J.; Lee, J.; Simmons, M.; Segal, M.; Ku, G. Y.; Ilson, D. H.; Capanu, M.; Hechtman, J. F.; Merghoub, T.; Shah, S.; Schultz, N.; Solit, D. B.; Janjigian, Y. Y.
Article Title:	Determinants of survival with combined HER2 and PD-1 blockade in metastatic esophagogastric cancer
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. ©2023 The Authors; Published by the American Association for Cancer Research.
Keywords:	genetics; clinical trial; antineoplastic agent; metabolism; phase 2 clinical trial; antineoplastic combined chemotherapy protocols; epidermal growth factor receptor 2; pathology; breast neoplasms; tumor marker; breast tumor; receptor, erbb-2; radioisotope; trastuzumab; radioisotopes; stomach neoplasms; zirconium; zirconium-89; esophagus tumor; esophageal neoplasms; stomach tumor; programmed death 1 receptor; humans; human; female; programmed cell death 1 receptor; biomarkers, tumor
Journal Title:	Clinical Cancer Research
Volume:	29
Issue:	18
ISSN:	1078-0432
Publisher:	American Association for Cancer Research
Date Published:	2023-09-15
Start Page:	3633
End Page:	3640
Language:	English
DOI:	10.1158/1078-0432.Ccr-22-3769
PUBMED:	37406106
PROVIDER:	scopus
PMCID:	PMC10502449
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85171392774&doi=10.1158%2f1078-0432.CCR-22-3769&partnerID=40&md5=ab4d02a10cc70f4a7d6b6933879fa389
Notes:	The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PubMed record and PDF. Corresponding MSK author is Steven B. Maron -- Source: Scopus