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.

• 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
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 29 Issue 18 Pg. 3633-3640 (09 15 2023) ISSN: 1557-3265 [Electronic] United States
• PMID: 37406106 (Publication Type: Clinical Trial, Phase II, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2023 The Authors; Published by the American Association for Cancer Research.

Chemical References

• Receptor, ErbB-2
• Zirconium-89
• Programmed Cell Death 1 Receptor
• Radioisotopes
• Zirconium
• Biomarkers, Tumor
• Trastuzumab

Topics

• Humans
• Female
• Receptor, ErbB-2 (metabolism)
• Programmed Cell Death 1 Receptor (therapeutic use)
• Radioisotopes (therapeutic use)
• Zirconium
• Biomarkers, Tumor (metabolism)
• Esophageal Neoplasms (drug therapy, genetics, chemically induced)
• Stomach Neoplasms (drug therapy, genetics, pathology)
• Trastuzumab (adverse effects)
• Breast Neoplasms (drug therapy)
• Antineoplastic Combined Chemotherapy Protocols (adverse effects)