Phase II feasibility and biomarker study of neoadjuvant trastuzumab and pertuzumab with chemoradiotherapy for resectable human epidermal growth factor receptor 2-positive esophageal adenocarcinoma: Trap study

Charlotte I. Stroes, Sandor Schokker, Aafke Creemers, Remco J. Molenaar, Maarten C.C.M. Hulshof, Stephanie O. van der Woude, Roel J. Bennink, Ron A.A. Mathôt, Kausilia K. Krishnadath, Cornelis J.A. Punt, Rob H.A. Verhoeven, Martijn G.H. van Oijen, Geert Jan Creemers, Grard A.P. Nieuwenhuijzen, Maurice J.C. van der Sangen, Laurens V. Beerepoot, Joos Heisterkamp, Maartje Los, Marije Slingerland, Annemieke CatsGeke A.P. Hospers, Maarten F. Bijlsma, Mark I. van Berge Henegouwen, Sybren L. Meijer, Hanneke W.M. van Laarhoven*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

PURPOSE Approximately 15% to 43% of esophageal adenocarcinomas (EACs) are human epidermal growth factor receptor 2 (HER2) positive. Because dual-agent HER2 blockade demonstrated a survival benefit in breast cancer, we conducted a phase II feasibility study of trastuzumab and pertuzumab added to neoadjuvant chemoradiotherapy (nCRT) in patients with EAC. PATIENTS AND METHODS Patients with resectable HER2-positive EAC received standard nCRT with carboplatin and paclitaxel and 41.4 Gy of radiotherapy, with 4 mg/kg of trastuzumab on day 1, 2 mg/kg per week during weeks 2 to 6, and 6 mg/kg per week during weeks 7, 10, and 13 and 840 mg of pertuzumab every 3 weeks. The primary end point was feasibility, defined as $ 80% completion of treatment with both trastuzumab and pertuzumab. An exploratory comparison of survival with a propensity score-matched cohort receiving standard nCRT was performed, as were exploratory pharmacokinetic and biomarker analyses. RESULTS Of the 40 enrolled patients (78% men; median age, 63 years), 33 (83%) completed treatment with trastuzumab and pertuzumab. No unexpected safety events were observed. R0 resection was achieved in all patients undergoing surgery, with pathologic complete response in 13 patients (34%). Three-year progression-free and overall survival (OS) were 57% and 71%, respectively (median follow-up, 32.1 months). Compared with the propensity score-matched cohort, a significantly longer OS was observed with HER2 blockade (hazard ratio, 0.58; 95% CI, 0.34 to 0.97). Results of pharmacokinetic analysis and activity on [18F]fluorodeoxyglucose positron emission tomography scans did not correlate with survival or pathologic response. Patients with HER2 3+ overexpression or growth factor receptor-bound protein 7 (Grb7) -positive tumors at baseline demonstrated significantly better survival (P = .007) or treatment response (P = .016), respectively. CONCLUSION Addition of trastuzumab and pertuzumab to nCRT in patients with HER2-positive EAC is feasible and demonstrates potentially promising activity compared with historical controls. HER2 3+ overexpression and Grb7 positivity are potentially predictive for survival and treatment response, respectively.

Original languageEnglish
Pages (from-to)462-471
Number of pages10
JournalJournal of Clinical Oncology
Volume38
Issue number5
DOIs
Publication statusPublished - 10 Feb 2020

Cite this