A Phase II Study with Lead-In Safety Cohort of 5-Fluorouracil, Oxaliplatin, and Lapatinib in Combination with Radiation Therapy as Neoadjuvant Treatment for Patients with Localized HER2-Positive Esophagogastric Adenocarcinomas

Abstract

Lessons Learned.Neoadjuvant 5‐fluorouracil, oxaliplatin, and lapatinib in combination with radiation therapy is safe for neoadjuvant treatment for patients with localized human epidermal growth receptor 2‐positive esophagogastric adenocarcinoma.Evaluation of this drug combination in a larger patient pool would allow for more accurate analysis of its efficacy. Background.The optimal design of neoadjuvant chemoradiation for the treatment of localized esophagogastric cancers is the subject of much debate. In this nonrandomized trial, we evaluated neoadjuvant 5‐fluorouracil (5‐FU), oxaliplatin, and lapatinib in combination with radiation therapy as neoadjuvant treatment for patients with localized human epidermal growth receptor 2 (HER2)‐positive esophagogastric adenocarcinomas.Methods.Patients received neoadjuvant 5‐FU (225 mg/m2 continuous intravenous infusion, days 1–42), oxaliplatin (85 mg/m2 intravenously [IV], days 1, 15, and 29), and lapatinib (six patients, 1,000 mg p.o., days 1–42; six patients, 750 mg p.o., days 1–42) plus radiation (1.8 Gy/day Monday through Friday for 50.4 Gy total). Following restaging, eligible patients underwent definitive resection, and pathologic response to neoadjuvant therapy was assessed. Planned enrollment was 42 patients. The primary endpoint was the pathologic complete response (pCR) rate.Results.Twelve patients (median age 64 years; 67% male) received a median of 5.6 weeks of treatment (range: 1.1–8.4). The pCR rate was 8%; four of the 12 patients underwent tumor resection and one patient had a pCR, with pathologic partial response in the remaining three. The most common lapatinib‐related adverse events included (all grades) nausea (67%) and diarrhea (58%), although these were all grade 1 or 2. Enrollment was halted due to low accrual.Conclusion.The treatment regimen was determined to be safe. The study was terminated early due to low accrual.

Bioinformatics Analysis of Choriocarcinoma-Related MicroRNA-Transcription Factor-Target Gene Regulatory Networks and Validation of Key miRNAs

“… 42 Lapatinib is widely used in patients with non-small cell lung cancer, 43 breast cancer, 44 aggressive prolactinomas 45 and oesophageal cancers. 46 The nonconventional drugs predicted by the study may have a new use in choriocarcinoma.…”

A systematic review of HER2 blockade for the curative treatment of gastroesophageal adenocarcinoma: Successes achieved and opportunities ahead

“…[7,16] In a phase II study, the low accrual of eligible patients led to early discontinuation of the study, resulting in low-quality evidence. [19] Therefore, multinational and multicenter clinical trials are needed to achieve sufficiently powered studies. Furthermore, the included trials in this review were heterogeneous.…”

“…The feasibility and pathological response with lapatinib, a tyrosine kinase inhibitor of both HER2 and the epidermal growth factor receptor (EGFR), has been investigated in two phase II studies. [19,20] Overall, both studies showed safety of the addition of lapatinib to chemotherapy. Although Smyth et al demonstrated a significant increase in grade ≥3 diarrhea with the addition of lapatinib (24% vs 0%), postoperative complication rates were similar in both arms.…”

Selected updates in molecular and genomic pathology of esophageal cancer

“…36 In a phase II study of lapatinib monotherapy in HER2-positive EAC, 12 patients (median age 64 years; 67% male) received a median of 5.6 weeks of treatment (range: 1.1-8.4), and among 4 out of 12 patients with tumor resection, one showed pathologic complete response; the remaining three showed pathologic partial response, which indicated that the treatment regimen was safe. 39 ECs with overexpression and amplification of HER2 are considered good candidates for HER2-targeted therapy, and the combination of trastuzumab and lapatinib is a new promising strategy for HER2-positive EC patients. 40,41 Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate that combines the HER2-targeted properties of trastuzumab with the cytotoxic activity of emtansine, enabling selective delivery of chemotherapy to HER2-overexpressing cells.…”

“…Preplanned exploratory subgroup analyses showed that OS in the lapatinib arm was prolonged in Asian and younger patients 36 . In a phase II study of lapatinib monotherapy in HER2‐positive EAC, 12 patients (median age 64 years; 67% male) received a median of 5.6 weeks of treatment (range: 1.1–8.4), and among 4 out of 12 patients with tumor resection, one showed pathologic complete response; the remaining three showed pathologic partial response, which indicated that the treatment regimen was safe 39 . ECs with overexpression and amplification of HER2 are considered good candidates for HER2‐targeted therapy, and the combination of trastuzumab and lapatinib is a new promising strategy for HER2‐positive EC patients 40,41 …”