Trastuzumab Plus Pertuzumab Added to Standard Therapy Found to Be Feasible in Esophageal Cancer

A new phase II study of trastuzumab (Herceptin) and pertuzumab (Perjeta) added to neoadjuvant chemoradiotherapy (nCRT) followed by surgery in patients with esophageal adenocarcinoma (EAC) has found the combined regimen to be feasible and worthy of further study.

The study, which was published in theJournal of ClinicalOncology, was powered so that the dual-agent HER2 blockade regimen would be regarded as feasible if at least 80% of patients completed treatment.

With a completion rate of 83%, 33 patients completed treatment with trastuzumab and pertuzumab without any dose modifications. Seven patients omitted at least one dose due to a decrease in their left ventricular ejection fraction (LVEF, n = 3), trial discontinuation (n = 3), or death (n = 1). Three patients (8%) of missed one dose of chemotherapy because of LVEF decrease (n = 2) or hospitalization (n = 1).

As expected, the most common AEs of any grade were fatigue (76%), diarrhea (73%), and nausea (70%). About half the patients (n = 19; 48%) had a grade 3+ AE, with diarrhea (20%) and dysphagia (18%) being the most frequent. Nearly one third of patients (n = 11, 28%) had at least one serious AE that required hospitalization, including vomiting (n = 4), nausea (n = 3), and GI hemorrhage (n = 2).

Three patients left the trial early and were excluded from the cardiac safety analysis. Among the remaining 37 patients, the mean LVEF prior to treatment was 64%; that declined to 59% following treatment. Five patients (14%) developed left ventricular systolic dysfunction (LVSD); however, none of these cardiotoxicities were severe enough to delay surgery.

All 38 patients who underwent surgery achieved R0 resection. One third of these patients (n = 13, 34%) went on to experience a pathologic complete response (pCR).

Follow-up was a median of 32.1 months (interquartile range, 28.3-39.4 months). Median progression-free survival (PFS) and overall survival (OS) were not reached during follow-up. The 1-year PFS rate was 82.5%, while the 3-year PFS rate was 72.3%. The 1-year OS rate was 90.0% and the 3-year OS was 71.3%.

Stroes et al found that patients receiving the full regimen of nCRT, trastuzumab, and pertuzumab had significantly lower hazards of death compared with patients receiving nCRT only (hazard ratio [HR], 0.58; 95% Confidence Interval [CI], 0.34-0.97).

“This is the first study to our knowledge demonstrating the feasibility of the addition of both trastuzumab and pertuzumab to standard nCRT with carboplatin and paclitaxel in patients with resectable HER2-positive EAC, with 83% of patients receiving the complete treatment schedule,” wrote the authors, led by Charlotte I. Stroes, MD, of the University of Amsterdam.

They concluded that the addition of trastuzumab and pertuzumab to nCRT is “safe and tolerable for patients with HER2-positive EAC, and preliminary efficacy results seem promising. Because data on an HER2-positive control group are lacking, a randomized phase III study is warranted to demonstrate the superiority of the addition of trastuzumab and pertuzumab.”

In addition to carboplatin, patients in the study received paclitaxel (50 mg/m²), and radiotherapy (23 x 1.8 Gy over 5 weeks). Patients received a 4 mg/kg loading dose of trastuzumab on day 1 followed by 2 mg/kg once per week during weeks 2 to 6, and 6 mg/kg once every 3 weeks during weeks 7 to 13. Pertuzumab was given at a dose of 840 mg once every 3 weeks. Surgery was performed in week 14 following treatment completion.

The investigators did not permit trastuzumab dose reductions, but pertuzumab could be reduced if grade 3 to 4 diarrhea or rash occurred. However, dose re-escalation was not allowed. Dose delays for both trastuzumab and pertuzumab were acceptable following treatment-related adverse events (AEs).

Of 40 enrolled patients, 33 were men (83%). The same number of patients had an ECOG performance score of 0. The median patient age was 63 and most tumors were cT3 (65%) and cN1 (58%).

Eligibility criteria included surgically resectable, histologically proven HER2-positive adenocarcinoma of the esophagus or gastroesophageal junction, ECOG performance status of 0 or 1, and adequate hematologic, renal, and hepatic function. Patients were excluded if they had metastatic disease, mediastinal nodes and nodes distal from the celiac trunk, or prior treatment for EAC.

The authors also performed an exploratory biomarker analysis to identify subgroups that benefited most from HER2 targeting. They found that the 29 patients with HER2 IHC3+ tumors at baseline had significantly better OS compared with HER2 IHC2+ patients with gene amplification (n = 11;P=0.016). “[I]t is still an open question whether high HER2 expression is a true predictive, and potentially prognostic, biomarker in this population,” they wrote.

Stroes et al also found that HER3 expression was positive in 23 patients (58%), while a similar number positively expressed Grb7 (n = 22, 55%). Treatment response was significantly better for patients with Grb7-positive tumors at baseline (P=0.001), leading them to identify Grb7 as a potential treatment response biomarker.

“This is in line with previous observations of Grb7 as a therapeutic target in esophageal and breast cancers, because it strongly binds HER2 and could play an essential role in HER2 signaling,” they wrote. “Therefore, patients with Grb7-overexpressing tumors may be more sensitive to HER2-targeting treatment.”

Reference:

Stroes CI, Schokker S, Creemers A, et al. 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.J Clin Oncol. Published online December 6, 2019. DOI https://doi.org/10.1200/JCO.19.01814.