As reported in The Lancet Oncology by Howard P. Safran, MD, and colleagues, the phase III NRG Oncology/RTOG-101 trial has shown no significant disease-free survival benefit with the addition of perioperative trastuzumab to neoadjuvant chemoradiation in previously untreated patients with HER2-overexpressing esophageal adenocarcinoma.

Howard P. Safran, MD

Study Details

The open-label U.S. multicenter trial included 203 patients with T1N1-2 or T2-3N0-2 disease enrolled between December 2010 and November 2015. Patients were randomly assigned to receive trastuzumab plus chemoradiation (n = 102) or chemoradiation alone (n = 101). Treatment consisted of weekly paclitaxel at 50 mg/m² and carboplatin at area under the curve = 2 for 6 weeks, with radiotherapy at 50.4 Gy in 28 fractions followed by surgery with or without trastuzumab given at 4 mg/kg in week 1 and at 2 mg/kg per week for 5 weeks during chemoradiotherapy, 6 mg/kg once at presurgery, and 6 mg/kg every 3 weeks for 13 treatments starting 21 to 56 days after surgery. The primary endpoint was disease-free survival.

Disease-Free Survival

Median follow-up was 2.8 years (interquartile range [IQR] = 1.4–5.7 years) among all patients and 6.0 years (IQR = 4.8–7.0 years) among surviving patients.

Median disease-free survival was 19.6 months (95% confidence interval [CI] = 13.5–26.2 months) in the trastuzumab group vs 14.2 months (95% CI = 10.5–23.0 months) in the control group (hazard ratio [HR] = 0.99, 95% CI = 0.71–1.39, P = .97). Rates at 2, 3, and 4 years were 41.8% vs 40.0%, 34.3% vs 33.4%, and 33.2% vs 30.1%.

Median overall survival was 38.5 months (95% CI = 26.2–70.4 months) in the trastuzumab group vs 38.9 months (95% CI = 29.0–64.5 months) in the control group (HR = 1.04, 95% CI = 0.71–1.50, P = .85). Rates at 2, 3, and 4 years were 60.8% vs 67.4%, 52.0% vs 51.8%, and 47.6% vs 46.2%.

Among 82 vs 78 patients who underwent surgical resection, pathologic complete response rates were 27% vs 29% (P = .71).

Adverse Events

Grade 3 treatment-related adverse events occurred in 43% of patients in the trastuzumab group vs 54% of the control group, and grade 4 events occurred in 21% vs 22%. The most common grade ≥ 3 treatment-related adverse events for both groups were hematologic (56% vs 57%) and gastrointestinal disorders (29% vs 21%). Treatment-related serious adverse events occurred in 36% vs 28% of patients, including gastrointestinal disorders in 14% of the trastuzumab group and sepsis in 5% of the control group. Grade 3 or 4 treatment-related cardiac disorders occurred in 5% vs 3% of patients. Treatment-related death occurred in five patients in the trastuzumab group (due to bronchopleural fistula, esophageal anastomotic leak, lung infection, sudden death, and death-not otherwise specified) and three patients in the control group (due to multiorgan failure in two and sepsis in one).

The investigators concluded, “The addition of trastuzumab to neoadjuvant chemoradiotherapy for HER2-overexpressing esophageal cancer was not effective. Trastuzumab did not lead to increased toxicities, suggesting that future studies combining it with or using other agents targeting HER2 in esophageal cancer are warranted.”

Dr. Safran, of the Department of Medical Oncology, Rhode Island Hospital, Providence, is the corresponding author for The Lancet Oncology article.

Disclosure: The study was funded by the National Cancer Institute and Genentech. For full disclosures of the study authors, visit thelancet.com.