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No benefit to adding trastuzumab to neoadjuvant chemoradiation for HER2 esophageal cancer

The Lancet Oncology
Reuters Health - 27/01/2022 - In patients with HER2-overexpressing esophageal cancer, adding trastuzumab to neoadjuvant chemoradiation was not effective in a phase 3 trial. 

HER2-positive esophagogastric cancer "does not behave the same way as HER2-positive breast cancer, (and) agents active in breast cancer (don't have) the same activity in esophagogastric cancer," Dr. David Ilson of Memorial Sloan Kettering Cancer Center in New York City told Reuters Health by email. 

"Although disappointing, the negative results of this trial indicate two things," he said. "One, trastuzumab is insufficient by itself to improve outcome in locally advanced HER2-positive esophagogastric cancer, and two, the results emphasize the need to conduct carefully designed clinical trials in which standard of care is compared to the addition of a new therapy like trastuzumab." 

As reported in The Lancet Oncology, 203 patients (median age, about 64; about 85%, men; 96% white) were randomly assigned to receive chemoradiotherapy with or without trastuzumab, followed by surgery. 

Chemoradiotherapy consisted of weekly intravenous paclitaxel (50 mg/m² intravenously over 1 h) and carboplatin (area under the curve 2, intravenously over 30-60 min) for six weeks with radiotherapy of 50.4 Gy in 28 fractions. 

Intravenous trastuzumab was given as 4 mg/kg in week one, 2 mg/kg per week for 5 weeks during chemoradiotherapy, 6 mg/kg once presurgery, and 6 mg/kg every 3 weeks for 13 treatments starting 21-56 days after surgery. 

Median follow-up was 2.8 years. 

Median disease-free survival was 19.6 months with chemoradiotherapy plus trastuzumab compared with 14.2 months for chemoradiotherapy alone (hazard ratio, 0.99). 

Grade 3 treatment-related adverse events occurred in 43% of patients in the trastuzumab group versus 54% in the chemoradiotherapy group; grade 4 events occurred in 21% versus 22%, respectively. The most common grade 3 or worse treatment-related adverse events for both groups were hematological (56% vs. 57%) or gastrointestinal disorders (29% vs. 21 %). Serious adverse events occurred in 36% versus 28%. 

Treatment-related deaths occurred in 5% of the trastuzumab group (bronchopleural fistula, esophageal anastomotic leak, lung infection, sudden death, and death not otherwise specified), and 3% of the chemoradiotherapy group (two multiorgan failure and one sepsis). 

Despite lack of efficacy, the authors note, "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. Ilson added, "The pathway forward to continue to target HER2 is clearly in combination strategies. The addition of the drug pertuzumab to trastuzumab did not significantly improve outcome in advanced disease, and it is unclear if this agent should be studied in locally advanced disease." 

"Promising data for immune checkpoint inhibitors added to trastuzumab and chemotherapy in metastatic disease, including the recently improved agent pembrolizumab, indicate this combination should be studied in locally advanced disease, and such a trial is being designed in the U.S. through RTOG/NRG," he said. "Other promising new HER2-targeted agents, including trastuzumab deruxtecan, margetuximab, zanidatamab, and tucatinib may also merit future study." 

The study was funded by the US National Cancer Institute and Genentech. Dr. Ilson and two coauthors have received fees from Genentech. 

SOURCE: https://bit.ly/3KOaHkQ and https://bit.ly/3KQ3P6p The Lancet Oncology, online January 14, 2022. 

By Marilynn Larkin 

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