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Failed study shows need for esophageal cancer biomarkers
The addition of cetuximab to concurrent chemoradiation failed to improve survival in patients with esophageal cancer, according to results from the randomized, multicenter NRG-RTOG 0436 phase 3 trial.
These results highlight the need for predictive biomarkers in this setting, according to the researchers.
“Carcinoma of the esophagus causes over 400,000 fatalities worldwide each year, and most patients are at an advanced stage of the disease at presentation,” Walter J. Curran, Jr., MD, NRG Oncology Group chair, executive director of Winship Cancer Institute of Emory University, and a HemOnc Today Editorial Board Member, said in a press release. “The knowledge acquired from this study will ultimately impact how researchers approach treatment methods for this patient population in the future.”
Epidermal growth factor receptor overexpression occurs in more than 50% of esophageal cancers.
Pilot data showed the addition of cetuximab (Erbitux, Eli Lilly) — an EGFR inhibitor — to chemoradiation for the treatment of locally advanced esophagogastric cancer yielded a 76% complete response rate, a 70% 1-year OS rate and a favorable safety profile.
Additional phase 2 trials in locally advanced esophageal cancer also demonstrated activity with this combination regimen.
Based on these data, Mohan Suntharalingam, MD, MBA, president and CEO of University of Maryland Medical Center, and colleagues evaluated the addition of cetuximab to paclitaxel, cisplatin and radiation therapy for patients with esophageal cancer treated without surgery.
The researchers enrolled 344 patients between June 30, 2008, and Feb. 8, 2013. However, a data monitoring committee recommended to stop further accrual. As a result, the study permanently closed and follow-up continued through April 12, 2015.
The researchers stratified and randomly assigned patients 1:1 to standard chemoradiation alone (25 mg/m² cisplatin, 50 mg/m² paclitaxel, 50.4 Gy/1.8 Gy fractions daily radiation; n = 169) or with cetuximab (400 mg/m² the first week, followed by 250 mg/m² weekly; n = 159).
The arms had similar patient demographics and tumor characteristics. Eighty percent of patients had T3 or T4 disease, 66% had N1 disease and 19% had celiac nodal involvement.
OS served as the primary endpoint. Secondary endpoints included local failure, toxic effects, clinical complete response, quality of life and quality-adjusted survival.
Median follow-up was 18.6 months for all patients and 42.7 months for surviving patients.
Researchers observed no statistical difference in OS between the treatment groups (HR = 0.9; 95% CI, 0.7-1.16).
A similar proportion of patients in the treatment and control arms achieved 24-month OS (44.9% vs. 44%) and 36-month OS (33.8% vs. 27.9%).
“The addition of cetuximab to chemoradiation yielded no significant benefit for the patients on the experimental treatment arm when compared to the standard treatment,” Suntharalingam said in a press release. “These results highlight the need for predictive biomarkers in order to improve and refine the treatment of esophageal cancer.”
Clinical complete response occurred in 56.3% of the treatment arm and 57.9% of the control arm. This finding did not differ when researchers evaluated patients with adenocarcinoma (52.7% vs. 53.9%) or squamous cell carcinoma (59.3% vs. 64.4%).
Researchers reported comparable rates of local failure in the treatment and control arms at 24 months (47% vs. 48.8%) and 36 months (49.1% vs. 48.8%; HR = 0.92; 95% CI, 0.66-1.28).
Grade 3 or higher hematologic toxic effects (45% vs. 44%) and gastrointestinal toxic effects (44% vs. 35%) occurred more frequently in the treatment arm.
The researchers acknowledged the study was limited by patient inclusion regardless of EGFR expression.
“Further research may be warranted to identify prognostic variables that may provide insight into potential populations with esophageal disease that could benefit from an EGFR inhibitor,” Suntharalingam and colleagues wrote.
In addition, the study’s statistical power for hypothesized improvement in OS was reduced from 80% to 74%.
“The continued effort to identify populations of patients with molecular overexpression of potential targets will ultimately improve the ability to refine the treatment approach in this challenging disease,” the researchers wrote. – by Kristie L. Kahl
Disclosures: Eli Lilly and NCI provided grants that funded the study. Suntharalingam reports no relevant financial disclosures. Please see the full study for a list of all other researchers’ relevant financial disclosures.