The addition of nivolumab (Opdivo) to neoadjuvant chemoradiation did not improve pathologic complete response (pCR) rates in patients with locoregional esophageal and gastroesophageal junction (GEJ) adenocarcinoma, according to results from the phase 2/3 ECOG-ACRIN EA2174 trial (NCT03604991). The study, presented at the 2024 ASCO Annual Meeting, found that the addition of nivolumab to standard chemotherapy and radiation did not yield a statistically significant increase in pCR rates compared to chemoradiation alone.
Trial Details and Results
The ECOG-ACRIN EA2174 trial randomized patients with localized esophageal or GEJ adenocarcinoma to either standard of care (SOC) carboplatin, paclitaxel, and radiation therapy or the same regimen with the addition of two doses of nivolumab during chemoradiation. The primary endpoint was the pCR rate. The results showed a pCR rate of 24.8% (95% CI, 17.8%-32.9%) in the nivolumab arm (n = 137) compared to 21.0% (95% CI, 14.5%-28.8%) in the chemoradiation alone arm (n = 138). This difference was not statistically significant (P = .27).
Notably, residual disease was present in 55.5% and 55.1% of patients in the nivolumab and chemoradiation arms, respectively, and a significant proportion of patients did not undergo surgery (19.7% vs 23.9%). Importantly, the addition of nivolumab did not introduce any unexpected toxicities or surgical complications.
Expert Commentary
According to Jennifer R. Eads, MD, physician lead of GI Cancer Research and director of the National Clinical Trials Network for Abramson Cancer Center at the University of Pennsylvania, this study answers a crucial question in the field. "Unfortunately, this part of the study was negative. However, what it does tell us is that the inclusion of immune checkpoint inhibitor therapy to chemotherapy and radiation in the neoadjuvant setting is not additionally efficacious and should not be included in further trial designs," Eads stated.
Implications for Future Research
Despite the negative findings, the ECOG-ACRIN EA2174 trial provides valuable insights into the treatment of esophageal adenocarcinoma. Eads highlighted that high dropout rates after surgery (42.5% in the nivolumab arm and 50.7% in the control arm) should be considered in future trial designs. Furthermore, the adjuvant element of the study, evaluating adjuvant nivolumab versus adjuvant nivolumab and ipilimumab, is still ongoing and may provide further insights.
Researchers collected tissue and blood samples from participants at baseline, after chemoradiation, at the time of surgery, and during adjuvant treatment. These samples will be used for next-generation sequencing (NGS) and circulating tumor DNA (ctDNA) analyses to identify potential biomarkers that may predict response to immune checkpoint inhibitor therapy and to determine if ctDNA is a reliable biomarker for assessing disease status at the molecular level.
Background and Rationale
Esophageal adenocarcinoma carries a poor prognosis, with many patients succumbing to the disease even when diagnosed at a localized stage. The current standard of care involves chemotherapy (carboplatin and paclitaxel) with radiation therapy followed by surgery. Adjuvant nivolumab is administered to patients with residual disease post-resection, a recent advancement that has improved outcomes. However, the pCR rate in the neoadjuvant setting has remained stagnant at approximately 25% to 30% despite numerous attempts to improve it with novel agents and chemotherapy combinations.
Immune checkpoint inhibitors have demonstrated benefit in the metastatic setting for esophageal and GEJ adenocarcinoma, prompting investigation into their role in the neoadjuvant setting. The hypothesis was that radiation, as part of the treatment strategy, could enhance tumor immunogenicity, potentially leading to improved outcomes with the addition of immunotherapy.
