Nivolumab Plus Neoadjuvant Chemoradiation Fails to Enhance pCR Rate in Esophageal/GEJ Adenocarcinoma

Jennifer R. Eads, MD

Although the phase 2/3 ECOG-ACRIN EA2174 trial (NCT03604991) failed to show improved pathologic complete response (pCR) rates with the addition of nivolumab (Opdivo) to neoadjuvant chemoradiation over chemoradiation alone, these results have answered a key question in the field for patients with locoregional esophageal and gastroesophageal junction (GEJ) adenocarcinoma, and will better inform efforts to improve standard regimens going forward, according to Jennifer R. Eads, MD.¹

Results from the trial were presented at the 2024 ASCO Annual Meeting, and showed a 24.8% pCR rate (95% CI, 17.8%-32.9%) among patients treated with neoadjuvant nivolumab, carboplatin, paclitaxel, and radiation (n = 137) vs a 21.0% pCR rate (95% CI, 14.5%-28.8%) with chemoradiation alone (n = 138). This increase was not deemed statistically significant (P = .27). Moreover, 55.5% and 55.1% of patients in these respective arms had residual disease; 19.7% vs 23.9% did not undergo surgery, respectively. No additional toxicity or surgical concerns were observed with the nivolumab regimen. Investigators also noted that dropout rates after surgery for patients with localized esophageal adenocarcinoma were high in both the experimental and control arms (42.5% vs 50.7%) and should be accounted for in future trial designs.

“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 explained during an interview with OncLive®.

In the interview, Eads discussed the need to improve pCR rates in the neoadjuvant setting for patients with residual disease; detailed results from this phase 2/3 study of standard chemotherapy and radiation with or without the addition of nivolumab; and highlighted ongoing analyses, including next-generation sequencing and circulating tumor DNA (ctDNA) studies, based on this research.

Eads serves as the physician lead of GI Cancer Research and director of the National Clinical Trials Network for Abramson Cancer Center at the University of Pennsylvania; and a professor of clinical medicine (hematology-oncology) at Penn Medicine in the Perelman Center for Advanced Medicine, in Philadelphia.

OncLive: What was the rationale for adding an immune checkpoint inhibitor to standard neoadjuvant chemotherapy and radiation for patients with esophageal adenocarcinoma?

Eads: Esophageal adenocarcinoma has poor prognosis. Most patients die of their disease, even if they are diagnosed with localized disease at the time of their initial diagnosis. The current standard of care for patients with a localized cancer of either the esophagus or the GEJ is chemotherapy with carboplatin, paclitaxel and radiation therapy followed by surgery. If they have residual disease present at the time of their surgical resection, they then go on to receive adjuvant nivolumab. That’s an advancement that we’ve seen in the past couple of years, which has resulted in improvements in this disease. Overall, in the neoadjuvant setting, despite many trials being done over the years looking at several different approaches, we have never really been able to [top] the pCR rate of approximately 25% to 30% despite trying to include novel agents [with] additional chemotherapy. Historically, pCR rate has been somewhat of a predictor of how patients do over time. We’ve been trying for a long time to find a way to improve the pCR rate in these patients, which generally needs to involve a chemoradiation approach.

Immune checkpoint inhibitor therapy is something that, fortunately, has been shown to have benefit in patients with esophageal and GEJ adenocarcinoma in the metastatic setting. The next obvious question was whether there was a role for adding an immune checkpoint inhibitor [to regimens] in the neoadjuvant setting. There has been a hypothesis that the presence of radiation as part of a treatment strategy helps to make a tumor more immunogenic. [We thought that] perhaps adding immunotherapy in that setting would improve outcomes.

What key methods and enrollment criteria were employed in ECOG-ACRIN EA2174?

We enrolled patients who had a localized esophageal or GEJ adenocarcinoma and who were considered candidates for surgical resection to receive either standard of care [SOC] carboplatin, paclitaxel, and radiation therapy vs carboplatin, paclitaxel, radiation and the addition of 2 doses of nivolumab during their chemoradiation treatment. They then underwent surgical resection and then, provided they had not developed any evidence of metastatic disease, underwent a second randomization to receive either adjuvant nivolumab or adjuvant nivolumab and ipilimumab [Yervoy].

What primary results from the neoadjuvant phase of the study were presented at the 2024 ASCO Annual Meeting?

At ASCO this year, we [presented] the results of the first randomization, which is the neoadjuvant element of the study. The primary end point for this portion of the study was the pCR rate, where we were looking to see whether the addition of nivolumab to chemotherapy and radiation would improve the pCR rate, as opposed to SOC chemotherapy and radiation. The results showed that for patients receiving chemotherapy and radiation, the pCR rate was 21% vs 24.8% with the addition of nivolumab to the chemotherapy and radiation. This was not a statistically significant difference between the 2 treatment arms.

Did the addition of nivolumab to chemoradiation result in any additional or unexpected toxicities?

Immune checkpoint inhibitor therapy had not been evaluated in combination with chemotherapy and radiation previously in esophageal cancer. As part of this trial, we did have a safety run-in element. [Results from] that [portion of the study] were presented at ASCO a couple of years ago. [In that presentation] we were able to demonstrate that adding an immune checkpoint inhibitor to chemotherapy and radiation did not have a significantly more toxic profile than receiving SOC chemotherapy and radiation.

Despite this portion of the trial being negative, what can the field learn from these results?

The adjuvant element of the study is still pending, so we’re still waiting to find out whether there’s a disease-free survival benefit between adjuvant nivolumab and adjuvant nivolumab and ipilimumab. The other thing we did with this trial was collect tissue from participants at baseline and at the time of their surgical resection, and we also collected blood specimens throughout the course of their treatment. [This included] at baseline following chemoradiation, at the time of surgery, and then at a couple of time points during the adjuvant course of treatment. We are planning on performing NGS analyses and ctDNA analyses to determine if there are pathways that we might be able to identify that may have rendered a patient more responsive to the addition of immune checkpoint inhibitor therapy. [We] also [want] to determine if ctDNA is a reliable biomarker for determining disease status at the molecular level.

Reference

Eads J, Graham N, Gibson MK, et al. A phase II/III study of peri-operative nivolumab (nivo) and ipilimumab (ipi) in patients (pts) with locoregional esophageal (E) and gastroesophageal junction (GEJ) adenocarcinoma: results of the neoadjuvant pathologic complete response (pCR) rate (ECOG-ACRIN EA2174). J Clin Oncol. 2024;42(suppl 16):4000. doi:10.1200/JCO.2024.42.16_suppl.4000