A "significant and clinically meaningful" improvement of disease-free survival was observed in a global, randomized, placebo-controlled, Phase III trial among patients who had already had their esophageal or gastroesophageal cancers treated with surgery, radiation, and chemotherapy. This increased from a median of 11.0 months in patients taking a placebo to 22.4 months among patients treated with adjuvant immunotherapy with the programmed cell death protein-1 (PD-1) checkpoint inhibitor nivolumab in the CheckMate 577 study reported in the New England Journal of Medicine (2021; doi: 10.1056/NEJMoa2032125).
"Basically, what we showed was [that] nivolumab provided vastly superior disease-free survival with a 31 percent reduction of the risk of recurrence or death and a doubling in the median disease-free survival," said first author Ronan J. Kelly, MD, MBA, from Baylor University Medical Center in Dallas, where he is Director of Oncology at the Charles A. Sammons Cancer Center and holds the W.W. Caruth Jr. Chair of Immunology.
CheckMate 577 had been conceived because there had been no established adjuvant treatments for patients who were still at high risk for recurrence after their neoadjuvant chemoradiotherapy and surgery for esophageal or gastroesophageal junction cancer, according to the study authors.
Study Details
Adults were recruited into the study who had resected stage II or III esophageal or gastroesophageal junction cancer, and had already received neoadjuvant chemoradiotherapy and yet continued to have residual pathological disease. Two-thirds of the group were randomly assigned to nivolumab treatment (240 mg every 2 weeks for 16 weeks, followed by a dosing of 480 mg every 4 weeks). The remaining patients had a placebo. In both arms of the study, treatment continued for a maximum of a year.
After a median follow-up of 24.4 months, the median disease-free survival was 22.4 months among 532 patients treated with nivolumab, as compared with 11.0 months among 262 patients on placebo. Disease-free survival improved with nivolumab across multiple prespecified subgroups, the authors noted. For the overall group, the hazard ratio was 0.69, with a highly statistically significant "p" value of 0.0003.
Grade 3 or 4 adverse events considered by the investigators to be related to the active drug or placebo occurred in 71 of 532 patients (13%) in the nivolumab group and 15 of 260 patients (6%) in the placebo group. Nine percent of patients in the nivolumab group and 3 percent of those on placebo group stopped the trial regimen because of adverse events.
The investigators concluded that, among patients with resected esophageal or gastroesophageal junction cancer who had received neoadjuvant chemoradiotherapy, disease-free survival had been significantly longer among those who received nivolumab adjuvant therapy than among those who received placebo.
Kelly told Oncology Times the prospect of relative freedom from toxicity offered by the immunotherapy had been one of the factors behind the design of CheckMate 577 and that this expectation had been justified by their findings.
"When people are in the adjuvant setting and they are recovering from surgery, you want to give them a treatment that's quite well-tolerated," he said. "If you look at the quality-of-life data on our study, we reported very similar patient outcomes [whether] they were treated on nivolumab or placebo-very similar, almost superimposable, in terms of what patients were reporting."
Neither did the investigators see any new or unusual side effects with the checkpoint inhibitor that they hadn't seen in the metastatic setting with nivolumab, Kelly noted. "Overall, it was very well-tolerated. In fact, 89 percent of patients got a maximum dose intensity of 90 percent."
Kelly said they still awaited data on overall survival, but there was promise. "What we showed was the disease-free survival. But we also showed the distant metastasis-free survival-which is not quite overall survival but-kind of-that intermediate step. And we saw a benefit in that also," he said.
The use of adjuvant nivolumab in this setting had been adopted since December 2020 in U.S. guidelines after being rated as "category one" evidence, and was awaiting approval from the FDA.
New Paradigm
When Kelly was asked if adjuvant immunotherapy with nivolumab in this disease setting was paradigm-changing, he said these patients had not previously seen much attention.
"We hadn't seen any breakthroughs in early-stage disease. In fact, this is the first novel treatment to ever have a breakthrough in that stage," he said. The only adjuvant immune-oncology drug to have been approved had been in melanoma. "So now we're coming with esophagogastric cancers as the second tumor type-which is very unusual for this tumor type to be 'leading the field' in that space," he said.
Kelly said it was a long, arduous journey for these patients-from chemotherapy, radiation, then surgery, learning how to eat again. "We knew that 75 percent are in a pretty bad place if they don't have a complete response," he stated. "So, now we have a novel treatment that's available to these patients to give them significant hope that can result in long-term survival. And I think that's a huge step forward.
"I think we're really entering a new era of cancer care. Because now we're taking checkpoint inhibitors from metastatic disease and we're moving them into early operable disease," he said.
Colleague Comments
In an accompanying comment article in the New England Journal of Medicine, David H. Ilson, MD, PhD, a medical oncologist at Memorial Sloan Kettering Cancer Center in New York, assessed the CheckMate 577 trial findings as "practice-changing in the treatment of esophageal cancer." He regarded the doubling of disease-free survival as almost certain to translate into an overall survival benefit. "The trial shows the first true advance in the adjuvant therapy of esophageal cancer in recent years and will become a new standard of care," he wrote.
Ilson pointed out, however, that most patients would still not gain benefit from adjuvant therapy with nivolumab. "More contemporary biomarkers, including the presence of persistent circulating tumor DNA after surgery, should be explored to better define high-risk populations and potentially monitor patients receiving adjuvant therapy."
But Ilson had been impressed with the study findings. "Improvement in survival among patients with esophageal cancer has been long awaited in those undergoing the arduous journey of chemotherapy, radiation, and surgery. The CheckMate 577 trial provides a welcome new therapeutic option," he wrote.
Peter M. Goodwin is a contributing writer.