Nivolumab may be ‘new standard’ in esophageal, gastroesophageal junction cancers
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Adjuvant nivolumab significantly prolonged DFS compared with placebo among patients with resected esophageal and gastroesophageal junction cancer, according to results of the CheckMate 577 trial presented during ESMO Virtual Congress 2020.
Nivolumab (Opdivo, Bristol Myers Squibb), a PD-1 inhibitor, also demonstrated an acceptable safety profile.
“Neoadjuvant chemoradiation therapy followed by surgery, or trimodality therapy, is a widely used standard of care for patients with resectable locally advanced esophageal or gastroesophageal junction cancer. However, the risk for recurrence following trimodality therapy remains high, especially in patients with residual pathological disease for which there is no established adjuvant treatment,” Ronan J. Kelly, MD, MBA, oncologist at Charles A. Sammons Cancer Center at Baylor University Medical Center, said during a presentation.
“Prior research has shown that nivolumab demonstrated superior survival in previously treated unresectable advanced or recurrent esophageal squamous cell carcinoma vs. chemotherapy and esophageal or gastroesophageal junction cancer vs. placebo," he added. "CheckMate 577 is the first global, randomized, double-blind, phase 3 trial to evaluate a checkpoint inhibitor in the adjuvant setting, after trimodality therapy, for esophageal and gastroesophageal junction cancer.”
The trial included 794 adults with stage II to stage III esophageal or gastroesophageal junction cancer.
Kelly and colleagues randomly assigned patients 2:1 to either 240 mg nivolumab (n = 532; median age, 62 years; 84% men; 81% white) or placebo (n = 262; median age, 61 years; 85% men; 82% white) once every 2 weeks for 16 weeks, followed by 480 mg nivolumab or placebo once every 4 weeks for a maximum treatment duration of 1 year.
All patients had received prior neoadjuvant chemoradiation and had residual pathologic disease. Researchers stratified patients based upon disease histology, pathologic lymph node status ( ypN1 vs. ypN0) and tumor cell PD-L1 expression ( 1% vs. 1%). Most patients (70%) had adenocarcinoma and nearly 60% had a pathologic lymph node status of ypN1 or greater.
DFS served as the primary endpoint.
Median follow-up for the prespecified interim analysis was 24.4 months (range, 6.2-44.9).
“The broad representation of geographical regions — including Europe, North America, Asia and the rest of the world — highlights the truly global nature of this study, which will continue as planned to allow for future analysis of the secondary endpoint of OS,” Kelly said.
Median duration of treatment was 10.1 months with nivolumab and 9 months with placebo.
Results showed a statistically significant and clinically meaningful improvement in DFS with nivolumab vs. placebo (median, 22.4 months vs. 11 months; HR = 0.69; 96.4% CI, 0.56-0.86), which corresponded to a 31% reduction in the risk for disease recurrence or death.
“Notably, there was an early and sustained separation of the DFS curves,” Kelly said. “The placebo group in this study reminds us that even following successful chemoradiation and an R0 surgical resection, patients who do not achieve a pathologic complete response have a high degree of disease recurrence in a relatively short period of time.”
Nivolumab conferred a DFS benefit across all prespecified subgroups —regardless of disease histology, pathologic lymph node status or tumor cell PD-L1 expression, Kelly added.
Eighty-nine percent of patients in the nivolumab group received treatment at a relative dose intensity of at least 90%.
Nivolumab appeared well-tolerated with an acceptable safety profile.
Treatment-related adverse events, mostly grade 1 or grade 2, occurred among 71% of patients in the nivolumab group and 46% of patients in the placebo group. The nivolumab group had a higher rate of serious treatment-related adverse events (8% vs. 3%) and events that led to discontinuation (9% vs. 3%). The most common reason for treatment discontinuation was treatment completion in the nivolumab group and disease progression in the placebo group.
“Nivolumab is the first adjuvant therapy to provide statistically significant and clinically meaningful improvement in DFS vs. placebo in resected esophageal and gastroesophageal junction cancer following neoadjuvant chemoradiation,” Kelly said. “The novelty of this study is highlighted by the fact that this is only the second tumor after melanoma where nivolumab has demonstrated a benefit in the neoadjuvant setting. These results represent the first advance in years for this group of patients, potentially establishing adjuvant nivolumab as a new standard of care.”
Perspective
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Andres Cervantes, MD, PhD
Esophageal cancers have very poor prognosis, with 5-year survival rates in Western countries ranging between 10% and 12%.
The CheckMate 577 trial addresses a relevant clinical question and covers an important medical need for patients with esophageal cancer. The strengths of the trial are the 2:1 randomization and placebo control.
However, there are some weaknesses. For one, mixing up the two very different subtypes of squamous cell and adenocarcinoma may increase heterogeneity and may cause some confusion in the interpretation of the data. In addition, preoperative radiation is not universally accepted as standard of care. DFS, rather than OS, as the primary endpoint also could be an issue, as DFS is not currently validated as a major endpoint for gastroesophageal cancers.
I have to congratulate the researchers for carrying out this important trial that showed a clinically meaningful difference in DFS, favoring nivolumab. Despite no major toxicity concerns, more patients abandoned the trial for reasons other than progression or end of treatment in the nivolumab group. Additionally, median follow-up was only 2 years, and so the current estimation for median DFS may change slightly. Adjuvant nivolumab is able to decrease both local and systemic relapses, indicating a potential interaction with radiation with an abscopal effect. Mature data on OS will be of great relevance in this trial.
Several ongoing trials are assessing the role of checkpoint inhibitors in localized gastroesophageal cancers, including KEYNOTE-585, EORTC 1707 VESTIGE and AIO-STO-0317 DANTE.
Perspective
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David H. Ilson, MD, PhD
Cancer of the esophagus and gastroesophageal junction is usually treated in the United States with trimodality therapy, concurrent chemoradiotherapy with weekly carboplatin and paclitaxel followed by surgery. Chemoradiotherapy improves survival over surgery alone and one-quarter of patients achieve a pathologic complete response to therapy. However, disease recurs in more than half of these patients, with the highest risk among patients with significant residual or node-positive disease. There is no compelling evidence that additional chemotherapy has any impact and, until now, there has been no effective adjuvant strategy to improve treatment outcome.
Investigators now report results of the CheckMate 577 study, which showed that DFS was substantially improved with nivolumab — with benefits seen for squamous cell and adenocarcinoma, ypN0 and ypN1 patients, and irrespective of PDL-1 status. Although OS data have not matured, this trial will likely establish a new care standard in the combined modality therapy of esophageal cancer and represents a landmark clinically significant and meaningful advance in this disease.
HemOnc Today Editorial Board Member
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Kelly RJ, et al. Abstract LBA9_PR. Presented at: European Society for Medical Oncology Virtual Congress 2020; Sept. 19-21, 2020.
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