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The phase 3 CheckMate 577 trial is the first to show a checkpoint inhibitor in the adjuvant setting after trimodality therapy demonstrate a statistically significant and clinically meaningful improvement in disease-free survival in patients with resected esophageal and gastroesophageal junction cancer.
Adjuvant therapy with nivolumab (Opdivo) demonstrated a statistically significant and clinically meaningful improvement in disease-free survival (DFS) among patients with resected esophageal and gastroesophageal junction cancer (EC/GEJC), reducing the risk for disease recurrence by 31%, compared with placebo, according to data from the CheckMate 577 trial (NCT02743494) presented at the Society of Surgical Oncology 2021 International Conference on Surgical Cancer Care.1
Of note, this is the first trial to demonstrate positive efficacy and safety of a checkpoint inhibitor in the adjuvant setting after trimodality therapy for EC/GEJC.
“These breakthrough results represent the first treatment advent in many years for patients with esophageal and gastroesophageal junction cancer, potentially establishing adjuvant nivolumab as a new standard of care for these difficult to treat tumors,” Guillaume Piessen, MD, PhD, University of Lille, Claude Huriez University Hospital in Lille, France, said during a presentation during the virtual meeting.
Although neoadjuvant chemoradiation therapy (CRT) followed by surgery, also known as trimodality therapy, is a standard of care for this patient population, the risk for recurrence is high, especially for the 70% to 75% of patients who do not achieve a pathological complete response, according to Piessen.
Therefore, in the global, randomized, double-blind, phase 3 trial, the investigators evaluated the efficacy and safety of adjuvant nivolumab therapy in patients with resected (R0) stage II/III EC/GEJC who received neoadjuvant CRT and had residual pathologic disease.
In total, 794 patients were randomized 2:1 to receive either 240 mg nivolumab (n = 532) or placebo (n = 262) once every 2 weeks for 16 weeks, followed by 480 mg nivolumab or placebo once every 4 weeks. Maximum treatment duration was 1 year. DFS served as the primary end point of the study, while overall survival (OS), and the rate of OS at 1, 2, and 3 years were the secondary end points.
The majority of patients treated with nivolumab were male (84%), white (81%), had an ECOG performance status of 0 (58%), had stage III disease (66%), received a diagnosis of adenocarcinoma (71%), and had a pathologic lymph node status of ypN1 or greater (60%). Median age was 62 years (range, 26-82). In addition, 70% of patients had less than 1% PD-L1 expression, and most underwent an esophagectomy for their procedure.
Median follow-up was 24.4 months (range, 6.2-44.9), while median duration of treatment for nivolumab was 10.1 months (range, <0.1-14.2).
At the pre-specified interim analysis, patients treated with adjuvant nivolumab demonstrated a statistically significant improvement in DFS compared with placebo (HR, 0.69; 96.4% CI, 0.56-0.86; P = .0003). Moreover, adjuvant nivolumab doubled median DFS, compared with placebo (22.4 months [95% CI, 16.6-34.0] vs 11.0 months [95% CI, 8.3-14.3], respectively).
A subgroup analysis–including age, sex, race, ECOG performance status, disease stage at initial diagnosis, histology, pathologic lymph node status, PD-L1 expression, and time from complete resection to randomization–also showed superior DFS with nivolumab compared with placebo.
Twenty-eight percent of patients discontinued treatment with nivolumab due to disease progression, and 11% discontinued because of treatment-related adverse events (TRAEs). The majority of TRAEs were grade 1 or 2. Grade 3/4 TRAEs with nivolumab and placebo occurred in 13% and 6% of patients, respectively, and included fatigue (1% vs <1%), diarrhea (<1% each), pruritus (<1% vs 0%), and rash (<1% each). The majority of TRAEs with potential immunologic etiology were low grade, with grade 3/4 events occurring in fewer than 1% of patients in the nivolumab arm. There were no grade 5 TRAEs.
“Collectively, the safety and overall health status data support the use of nivolumab as an appropriate treatment in an adjuvant setting where safety and tolerability are important considerations,” Piessen said. “Nivolumab was well tolerated with an acceptable safety profile relative to placebo.”
The study will continue as planned to allow for future analysis of the secondary end point of overall survival, he added.
Based on these data, the FDA accepted the supplemental biologics license application for nivolumab to treat patients with resected EC/GEJC in the adjuvant setting, after neoadjuvant CRT. Moreover, the agency granted the application priority review and assigned a Prescription Drug User Fee Act (PDUFA) date of May 20, 2021.2
1. Piiessen G. Adjuvant Nivolumab in Resected Esophageal or Gastroesophageal Junction Cancer Following Neoadjuvant Chemoradiation Therapy: First Results of the CheckMate 577 Study. Presented at: Society of Surgical Oncology 2021 International Conference on Surgical Cancer Care; March 18-19, 2021; Virtual. Abstract 94.
2. Bristol Myers Squiibb. U.S. Food and Drug Administration Accepts for Priority Review Application for Opdivo (nivolumab) as Adjuvant Therapy for Patients with Resected Esophageal or Gastroesophageal Junction Cancer. News Release. Bristol Myers Squibb. January 20, 2021. Accessed March 19, 2021. https://bit.ly/3sfQKdd