Adjuvant treatment with the immune checkpoint inhibitor nivolumab significantly prolonged disease-free survival compared with placebo in patients with esophageal or gastroesophageal junction cancer, and treatment was extremely well tolerated, the phase III, CheckMate 577 study found.
In patients who received adjuvant nivolumab for one year, the median disease-free survival interval was twice as long at 22.4 months (95% CI, 16.6-34 months) compared with 11 months (95% CI, 8.3-14.3 months) for placebo controls, reducing the risk for disease recurrence or death by 31% at a hazard ratio of 0.69 (95% CI, 0.56-0.86; P<0.001), Ronan Kelly, MD, Baylor University Medical Center, Houston, Texas, and colleagues reported in the New England Journal of Medicine.
Only 9% of patients treated with adjuvant nivolumab discontinued treatment because of treatment-related adverse events (AEs), investigators added, and the year-long course of adjuvant nivolumab did not affect patient-reported quality of life.
“CheckMate 577 is a practice-changing trial in the treatment of esophageal cancer,” David Ilson, MD, PhD, Memorial Sloan Kettering Cancer Center, New York City, wrote in an editorial accompanying the study. “[This] trial shows the first true advance in the adjuvant therapy of esophageal cancer in recent years and will become a new standard of care.”
Patients with stage II or III esophageal or gastroesophageal junction cancer were initially treated with neoadjuvant chemoradiotherapy followed by surgery. All patients had residual pathological disease following surgery and 58% had a pathological lymph-node status of at least ypN1, the authors noted.
Some 532 participants were then randomized to receive adjuvant nivolumab and another 262 received placebo.
Nivolumab was given at a dose of 240 mg every two weeks for 16 weeks, followed by a dose of 480 mg every four weeks for one year.
“Dose modifications were not permitted but nivolumab or placebo could be interrupted or delayed for a maximum of 6 weeks during the first 16 weeks or for a maximum of 10 weeks during the remainder of the trial intervention period,” Ilson and colleagues explained.
The majority of patients had adenocarcinoma, as is characteristic of esophageal or gastroesophageal junction cancer in the West, the researchers noted. However, the disease-free survival benefit seen with additional immunotherapy was achieved regardless of histologic type.
Moreover, hazard ratios for disease recurrence or death consistently favored nivolumab across all prespecified subgroups and were not affected by tumor-cell programmed death-ligand1 (PD-L1) expression :
- Node-negative disease: HR: 0.67 versus 0.67 for node-positive disease.
- Tumor stages (ypT0): HR: 0.35; ypT1 or ypT2: HR 0.60; ypT3 or ypT4: HR 0.84.
- HER2-positive disease: HR: 0.78 versus 0.69 for HER2-negative disease.
- PD-L1-positive tumors: HR: 0.73 versus 0.75 for PD-L1-negative tumors.
In addition, distant recurrence was less frequent among patients who received adjuvant nivolumab, occurring in 29% of this group of patients compared with 39% of placebo controls. The same was true for locoregional recurrence, which occurred in 12% of patients who received additional nivolumab compared with 17% of placebo controls.
Median distant metastasis-free survival rates were 28.2 months (95% CI, 21.3 months to could not be estimated) for patients who received the immune checkpoint inhibitor compared to 17.6 months (95% CI, 112.5-25.4 months) for placebo patients.
“[T]hus, the risk of distant recurrence or death was 26% lower with nivolumab than with placebo (hazard ratio, 0.74, 95% CI, 0.60 to 0.92),” the investigators wrote.
Grade 3 and 4 AEs related to treatment were more common at 13% in nivolumab-treated group compared with 6% of those who received placebo, while the incidence of treatment-related serious AEs of any grade was also slightly higher at 8% in the nivolumab group compared with 3% for those receiving placebo. The most common AEs in the nivolumab group were fatigue, diarrhea, pruritus, and rash, while diarrhea and fatigue were the most common AEs among placebo patients.
Patient-reported outcomes were also not different between the two treatment groups, with scores on both the FACT-E assessment and the EQ-5D-3L questionnaire showing similar improvement from baseline at most time points across the year-long trial.
“These findings indicate that health-related quality of life was maintained during the treatment period,” the researchers wrote. they also pointed out that neoadjuvant chemoradiotherapy followed by surgery is currently the standard of care for resectable, locally advanced esophageal or gastroesophageal junction cancer; “However, a pathological complete response is often not achieved, and most patients have a poor prognosis.”
Indeed, between 70%-75% of patients with esophageal or gastroesophageal junction cancer who do not achieve a pathological complete response after standard of care are at risk for recurrence.
Despite the poor prognosis of patients enrolled in CheckMate 577, nivolumab significantly improved the primary outcome of disease-free survival along with the risk of recurrence of death compared with placebo, the authors emphasized.
However, they cautioned that the disease-free survival benefit was greater among patients who received nivolumab at least 10 weeks after surgery than in those who received it sooner—a finding that suggests that a prolonged recovery may be required after intensive preoperative therapy such as patients enrolled in the CheckMate 577 trial received.
As the editorialist also noted, the debate as to whether chemotherapy alone or combined chemoradiotherapy is the preferred approach for the treatment of esophageal cancer prior to surgery is still on-going and studies examining both approaches aim to address this controversy. Nevertheless, “[p]rogress with combined-modality therapy has remained slow and incremental, with the recognition that most patients will die from locally recurrent or persistent disease or metastatic disease,” Ilson noted.
Although most studies have indicated that the benefit of immune checkpoint inhibitors is limited to patients whose tumors express higher levels of PD-L1, the results of CheckMate 577 suggest that adjuvant nivolumab was similarly effective regardless of tumor cell PD-L1 expression.
Now, whether the adjuvant use of immune checkpoint inhibitor therapy might improve outcomes in patients with esophageal cancer undergoing chemoradiotherapy without surgery is the subject of another study, the KEYNOTE-975 trial in the immune checkpoint inhibitor, pembrolizumab, is being evaluated.
The same drug is again being explored in patients with esophageal cancer undergoing perioperative chemotherapy without radiotherapy in the KEYNOTE-585 trial.
In the meantime, “t]he CheckMate 577 trial provides a welcome new therapeutic option for …patients [with esophageal cancer],” Ilson wrote.
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Adjuvant treatment for one year with the immune checkpoint inhibitor, nivolumab, doubled the median disease-free survival interval compared with placebo and was extremely well tolerated.
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The CheckMate 577 trial is the first trial showing meaningful improvement in patient outcomes in the setting of esophageal and gastroesophageal junction cancer and as such, should become the new standard of care following neoadjuvant chemoradiation and surgery.
Pam Harrison, Editor-in-Chief, BreakingMED™
The study was upported by Bristol Myers Squibb and Ono Pharmaceutical.
Kelly reported receiving advisory board fees from Astellas Pharma, AstraZeneca, Daiichi Sankyo, Eisai, EMD Serono, Merck, Novartis, Ono Pharmaceutical, Pieris Pharmaceuticals, and Takeda Oncology, grant support, paid to Johns Hopkins University, and advisory board fees from Bristol Myers Squibb, lecture fees from Cardinal Health, and grant support, paid to the Baylor Scott and White Research Institute, and advisory board fees from Eli Lilly.
Ilson reported personal fees from Bayer, personal fees from Lilly, personal fees from Macrogenics, personal fees from Merck, personal fees from AMGEN, personal fees from Astra Zeneca, personal fees from Idience, outside the submitted work.
Cat ID: 120
Topic ID: 78,120,730,188,120,935,192,925
