Statistically Significant DFS Improvement Observed with Adjuvant Nivolumab in Resected Esophageal/GEJ Cancers

Adjuvant nivolumab (Opdivo) prolonged disease-free survival (DFS) as treatment of patients with resected esophageal or gastroesophageal junction (GEJ) cancer compared with placebo, meeting the primary end point of the phase 3 CheckMate-577 clinical trial, according to prespecified interim analysis data announced in a press release from Bristol Myers Squibb.

The improvement in DFS observed with nivolumab administered after neoadjuvant chemoradiation therapy (CRT) was deemed statistically significant in comparison to placebo. Nivolumab also showed a similar safety profile to that observed in previous clinical trials. CheckMate-577 makes esophageal/GEJ the second tumor to benefit from adjuvant nivolumab, after positive results observed in patients with melanoma.

“Approximately 50% of patients with esophageal or gastroesophageal junction cancer who undergo neoadjuvant chemoradiation therapy followed by tumor resection will have disease recurrence within four years, and among those who do not respond completely to neoadjuvant treatment, recurrence will occur sooner,” said Ronan J. Kelly MD, MBA, director of the Charles A. Sammons Cancer Center at Baylor University Medical Center, in a statement. “Medical oncologists have had limited to no treatment options to offer esophageal cancer patients who undergo neoadjuvant chemoradiation therapy followed by surgery and fail to demonstrate a complete pathological response. For the first time, we have a potential therapeutic option with nivolumab in the adjuvant setting for these patients.”

Typically, esophageal/GEJ cancer is treated with chemoradiotherapy followed by surgical resection; however, the 3- and 5-year survival rates for this treatment method only range from 30% to 40%. Also, following resection, no effective standard-of-care therapy exists for esophageal/GEJ cancer.

The option to combine nivolumab plus ipilimumab for treatment of this patient population was evaluated previously in the phase 1/2 CheckMate-032 clinical trial (NCT01928394) of nivolumab plus ipilimumab in patients with advanced and metastatic solid tumors.

As previously reported by Targeted Oncology, both nivolumab monotherapy and nivolumab combined with ipilimumab demonstrated clinically meaningful antitumor activity with durable responses and promising long-term overall survival in the subgroup of patients with metastatic esophagogastric cancer.

In 160 patients, the objective response rates (ORRs) among patients treated with nivolumab monotherapy administered at 3 mg/kg was 12% (95% CI, 5%-23%). Responses included 1 complete response per investigator assessment and 6 partial responses. In addition, 12 patients had stable disease and 34 had progressive disease.

The disease control rate in the nivolumab arm was 32%. The median time to response in the nivolumab monotherapy group was 1.6 months (range, 1.2-4.0), and response lasted for a median duration of 7.1 months (95% CI, 3.0-13.2).

The median progression-free survival in the study was 1.4 months (95% CI, 1.2-1.5), and the median overall survival (OS) was 6.2 months (95% CI, 3.4-12.4).

Sixty-nine percent of patients with metastatic esophagogastric cancer who received nivolumab alone in CheckMate-032 experienced treatment-related adverse events (TRAEs). The most common TRAEs observed included fatigue (34%), pruritus (17%), as well as decreased appetite and diarrhea, which occurred in 15% of patients each.

The findings from the phase 1/2 trial suggested that nivolumab is a potential therapeutic option for advanced esophagogastric cancer.

In the randomized, multicenter, double-blind, phase 3 CheckMate-577 trial (NCT02743494), 760 patients are being evaluated receiving treatment with adjuvant nivolumab versus placebo. The secondary end point of the study is OS.

Patients were eligible to enroll with a stage II/III carcinoma of the esophagus or GEJ given they completed pre-operative chemoradiotherapy followed by surgery and were also diagnosed with residual pathologic disease following curative surgery. The study excluded patients who had been diagnosed with cervical esophageal carcinoma or stage IV resectable disease. Patients who never received concurrent chemoradiotherapy prior to surgery and who received a vaccine within 30 days of the first study treatment were ineligible to enroll.

With the positive data, Bristol Myers Squibb plans to present results from CheckMate-577 at an upcoming medical meeting and submit them to health authorities. Until then, the study continues to evaluate the OS end points.

“Opdivo is the first and only therapy to improve disease-free survival, along with a manageable safety profile, for patients with esophageal or gastroesophageal junction cancer following neoadjuvant chemoradiation therapy and surgery,” said Ian M. Waxman, MD, development lead, Gastrointestinal Cancers, Bristol Myers Squibb, in a statement. “The results from CheckMate-577 are immensely important for physicians and patients and have the potential to establish Opdivo as a new standard of care. We plan to provide our data to health authorities worldwide with the goal of bringing Opdivo as an adjuvant therapy to these patients with high unmet need.”

_References:

_{1. CheckMate-577, a phase 3 trial evaluating Opdivo (nivolumab) as adjuvant therapy for patients with resected esophageal or gastroesophageal junction cancer, meets primary endpoint of disease-free survival. News release. Bristol Myers Squibb. August 11, 2020. Accessed August 11, 2020. https://bit.ly/2PL0tXi}

_{2. Janjigian YY, Bendell J, Calvo E, et al. CheckMate-032 study: efficacy and safety of nivolumab and nivolumab plus ipilimumab in patients with metastatic esophagogastric cancer. J Clin Oncol. 2018;36(28):2836-2844. doi: 10.1200/JCO.2017.76.6212}