In a single-institution phase II study reported in The Lancet Oncology, Cytryn et al found that the combination of regorafenib, nivolumab, and FOLFOX (fluorouracil, leucovorin, and oxaliplatin) showed activity as a first-line treatment regimen for patients with HER2-negative metastatic esophagogastric adenocarcinoma.

Study Details

In the investigator-initiated trial, 39 patients enrolled between February 2021 and May 2022 at Memorial Sloan Kettering Cancer Center received FOLFOX (fluorouracil at 400 mg/m² bolus followed by 2,400 mg/m² over 48 hours, leucovorin at 400 mg/m², and oxaliplatin at 85 mg/m²) and nivolumab at 240 mg on days 1 and 15 plus regorafenib at 80 mg on days 1 to 21 of 28-day cycles. Treatment was continued until disease progression or unacceptable toxicity. The primary endpoint of the study was 6-month progression-free survival in the population of patients who received at least one dose of all study treatments (n = 35). The regimen was to be considered worthy of further investigation if at least 24 of 35 patients were progression-free at 6 months.

6-Month Progression-Free Survival

At data cutoff in March 2023, median follow-up was 18.1 months (interquartile range = 12.7–204 months). Among the 35 evaluable patients, 25 (71%, 95% confidence interval [CI] = 54%–85%) were progression-free at 6 months. Median progression-free survival was 13.0 months (95% CI = 7.6 months to not reached), with a 12-month rate of 51% (95% CI = 37%–71%).

A total of 17 patients received second-line treatment, most commonly ramucirumab and paclitaxel (n = 10). Median overall survival was not reached, with rates at 6 and 12 months of 97% (95% CI = 92%–100%) and 85% (95% CI = 74%–98%), respectively.

Adverse Events

Among 39 patients in the safety population (those who received a dose of any study drug), the most common adverse events of any grade were fatigue (92%), paresthesia or peripheral neuropathy (77%), and palmar-plantar erythrodysesthesia syndrome (67%). Grade 3 or 4 adverse events occurred in 77% of patients, most commonly decreased neutrophil count (46%), hypertension (15%), dry skin/pruritus/rash (13%), and anemia (10%). Serious treatment-related adverse events occurred in 26% of patients, most commonly acute kidney injury (8%). Adverse events led to discontinuation of oxaliplatin in 31 patients, fluorouracil in 1, nivolumab in 5, and regorafenib in 7. No treatment-related deaths were reported.

The investigators concluded, “Regorafenib can be safely combined with nivolumab and chemotherapy and showed promising activity in HER2-negative metastatic esophagogastric cancer. A randomized, phase III clinical trial is planned.”

Yelena Y. Janjigian, MD, of the Gastrointestinal Oncology Service, Memorial Sloan Kettering Cancer Center, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was funded by Bristol Myers Squibb, Bayer, and the National Cancer Institute. For full disclosures of the study authors, visit thelancet.com.