In a Chinese single-institution phase II trial reported in The Lancet Oncology, Zhu et al found that stereotactic body radiotherapy (SBRT) followed by pembrolizumab plus trametinib improved overall survival vs SBRT followed by gemcitabine in patients with postresection, KRAS-mutant, PD-L1–positive locally recurrent pancreatic adenocarcinoma.
Study Details
In the open-label trial, 170 patients with locally recurrent disease after surgery and chemotherapy with mFOLFIRINOX (fluorouracil, oxaliplatin, irinotecan, and leucovorin) or fluorouracil were enrolled between October 2016 and October 2017 at Changhai Hospital, affiliated with the Naval Medical University in Shanghai. Patients were randomly assigned to receive SBRT followed by pembrolizumab/trametinib (n = 85) or gemcitabine (n = 85). SBRT was given at 35 Gy to 40 Gy in five fractions, and was followed 1 week later either by pembrolizumab at 200 mg once every 3 weeks and trametinib at 2 mg once daily until disease progression or unacceptable toxicity, or by gemcitabine at 1,000 mg/m² on days 1 and 8 of 21-day cycles for eight cycles. The primary endpoint was overall survival.
Photo credit: Getty
Overall Survival
At clinical cutoff (November 2020), median follow-up was 13.1 months (interquartile range = 10.2–17.1 months). Median overall survival was 14.9 months (95% confidence interval [CI] = 12.7–17.1) months in the pembrolizumab/trametinib group vs 12.8 months (95% CI = 11.2–14.4 months) in the gemcitabine group (hazard ratio [HR] = 0.69, 95% CI = 0.51–0.95, P = .021). Rates at 1 and 2 years were 62.4% vs 56.5% and 1.5% vs 0%. Median progression-free survival was 8.2 months (95% CI = 6.9–9.5 months) vs 5.4 months (95% CI = 3.2–7.6 months; HR = 0.60, 95% CI = 0.44–0.81, P = .0009), with 1-year rates of 21.2% vs 8.2%.
Adverse Events
Grade ≥ 3 adverse events occurred in 31% of patients in the pembrolizumab/trametinib group vs 20% in the gemcitabine group. The most common adverse events were increased alanine aminotransferase (ALT) or aspartate aminotransferase (AST; 12% vs 7%) and increased bilirubin (5% vs 0%) in the pembrolizumab/trametinib group, and neutropenia (1% vs 11%), increased ALT/AST, and thrombocytopenia (1% vs 5%) in the gemcitabine group. Serious adverse events occurred in 22% vs 14% of patients, most commonly increased ALT/AST (12%) and neutropenia (11%), respectively. No treatment-related deaths were observed.
The investigators concluded, “The combination of SBRT plus pembrolizumab and trametinib could be a novel treatment option for patients with locally recurrent pancreatic cancer after surgery. Phase III trials are needed to confirm our findings.”
Gang Jin, MD, of the Department of Hepatobiliary and Pancreatic Surgery, Changhai Hospital affiliated to Naval Medical University, Shanghai, and Huojon Zhang, MD, of the Department of Radiation Oncology, Changhai Hospital affiliated to Naval Medical University, Shanghai, are the corresponding authors for The Lancet Oncology article.
Disclosure: The study was funded by Shanghai Shenkang Center and Changhai Hospital. For full disclosures of the study authors, visit thelancet.com.
