Efficacy of losartan plus modified FOLFIRINOX versus modified FOLFIRINOX in advanced pancreatic cancers: A randomized clinical trial (AFPAC Study)
Anant Ramaswamy, Prabhat Bhargava, Vikram Gota, Sujay Srinivas, Noorzia Sultana, Sarika Mandavkar, Poonam Jadhav, Khushboo Gandhi, Neha Mer, Nafisa Khan, Manan Vora, Himanshu Gujarathi, Manish Bhandare, Vikram Chaudhari, Shailesh V. Shrikhande, Vikas Ostwal
Abstract
BACKGROUND: The addition of angiotensin receptor blockers like losartan (L) has been shown to improve outcomes in small prospective studies of pancreatic ductal adenocarcinomas (PDAC). METHODS: Patients diagnosed with treatment-naive locally advanced/metastatic PDAC with Eastern Cooperative Oncology Group performance status 0-1 and adequate end- organ function were randomly assigned (1:1) to either chemotherapy (mFOLFIRINOX or mFOLFIRINOX plus oral losartan 50 mg per day). The current unplanned analysis was conducted to identify an early signal of efficacy. Plasma TGF-β levels were measured at baseline, post cycle 1, and post cycle 4 in both arms. RESULTS: With a median follow-up of 16.8 months, a total of 88 patients were randomized in the mFOLFIRINOX and mFOLFIRINOX-L arms (44 patients per arm). The number of deaths at 6 months, 6-month overall survival (OS), and median OS was 12, 72.7% (95% confidence interval [CI], 59.3-86.1), and 10.4 months versus 11, 73.2% (95% CI, 59.4-87), and 9.1 months, respectively, with a hazard ratio of 0.76 (95% CI, 0.47-1.22, p = .392). There were no differences in response rates (22% vs. 23%) between the mFOLFIRINOX and FOLFIRINOX-L arms, respectively. Nine patients (22%; n = 41) required temporary cessation of losartan due to accompanying chemotherapy-related adverse events. The trend of plasma TGF-β levels across time points was not significantly different between the two arms (ANOVA p > .05). CONCLUSIONS: The addition of losartan to mFOLFIRINOX in the AFPAC study did not provide an early signal of efficacy in improving progression-free survival in advanced PDAC. The trial will not proceed to full accrual of phase 3 design.