Phase II Trial of Vemurafenib and Sorafenib Combination in Advanced KRAS-Mutated Metastatic Pancreatic Cancer

ABSTRACT Introduction Prognosis of metastatic pancreatic cancer remains poor. KRAS mutations are common in pancreatic cancer and are an attractive therapeutic target. Based on a next-generation mechanistic dynamic model, we hypothesized that a combination of type I½ RAF inhibitor (vemurafenib) and type II RAF inhibitor (sorafenib) would have clinical activity in KRAS -mutated advanced pancreatic cancer. Methods We conducted an open-label pilot phase II trial of vemurafenib and sorafenib combination in advanced pancreatic cancer with KRAS mutations. Eligible patients had progressed on two or more prior treatment regimens, had adequate performance status, adequate organ function and measurable disease, and were able to swallow oral medication. The primary objective was disease control rate (partial or complete response or stable disease ≥ 16 weeks). Secondary objectives included safety, progression-free (PFS) and overall survival (OS), and changes in plasma phospho-ERK and phospho-AKT. Results Nine patients with KRAS- mutated pancreatic cancer were enrolled. The median age was 62.8 years and the median prior lines of treatment was 3. Four of the initial five patients had treatment interruption due to adverse events, and the subsequent four patients were treated at a reduced dose. Three grade 3 adverse events were reported and included anemia ( n = 1), hypophosphatemia ( n = 1), and maculopapular rash ( n = 1); rash and anemia were deemed treatment related. Disease control rate was 0%. Median PFS was 1.6 months (95% CI, 0.5–not available), and median OS was 2.9 months (95% CI, 0.6–5.4). Compared to baseline, the best response for relative plasma phospho-ERK levels were −39 to +11% and −32 to +49% for plasma phospho-AKT levels. Conclusion The combination of vemurafenib and sorafenib in KRAS -mutated refractory pancreatic cancer did not yield disease control in this pilot phase II study. The lack of clinical efficacy may be due to inadequate inhibition of RAS-to-ERK signaling as toxicities necessitated dose reduction. Clinicaltrials.gov ID NCT05068752