Abstract A002: Phase II Trial of Vemurafenib + Sorafenib in Advanced KRAS Mutated Pancreas Cancer
Authors: Borazanci Erkut , Jameson Gayle , Khawaja Muhammad , Cridebring Derek , Shannon Patricia , Gordon Michael , Han Haiyong , Moore Jaeger , Von Hoff Daniel , Posner Richard , Hlavacek William , Kolch Walter , Kholodenko Boris , Rukhlenko Oleksii 
Published: September 2024

Abstract
Background Pancreatic ductal adenocarcinoma (PDAC) continues to be a lethal disease. It has been established that 90% of PDAC patients harbor somatic oncogenic point mutations in KRAS, which leads to the activation of the RAS-to-ERK signaling pathway. This pathway is resistant to almost all known small molecule inhibitors and often gets reactivated after initial inhibition. Recent work has shown that combination of Type I½ and Type II RAF inhibitors synergistically suppresses both RAS-to-ERK signaling and proliferation of RAS-mutant cells, overcoming the resistance and reactivation effects. We conducted a phase 2 clinical trial of the combination of Type I½ RAF inhibitor vemurafenib and Type II RAF inhibitor sorafenib in KRAS-mutant PDAC. Methods Patients with KRAS mutated refractory PDAC that has progressed on ≥ 2 prior chemotherapy regimens for advanced disease were eligible for this study. Combination treatment included vemurafenib at 720 mg, po, BID (later reduced to 480 mg po BID) + sorafenib at 400 mg, po, BID (later reduced to 200 mg po QD) x 28 days. Tumor assessments were done every 8 weeks. The primary endpoint was disease control rate (DCR) at 16 weeks. Secondary endpoints included safety, PFS, OS, and changes in phosphorylated ERK (ppERK) and phosphorylated AKT (pAKT) levels in plasma. Results: Nine patients were enrolled in the study with a median age of 62 years (range 48-85); male (56%) male; white (78%). All grade treatment-related adverse events (TRAE): anemia (11%), arthralgia (11%), diarrhea (11%), dry skin (22%) erythema (22%), fatigue (11%), hyperkeratosis (11%), hypertension (22%), hypokalemia (11%), hypophosphatemia (33%), nausea (22%), pain (11%), peripheral swelling (11%), rash (69%), squamous cell carcinoma (11%), vomiting (22%). TRAE ≥ grade 3: rash (11%) and anemia (11%). DCR at 16 weeks was 0%. Median PFS was 7.14 weeks (range 2.14 -13.00), and OS was 12.71 weeks (range 2.57-24.86). All patients discontinued study treatment due to disease progression. ppERK plasma level was reduced by 10-40% after treatment, indicating a partial suppression of ERK activity. Conclusions The lack of efficacy in the current study could be explained by insufficient inhibition of RAS-to-ERK signaling due to dose limitations. Previous work found two synergistic drug combinations that effectively suppress the activity of RAS-to-ERK signaling: (i) combination of Type I½ and Type II RAF inhibitors, and (ii) combination of Type II RAF inhibitor and MEK inhibitor. Our recent in-silico and in-vitro results suggest that the former combination is optimal for cells with a low KSR1 level, while the latter combination is optimal for cells with a high KSR1 level. Importantly, a triple combination of (i) Type I½ RAF inhibitor, (ii) Type II RAF inhibitor and (iii) MEK inhibitor was effective for all KSR1 levels. Such triple combination has been previously shown to be well tolerable and may allow for lower dosing to achieve clinical efficacy. We suggest adding a MEK inhibitor, cobimetinib, for a future study.
Citation Format: Erkut Borazanci, Gayle Jameson, Muhammad Khawaja, Derek Cridebring, Patricia Shannon, Michael Gordon, Haiyong Han, Jaeger Moore, Daniel Von Hoff, Richard Posner, William Hlavacek, Walter Kolch, Boris Kholodenko, Oleksii Rukhlenko. Phase II Trial of Vemurafenib + Sorafenib in Advanced KRAS Mutated Pancreas Cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr A002.