Nab-paclitaxel and gemcitabine (modified) in combination with oral cobimetinib and encorafenib following FOLFIRINOX in patients with metastatic G12D and G12V pancreatic cancer.
Authors: Bach Ardalan, Jose Ignacio Azqueta, Jonathan England, Danny Sleeman, Rosali Gonzalez
Journal: Journal of Clinical Oncology (2024)

e16330 Background: Pancreatic cancer is the only human cancer in which most of the tumors are KRAS mutated. A majority of the mutations occur in codon 12. Mutations percentages are as follows: G12D (50%), G12V (35%) and G12R(12%). We are reporting on a pilot study in patients with advanced pancreatic cancer who have failed, or have become resistant to FOLFIRINOX. Thereafter the patients were placed on Nab-paclitaxel and Gemcitabine in combination with oral Cobimetinib and encorafenib. Methods: Patients with advanced pancreatic cancers are typically offered modified FOLFIRINOX followed by Nab-paclitaxel and Gemcitabine. After obtaining a written informed consent, we conducted a single arm study of patients with pathologic proven unresectable metastatic pancreatic cancer. Patients who had failed FOLFRINOX were placed on a modified regimen of Gemcitabine (1000mg/m2) and Nab-paclitaxel (125 mg/M2) on days 1 and 15 every 28-day cycle. Oral medications, Cobimetinib 20 mg bid and encorafenib of 150 mg bid were given. The oral chemotherapies were administered weekdays only during the 28-day cycle. The primary end point was to determine the response rate from the time the patients were placed on Nab-paclitaxel and Gemcitabine and the oral medication. The secondary endpoint was to assess the overall survivorship from the beginning of the therapy, and overall toxicities of the combination therapy. Twelve patients with advanced metastatic pancreatic cancer were enrolled on this pilot study. Six patients were male, and the median age was 67 years. Liver metastases were present in eight patients. Treatment was continued as long as there was no disease progression. CBC, CMP, CA19-9 was performed every other week. CT and PET scan was ordered every eight weeks. Results: Overall follow up is from 5 to 19 months (median 14 months). Segmental median survival from the start of oral therapy in conjunction with Nab-paclitaxel and Gemcitabine is 5 months (2-9 months). As from now,all patients are alive and 10 of 12 patients are on therapy. One patient who achieved pathologic response in the liver was deemed operable, and pathologically the distal pancreatectomy demonstrated NO disease. The other patient has progressed and is not on treatment. Grade 3 non-hematological toxicities included nausea, vomiting and fatigue in 3 of 12 patients. Hematological toxicities included neutropenia and neutrophil support was needed in 6 out of 12 patients. Median survivorship has NOT been reached. In this small study, we have observed a rapid and dramatic reduction in tumor volume. Conclusions: The combination of MEK and BRAF inhibitors with chemotherapy may be potentially active in pancreatic tumors (G12D and G12V). Based on the data presented, Nab-paclitaxel and Gemcitabine in combination with oral Cobimetinib and encorafenib needs to be further explored in a larger cohort of patients.