Phase I, Pharmacogenomic, Drug Interaction Study of Sorafenib and Bevacizumab in Combination with Paclitaxel in Patients with Advanced Refractory Solid Tumors.

VEGF blockade does not uniformly result in clinical benefit. We evaluated safety, dose-limiting toxicities (DLT), recommended phase II dose (RP2D), antitumor efficacy, and exploratory biomarkers including pharmacogenomics and pharmacokinetics with sorafenib, bevacizumab, and paclitaxel in patients with refractory cancers. The study had a "3 + 3" design, using paclitaxel 80 mg/m2 every week for 3 weeks, in every 4 week cycles, bevacizumab 5 mg/kg every 2 weeks, and sorafenib 200 or 400 mg twice a day, 5 or 7 days/week (5/7, 7/7). The MTD cohort was expanded. Twenty-seven patients enrolled in 3 cohorts: sorafenib 200 mg twice a day 5/7, 200 mg twice a day 7/7, and 400 mg twice a day 5/7. DLTs were grade 3 neutropenia >7 days (cohort 1, 1), grade 3 hypertension (cohort 2, 1), grade 3 hand-foot skin reaction (HFSR; cohort 3, 2). MTD was sorafenib 200 mg twice a day 7/7. Six DLTs occurred in cohort 2 expansion: grade 3 HFSR (2), grade 2 HFSR with sorafenib delay >7 days (2), grade 4 cerebrovascular accident (1), grade 3 neutropenia >7 days (1). RP2D was sorafenib 200 mg twice a day 5/7. Most patients (62%) dose reduced sorafenib to 200 mg daily 5/7 after a median 3 (range, 2-17) cycles. Response rates were 48% overall (27) and 64% for ovarian cancers (14). VEGF-A-1154AA and -7TT recessive homozygous genotypes conferred worse overall survival versus alternative genotypes (7 vs. 22 months). Intermittent, low-dose sorafenib (200 mg twice a day 5/7) combined with bevacizumab and paclitaxel was tolerable and had high antitumor efficacy in patients with refractory cancer (NCT00572078).

Pathological complete response with anti-PD-1 therapy in a patient with microsatellite instable high, BRAF mutant metastatic colon cancer: a case report and review of literature.

IMPORTANCE: Mismatch repair (MMR) and BRAF mutation status are established independent prognostic factors for colorectal cancer (CRC). MMR deficient tumors are considered to have better prognosis whereas BRAF mutation is associated with poor prognosis. Studies evaluating the combined effect of BRAF and MMR status suggest MSI-high and BRAF mutant patients have a poorer prognosis as compared to MSI-high and BRAF wild type patients. Emerging evidence suggests MMR status predicts the immune response to anti-PD-1 therapy in CRC patients; however little is known about combined MMR and BRAF mutation status in this context. Therefore, it is important to identify whether there is a differential response to anti-PD-1 therapy based on BRAF status in the subset of MSI-high CRC patients. OBSERVATIONS: We report the first case of MSI-high, BRAF mutant metastatic CRC that had an excellent response (pathologic complete response) to anti-PD-1 therapy. We take this opportunity to review the similar cases in literature and discuss combined MMR and BRAF status as a potential biomarker for anti-PD-1 therapy. CONCLUSION AND RELEVANCE: The case presented illustrates that anti-PD-1 therapy can be effectively used to treat CRC patients with MSI-high and BRAF mutant status which is usually considered a poor prognostic category as opposed to MSI-high and BRAF wild type tumors. Future studies with anti-PD-1 therapy distinguishing these molecular subgroups will improve our knowledge of whether BRAF status can add to MMR status as a predictive biomarker for anti-PD-1 therapy in patients with metastatic CRC.