Regorafenib is an oral tyrosine kinase inhibitor (TKI) approved for the treatment of refractory metastatic colorectal cancer (mCRC), advanced gastrointestinal stromal tumors (GIST) previously treated with imatinib and sunitinib, and unresectable hepatocellular carcinoma (HCC) following progression on sorafenib. Regorafenib was initially approved for mCRC based on improved overall survival (OS) in the randomized, placebo-controlled, phase 3 CORRECT trial, which was confirmed in an expanded population of Asian patients in the randomized, placebo-controlled phase 3 CONCUR trial. Approvals in GIST, and more recently in HCC, were based on the results from the randomized, placebo-controlled, phase 3 GRID and RESORCE trials, respectively. In this review, we provide a comprehensive summary of the clinical evidence for approval of regorafenib in mCRC, GIST, and HCC, present emerging evidence of regorafenib activity in other tumor types (namely, gastroesophageal cancer, sarcomas, biliary tract cancer, and glioblastoma), and discuss trials in progress within the context of regorafenib's mechanism of action. We describe recent advances and key lessons learned with regorafenib, including the importance of managing common drug-related toxicities using dose-optimization strategies, the search for biomarkers to predict response to treatment, and highlight some of the unaddressed questions and future directions for regorafenib across tumors.

PURPOSE: The positive BEACON colorectal cancer (CRC) safety lead-in, evaluating encorafenib + cetuximab + binimetinib in previously treated patients with BRAF^V600E-mutated metastatic CRC (mCRC), prompted the design of the phase II ANCHOR CRC study (ClinicalTrails.gov identifier: NCT03693170 ). ANCHOR CRC aimed to evaluate efficacy, safety, and quality of life with first-line encorafenib + binimetinib + cetuximab in BRAF^V600E-mutated mCRC. METHODS: In this multicenter, open-label, single-arm study, patients with BRAF^V600E-mutated mCRC received oral encorafenib 300 mg once daily and binimetinib 45 mg twice daily in 28-day cycles, plus intravenous cetuximab 400 mg/m² once on day 1 of cycle 1, then 250 mg/m² once weekly for the first seven cycles, and 500 mg/m² once on Days 1 and 15 from cycle 8 onward. The primary end point was locally assessed confirmed objective response rate (cORR), and secondary end points included centrally assessed cORR, progression-free survival, overall survival (OS), quality of life, and safety and tolerability. RESULTS: Among 95 patients, the locally assessed cORR was 47.4% (95% CI, 37.0 to 57.9) with all partial responses. Since the lower limit of the 95% CI exceeded 30%, the primary end point was met. With a median follow-up duration of 20.1 months, the median progression-free survival on the basis of local assessments was 5.8 months and the median OS was 18.3 months. Treatment was well tolerated, with no unexpected toxicities. Using Patient Global Impression of Changes, substantial improvement in symptoms was consistently reported in ≥ 30% of patients from cycle 3 to cycle 10. CONCLUSION: The ANCHOR CRC study showed that the scientifically driven combination of encorafenib + binimetinib + cetuximab was active in the first-line setting of BRAF^V600E-mutated mCRC with a manageable safety profile. Further first-line evaluation is ongoing (ClinicalTrails.gov identifier: NCT04607421 ).

Background: Our study investigated the demographic characteristics of Mayo Clinic Colon and Rectal Cancer Registry patients and sought to associate tumor location with overall survival. Methods: Using the cohort of patients seen at Mayo Clinic (Minnesota, Arizona, Florida) from 1972 to 2017, we obtained 26,908 colorectal adenocarcinoma patient records. Overall survival of patients with colorectal cancer was analyzed by sidedness (right vs. left) and location (right vs. left vs. rectum). Kaplan–Meier method was used to analyze all demographic and cancer variables available within the dataset to trace survival over a 35-year period. Subgroups within variables were compared to each other using log-rank test and considered significantly different at P < 0.05. Cox proportional hazards regression model was used to assess impact of tumor location while controlling for age, year of diagnosis, sex, tumor stage, and tumor grade. Cox regression models were used to evaluate the independent effect of cancer location on overall survival after adjusting for age, gender, year of diagnosis, and cancer stage. To further explore the potential interaction effect of cancer location with cancer stage and year of diagnosis, similar multivariable Cox model was fit stratified by cancer stage (1–3 vs. 4) and by year of diagnosis (2000). Results: Overall survival differed significantly within all variables studied after Kaplan–Meier method analysis (P < 0.0001). Survival was higher in the left-side group when evaluated by tumor sidedness, and rectal cancer patients had the highest median survival (101.3 months). Right-sided cancer patients had the worst prognosis in both tumor location and sidedness analyses, with a median survival of 76.6 months. However, the stratified analysis showed that, the difference in survival between left- and right-sided cancer only existed in late cancer stage (stage 4) patients but not in early cancer stage; therefore, screening for CRC to pick cancer at an early stage can influence overall survival significantly. Conclusion: These observations confirm some of the previous and recent studies on sidedness of colorectal cancer patients. Our analysis is novel in that it included patients of all stages rather than just stage IV metastatic patients. This initial study provides a platform to investigate more biologic and clinical factors associated with tumor location. Merging this dataset with other available datasets and previously conducted studies within the institution will provide a robust platform for multiple future studies and collaborations. Finally, appropriate screening can result in a decrease in incidence and mortality of CRC.

In the precision medicine era, molecular testing in advanced cancer is foundational to patient management. Molecular tumor boards (MTBs) can be effective in processing comprehensive genomic profiling (CGP) results and providing expert recommendations. We assessed an MTB and its role in a community setting. This retrospective analysis included patients with MTB recommendations at a community-based oncology practice January 2015 to December 2018; exclusions were death within 60 days of the MTB and/or no metastatic disease. Potentially actionable genomic alterations from CGP (immunohistochemistry, in-situ hybridization, next-generation sequencing) were reviewed bi-weekly by MTB practice experts, pathologists, genetic counselors, and other support staff, and clinical care recommendations were provided. Subsequent chart reviews determined implementation rates of recommendations. In 613 patients, the most common cancers were lung (23%), breast (19%), and colorectal (17%); others included ovarian, endometrial, bladder, and melanoma. Patients received 837 actionable recommendations: standard therapy (37%), clinical trial (31%), germline testing and genetic counseling (17%), off-label therapy (10%), subspecialty multidisciplinary tumor board review (2%), and advice for classifying tumor of unknown origin (2%). Of these recommendations, 36% to 78% were followed by the treating physician. For clinical trial recommendations (n = 262), 13% of patients enrolled in a clinical trial. The median time between CPG result availability and MTB presentation was 12 days. A community oncology-based comprehensive and high-throughput MTB provided useful clinical guidance in various treatment domains within an acceptable timeframe for patients with cancer in a large community setting.

Colorectal cancer is the second leading cause of cancer deaths worldwide, with a 5-year relative survival of 14% in patients with metastatic colorectal cancer (mCRC). Patients with BRAF V600E mutations, which occur in ∼10%-15% of patients with mCRC, have a poorer prognosis compared with those with wild-type BRAF tumours. The combination of the BRAF inhibitor encorafenib with the epidermal growth factor receptor inhibitor cetuximab currently represents the only chemotherapy-free targeted therapy approved in the USA and Europe for previously treated patients with BRAF V600E-mutated mCRC. As a class, BRAF inhibitors are associated with dermatologic, gastrointestinal, and renal events, as well as pyrexia and secondary skin malignancies. Adverse event (AE) profiles of specific BRAF inhibitors vary, however, and are affected by the specific agents given in combination. In patients with mCRC, commonly reported AEs of cetuximab monotherapy include infusion reactions and dermatologic toxicities. Data from the phase III BEACON CRC study indicate that the combination of encorafenib with cetuximab has a distinct safety profile. Here we review the most frequently reported AEs that occurred with this combination in BEACON CRC and best practices for managing and mitigating AEs that require more than standard supportive care.