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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., Competing Interests: Disclosure JT declares a consulting or advisory role with Array BioPharma, AstraZeneca, Bayer, BeiGene, Biocartis, Boehringer Ingelheim, Chugai Pharma, Eli Lilly, Foundation Medicine, Genentech, Genmab, HalioDX SAS, Halozyme, Imugene Limited, Inflection Biosciences Limited, Ipsen, Kura, Menarini, Merck Serono, Merck Sharp & Dohme, Merrimack, Merus, Molecular Partners, Novartis, Peptomyc, Pfizer, Pharmacyclics, ProteoDesign SL, Rafael Pharmaceuticals, Roche, Roche Diagnostics, Sanofi, Seattle Genetics, Servier, Symphogen, Taiho Pharmaceutical, and VCN Biosciences. TLT declares a consulting or advisory role with Pfizer and an academic advisory role for continuing medical education. AG declares honoraria from Aptitude Health and Elsevier; consulting or advisory role with Amgen (Inst), Array BioPharma (Inst), Bayer (Inst), Boston Biomedical (Inst), Bristol Myers Squibb (Inst), Daiichi Sankyo (Inst), Eli Lilly (Inst), Genentech (Inst), and Guardant Health (Inst); institutional research funding from Array BioPharma, Bayer, Boston Biomedical, Daiichi Sankyo, Eisai, Eli Lilly, Genentech, and Pfizer; travel, accommodations, and expenses from Amgen, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Boston Biomedical, Genentech, and Merck Sharp & Dohme. RY declares institutional research funding from Array BioPharma and Boehringer Ingelheim; consulting fees from Array BioPharma, Mirati Therapeutics and Natera. EVC declares a consulting or advisory role with Array, AstraZeneca, Bayer, Biocartis, Bristol Myers Squibb, Celgene, Eli Lilly, Ipsen, Merck KGaA, Merck Sharp & Dohme, Novartis, Pierre Fabre, Roche, Servier, Sirtex, and Taiho; institutional research funding from Amgen, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Eli Lilly, Ipsen, Merck, Merck KGaA, Novartis, Roche, and Servier. EVC declares consulting or advisory role for AstraZeneca, Bayer, Biocartis, Bristol Myers Squibb, Celgene, Eli Lilly, Ipsen, Merck Sharp & Dohme, Merck KGaA, Novartis, Pierre Fabre, Roche, Servier, Sirtex, Taiho, and Pfizer; institutional research funding from Amgen (Inst), Bayer (Inst), Boehringer Ingelheim (Inst), Eli Lilly (Inst), Novartis (Inst), Roche (Inst), Celgene (Inst), Ipsen (Inst), Merck (Inst), Merck KGaA (Inst), Servier (Inst), and Bristol Myers Squibb (Inst). HW declares honoraria from Amgen, Array BioPharma, Celgene, ERYTECH Pharma, Genentech, Merck KGaA, Pierre Fabre, Servier, Shire, Sirtex Medical, and Zymeworks; a consulting or advisory role with ERYTECH Pharma, Incyte, Roche Pharma AG, Shire, and Sirtex Medical; speakers' bureau with Celgene, Merck KGaA, Servier, and Sirtex Medical; institutional research funding from Merck KGaA, Merck Sharp & Dohme, Pfizer, and Sirtex Medical. JD declares a consulting or advisory role with BeiGene, Bionomics, Eisai, Eli Lilly, and Ignyta; institutional research funding from BeiGene, Bionomics, Bristol Myers Squibb, Eli Lilly, GlaxoSmithKline, MedImmune, Novartis, and Roche. FC declares a consulting or advisory role with Amgen, Bayer, Genentech, Merck KGaA, and Pfizer; institutional research funding from Amgen, Bayer, Bristol Myers Squibb, Genentech, Ipsen, Merck KGaA, Merck Sharp & Dohme, Servier, and Symphogen. TY declares institutional research funding from Chugai Pharma, GlaxoSmithKline, Sanofi, and Sumitomo Dainippon. AG, KM, and JC-B declare employment with Pfizer Inc. SK declares stock and other ownership interests in MolecularMatch and Navire; a consulting or advisory role with Amal Therapeutics, Amgen, Biocartis, Boehringer Ingelheim, Eli Lilly, EMD Serono, Genentech, Holy Stone, Karyopharm Therapeutics, Merck, Navire Pharma, Novartis, Roche, and Symphogen; institutional research funding from Amgen, Array BioPharma, Biocartis, EMD Serono, Genentech, Guardant Health, MedImmune, Novartis, and Sanofi. LV has declared no conflicts of interest. Ethics approval The BEACON CRC study was conducted in accordance with the requirements of each country's regulatory authorities as well as the provisions of the Declaration of Helsinki and Good Clinical Practice guidelines, as defined by the International Council for Harmonisation. All patients who participated in the trial provided written informed consent. This trial was approved by the institutional review board or independent ethics committee at each centre. Data sharing The majority of data presented are from previously published sources. A small amount of unpublished data from the BEACON CRC study has been included and is not publicly available., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Purpose: BEACON CRC evaluated encorafenib plus cetuximab with or without binimetinib versus investigators' choice of irinotecan or FOLFIRI plus cetuximab in patients with BRAF V600E-mutant metastatic colorectal cancer (mCRC), after progression on 1-2 prior regimens. In the previously reported primary analysis, encorafenib, binimetinib plus cetuximab (ENCO/BINI/CETUX; triplet) and encorafenib plus cetuximab (ENCO/CETUX; doublet) regimens improved overall survival (OS) and objective response rate (ORR; by blinded central review) versus standard of care. The purpose of this analysis was to report updated efficacy and safety data., Methods: In this open-label, phase III trial, 665 patients with BRAF V600E-mutant mCRC were randomly assigned 1:1:1 to receive triplet, doublet, or control. Primary end points were OS and independently reviewed ORR comparing triplet to control. OS for doublet versus control was a key secondary end point. Updated analyses include 6 months of additional follow-up and ORR for all randomized patients., Results: Patients received triplet (n = 224), doublet (n = 220), or control (n = 221). Median OS was 9.3 months (95% CI, 8.2 to 10.8) for triplet and 5.9 months (95% CI, 5.1 to 7.1) for control (hazard ratio [HR], 0.60 [95% CI, 0.47 to 0.75]). Median OS for doublet was 9.3 months (95% CI, 8.0 to 11.3) (HR v control, 0.61 [95% CI, 0.48 to 0.77]). Confirmed ORR was 26.8% (95% CI, 21.1% to 33.1%) for triplet, 19.5% (95% CI, 14.5% to 25.4%) for doublet, and 1.8% (95% CI, 0.5% to 4.6%) for control. Adverse events were consistent with the prior primary analysis, with grade ≥ 3 adverse events in 65.8%, 57.4%, and 64.2% for triplet, doublet, and control, respectively., Conclusion: In the BEACON CRC study, encorafenib plus cetuximab improved OS, ORR, and progression-free survival in previously treated patients in the metastatic setting compared with standard chemotherapy. Based on the primary and updated analyses, encorafenib plus cetuximab is a new standard care regimen for previously treated patients with BRAF V600E mCRC.

Purpose: Low-grade serous ovarian carcinomas (LGSOCs) have historically low chemotherapy responses. Alterations affecting the MAPK pathway, most commonly KRAS/BRAF, are present in 30%-60% of LGSOCs. The purpose of this study was to evaluate binimetinib, a potent MEK1/2 inhibitor with demonstrated activity across multiple cancers, in LGSOC., Methods: This was a 2:1 randomized study of binimetinib (45 mg twice daily) versus physician's choice chemotherapy (PCC). Eligible patients had recurrent measurable LGSOC after ≥ 1 prior platinum-based chemotherapy but ≤ 3 prior chemotherapy lines. The primary end point was progression-free survival (PFS) by blinded independent central review (BICR); additional assessments included overall survival (OS), overall response rate (ORR), duration of response (DOR), clinical-benefit rate, biomarkers, and safety., Results: A total of 303 patients were randomly assigned to an arm of the study at the time of interim analysis (January 20, 2016). Median PFS by BICR was 9.1 months (95% CI, 7.3 to 11.3) for binimetinib and 10.6 months (95% CI, 9.2 to 14.5) for PCC (hazard ratio,1.21; 95%CI, 0.79 to 1.86), resulting in early study closure according to a prespecified futility boundary after 341 patients had enrolled. Secondary efficacy end points were similar in the two groups: ORR 16% (complete response [CR]/partial responses[PRs], 32) versus 13% (CR/PRs, 13); median DOR, 8.1 months (range, 0.03 to ≥ 12.0 months) versus 6.7 months (0.03 to ≥ 9.7 months); and median OS, 25.3 versus 20.8 months for binimetinib and PCC, respectively. Safety results were consistent with the known safety profile of binimetinib; the most common grade ≥ 3 event was increased blood creatine kinase level (26%). Post hoc analysis suggests a possible association between KRAS mutation and response to binimetinib. Results from an updated analysis (n = 341; January 2019) were consistent., Conclusion: Although the MEK Inhibitor in Low-Grade Serous Ovarian Cancer Study did not meet its primary end point, binimetinib showed activity in LGSOC across the efficacy end points evaluated. A higher response to chemotherapy than expected was observed and KRAS mutation might predict response to binimetinib.

Background: Patients with metastatic colorectal cancer with the BRAF V600E mutation have a poor prognosis, with a median overall survival of 4 to 6 months after failure of initial therapy. Inhibition of BRAF alone has limited activity because of pathway reactivation through epidermal growth factor receptor signaling., Methods: In this open-label, phase 3 trial, we enrolled 665 patients with BRAF V600E-mutated metastatic colorectal cancer who had had disease progression after one or two previous regimens. Patients were randomly assigned in a 1:1:1 ratio to receive encorafenib, binimetinib, and cetuximab (triplet-therapy group); encorafenib and cetuximab (doublet-therapy group); or the investigators' choice of either cetuximab and irinotecan or cetuximab and FOLFIRI (folinic acid, fluorouracil, and irinotecan) (control group). The primary end points were overall survival and objective response rate in the triplet-therapy group as compared with the control group. A secondary end point was overall survival in the doublet-therapy group as compared with the control group. We report here the results of a prespecified interim analysis., Results: The median overall survival was 9.0 months in the triplet-therapy group and 5.4 months in the control group (hazard ratio for death, 0.52; 95% confidence interval [CI], 0.39 to 0.70; P<0.001). The confirmed response rate was 26% (95% CI, 18 to 35) in the triplet-therapy group and 2% (95% CI, 0 to 7) in the control group (P<0.001). The median overall survival in the doublet-therapy group was 8.4 months (hazard ratio for death vs. control, 0.60; 95% CI, 0.45 to 0.79; P<0.001). Adverse events of grade 3 or higher occurred in 58% of patients in the triplet-therapy group, in 50% in the doublet-therapy group, and in 61% in the control group., Conclusions: A combination of encorafenib, cetuximab, and binimetinib resulted in significantly longer overall survival and a higher response rate than standard therapy in patients with metastatic colorectal cancer with the BRAF V600E mutation. (Funded by Array BioPharma and others; BEACON CRC ClinicalTrials.gov number, NCT02928224; EudraCT number, 2015-005805-35.)., (Copyright © 2019 Massachusetts Medical Society.)

Purpose: To determine the safety and preliminary efficacy of selective combination targeted therapy for BRAF V600E-mutant metastatic colorectal cancer (mCRC) in the safety lead-in phase of the open-label, randomized, three-arm, phase III BEACON Colorectal Cancer trial ( ClinicalTrials.gov identifier: NCT02928224; European Union Clinical Trials Register identifier: EudraCT2015-005805-35)., Patients and Methods: Before initiation of the randomized portion of the BEACON Colorectal Cancer trial, 30 patients with BRAF V600E-mutant mCRC who had experienced treatment failure with one or two prior regimens were to be recruited to a safety lead-in of encorafenib 300 mg daily, binimetinib 45 mg twice daily, plus standard weekly cetuximab. The primary end point was safety, including the incidence of dose-limiting toxicities. Efficacy end points included overall response rate, progression-free survival, and overall survival., Results: Among the 30 treated patients, dose-limiting toxicities occurred in five patients and included serous retinopathy (n = 2), reversible decreased left ventricular ejection fraction (n = 1), and cetuximab-related infusion reactions (n = 2). The most common grade 3 or 4 adverse events were fatigue (13%), anemia (10%), increased creatine phosphokinase (10%), increased AST (10%), and urinary tract infections (10%). In 29 patients with BRAF V600E-mutant tumors (one patient had a non- BRAF V600E-mutant tumor and was not included in the efficacy analysis), the confirmed overall response rate was 48% (95% CI, 29.4% to 67.5%), median progression-free survival was 8.0 months (95% CI, 5.6 to 9.3 months), and median overall survival was 15.3 months (95% CI, 9.6 months to not reached), with median duration of follow-up of 18.2 months (range, 16.6 to 19.8 months)., Conclusion: In the safety lead-in, the safety and tolerability of the encorafenib, binimetinib, and cetuximab regimen is manageable and acceptable for initiation of the randomized portion of the study. The observed efficacy is promising compared with available therapies and, if confirmed in the randomized portion of the trial, could establish this regimen as a new standard of care for previously treated BRAF V600E-mutant mCRC.

Background The MAPK pathway plays a central role in regulation of several cellular processes, and its dysregulation is a hallmark of biliary tract cancer (BTC). Binimetinib (MEK162), a potent, selective oral MEK1/2 inhibitor, was assessed in patients with advanced BTC. Patients and Methods An expansion cohort study in patients who received ≤1 line of therapy for advanced BTC was conducted after determination of the maximum tolerated dose in this Phase 1 trial. Patients received binimetinib 60 mg twice daily. The primary objectives were to characterize the safety profile and pharmacokinetics of binimetinib in advanced BTC. Secondary objectives included assessment of clinical efficacy, changes in weight and lean body mass, and pharmacodynamic effects. Tumor samples were assessed for mutations in relevant genes. Results Twenty-eight patients received binimetinib. Common adverse events (AEs) were mild, with rash (82%) and nausea (54%) being most common. Two patients experienced grade 4 AEs, one generalized edema and the other pulmonary embolism. The pharmacokinetics in this patient population were consistent with those previously reported (Bendell JC et al., Br J Cancer 2017;116:575-583). Twelve patients (43%) experienced stable disease and two had objective responses (1 complete response, 1 partial response) per Response Evaluation Criteria in Solid Tumors and stable metabolic disease by positron emission tomography/computed tomography. Most patients (18/25; 72%) did not have KRAS, BRAF, NRAS, PI3KCA, or PTEN mutations, nor was there correlation between mutation status and response. The average non-fluid weight gain was 1.3% for lean muscle and 4.7% for adipose tissue. Conclusion Binimetinib was well tolerated and showed promising evidence of activity in patients with BTC. Correlative studies suggested the potential for binimetinib to promote muscle gain in patients with BTC.

Study Objectives: To evaluate the safety, tolerability, and pharmacokinetics of increasing dose levels of oral dolasetron mesylate, a new 5-HT3 antagonist., Design: Double-blind, placebo-controlled, dose-ranging phase I study., Setting: A clinical research center., Patients: Forty healthy male volunteers., Interventions: Eight subjects at each dose level were randomized in a ratio of 3:1 to receive either dolasetron mesylate 25, 50, 100, 150, or 200 mg in a single oral dose on days 1 and 9, and twice/day on days 2-8, or placebo for 9 days., Measurements and Main Results: Dolasetron was well tolerated at all dose levels. The adverse event rates for dolasetron- and placebo-treated subjects who experienced at least one adverse event were 80% and 50%, respectively. Most frequently reported by subjects receiving dolasetron were headache, constipation, flatulence, and lightheadedness. They generally were mild, and none was severe. No dose-response relationship was apparent for any adverse event. There were no clinically significant changes in mean laboratory values or vital signs. Asymptomatic treatment-related electrocardiographic changes were consistent with the drug's electrophysiologic properties. These changes have been well characterized and have thus far been clinically unimportant. Pharmacokinetics of the reduced metabolite were dose independent, and multiple-dose exposure of this metabolite can be predicted from its single-dose values., Conclusion: Oral dolasetron mesylate was well tolerated when administered in doses up to 200 mg/day for 9 days in healthy volunteers.