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Background: Aberrant Wnt pathway signaling has been implicated in the development of many cancers. Targeting of low-density lipoprotein receptor-related protein 5/6 (LRP5/6) co-receptors inhibits Wnt signaling and may be a novel therapy. BI 905677 is an LRP5/6 antagonist that has demonstrated preclinical antitumor activity. Patients and methods: This (NCT03604445) was a phase I, dose-escalation study evaluating BI 905677 for patients with advanced solid tumors over two dosing schedules (A: i.v. infusion every 3 weeks, 3-week cycles; B: i.v. infusion every 2 weeks, 4-week cycles). Adult patients were eligible if they had exhausted treatment options and had an Eastern Cooperative Oncology Group performance status of 0-1. The primary endpoints were the maximum tolerated dose (MTD) and safety. Other endpoints were pharmacokinetics, pharmacodynamics, and efficacy. Results:In total, 37 patients received BI 905677 over nine dose cohorts (0.05-3.6 mg/kg/every 3 weeks). Dose-limiting toxicities were only reported during cycle 1 in the 3.6 mg/kg cohort and the MTD was established at 2.8 mg/kg every 3 weeks. Enrollment for schedule B was not pursued. The most frequently reported adverse events were diarrhea (35.1%), vomiting (21.6%), and C-telopeptide increase (18.9%). All patients in the 3.6 mg/kg cohort experienced a dose-limiting toxicity, suggesting a narrow therapeutic index. Paired pre-treatment and on-treatment biopsies, where available, showed decreased Axin2 expression by reverse transcriptase polymerase chain reaction with treatment, suggesting target inhibition. Best response observed was stable disease in 14 (38%) patients. Conclusion: The MTD of BI 905677 was set at 2.8 mg/kg every 3 weeks. BI 905677 was well tolerated but a narrow therapeutic range and minimal efficacy led to early termination of the trial.

Background: Enco + cetux (doublet) has been approved in the US, EU, and Japan for the treatment of BRAF V600E-mutant mCRC after progression on 1-2 prior regimens. In the BEACON CRC study (NCT02928224), median OS (95% CI) with the doublet was 9.3 months (8.0-11.3) vs 5.9 months (5.1-7.1) with cetux + irinotecan or FOLFIRI (control) in patients (pts) with BRAF V600E-mutant mCRC (HR 0.61 [95% CI: 0.5-0.8]). This post hoc analysis investigates OS by prior therapies to the doublet treatment in pts with BRAF V600E-mutant mCRC from the BEACON CRC study. Methods : OS of pts treated with the doublet or control were compared according to prior treatment with bevacizumab, oxaliplatin or FOLFOXIRI and duration of prior anticancer therapy (ACT). Results : Sixty-four per cent and 55% of pts in the doublet and control arm respectively received prior bevacizumab. Of pts who had one prior therapy, 95% and 88% received prior oxaliplatin and 20% and 14% received prior FOLFOXIRI, respectively. In the doublet arm, pts who had bevacizumab < 4 months before start of study treatment had a median OS of 8.3 months (95% CI: 6.2-11.2); those who had bevacizumab >=4 months prior had a median OS of 10.7 (95% CI: 7.5-17.7). Within each treatment arm, OS was similar regardless of prior treatment with oxaliplatin or FOLFOXIRI. The duration of prior ACT was similar across study arms, ranging from 5.6 to 5.8 months for the first line of ACT. Conclusions : In the BEACON CRC study, pts treated with the doublet for BRAF V600E-mutant mCRC demonstrated similar OS regardless of prior therapies or duration of prior therapy use. This exploratory post hoc analysis provides data that reflect the prior treatment landscape clinicians may face when deciding subsequent treatment regimens for pts with BRAF V600E-mutant mCRC.

Background: In the BEACON study, encorafenib + binimetinib + cetuximab (enco/bini/cetux; triplet) and enco + cetux (doublet) improved OS and ORR vs standard of care in previously treated BRAF V600E-mutant mCRC pts. Molecular profiling of tumours from this study was performed to identify molecular correlates of outcome. Methods : Baseline tumour samples were analysed by whole-exome sequencing (WES) and whole transcriptome sequencing (WTS). BRAF-mutant (BM) and consensus molecular subtypes (CMS) were determined and pathway activities evaluated with gene set variation analysis. Tumour response was evaluated for each subtype. Additional association and interaction analyses between molecular features and outcomes by treatments are ongoing and will be presented. Results : Baseline tumour samples were analysed by WES and/or WTS for 79.2% of pts. Of the 460 pts analysed by WTS (73.7% in the triplet arm, 66.4% in the doublet arm, 67.4% in the control arm), 84.6% were classified as CMS1 or CMS4. Overall 32.2% of pts were classified as BM1 and the majority (84.5%) of these were CMS4. Many of those classified as BM2 (67.8%) were CMS1 (64.7%). In the BM1 and CMS4 tumours, expression of inflammatory response and epithelial mesenchymal transition genes were elevated, and expression of cell cycle genes was reduced. Response rate in pts with CMS4 and/or BM1 tumors was higher in the triplet arm (CMS4: 33.3% [95% CI: 21.7-46.7]; BM1: 33.3% [95% CI: 21.4-47.1]) vs the doublet arm (CMS4: 19.2% [95% CI: 9.6-32.5]; BM1: 14.9% [95% CI: 6.2-28.3]). Conclusions : Molecular characteristics and biological properties observed in BRAF V600E-mutant mCRC suggest a subset of pts with specific molecular features may derive greater clinical benefit from triplet vs doublet therapy. These findings support further investigating the biological landscape in BRAF-mutant mCRC to enable potential hypotheses for pt selection to improve clinical outcome in future studies.

BACKGROUND: In the BEACON CRC study (NCT02928224), encorafenib plus cetuximab with binimetinib {9.3 versus 5.9 months; hazard ratio (HR) [95% confidence interval (CI)]: 0.60 [0.47-0.75]} or without binimetinib [9.3 versus 5.9 months; HR (95% CI): 0.61 (0.48-0.77)] significantly improved overall survival (OS) compared with the previous standard of care (control) in patients with BRAF V600E metastatic colorectal cancer (mCRC). Quality of life (QoL) was a secondary endpoint, assessed using validated instruments. PATIENTS AND METHODS: BEACON CRC was a randomized, open-label, phase III study comparing encorafenib plus cetuximab with or without binimetinib and the investigator's choice of irinotecan plus cetuximab or FOLFIRI plus cetuximab (chemotherapy control) in patients with previously treated BRAF V600E mCRC. Patient-reported QoL assessments included the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC) and Functional Assessment of Cancer Therapy-Colorectal (FACT-C). The primary outcome for these tools was time to definitive 10% deterioration. RESULTS: Encorafenib plus cetuximab, both with and without binimetinib, was associated with longer median times to definitive 10% deterioration versus the control group in the EORTC Global Health Status scale [HR (95% CI): 0.65 (0.52-0.80) versus 0.61 (0.49-0.75), respectively] and the FACT-C functional well-being subscale [HR (95% CI): 0.62 (0.50-0.76) versus 0.58 (0.47-0.72), respectively]. Consistent results were observed across all subscales of the EORTC and FACT-C instruments. QoL was generally maintained during treatment for the global EORTC and FACT-C scales. CONCLUSIONS: In addition to improving OS, encorafenib plus cetuximab with or without binimetinib delays QoL decline in previously treated patients with BRAF V600E-mutant mCRC.

Background: BEACONCRC is a randomized, phase 3 study which evaluated the triplet of encorafenib (ENCO) + binimetinib (BINI) + cetuximab (CETUX) and the doublet of ENCO + CETUX vs. investigator's choice of irinotecan + CETUX or FOLFIRI + CETUX in patients (pts) with BRAFV600E metastatic colorectal cancer (mCRC) whose disease had progressed after 1-2 prior regimens in the metastatic setting. Primary endpoints were overall survival (OS) and objective response rate (ORR; by blinded central review) for triplet vs control. In a previous interim analysis, triplet and doublet improvedOS andORRversus standard of care. Here we report on an updated analysis. Method(s): Updated analysis includes 6 months of additional follow-up and response data for all randomized pts. The study is ongoing. Result(s): Patients received triplet (n = 224), doublet (n = 220), or control (n = 221). Median OS was 9.3 months (95% confidence interval [CI]:8.2, 10.8) for triplet and 5.9 months (95% CI:5.1-7.1) for control (hazard ratio [HR] (95% CI): 0.60 (0.47-0.75)). Median OS for doublet was 9.3 months (95% CI: 8.0-11.3) (HR vs control: 0.61 (0.48- 0.77). Confirmed ORR was 26.8% (95% CI: 21.1%-33.1%) for triplet, 19.5% (95% CI: 14.5%-25.4%) for doublet, and 1.8% (95% CI: 0.5%- 4.6%) for control. Retrospective subgroup analyses suggested some pts may benefit more from triplet than doublet therapy (Table). Both triplet and doublet showedimprovedOS compared to control in all subgroups. Adverse events were consistent with prior analysis, with grade >=3 adverse events in 65.8%, 57.4%, and 64.2% for triplet, doublet and control, respectively. Conclusion(s): The updated analysis of the BEACON CRC study confirmed that encorafenib + cetuximab with or without binimetinib improved OS and ORR in previously treated pts with BRAF V600E mCRC compared with standard chemotherapy.

BRAF V600E mutations are identified in <=15% of metastatic colorectal cancer (mCRC) patients and confer a poor prognosis. In patient's refractory to initial therapy, ORR to standard chemotherapy and biologic combinations are generally <10%, with median PFS and OS of ~2 and 4-6 months, respectively. The BEACON CRC Study (NCT02928224) was a multicentre, randomized, open-label, 3-arm, phase 3 study evaluating ENCO + CETUX +/- BINI (triplet or doublet combination) versus investigator's choice of Irinotecan or FOLFIRI + CETUX (control) in patients with BRAF V600E-mutant mCRC who had failed one or two prior regimens in the metastatic setting. Primary endpoints were OS and ORR (blinded central review) for the triplet versus control arm; secondary endpoints included OS for the doublet versus control arm, as well as PFS, duration of response and safety. A total of 665 patients were randomly assigned to receive: triplet combination (n= 224), doublet combination (n= 220) or control regimen (n= 221). Median OS was 9.0 months (95% CI, 8.0-11.4) for the triplet versus 5.4 months (95% CI, 4.8-6.6) for control regimens (HR: 0.52; 95% CI, 0.39-0.70; P < .0001). ConfirmedORR(blinded central review) was 26% (95% CI, 18-35%) for the triplet versus 2% (95% CI, <1% to 7%) for control (P < .0001). Median OS for the doublet was 8.4months (95% CI, 7.5-11.0) (HR vs control, 0.60; 95% CI, 0.45-0.79; P = .0003). Adverse events (AEs) were consistent with prior trials with each combination. AEs >=grade 3 occurred in 58%, 50% and 61% of patients in the triplet, doublet and control arms, respectively. ENCO + BINI + CETUX improved OS and ORR in patients with BRAF V600E-mutant mCRC compared with current standard of care chemotherapy and had a safety profile consistent with the known safety profile of each agent. This targeted therapy regimen should be a new standard of care for this patient population.

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.

PURPOSE: BEACON CRC evaluated encorafenib plus cetuximab with or without binimetinib versus investigators' choice of irinotecan or FOLFIRI plus cetuximab in patients with BRAFV600E-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 ca

Background BRAFV600E mutations are identified in 8-15% of metastatic colorectal cancer (mCRC) patients and confer a poor prognosis. In patients with BRAFV600E-mutant mCRC, the combination of encorafenib (ENCO) + cetuximab (CETUX) ± binimetinib (BINI) in second- and third-line therapy has demonstrated improved outcomes compared to standard therapies (BEACON CRC study). The ANCHOR CRC study was designed to investigate the triplet combination (ENCO + BINI + CETUX) in the first line setting of this population. Methods ANCHOR CRC is an open-label, single arm, two-stage design, phase 2 study in patients with BRAFV600E-mutant mCRC who did not receive any prior systemic therapy for metastatic disease. Patients received ENCO 300 mg orally QD + BINI 45 mg orally BID and CETUX IV weekly (250mg/m2 after a first dose of 400mg/m2) for the first 28 weeks and then once every two weeks (500mg/m2). The primary endpoint was confirmed Objective Response Rate (cORR) based on local review; secondary endpoints included duration of response (DOR), progression-free survival (PFS), overall survival (OS) and safety. Analysis for Stage 1 was performed after the first 40 evaluable patients with a centrally confirmed BRAFV600E mutation had completed four post-baseline tumor assessments or discontinued. At least 12 responses in Stage 1 were needed to initiate Stage 2 and to enroll 50 additional patients to complete the recruitment with a total of 90 patients in the study. Stage 1 analysis results are presented here. Results Forty-one BRAFV600E-mutant mCRC patients with a median age of 67 years old (61% of the patients were ≥ 65 years old) were enrolled in Stage 1 and received the triplet combination as first line metastatic treatment. At study entry, 56% of patients presented with ECOG PS 1, 78% had metastases to at least 2 organs and 51% had peritoneal metastasis. Forty patients were evaluable for efficacy (BRAFV600E mutation was not centrally confirmed for one patient). The investigator assesse

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