TR study of ‘A multi-center proof-of-concept phase2 study of encorafenib + binimetinib + cetuximab in patients with BRAF non-V600E mutated metastatic colorectal cancer (BIGBANG study)"
Ontology highlight
ABSTRACT:
DISEASE(S): Colorectal Cancer
PROVIDER: 2647002 | ecrin-mdr-crc |
REPOSITORIES: ECRIN MDR
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Project description:BRAFV600-mutated colorectal cancer (CRC) accounts for 8% to 12% of all CRC diagnoses. These tumors are often associated with specific patient features, including right-sided primary tumor location, peritoneal and non-regional lymph node involvement, and poor prognosis. In approximately 30% of cases, a simultaneous mismatch repair deficient (dMMR)/microsatellite instability-high (MSI-H) phenotype is identified. The prognostic impact of the BRAF mutation appears to be less marked in patients with MSI-H CRC than in patients with microsatellite stable (MSS) tumor. The treatment of BRAFV600-mutated CRC is still a challenge for the clinicians, mainly due to the poor survival outcomes obtained with traditional chemotherapy regimens. In recent years, two novel treatment strategies have offered remarkable changes in the treatment of this specific patient subgroup. The first approach has included targeted therapies directed against BRAF and MEK, with support from the epidermal growth factor receptor (EGFR) blockade. The second approach has included immunotherapeutic agents that have been shown to be particularly promising for patients with simultaneous dMMR/MSI-H phenotype. Here we review the clinical trials that specifically enrolled patients with BRAF-mutated CRC, from the phase I/II studies to the phase III trial BEACON CRC. We also examine the future directions towards a molecularly guided therapy for patients with BRAF-mutated CRC and the crucial role of a molecularly and clinically based algorithm in order to offer the best choice of treatment for these patients.
| S-EPMC7260582 | biostudies-literature
Project description:Interventions: Combination therapy of encorafenib + binimetinib+ cetuximab One cycle is 28 days. Binimetinib: 45 mg, twice daily, oral Encorafenib: 300 mg, once daily, oral Cetuximab: 400 mg/m2 for initial dose, 250 mg/m2 for subsequent doses, weekly, intravenous infusion
Primary outcome(s): Confirmed objective response rate by investigators’ assessment
Study Design: Single arm Non-randomized
| 2646999 | ecrin-mdr-crc
Project description:BackgroundTriplet and doublet regimens of encorafenib plus cetuximab with and without binimetinib, respectively, were approved in Japan for unresectable, metastatic, BRAF V600E-mutated colorectal cancer (mCRC) that had progressed after 1-2 prior chemotherapies. This early post-marketing phase vigilance (EPPV) study collected adverse drug reactions (ADRs) from Japanese patients to ensure safety measures as appropriate.MethodsPatients with BRAF V600E mCRC who received the triplet or doublet regimens in Japan were selected for this study. ADRs were collected as spontaneous reports between November 27, 2020 and May 26, 2021. Serious ADRs were evaluated according to guidelines of the International Council for Harmonisation and the EudraVigilance list of Important Medical Event Terms.ResultsAn estimated 550 Japanese patients with mCRC received the triplet or doublet regimens during the 6-month EPPV period. Overall, 101 and 42 patients reported ADRs and serious ADRs, respectively. No ADRs leading to death were reported. The most frequently reported ADRs were nausea (17 patients), serous retinal detachment (16), decreased appetite (12), diarrhea (11), and vomiting (11). Among the important identified/potential risks that are defined in the risk management plans for encorafenib and binimetinib, eye disorder-related ADRs were observed in 32 patients, rhabdomyolysis-related ADRs in 12, hemorrhage-related ADRs in 7, and hepatic dysfunction-related ADRs in 7. Of 22 patients with serious eye disorders, 20 recovered or were recovering during the EPPV period.ConclusionThe safety profile in this EPPV study was similar to that from the phase III BEACON CRC study and no new safety concerns were identified.
| S-EPMC9823055 | biostudies-literature
Project description: Not available
| S-EPMC9660876 | biostudies-literature
Project description:BackgroundEncorafenib plus cetuximab with or without binimetinib showed increased objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) compared with chemotherapy plus anti-EGFR in previously treated patients with BRAF V600E-mutated (mut) metastatic colorectal cancer (mCRC). Although no formal comparison was planned, addition of binimetinib to encorafenib plus cetuximab did not provide significant efficacy advantage.Patients and methodsThis real-life study was aimed at evaluating safety, activity, and efficacy of encorafenib plus cetuximab with or without binimetinib in patients with BRAF V600E-mut mCRC treated at 21 Italian centers within a nominal use program launched in May 2019.ResultsOut of 133 patients included, 97 (73%) received encorafenib plus cetuximab (targeted doublet) and 36 (27%) the same therapy plus binimetinib (targeted triplet). Most patients had Eastern Cooperative Group Performance Status (ECOG-PS) of 0 or 1 (86%), right-sided primary tumor (69%), and synchronous disease (66%). Twenty (15%) tumors were DNA mismatch repair deficiency (dMMR)/microsatellite instability (MSI)-high. As many as 44 (34%) patients had received two or more prior lines of therapy, 122 (92%) were previously exposed to oxaliplatin, and 109 (82%) to anti-vascular endothelial growth factor (anti-VEGF). Most frequent adverse events were asthenia (62%) and anti-EGFR-related skin rash (52%). Any grade nausea (P = 0.03), vomiting (P = 0.04), and diarrhea (P = 0.07) were more frequent with the triplet therapy, while melanocytic nevi were less common (P = 0.06). Overall, ORR and disease control rate (DCR) were 23% and 69%, respectively, with numerically higher rates in the triplet group (ORR 31% versus 17%, P = 0.12; DCR 78% versus 65%, P = 0.23). Median PFS and OS were 4.5 and 7.2 months, respectively. Worse ECOG-PS, peritoneal metastases, and more than one prior treatment were independent poor prognostic factors for PFS and OS. Clonality of BRAF mutation measured as adjusted mutant allele fraction in tumor tissue was not associated with clinical outcome.ConclusionsOur real-life data are consistent with those from the BEACON trial in terms of safety, activity, and efficacy. Patients in good general condition and not heavily pretreated are those more likely to derive benefit from the targeted treatment.
| S-EPMC9271503 | biostudies-literature
Project description:Encorafenib, a BRAF kinase inhibitor, in combination with binimetinib, a selective MEK inhibitor have known gastrointestinal adverse events; however, adverse colitis events have not been well studied. We report a case series of 4 patients with melanoma who developed inflammatory colitis after BRAF and MEK inhibition with encorafenib and binimetinib, respectively. In the setting of immune checkpoint inhibitor use, BRAF and MEK inhibitors can cause significant inflammatory colitis with endoscopic patterns of predominant right colon ulcerations. It can lead to significant morbidity and frequent interruption of cancer treatment. Early recognition and prompt intervention are critical to improving patient outcomes.
| S-EPMC9247533 | biostudies-literature
Project description:BackgroundIn 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 methodsBEACON 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.ResultsEncorafenib 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.ConclusionsIn addition to improving OS, encorafenib plus cetuximab with or without binimetinib delays QoL decline in previously treated patients with BRAF V600E-mutant mCRC.
| S-EPMC9271477 | biostudies-literature
Project description:PurposeTo 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 methodsBefore 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.ResultsAmong 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).ConclusionIn 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.
| S-EPMC7370699 | biostudies-literature
Project description:BACKGROUND:Sixty percent of patients with stage IV melanoma may develop brain metastases, which result in significantly increased morbidity and a poor overall prognosis. Phase 3 studies of melanoma usually exclude patients with untreated brain metastases; therefore, clinical data for intracranial responses to treatments are limited. METHODS:A multicenter, retrospective case series investigation of consecutive BRAF-mutant patients with melanoma brain metastases (MBMs) treated with a combination of BRAF inhibitor encorafenib and MEK inhibitor binimetinib was conducted to evaluate the antitumor response. Assessments included the intracranial, extracranial, and global objective response rates (according to the modified Response Evaluation Criteria in Solid Tumors, version 1.1); the clinical benefit rate; the time to response; the duration of response; and safety. RESULTS:A total of 24 patients with stage IV BRAF-mutant MBMs treated with encorafenib plus binimetinib in 3 centers in the United States were included. Patients had received a median of 2.5 prior lines of treatment, and 88% had prior treatment with BRAF/MEK inhibitors. The intracranial objective response rate was 33%, and the clinical benefit rate was 63%. The median time to a response was 6 weeks, and the median duration of response was 22 weeks. Among the 21 patients with MBMs and prior BRAF/MEK inhibitor treatment, the intracranial objective response rate was 24%, and the clinical benefit rate was 57%. Similar outcomes were observed for extracranial and global responses. The safety profile for encorafenib plus binimetinib was similar to that observed in patients with melanoma without brain metastases. CONCLUSIONS:Combination therapy with encorafenib plus binimetinib elicited intracranial activity in patients with BRAF-mutant MBMs, including patients previously treated with BRAF/MEK inhibitors. Further prospective studies are warranted and ongoing.
| S-EPMC7004095 | biostudies-literature
Project description:Combination treatment using BRAF/MEK inhibitors is a promising therapy for patients with advanced BRAFV600E/K mutant melanoma. However, acquired resistance largely limits the clinical efficacy of this drug combination. Identifying resistance mechanisms is essential to reach long-term, durable responses. During this study, we developed six melanoma cell lines with acquired resistance for BRAFi/MEKi treatment and defined the molecular alterations associated with drug resistance. We observed that the invasion of three resistant cell lines increased significantly compared to the sensitive cells. RNA-sequencing analysis revealed differentially expressed genes that were functionally linked to a variety of biological functions including epithelial-mesenchymal transition, the ROS pathway, and KRAS-signalling. Using proteome profiler array, several differentially expressed proteins were detected, which clustered into a unique pattern. Galectin showed increased expression in four resistant cell lines, being the highest in the WM1617E+BRes cells. We also observed that the resistant cells behaved differently after the withdrawal of the inhibitors, five were not drug addicted at all and did not exhibit significantly increased lethality; however, the viability of one resistant cell line (WM1617E+BRes) decreased significantly. We have selected three resistant cell lines to investigate the protein expression changes after drug withdrawal. The expression patterns of CapG, Enolase 2, and osteopontin were similar in the resistant cells after ten days of "drug holiday", but the Snail protein was only expressed in the WM1617E+BRes cells, which showed a drug-dependent phenotype, and this might be associated with drug addiction. Our results highlight that melanoma cells use several types of resistance mechanisms involving the altered expression of different proteins to bypass drug treatment.
| S-EPMC8656772 | biostudies-literature