encorafenib and Colonic-Neoplasms

Encorafenib is a B-Raf proto-oncogene serine/threonine-protein kinase (BRAF) inhibitor, approved in the EU and USA, in combination with the epidermal growth factor receptor (EGFR) inhibitor cetuximab, for the treatment of patients with BRAF

Topics: Cetuximab; Colonic Neoplasms; ErbB Receptors; Humans; Nursing Care; Proto-Oncogene Proteins B-raf; Rectal Neoplasms

The BRAF inhibitor encorafenib in combination with cetuximab was recently approved for patients with BRAF. AEIs, including dermatological AEs, arthralgia/myalgia, nausea/vomiting, diarrhea, abdominal pain, fatigue/asthenia and nephrotoxicity, were examined in the doublet therapy group. Clinical characteristics associated with these AEs, AE grade, time to onset and time to resolution were also studied.. Safety analysis included 216/220 patients randomized to doublet therapy. The most commonly occurring AEI was dermatological toxicity (75.5%), followed by arthralgia/myalgia (56.0%) and fatigue/asthenia (56.0%). Other than nephrotoxicity (7 patients; 5/7 with Grade 3 or 4), most AEs were Grade 1 or 2. Most AEs were more common in women than men (nausea/vomiting, diarrhea, abdominal pain, dermatological AEs, and arthralgia/myalgia). Nausea/vomiting, abdominal pain and fatigue/asthenia were more common in patients aged ≥70 years. Most AEs developed early, within the first 1-2 months of treatment, and resolved within 1-2 weeks. In addition, survival outcomes were better in patients experiencing arthralgia/myalgia or dermatological toxicities.. This analysis indicated that, except for rare cases of nephrotoxicity, encorafenib+cetuximab is well tolerated in most patients, with most AEIs being mild-to-moderate in severity, occurring early and resolving rapidly.. the BEACON study (ClinicalTrials.gov, NCT02928224; EudraCT, 2015-005805-35).

Topics: Antineoplastic Combined Chemotherapy Protocols; Asthenia; Cetuximab; Colonic Neoplasms; Colorectal Neoplasms; Fatigue; Female; Humans; Male; Mutation; Myalgia; Nausea; Proto-Oncogene Proteins B-raf; Rectal Neoplasms; Vomiting

Encorafenib 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.. This 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.. Out 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.. Our 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.

Topics: Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Carbamates; Cetuximab; Colonic Neoplasms; Colorectal Neoplasms; Humans; Proto-Oncogene Proteins B-raf; Sulfonamides

The BEACON CRC randomised controlled trial (NCT02928224) in BRAF-mutant metastatic colorectal cancer (mCRC) patients showed improved overall survival for the combination treatment of encorafenib (BRAF inhibitor) with cetuximab (EGFR inhibitor) compared with cetuximab with chemotherapy (FOLFIRI (folinic acid, fluorouracil and irinotecan) or irinotecan). We aimed to evaluate the cost-effectiveness of encorafenib with cetuximab in adult patients with BRAF-mutant mCRC after prior systemic therapy, from the perspective of the French healthcare system.. A partitioned survival analysis model was developed to assess the cost-effectiveness of encorafenib with cetuximab using data from BEACON CRC (encorafenib with cetuximab and cetuximab with FOLFIRI or irinotecan). For two further comparator treatments (FOLFIRI alone and bevacizumab with FOLFIRI), a systemic literature review identified appropriate clinical trial data for indirect comparison. Piecewise modelling extrapolation was used to fulfil a lifetime horizon in the model. A discount rate of 2.5% was used. Treatment-emergent adverse events ≥grade 3 with an incidence of ≥2% were included, as well as relative dose intensity and utility values.. The effectiveness outcomes of the model were expressed in terms of incremental life years gained and incremental quality-adjusted life years (QALY) gained. The cost-effectiveness of encorafenib with cetuximab was assessed using the incremental cost-effectiveness ratio (ICER). Results were presented probabilistically to account for parametric uncertainty. Deterministic and scenario analyses were conducted.. The ICER for encorafenib with cetuximab versus cetuximab with FOLFIRI or irinotecan, FOLFIRI alone and bevacizumab with FOLFIRI was €69 823/QALY, €70 421/QALY and €72 336/QALY, respectively. Encorafenib with cetuximab was considered cost-effective compared with the three comparators at a willingness to pay threshold of €90 000/QALY, with probabilities of being cost-effective of 89.8%, 98.2% and 86.4%, respectively.. This analysis showed encorafenib with cetuximab to be a cost-effective treatment in mCRC patients with a BRAF V600E mutation.

Topics: Adult; Bevacizumab; Cetuximab; Colonic Neoplasms; Cost-Benefit Analysis; France; Humans; Irinotecan; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Rectal Neoplasms

Patients with BRAF V600E mutated metastatic colorectal cancer (mCRC) have a poor prognosis. The introduction of BRAF targeted therapy with encorafenib and weekly administered cetuximab have shown improved survival with a median progression free survival (PFS) of 4.3 months. However, a regimen with cetuximab given every second week may have comparable efficacy and is more convenient for patients. While BRAF targeted therapy is a new standard therapy in pre-treated patients with BRAF V600E mutated mCRC, resistance invariably occurs and is an emerging challenge. The aim of this study is to investigate the efficacy and tolerability of cetuximab given every second week in combination with daily encorafenib and to explore the correlation between markers of resistance and outcome.. The study is an open label, single arm, phase II study, investigating the efficacy and tolerability of cetuximab given every second week in combination with encorafenib in patients with BRAF V600E mutated mCRC. Furthermore, we will be investigating mechanisms of response and resistance against BRAF targeted therapy though comprehensive genomic profiling on tumor tissue and blood for circulating tumor DNA analysis. A total of 53 patients (19 + 34 in two steps) will be included according to Simon's optimal two stage design. The primary end point of the study is 2 months PFS rate.. By combining BRAF inhibitor with cetuximab given every second week we can halve the number of visits in the hospital compared to the currently approved regimen with weekly cetuximab. This seems particularly relevant in a group of patients with a median overall survival of 9.3 months. Resistance after initial response to targeted therapy can be either adaptive (e.g., epigenetic, or transcriptomic alterations) or acquired (selective genetic alterations - e.g., activating de novo mutations) resistance. It is of great importance to untangle these complex mechanisms of resistance in patients with BRAF V600E mutated mCRC to improve treatment strategies in the future potentially even further.. EU Clinical Trial Register, Eudract no. 2020-003283-10 . Registered on 11 November 2020.

Topics: Antineoplastic Combined Chemotherapy Protocols; Cetuximab; Colonic Neoplasms; Colorectal Neoplasms; Humans; Mutation; Proto-Oncogene Proteins B-raf; Rectal Neoplasms

Encorafenib + cetuximab (E+C) is an effective therapeutic option in chemorefractory BRAFV600E metastatic colorectal cancer (mCRC). However, there is a need to improve the efficacy of this molecular-targeted therapy and evaluate regimens suitable for untreated BRAFV600E in patients with mCRC.. We performed a series of in vivo studies using BRAFV600E mCRC tumor xenografts. Mice were randomized to receive 5-fluoruracil (5-FU), irinotecan, or oxaliplatin regimens (FOLFIRI or FOLFOX), (E+C) or the combination. Patients received long-term treatment until disease progression, with deescalation strategies used to mimic maintenance therapy. Transcriptomic changes after progression on cytotoxic chemotherapy or targeted therapy were assessed.. Antitumor activity of either FOLFIRI or E+C was better as first-line treatment as compared with second-line, with partial cross-resistance seen between a cytotoxic regimen and targeted therapy with an average 62% loss of efficacy for FOLFIRI after E+C and a 45% loss of efficacy of E+C after FOLFIRI (P < 0.001 for both). FOLFIRI-treated models had upregulation of epithelial-mesenchymal transition (EMT) and MAPK pathway activation, where E+C treated models had suppressed MAPK signaling. In contrast, with chemotherapy with E+C, EMT and MAPK signaling remained suppressed. FOLFOX or FOLFIRI, each in combination with E+C, were the most active first-line treatments as compared with E+C or to chemotherapy alone. Furthermore, FOLFOX in combination with E+C as first-line induction therapy, followed by E+C ± 5-FU as maintenance therapy, was the most effective strategy for long-term disease control.. These results support the combination of cytotoxic chemotherapy and molecular-targeted therapy as a promising therapeutic approach in the first-line treatment of BRAFV600E mCRC.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Cetuximab; Colonic Neoplasms; Colorectal Neoplasms; Fluorouracil; Humans; Leucovorin; Mice; Xenograft Model Antitumor Assays

Topics: Antineoplastic Combined Chemotherapy Protocols; Carbamates; Cetuximab; Colonic Neoplasms; Colorectal Neoplasms; Humans; Nevus, Pigmented; Proto-Oncogene Proteins B-raf; Sulfonamides

Encorafenib is a BRAF inhibitor increasingly used as a second-line treatment for metastatic melanoma and colorectal cancer. BRAF inhibitors have been reported to be associated with new and changing melanocytic lesions, including eruptive naevi. We describe two cases of eruptive naevi secondary to encorafenib used for the treatment of BRAF-mutant metastatic colorectal cancer.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carbamates; Colonic Neoplasms; Exanthema; Humans; Mutation; Nevus, Pigmented; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Rectal Neoplasms; Skin Neoplasms; Sulfonamides

Cardiovascular adverse events (CVAEs) associated with BRAF inhibitors alone versus combination BRAF/MEK inhibitors are not fully understood.. This study included all adult patients who received BRAF inhibitors (vemurafenib, dabrafenib, encorafenib) or combinations BRAF/MEK inhibitors (vemurafenib/cobimetinib; dabrafenib/trametinib; encorafenib/binimetinib). We utilized the cross-sectional FDA's Adverse Events Reporting System (FAERS) and longitudinal Truven Health Analytics/IBM MarketScan database from 2011 to 2018. Various CVAEs, including arterial hypertension, heart failure (HF), and venous thromboembolism (VTE), were studied using adjusted regression techniques.. In FAERS, 7752 AEs were reported (40% BRAF and 60% BRAF/MEK). Median age was 60 (IQR 49-69) years with 45% females and 97% with melanoma. Among these, 567 (7.4%) were cardiovascular adverse events (mortality rate 19%). Compared with monotherapy, combination therapy was associated with increased risk for HF (reporting odds ratio [ROR] = 1.62 (CI = 1.14-2.30); p = 0.007), arterial hypertension (ROR = 1.75 (CI = 1.12-2.89); p = 0.02) and VTE (ROR = 1.80 (CI = 1.12-2.89); p = 0.02). Marketscan had 657 patients with median age of 53 years (IQR 46-60), 39.3% female, and 88.7% with melanoma. There were 26.2% CVAEs (CI: 14.8%-36%) within 6 months of medication start in those receiving combination therapy versus 16.7% CVAEs (CI: 13.1%-20.2%) among those receiving monotherapy. Combination therapy was associated with CVAEs compared to monotherapy (adjusted HR: 1.56 (CI: 1.01-2.42); p = 0.045).. In two independent real-world cohorts, combination BRAF/MEK inhibitors were associated with increased CVAEs compared to monotherapy, especially HF, and hypertension.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Azetidines; Benzimidazoles; Carbamates; Carcinoma, Non-Small-Cell Lung; Cardiotoxicity; Cardiovascular Diseases; Colonic Neoplasms; Cross-Sectional Studies; Female; Heart Failure; Humans; Hypertension; Imidazoles; Lung Neoplasms; Male; Melanoma; Middle Aged; Mitogen-Activated Protein Kinase Kinases; Oximes; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Registries; Regression Analysis; Skin Neoplasms; Sulfonamides; Vemurafenib; Venous Thromboembolism; Young Adult

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Carbamates; Cetuximab; Colonic Neoplasms; ErbB Receptors; Female; Humans; Mutation; Proto-Oncogene Proteins B-raf; Sulfonamides; Treatment Outcome

The limited knowledge of the molecular alterations that characterize poorly differentiated neuroendocrine carcinomas has limited the clinical development of targeted agents directed to driver mutations. Here we aim to identify new molecular targets in colon neuroendocrine carcinomas (co-NEC) and proof the efficacy of matching drugs.. We performed a multi-omic analysis of co-NEC to identify genetic or epigenetic alterations that could be exploited as effective drug targets. We compared co-NEC samples with colorectal carcinomas (CRC) to identify neuroendocrine-specific traits. Patients with co-NEC and patient-derived xenografts were treated with a BRAFV600E-blocking drug to demonstrate sensitivity.. co-NEC and CRC are similar in their mutational repertoire, although co-NECs are particularly enriched in. The identification of

Topics: Animals; Carbamates; Carcinoma, Neuroendocrine; Cetuximab; Colonic Neoplasms; Drug Resistance, Neoplasm; Epigenesis, Genetic; ErbB Receptors; Humans; Mice; Mice, Inbred NOD; Mice, SCID; Mutation; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Sulfonamides; Treatment Outcome; Xenograft Model Antitumor Assays