Braftovi (encorafenib)

In this review, we summarize the efficacy and safety of encorafenib plus binimetinib from the PHAROS study. In addition, we discuss strategies to manage adverse reactions with this combination therapy with the intent of minimizing unnecessary treatment discontinuations in these patients.

P3, N=921, Active, not recruiting, Pfizer | Trial completion date: Mar 2024 --> Jul 2024

P1, N=53, Active, not recruiting, Pfizer | N=36 --> 53

P1, N=27, Recruiting, M.D. Anderson Cancer Center | Suspended --> Recruiting

P3, N=400, Recruiting, Massachusetts General Hospital | Trial completion date: Apr 2026 --> Dec 2027 | Trial primary completion date: Apr 2025 --> Dec 2026

P1, N=30, Recruiting, National Cancer Institute (NCI) | Not yet recruiting --> Recruiting | N=22 --> 30 | Trial completion date: Jun 2024 --> Jun 2025 | Initiation date: Feb 2024 --> Nov 2024 | Trial primary completion date: Jun 2024 --> Jun 2025

P2, N=119, Recruiting, Intergroupe Francophone de Cancerologie Thoracique | Trial primary completion date: Feb 2024 --> Sep 2024

Encorafenib and binimetinib exhibit positive tumor responses in patients with recurrent BRAF-V600E mutant HGG in this small series, warranting therapeutic consideration. Although toxicity remains a concern for BRAF-targeted therapies, no new safety signal was observed in these patients.

While the BRAFV600E inhibitor encorafenib in combination with the EGFR inhibitor cetuximab (Enc+Cet) was recently approved for this indication, overall survival is only increased by 3.6 months and objective responses are observed in only 20% of patients. Combining encorafenib with DT2216 significantly increased apoptosis induction in vitro, while combining encorafenib with AZD0466 was well tolerated in mice and further reduced growth of BRAFV600E CRC xenografts compared to either agent alone. Collectively, these findings demonstrate that combined BRAF and BCL-XL inhibition significantly enhances apoptosis in pre-clinical models of BRAFV600E CRC and is a combination regimen worthy of clinical investigation to improve outcomes for these patients.

P2, N=5, Terminated, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Trial completion date: Jul 2027 --> Oct 2023 | Active, not recruiting --> Terminated; NCI decided to terminate ABTC Consortium due to NCI moving in different direction for Brain Cancer

In 52 cases, six cases (4 of SD cases and 2 of PR cases) was administered encorafenib-based chemotherapies based on BRAF gene mutation... Around 13% of gastrointestinal cancer patients with liver metastasis might have a druggable benefit by CGP testing. BRAF mutation might be promising target for patients with liver metastasis. ZNF217, SRC, ARFRP1, BARD1, FGF10 might be associated with metastatic process to liver in gastrointestinal cancer.

P3, N=922, Active, not recruiting, Pfizer | Trial completion date: Nov 2023 --> Mar 2024

P1/2, N=102, Active, not recruiting, Erasca, Inc. | Recruiting --> Active, not recruiting | Phase classification: P1b/2 --> P1/2 | N=200 --> 102

The results from these clinical studies suggest that encorafenib does not cause clinically relevant CYP2B6 induction or inhibition but is an inhibitor of BCRP and may also inhibit OATP1B1/3 to a lesser extent. Based on these results, it may be necessary to consider switching statins or reducing statin dosage accordingly for coadministration with encorafenib.

P1/2, N=33, Recruiting, University of Utah | Not yet recruiting --> Recruiting

P1, N=27, Suspended, M.D. Anderson Cancer Center | Phase classification: P1b --> P1 | Not yet recruiting --> Suspended

These results support the use of encorafenib plus binimetinib combination treatment as a new treatment option in people with BRAF V600E-mutant metastatic NSCLC. The side effects of encorafenib plus binimetinib in this study were similar to the side effects seen with encorafenib plus binimetinib in people with a type of skin cancer called metastatic melanoma.

Treatment with encorafenib plus binimetinib met the primary endpoint criteria and demonstrated clinical benefit in patients with BRAFV600E-mutated thyroid cancer regardless of its histological type, such as DTC or ATC, with no new safety concerns identified. Encorafenib plus binimetinib could thus be a new treatment option for BRAF V600-mutated thyroid cancer.

P3, N=176, Active, not recruiting, Pfizer | Recruiting --> Active, not recruiting

It was identified that top-hit molecules had better binding and interaction activity than standard in all three classes of mutants.

P2, N=95, Completed, Pierre Fabre Medicament | Active, not recruiting --> Completed

P2, N=6, Terminated, Academic and Community Cancer Research United | N=29 --> 6 | Trial completion date: Dec 2024 --> Nov 2023 | Active, not recruiting --> Terminated; Slow accrual

P2, N=103, Active, not recruiting, Pierre Fabre Medicament | Trial primary completion date: Apr 2024 --> Dec 2023

P2, N=70, Not yet recruiting, Spanish Cooperative Group for the Treatment of Digestive Tumours (TTD)

This activity is supported by educational grants from Natera Inc and Pfizer Inc. Similarities and differences between BRAF V600E and non-V600 mutations in mCRC; implications for disease management Potential clinical or biological factors, such as patient characteristics, tumor sidedness, histology and co-mutations, associated with the presence of BRAF V600 mutations in CRC Long-term findings from the Phase III BEACON CRC study evaluating encorafenib/cetuximab with or without binimetinib versus standard therapy for patients with mCRC and BRAF V600E mutations FDA approval and appropriate integration of encorafenib/cetuximab for patients with BRAF V600E-mutated mCRC Rationale for the evaluation of earlier use of BRAF-targeted therapy; findings from the Phase II ANCHOR CRC trial evaluating encorafenib/binimetinib/cetuximab for patients with treatment-naïve BRAF V600E-mutated mCRC Design, eligibility criteria and key endpoints of the Phase III BREAKWATER trial comparing encorafenib/cetuximab with or without chemotherapy to standard chemotherapy for patients with previously untreated BRAF V600E-mutated mCRC; safety lead-in results and estimated completion date

Our primary objective was to identify subgroups with different treatment responses using Latent Class Mixed Model (LCMM).We used a public dataset and focused on one treatment, encorafenib, and two indications, melanoma and colorectal cancer, for which efficacy depends on a specific mutation BRAF V600E...LCMM is a suitable tool for MCT to explore treatment response subgroups of PDX. Once these subgroups are defined, characterization of their phenotypes/genotypes could be performed to explore treatment response predictors.

No abstract available

BRAF/MEK inhibitors were encorafenib plus binimetinib and checkpoint inhibitors ipilimumab plus nivolumab. We also describe preliminary results of predefined biomarkers analyses that identify a trend toward improved 4-year overall survival and total progression-free survival in patients with loss-of-function mutations affecting JAK or low baseline levels of serum interferon gamma (IFNy). These long-term survival outcomes confirm immunotherapy as the preferred first-line treatment approach for most patients with BRAFV600-mutant metastatic melanoma, and the biomarker analyses are hypothesis-generating for future investigations of predictors of durable benefit with dual checkpoint blockade and targeted therapy.

P1/2, N=33, Not yet recruiting, University of Utah

P1/2, N=78, Recruiting, Peter MacCallum Cancer Centre, Australia | Phase classification: P1b --> P1/2 | Trial completion date: Dec 2023 --> Dec 2024 | Trial primary completion date: Dec 2023 --> Dec 2024

P3, N=240, Recruiting, Pfizer | N=624 --> 240

P3, N=800, Not yet recruiting, UNICANCER

In our study, the MEKi binimetinib, cobimetinib and trametinib combined with the BRAF inhibitors (BRAFi) encorafenib, vemurafenib and dabrafenib were investigated for their ability to inhibit proliferation, induce apoptosis and alter the expression of immune modulatory molecules in sensitive NRAS-mutant melanoma cells using two- and three-dimensional cell culture models as well as RNA sequencing analyses. The BRAFi/MEKi-resistant, NRAS-mutant melanoma cells counteracted the molecular and immunological effects of BRAFi/MEKi by upregulating downstream mitogen-activated protein kinase pathway molecules, inhibiting apoptosis and promoting immune escape mechanisms. Together, our study reveals potent molecular and immunological effects of BRAFi/MEKi in sensitive NRAS-mutant melanoma cells that may be exploited in new combinational treatment strategies for patients with NRAS-mutant melanoma.

In in vitro and ex vivo settings, the combination therapy was observed to elicit a response; however, it did not amplify the efficacy observed with binimetinib alone, whereas in a patient, the combinational treatment remained ineffective. The preclinical in vivo data showed no increased combinatorial effect. However, the in vivo effect of binimetinib as monotherapy was unexpectedly high in the tested regimen. Nevertheless, binimetinib proved to be advantageous in the treatment of melanoma in vivo and led to high rates of apoptosis in vitro; hence, it still seems to be a good base for combination with other substances in the treatment of patients with NRAS-mutant melanoma.

P2, N=52, Active, not recruiting, M.D. Anderson Cancer Center | Suspended --> Active, not recruiting

Adults ≥18 years old with ≥1 claim for enco (first claim for enco on/after 4/1/2020) with concurrent cetux, as approved, or with EGFR panitumumab (pani), ≥2 ICD-9/10 codes for malignancy of the colon or rectum ≥30 days apart in the 1 year before index date, and ≥1 day of pharmacy and medical continuous enrollment during the index date were included...Among the enco patients who had a previous treatment computed in claims, FOLFOX +/- bevacizumab (beva) and FOLFIRI + beva were the most common. This study provides current RW demographics, disease characteristics and treatment patterns among BRAF mCRC patients treated with enco in the US.

The purpose of this study is to analyze the post-approval real-world persistence and adherence to treatment with enco in combination with cetux or with panitumumab (pani), an alternative EGFR, in mCRC, based on a claims database in the US. This up-to-date study provides current real-world evidence on the use of enco + EGFR in mCRC BRAF-m patients in the US. The results show high levels of adherence to the treatment, suggesting high tolerability to encorafenib, and persistence consistent with clinical trial evidence.

P1/2, N=34, Active, not recruiting, Pfizer | Phase classification: P1b/2 --> P1/2 | Trial primary completion date: Jun 2024 --> May 2023

A 69-year-old veteran was initially diagnosed with stage III colorectal cancer and progressed to having liver, pancreatic, and omental lymph node involvement despite completing adjuvant FOLFOX (fluorouracil, leucovorin calcium, and oxaliplatin) after surgery. The patient was treated with FOLFIRI (fluorouracil, leucovorin calcium, and irinotecan hydrochloride) and bevacizumab, followed by encorafenib and cetuximab on progression. Subsequently, he received pembrolizumab but continued to progress. The patient was later placed on trifluridine/tipiracil and bevacizumab concurrent with a ketogenic diet...On progression, the patient was transitioned to ipilumimab and nivolumab and continued to adhere to the ketogenic diet...In this report, we reviewed the latest literature about cellular mechanism of the ketogenic diet and the efficacy and relationship with chemotherapy and immunotherapy. We are about to open a ketogenic diet protocol at the Veterans Affairs Central California Health Care System in Fresno.

Novel systemic therapies with intracranial utility include new anaplastic lymphoma kinase inhibitors like brigatinib and ensartinib; selective "rearranged during transfection" inhibitors like selpercatinib and pralsetinib; B-raf proto-oncogene inhibitors like encorafenib and vemurafenib; Kirsten rat sarcoma viral oncogene inhibitors like sotorasib and adagrasib; ROS1 gene rearrangement (ROS1) inhibitors, anti-neurotrophic tyrosine receptor kinase agents like larotrectinib and entrectinib; anti-human epidermal growth factor receptor 2/epidermal growth factor receptor exon 20 agent like poziotinib; and antibody-drug conjugates like trastuzumab-emtansine and trastuzumab-deruxtecan. This review highlights the modern multidisciplinary management of BM, emphasizing the integration of systemic and local therapies.

P1, N=36, Active, not recruiting, Pfizer | Recruiting --> Active, not recruiting | N=196 --> 36

P2, N=12, Completed, University of Heidelberg Medical Center | Active, not recruiting --> Completed | Trial completion date: Dec 2022 --> Mar 2023 | Trial primary completion date: Dec 2022 --> Mar 2023