RAF inhibitor re-challenge therapy in BRAF-aberrant pan-cancers: the RE-RAFFLE study.

Previous studies have shown the clinical benefit of rechallenging the RAF pathway in melanoma patients previously treated with BRAF inhibitors. 44 patients with multiple tumors harboring RAF alterations were rechallenged with a second RAF inhibitor, either as monotherapy or in combination with other therapies, after prior therapy with a first RAF inhibitor. This retrospective observational study results showed that rechallenging with RAFi(s) led to an overall response rate of 18.1% [PR in thyroid (1 anaplastic; 3 papillary), 1 ovarian, 2 melanoma, 1 cholangiocarcinoma, and 1 anaplastic astrocytoma]. The clinical benefit rate was 54.5%; more than 30% of patients had durable responses with PR and SD lasting > 6 months. The median progression-free survival on therapy with second RAF inhibitor in the rechallenge setting either as monotherapy or combination was shorter at 2.7 months (0.9-30.1 m) compared to 8.6 months (6.5-11.5 m) with RAF-1i. However, the median PFS with RAF-2i responders (PFS-2) improved at 12.8 months compared to 11.4 months with RAF-1i responders. The median OS from retreatment with RAF-2i was 15.5 months (11.1-30.8 m). Further prospective studies are needed to validate these results and expand targeted therapy options for RAF-aberrant cancers.

Advances in the Treatment of Pediatric Low-Grade Gliomas.

PURPOSE OF REVIEW: Pediatric low-grade gliomas (pLGGs) often result in significant long-term morbidities despite high overall survival rates. This review aims to consolidate the current understanding of pLGG biology and molecular features and provide an overview of current and emerging treatment strategies. RECENT FINDINGS: Surgical resection remains a primary treatment modality, supplemented by chemotherapy and radiotherapy in specific cases. However, recent advances have elucidated the molecular underpinnings of pLGGs, revealing key genetic abnormalities such as BRAF fusions and mutations and the involvement of the RAS/MAPK and mTOR pathways. Novel targeted therapies, including MEK, BRAF and pan-RAF inhibitors, have shown promise in clinical trials, demonstrating significant efficacy and manageable toxicity. Understanding of pLGGs has significantly improved, leading to more personalized treatment approaches. Targeted therapies have emerged as effective alternatives, potentially reducing long-term toxicities. Future research should focus on optimizing therapy sequences, understanding long-term impacts, and ensuring global accessibility to advanced treatments.

Future perspective of targeted treatments in pediatric low-grade glioma (pLGG): the evolution of standard-of-care and challenges of a new era.

While surgery, when possible, remains the mainstay of pediatric low-grade glioma (pLGG) management, adjuvant therapy has significantly evolved over time. Radiation therapy was commonly used in the late 1990s for tumors that could not be resected or recurred. This resulted in significant late morbidity in this population and mortality related to secondary malignancies and chronic health conditions. Chemotherapy became the mainstay of adjuvant therapy but children still experienced late morbidity secondary to exposure to multiple lines of treatment over time. Targeted therapies emerged after the identification of frequent genetic alterations in the mitogen activated protein kinase (MAPK) pathway including KIAA1549-BRAF fusions and BRAF-V600 mutations and the near universal upregulation of the MAPK pathway in these tumors. Both BRAF and MEK inhibitors have shown efficacy in the treatment of pLGG and have led to prolonged stability in some cases. Multiple phase III clinical trials are now comparing targeted therapy to standard-of-care chemotherapy regimens setting the stage for targeted therapy to replace chemotherapy as the first-line treatment in some cases. Targeted therapy, however, is not without its challenges. There are clear examples of resistance and mechanisms of resistance have not been fully elucidated. There is also no clear duration for these therapies and rebound growth is a well-known phenomenon especially in BRAF-V600 mutant tumors. Targeted therapies are also fairly recent developments and long-term toxicities and functional outcomes are still being monitored. Very young and adolescent/young adult LGGs also carry molecular features that may not be addressed by inhibition of the MAPK pathway. Adjuvant therapy for pLGG has evolved from radiation for all unresectable or residual tumors to molecularly driven targeted therapies with improved quality of life, late effects, and less off-target toxicities. While there is still much to learn in regard to newer targeted therapies for pLGG, the era of targeted therapies for pediatric LGG is upon us.

RAF and MEK Inhibitors in Non-Small Cell Lung Cancer.

Lung cancer, despite recent advancements in survival rates, represents a significant global health burden. Non-small cell lung cancer (NSCLC), the most prevalent type, is driven largely by activating mutations in Kirsten rat sarcoma viral oncogene homologue (KRAS) and receptor tyrosine kinases (RTKs), and less in v-RAF murine sarcoma viral oncogene homolog B (BRAF) and mitogen-activated protein-kinase kinase (MEK), all key components of the RTK-RAS-mitogen-activated protein kinase (MAPK) pathway. Learning from melanoma, the identification of BRAFV600E substitution in NSCLC provided the rationale for the investigation of RAF and MEK inhibition as a therapeutic strategy. The regulatory approval of two RAF-MEK inhibitor combinations, dabrafenib-trametinib, in 2017, and encorafenib-binimetinib, in 2023, signifies a breakthrough for the management of BRAFV600E-mutant NSCLC patients. However, the almost universal emergence of acquired resistance limits their clinical benefit. New RAF and MEK inhibitors, with distinct biochemical characteristics, are in preclinical and clinical development. In this review, we aim to provide valuable insights into the current state of RAF and MEK inhibition in the management of NSCLC, fostering a deeper understanding of the potential impact on patient outcomes.

Promising response to vemurafenib and cobimetinib treatment for BRAF V600E mutated craniopharyngioma: a case report and literature review.

Craniopharyngiomas are tumors that arise from the remnants of Rathke's pouch along the nasopharynx to the diencephalon. Current standard of care includes maximal surgical resection versus adjuvant radiation if a maximal resection is unfeasible. Pharmacological therapy with MAPK targeted agents is an emerging therapeutic option for tumors with BRAF V600E mutations. We report a 45-year-old male with a strictly third ventricle papillary craniopharyngioma with a BRAF V600E mutation. After initial surgery with subtotal resection, the patient demonstrated durable response to targeted BRAF and MEK inhibitor therapy with vemurafenib and cobimetinib. Our report suggests that targeted therapy may reduce the need for radiation and impact surgical interventions in select cases.

Advances in our understanding of genetic markers and targeted therapies for pediatric LCH.

INTRODUCTION: Langerhans cell histiocytosis (LCH) is a rare myeloid neoplasm, encompassing a diverse clinical spectrum ranging from localized bone or skin lesions to a multisystemic life-threatening condition. Over the past decade, there has been an expansion in understanding the molecular biology of LCH, which translated into innovative targeted therapeutic approaches. AREAS COVERED: In this article, we will review the molecular alterations observed in pediatric LCH and the relationship between these molecular changes and the clinical phenotype, as well as targeted therapies in LCH. EXPERT OPINION: Mitogen-activated protein kinase (MAPK) pathway mutation is a hallmark of LCH and is identified in 80% of the cases. Notably, BRAFV600E mutation is seen in ~50-60% of the cases, ~30% has other MAPK pathway mutations, while 15-20% have no detected mutations. While the first line therapeutic approach is vinblastine and prednisone, targeted therapies - specifically BRAF/MEK inhibitors - emerged as a promising second-line salvage strategy, particularly when a mutation is identified. Most patients respond to BRAF/MEK inhibitors but at least 75% reactivate after stopping, however, most patients respond again when restarting inhibitors.

Efficacy and safety of BRAF/MEK inhibitors in BRAFV600E-mutated anaplastic thyroid cancer: a systematic review and meta-analysis.

PURPOSE: Approximately 45% of anaplastic thyroid cancer (ATC) patients harbor a BRAFV600E mutation and are eligible for target therapy (TT) with BRAF and MEK inhibitors (BRAFi/MEKi), nevertheless, few data advocate for this. Hence, we've conducted a systematic review and meta-analysis investigating the effectiveness and safety of BRAFi/MEKi in BRAFV600E ATC patients. METHODS: PubMed, Embase, and the Cochrane Library were systematically searched for BRAFi/MEKi TT in BRAFV600E ATC patients. Outcomes included objective response rate (ORR), disease control rate (DCR), overall survival (OS), progression-free survival (PFS), duration of response (DOR) and adverse events (AEs). RESULTS: Nine studies with 168 patients were included. Median follow-up ranged from 2.0 to 47.9 months. 75% of patients had stage IVc. In a pooled analysis, ORR was 68.15% (95% CI 55.31-80.99, I2 = 47%) and DCR was 85.39% (95% CI 78.10-92.68, I2 = 0), with a median DOR of 14.4 months (95% CI 4.6-14.4) and a median PFS of 6.7 months (95% CI 4.7-34.2). Moreover, 1-year OS rate was 64.97% (95% CI 48.76-81.17, I2 = 84%) and 2-years OS rate was 52.08% (95% CI 35.71-68.45, I2 = 79%). Subgroup analysis showed patients in the neoadjuvant setting had higher rates of 1 and 2-years OS and observational studies tended to report higher rates of ORR than clinical trials. No new or unexpected adverse events were found. CONCLUSIONS: Our study demonstrated BRAFi/MEKi have a decent activity for BRAFV600E ATC patients, especially in the neoadjuvant setting, with a tolerable safety profile. However, further clinical trials are warranted to investigate these findings.

Pharmacological inhibition of PDGF-C/neuropilin-1 interaction: A novel strategy to reduce melanoma metastatic potential.

Activation of neuropilin-1 (NRP-1) by platelet derived growth factor (PDGF)-C sustains melanoma invasiveness. Therefore, in the search of novel agents capable of reducing melanoma spreading, PDGF-C/NRP-1 interaction was investigated as a potential druggable target. Since the PDGF-C region involved in NRP-1 binding is not yet known, based on the sequence and structural homology between PDGF-C and vascular endothelial growth factor-A (VEGF-A), we hypothesized that the NRP-1 b1 domain region involved in the interaction with VEGF-A might also be required for PDGF-C binding. Hence, this region was selected from the protein crystal structure and used as target in the molecular docking procedure. In the following virtual screening, compounds from a DrugBank database were used as query ligands to identify agents potentially capable of disrupting NRP-1/PDGF-C interaction. Among the top 45 candidates with the highest affinity, five drugs were selected based on the safety profile, lack of hormonal effects, and current availability in the market: the antipsychotic pimozide, antidiabetic gliclazide, antiallergic cromolyn sodium, anticancer tyrosine kinase inhibitor entrectinib, and antihistamine azelastine. Analysis of drug influence on PDGF-C in vitro binding to NRP-1 and PDGF-C induced migration of human melanoma cells expressing NRP-1, indicated gliclazide and entrectinib as the most specific agents that were active at clinically achievable and non-toxic concentrations. Both drugs also reverted PDGF-C ability to stimulate extracellular matrix invasion by melanoma cells resistant to BRAF inhibitors. The inhibitory effect on tumor cell motility involved a decrease of p130Cas phosphorylation, a signal transduction pathway activated by PDGF-C-mediated stimulation of NRP-1.

Dabrafenib and trametinib administration in patients with BRAF V600E/R or non-V600 BRAF mutated advanced solid tumours (BELIEVE, NCCH1901): a multicentre, open-label, and single-arm phase II trial.

Background: BRAF V600 mutations are common in melanoma, thyroid, and non-small-cell lung cancers. Despite dabrafenib and trametinib being standard treatments for certain cancers, their efficacy across various solid tumours remains unelucidated. The BELIEVE trial assessed the efficacy of dabrafenib and trametinib in solid tumours with BRAF V600E/R or non-V600 BRAF mutations. Methods: Between October 1, 2019, and June 2022, at least 50 patients with measurable and seven without measurable diseases examined were enrolled in a subcohort of the BELIEVE trial (NCCH1901, jRCTs031190104). BRAF mutated solid tumour cases other than BRAF V600E mutated colorectal cancer, melanoma, and non-small cell lung cancer cases were included. Patients with solid tumours received dabrafenib (150 mg) twice daily and trametinib (2 mg) once daily until disease progression or intolerable toxicity was observed. The primary endpoint was overall response rate (ORR), and secondary endpoints included progression-free survival (PFS), 6-month PFS, and overall survival (OS). Bayesian analysis was performed using a prior distribution with a 30% expected response rate [Beta (0.6, 1.4)]. Findings: Fourty-seven patients with measurable disease, mainly with the BRAF V600E mutation (94%), and three others with non-V600E BRAF mutations (V600R, G466A, and N486_P490del) were enrolled. The primary sites included the thyroid gland, central nervous system, liver, bile ducts, colorectum, and pancreas. The confirmed ORR was 28.0%; the expected value of posterior distribution [Beta (14.6, 37.4)] was 28.1%, although the primary endpoint was achieved, not exceeding an unexpectedly high response rate of 60% obtained using Bayesian analysis. The disease control rate (DCR) was 84.0%. The median PFS was 6.5 months (95% confidence interval [CI]; 4.2-7.2 months, 87.8% at 6 months). Responses were observed across seven tumour types. Median OS was 9.7 months (95% CI, 7.5-12.2 months). Additional patients without measurable diseases had a median PFS of 4.5 months. Adverse events (AEs) were consistent with previous reports, with 45.6% of patients experiencing grade ≥3 AEs. Interpretation: This study reported promising efficacy against BRAF V600-mutant tumours. Dabrafenib and trametinib would offer a new therapeutic option for rare cancers, such as high-grade gliomas, biliary tract cancer, and thyroid cancer. Funding: This study was funded by the Japan Agency for Medical Research and Development (22ck0106622h0003) and a Health and Labour Sciences Research Grant (19EA1008).

Oral Adverse Events Associated with BRAF and MEK Inhibitors in Melanoma Treatment: A Narrative Literature Review.

BACKGROUND: Melanoma cancer represents the most lethal type of skin cancer originating from the malignant transformation of melanocyte cells. Almost 50% of melanomas show the activation of BRAF mutations. The identification and characterization of BRAF mutations led to the development of specific drugs that radically changed the therapeutic approach to melanoma. METHODS: We conducted a narrative review of the literature according to a written protocol before conducting the study. This article is based on previously conducted studies. We identified articles by searching electronic databases (Medline, Google Scholar and PubMed). We used a combination of "melanoma", "Braf-Mek inhibitors", " targeted therapy" and "oral side effects". RESULTS: Eighteen studies were reported in this article showing the relationship between the use of targeted therapy in melanoma cancer and the development of oral side effects, such as mucositis, hyperkeratosis and cellular proliferation. CONCLUSION: Targeted therapy plays an important role in the treatment of melanoma cancer, showing a notable increase in response rate, prolonged progression-free survival and overall survival in BRAF-mutated melanoma patients. Oral side effects represent a common finding over the course of treatment. However, these adverse effects can be easily managed in a multidisciplinary approach involving collaboration between medical oncologists and dental doctors.

Genetic alterations in thyroid cancer mediating both resistance to BRAF inhibition and anaplastic transformation.

A subset of thyroid cancers present at advanced stage or with dedifferentiated histology and have limited response to standard therapy. Tumors harboring the BRAF V600E mutation may be treated with BRAF inhibitors; however, tumor response is often short lived due to multiple compensatory resistance mechanisms. One mode of resistance is the transition to an alternative cell state, which on rare occasions can correspond to tumor dedifferentiation. DNA sequencing and RNA expression profiling show that thyroid tumors that dedifferentiate after BRAF inhibition are enriched in known genetic alterations that mediate resistance to BRAF blockade, and may also drive tumor dedifferentiation, including mutations in the PI3K/AKT/MTOR (PIK3CA, MTOR), MAP/ERK (MET, NF2, NRAS, RASA1), SWI/SNF chromatin remodeling complex (ARID2, PBRM1), and JAK/STAT pathways (JAK1). Given these findings, recent investigations have evaluated the efficacy of dual-target therapies; however, continued lack of long-term tumor control illustrates the complex and multifactorial nature of these compensatory mechanisms. Transition to an immune-suppressed state is another correlate of BRAF inhibitor resistance and tumor dedifferentiation, suggesting a possible role for concurrent targeted therapy with immunotherapy. Investigations into combined targeted and immunotherapy are ongoing, but early results with checkpoint inhibitors, viral therapies, and CAR T-cells suggest enhanced anti-tumor immune activity with these combinations.

Case report: Targeted treatment strategies for Erdheim-Chester disease.

Introduction: Erdheim-Chester disease (ECD) is a rare disease that belongs to the group of Dendritic and histiocytic neoplasms. Only 2000 cases have been reported worldwide. It can present with a wide range of symptoms, making a differential diagnosis especially difficult. The primary and most important diagnostic tool is a biopsy of the affected organ/tissue. Nowadays the analysis of different mutations affecting the BRAF and MAPK pathways makes it possible to use targeted treatments, such as vemurafenib, dabrafenib, or cobimetinib. Objective: Our aim is to present the results of three male patients treated in our hematology department. Results: Our BRAF mutation-positive patient presented with retroperitoneal tissue proliferation and diabetes insipidus. The initial therapy of choice was dabrafenib. After 3 months of treatment, 18F-fluoro-deoxyglucose positron emission tomography (FDG-PET)/computed tomography (CT) scans showed regression, and after 2 years of treatment, no disease activity was detected. In our second patient, a recurrent febrile state (not explained by other reasons) and diabetes insipidus suggested the diagnosis. A femoral bone biopsy confirmed BRAF-negative ECD. The first-line therapy was interferon-alpha. After 3 months of treatment, no response was observed on 18FDG-PET/CT, and treatment with cobimetinib was started. The control 18FDG-PET/CT imaging was negative. Our third patient was evaluated for dyspnea, and a CT scan showed fibrosis with hilar lymphadenomegaly. A lung biopsy confirmed BRAF-negative ECD. We started treatment with interferon-alpha, but unfortunately, no improvement was observed. Second-line treatment with cobimetinib resulted in a partial metabolic response (PMR) according to control 18FDG-PET/CT. Conclusions: Our results demonstrate that an appropriately chosen treatment can lead to a good therapeutic response, but dose reduction may be necessary due to side effects. With advanced targeted therapeutic treatment options, survival and quality of life are significantly improved.

Case report: complete long-lasting response to multimodal third line treatment with neurosurgical resection, carmustine wafer implantation and dabrafenib plus trametinib in a BRAFV600E mutated high-grade glioma.

Dabrafenib plus trametinib is a promising new therapy for patients affected by BRAFV600E-mutant glioma, with high overall response and manageable toxicity. We described a complete and long-lasting response in a case of recurrent anaplastic pleomorphic xanthoastrocytoma CNS WHO-grade 3 BRAFV600E mutated. Due to very poor prognosis, there are a few described cases of high-grade glioma (HGG) patients treated with the combined target therapy as third-line treatment. The emergence of optimized sequencing strategies and targeted agents, including multimodal and systemic therapy with dabrafenib plus trametinib, will continue to broaden personalized therapy in HGG improving patient outcomes.

Genetics-guided therapy in neuroendocrine carcinoma: response to BRAF- and MEK-inhibitors.

Background: Metastatic neuroendocrine carcinoma (NEC) is associated with short survival. Other than platinum-based chemotherapy, there is no clear standard regimen. Current guidelines suggest that combination treatment with BRAF-inhibitors should be considered for patients with BRAF V600E-mutated NEC. However, since only eight such patients have been reported in the literature, our object was to confirm the validity of this recommendation. Methods: This was a single-center retrospective cohort study conducted at Uppsala University Hospital. The included patients 1) had a histopathologically confirmed diagnosis of NEC, 2) were diagnosed between January 1st, 2018 and December 31st, 2023, 3) had tumor tissue genetically screened by a broad next-generation sequencing (NGS) panel, and 4) showed a tumor mutation for which there is a currently available targeted therapy. Results: We screened 48 patients diagnosed with NEC between January 1st, 2018 and December 31st, 2023. Twelve had been analyzed with a broad NGS-panel, and two had a targetable mutation. Both these patients harbored a BRAF V600E-mutated colon-NEC and were treated with BRAF- and MEK-inhibitors dabrafenib and trametinib in second-line. At first radiological evaluation (RECIST 1.1), both patients had a reduction of tumor size, which decreased by 31 and 40%. Both had short response periods, and their overall survival was 12 and 9 months. Conclusions: BRAF-mutated NEC is sensitive to treatment with BRAF- and MEK-inhibitor combination. These results further support that DNA sequencing should be considered as standard of care in NECs to screen for potential treatment targets.

Recommendations for the Management of Patients with Hairy-Cell Leukemia and Hairy-Cell Leukemia-like Disorders: A Work by French-Speaking Experts and French Innovative Leukemia Organization (FILO) Group.

INTRODUCTION: Hairy-cell leukemia (HCL) is a rare B-cell chronic lymphoproliferative disorder (B-CLPD), whose favorable prognosis has changed with the use of purine nucleoside analogs (PNAs), such as cladribine (CDA) or pentostatin (P). However, some patients eventually relapse and over time HCL becomes resistant to chemotherapy. Many discoveries have been made in the pathophysiology of HCL during the last decade, especially in genomics, with the identification of the BRAFV600E mutation and cellular biology, including the importance of signaling pathways as well as tumor microenvironment. All of these new developments led to targeted treatments, especially BRAF inhibitors (BRAFis), MEK inhibitors (MEKis), Bruton's tyrosine kinase (BTK) inhibitors (BTKis) and recombinant anti-CD22 immunoconjugates. RESULTS: The following major changes or additions were introduced in these updated guidelines: the clinical relevance of the changes in the classification of splenic B-cell lymphomas and leukemias; the increasingly important diagnostic role of BRAFV600E mutation; and the prognostic role of the immunoglobulin (IG) variable (V) heavy chain (H) (IGHV) mutational status and repertory. We also wish to insist on the specific involvement of bones, skin, brain and/or cerebrospinal fluid (CSF) of the disease at diagnosis or during the follow-up, the novel targeted drugs (BRAFi and MEKi) used for HCL treatment, and the increasing role of minimal residual disease (MRD) assessment. CONCLUSION: Here we present recommendations for the diagnosis of HCL, treatment in first line and in relapsed/refractory patients as well as for HCL-like disorders including HCL variant (HCL-V)/splenic B-cell lymphomas/leukemias with prominent nucleoli (SBLPN) and splenic diffuse red pulp lymphoma (SDRPL).

BRAF Inhibitors in BRAF-Mutated Colorectal Cancer: A Systematic Review.

Colorectal cancer (CRC) is the second-leading cause of cancer-related deaths globally. BRAF mutation is present in about 10% of CRC patients and is associated with a poor response to chemotherapy. These patients have a relatively poor prognosis. This review aims to assess the efficacy and safety of BRAF inhibitors in BRAF-mutated CRC patients. A literature search was performed on PubMed and Embase, and clinical trials relevant to BRAF inhibitors in CRC were included. Data were extracted for efficacy and safety variables. Two randomized clinical trials (n = 765) and eight non-randomized trials (n = 281) were included based on inclusion criteria. In RCTs, an overall response was reported in 23% of the patients treated with BRAF inhibitor-based regimens compared to 2.5% with control regimens. The hazard ratio of overall survival was also significantly better with triplet encorafenib therapy at 0.52 (95% CI = 0.39-0.70). In single-arm trials, ORR was 17% and 34% in two-drug and three-drug regimens, respectively. BRAF inhibitor-based regimens were safe and effective in the treatment of BRAF-mutated CRC. Large-scale randomized trials are needed to find a suitable population for each regimen. PROSPERO registration No. CRD42023471627.