BRAF Combination Research Articles

A Practical Review of Encorafenib and Binimetinib Therapy Management in Patients with BRAF V600E-Mutant Metastatic Non-Small Cell Lung Cancer.

According to current guidelines, targeted therapy with a combination of BRAF plus MEK inhibitors is the preferred first-line treatment for patients with BRAF V600E-mutant metastatic non-small cell lung cancer (NSCLC). In the open-label, single-arm, phase2 PHAROS trial (NCT03915951), the combination of encorafenib, a potent BRAF inhibitor, and binimetinib, a potent MEK inhibitor, demonstrated durable antitumor activity with a manageable safety profile in this patient population. On the basis of the results of this study, the combination of encorafenib plus binimetinib was approved by the US Food and Drug Administration on October 11, 2023, for patients with BRAF V600E-mutant metastatic NSCLC. 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.

Successful treatment of pediatric patients with high-grade gliomas featuring leptomeningeal metastases by targeting BRAF V600E mutations with dabrafenib plus trametinib: two illustrative cases.

A combination of BRAF and MEK inhibitors is reported to be effective for gliomas with the BRAF V600E mutation; however, its efficacy in gliomas with leptomeningeal metastases (LMM) is still unknown. In this report, we describe two pediatric patients with high-grade glioma featuring the BRAF V600E mutation who were treated with dabrafenib and trametinib for LMM. Both 2 cases underwent craniotomy for primary intracranial lesions and were diagnosed as a high-grade glioma with BRAF V600E mutation; one case was consistent with anaplastic pleomorphic xanthoastorocytoma, the other was epithelioid glioblastoma. They received standard treatment for the lesions but subsequently were found to have new lesions including multiple spinal dissemination. We started administering dabrafenib and trametinib. Within a few days of starting treatment, the symptoms improved dramatically and MRI performed one month after the prescription of the two drugs demonstrated remission of both brain and spinal lesions. This report shows that dabrafenib and trametinib are effective not only for recurrent lesions but also for LMM in pediatric patients.

Design and synthesis of new 1,2,4-oxadiazole/quinazoline-4-one hybrids with antiproliferative activity as multitargeted inhibitors.

The combination of BRAF and tyrosine kinase (TK) inhibitors has been demonstrated to be highly effective in inhibiting tumor development and is an approach for overcoming resistance in clinical trials. Accordingly, a novel series of 1,2,4-oxadiazole/quinazoline-4-one hybrids was developed as antiproliferative multitargeted inhibitors. The structures of the newly synthesized compounds 9a-o were validated using IR, NMR, MS, and elemental techniques. 9a-o were tested as antiproliferative agents. The results showed that the majority of the tested compounds showed significant antiproliferative action with 9b, 9c, 9h, 9k, and 9l being the most potent. Compounds 9b, 9c, 9h, 9k, and 9l were tested as EGFR and BRAFV600E inhibitors. These in vitro tests revealed that compounds 9b, 9c, and 9h are strong antiproliferative agents that may act as dual EGFR/BRAFV600E inhibitors. 9b, 9c, and 9h were further investigated for their inhibitory effect on mutant EGFR (EGFRT790M), and the results showed that the tested compounds had considerable inhibitory action. Cell cycle study and apoptosis detection demonstrated that compound 9b exhibits cell cycle arrest at the G2/M transition. Molecular docking simulations reveal the binding mechanism of the most active antiproliferative agents.

The value of Korean, American, and Chinese ultrasound risk stratification systems combined with BRAF(V600E) mutation for detecting papillary thyroid carcinoma in cytologically indeterminate thyroid nodules.

To investigate the value of Korean, American, and Chinese ultrasound risk stratification systems combined with BRAF(V600E) mutation in the detection of papillary thyroid carcinoma (PTC)within cytologically indeterminate thyroid nodules (CITNs). A single-center retrospective study encompassed 511 CITNs selected from 509 patients between January 2020 and July 2023.Each nodule underwent surgical treatment and was classified according to three distinct systems. Receiver operating characteristic (ROC) curves were plotted using histopathological diagnosis as the reference standard, and diagnostic performance was compared. The three ultrasound stratification systems showed an elevated malignant risk with increasing grades (all P for trend2 < 0.001). The cut-off values for Korean, American, and Chinese systems were 5, 5, and 4c, and their respective area under the curves (AUCs) were 0.735, 0.778, and 0.783.The combination of BRAF (V600E) mutation significantly enhanced the diagnostic efficacy for the Korean(0.773vs0.735, P < 0.001), American (0.809vs0.778, P < 0.001) and Chinese (0.815vs0.783, P < 0.001) stratification systems in distinguishing CITNs without compromising specificity. When the three stratification systems were applied individually or combined with BRAF (V600E) mutation, the AUCs of the American and Chinese systems were similar (all P > 0.05), both of which were higher than the AUC of the Korean system (all P < 0.05). The American system exhibited higher specificity compared to the Chinese and Korean systems (all P < 0.001), whereas the Chinese system demonstrated higher sensitivity and accuracy when compared to the American and Korean systems (all P < 0.001). Korean, American and Chinese stratification systems present potential in the differential diagnosis of CITNs. BRAF (V600E) mutation can significantly improve the detection rate of malignant nodules within CTNs, particularly PTC. Notably, the American and Chinese systems demonstrate superior overall diagnostic performance among these systems.

Management of cutaneous melanoma: update on current treatment from surgical perspective

Incidence and mortality rate of cutaneous melanoma substantially varies across the globe depending upon early detection and management. Therapeutic developments have revolutionized the treatment. The aim of this paper is to discuss the treatment options for localized and advanced disease in the context of surgery, adjuvant, and neoadjuvant treatment. PubMed, Medline, Guidelines of European Society of Medical Oncology, National Institute of Clinical Excellence, American Joint Committee on Cancer on Melanoma, publications from 2012-2022 were searched. Low risk node negative disease (stage I and IIA) melanoma patients should have curative surgical wide local excision along with SLNB with no adjuvant therapy. High risk node negative disease (stage IIB and IIC) should be treated with curative surgery and SLNB followed by adjuvant immunotherapy. Low risk node positive disease (stage IIIA) surgical resection with SLNB followed by adjuvant systemic therapy, depending upon BRAF mutation status of tumour. High risk node positive microscopic disease (stage IIIB, IIIC, IIID) BRAF V600 mutation, primary resection with SLNB followed by nivolumab or combination of BRAF + MEK inhibitors. For BRAF wild-type tumours, adjuvant immunotherapy with programmed cell death-1 (PD-1) inhibitor. Patient with macroscopic disease that is resectable neoadjuvant combination immunotherapy followed by surgery with lymph node dissection. Metastatic disease (stage IV) regardless, adjuvant combination immunotherapy followed by maintenance nivolumab. Surgical excision is the treatment of choice for most patients with loco regional cutaneous melanoma and is curative in most cases. Checkpoint inhibitors and targeted therapies are important advances in adjuvant, neo adjuvant settings. Despite all the progress, melanoma remains challenging to treat.

Kinetics of RTK activation determine ERK reactivation and resistance to dual BRAF/MEK inhibition in melanoma

The combination of BRAF and MEK inhibitors (BRAFi/MEKi) has shown promising response rates in treating BRAF-mutant melanoma by inhibiting ERK activation. However, treatment efficacy is limited by the emergence of drug-tolerant persister cells (persisters). Here, we show that the magnitude and duration of receptor tyrosine kinase (RTK) activation determine ERK reactivation and persister development. Our single-cell analysis reveals that only a small subset of melanoma cells exhibits effective RTK and ERK activation and develops persisters, despite uniform external stimuli. The kinetics of RTK activation directly influence ERK signaling dynamics and persister development. These initially rare persisters form major resistant clones through effective RTK-mediated ERK activation. Consequently, limiting RTK signaling suppresses ERK activation and cell proliferation in drug-resistant cells. Our findings provide non-genetic mechanistic insights into the role of heterogeneity in RTK activation kinetics in ERK reactivation and BRAFi/MEKi resistance, suggesting potential strategies for overcoming drug resistance in BRAF-mutant melanoma.

Extracellular Vesicles in Cancer Drug Resistance: Implications on Melanoma Therapy.

Extracellular vesicles (EVs) are involved in the pathogenesis of neoplastic diseases. Their role in mediating drug resistance has been widely described in several types of cancers, including melanoma. EVs can mediate drug resistance through several different mechanisms, such as drug-sequestration, transfer of pro-survival proteins and RNA, induction of cancer stem cell-like features and interaction with cells of the tumor microenvironment and immune-system. Melanoma is a highly immunogenic tumor originating from the malignant transformation of melanocytes. Several therapeutic strategies currently used in the treatment of melanoma and the combination of BRAF and MEK-inhibitors, as well as immune check-point inhibitors (ICI), have consistently improved the overall survival time of melanoma patients. However, the development of resistance is one of the biggest problems leading to a poor clinical outcome, and EVs can contribute to this. EVs isolated from melanoma cells can contain "sequestered" chemotherapeutic drugs in order to eliminate them, or bioactive molecules (such as miRNA or proteins) that have been proven to play a crucial role in the transmission of resistance to sensitive neoplastic cells. This leads to the hypothesis that EVs could be considered as resistance-mediators in sensitive melanoma cells. These findings are a pivotal starting point for further investigations to better understand EVs' role in drug resistance mechanisms and how to target them. The purpose of this review is to summarize knowledge about EVs in order to develop a deeper understanding of their underlying mechanisms. This could lead to the development of new therapeutic strategies able to bypass EV-mediated drug-resistance in melanoma, such as by the use of combination therapy, including EV release inhibitors.

A Mathematical Model for the Treatment of Melanoma with the BRAF/MEK Inhibitor and Anti-PD-1

Skin cancer treatment is a combination of BRAF and MEK kinase inhibitors administered as tablets, along with immunotherapy treatment (treatment into the vein) with a group of drugs that inhibit the activity of the immune barrier proteins PD-1 and PDL1. Here, we propose a new approach to the therapy for melanoma with the BRAF/MEK inhibitor and anti-PD-1. With the help of explicit analytical functions, we were able to model this combined treatment and present the treatment in a mathematical model described by a system of differential equations including variables, such as Treg, IL12, Il10, TGF-β, and cytokine, which are significant variables that are all critical factors which determine the effectiveness of therapies. The most significant advantage of a treatment described by a mathematical model with explicit analytical functions is the control of parameters, such as time and dose, which are variable critical parameters in the treatment, that is, these parameters can be adapted to the patient’s personalized treatment. In the current study, we showed that by simultaneously changing and combining these two parameters, we could decrease the tumor volume. To validate the numerical results, we computed the relative error between the results obtained from the mathematical model and clinical data.

BRAF Inhibitors in Non-Small Cell Lung Cancer.

Simple SummaryThe identification of BRAF mutations in 1.5–3.5% of NSCLC patients represents a step forward towards new targeted agents for tackling NSCLC. The positive results and favourable safety profile observed with the combination of dabrafenib and trametinib for the treatment of BRAF V600E metastatic NSCLC patients, led to the approval of these two agents in this setting. In this review, we will discuss the clinical, prognostic and therapeutic implications of BRAF mutations in NSCLC patients. Moreover, we will review MEKs’ functions and their role as a potential targeted treatment, both alone and combined with anti-BRAF therapies. Finally, we will discuss ongoing studies and future perspectives in this field. The clinical research on BRAF inhibitors in NSCLC is just beginning, and a number of relevant questions remain to be addressed regarding the role of other BRAF inhibitors in NSCLC, the possibility of facing resistance mechanisms to BRAF inhibitors, and the efficacy of other therapeutic strategies for BRAF-mutated NSCLC.RAF family proteins are serine–threonine kinases that play a central role in the MAPK pathway which is involved in embryogenesis, cell differentiation, cell proliferation and death. Deregulation of this pathway is found in up to 30% of all human cancers and BRAF mutations can be identified in 1.5–3.5% of NSCLC patients. Following the positive results obtained through the combination of BRAF and MEK inhibitors in BRAF-mutant melanoma, the same combination was prospectively assessed in BRAF-mutant NSCLC. In cohort B of the BRF113928 trial, 57 pretreated NSCLC patients were treated with dabrafenib plus trametinib: an ORR of 68.4%, a disease control rate of 80.7%, a median PFS of 10.2 months and a median OS of 18.2 months were observed. Similar results were reported in the first-line setting (cohort C), with an ORR of 63.9%, a DCR of 75% and a median PFS and OS of 10.2 and 17.3 months, respectively. The combination was well tolerated: the main adverse events were pyrexia (64%), nausea (56%), diarrhoea (56%), fatigue (36%), oedema (36%) and vomiting (33%). These positive results led to the approval of the combination of dabrafenib and trametinib for the treatment of BRAF V600E metastatic NSCLC patients regardless of previous therapy. Ongoing research should better define the role of new generation RAF inhibitors for patients with acquired resistance, the activity of chemo-immunotherapy or the combination of TKIs with chemotherapy or with immunotherapy in patients with BRAF-mutated cancers.

Иммунотерапия метастатической меланомы: опыт шестилетнего наблюдения

Purpose – to evaluate the efficacy of nivolumab in oncologic patients with advanced cutaneous melanoma after six-year follow-up in real-life clinical practice. Materials and methods. In the St. Petersburg ‘City Clinical Oncology Dispensary’, under our supervision in the period from 2015 to 2022, 12 patients with a diagnosis of metastatic or recurrent skin melanoma were prescribed nivolumab. The study included patients aged 40 to 84 years (average age 59.66 ± 12.91 (95% CI 51.46–67.87). Among the 12 patients diagnosed with advanced melanoma included in this analysis, there were 8 women (66.7%) and 4 men (33.3%). The mean time from the moment of melanoma diagnosis to the development of the metastatic stage was 59.83 ± 15.1 months (95% CI 26.61–93.06). The number of metastatically affected organs varied from 1 to 4. Results. The duration of treatment of patients with nivolumab ranged from 5 to 32 months. The median duration of treatment with nivolumab was 6 months. Long-term results of treatment with nivolumab were as follows: 6-year PFS was 40%, 6-year OS was 50%. The median progression-free time and median overall survival in this group were comparable and amounted to 64 months (95% CI 63.0–80.0). A subgroup analysis revealed that in the group of patients with an objective response achieved on the background of nivolumab therapy, 6-year PFS and OS were better. The six-year PFS in the objective response and stabilization groups was 60% and 25%, respectively (p = 0.0040). Overall survival at 6 years was 75% in the group of patients with an objective response and 25% in patients with a maximum response to stabilization therapy (p = 0.0032). Conclusion. Our results (median overal survival 64 months, 6-year OS 50%) are consistent with the results of the CheckMate 067 study, as well as with other standard drug approaches in first-line treatment of metastatic melanoma, such as pembrolizumab, for which a 5-year OS is 43.2%, or the combination of BRAF and MEK inhibitors, in the presence of a BRAF mutation, with a 5-year OS of 31% to 35%. 6-year follow-up results in real clinical practice demonstrate sustained, improved clinical outcomes with nivolumab in patients with metastatic melanoma.

Abstract 2434: The role of a more invasive phenotype in response to MAPK-directed therapies in thyroid cancer

Abstract Advanced papillary thyroid cancer (PTC) and anaplastic thyroid cancer (ATC) are the leading causes of endocrine cancer death. Mutations in the MAP kinase (MAPK) pathway are common in PTC and ATC, especially in BRAF, with a prevalence of 40-60%. Despite the importance of the MAPK pathway in thyroid cancer, therapies targeting this pathway are not approved for BRAF-mutant PTC patients. While the combination of BRAF and MEK inhibition is approved for patients with BRAF-mutant ATC, these patients often progress. An emerging mechanism of resistance to targeted therapies is an invasive phenotype switch in which cells transition from a proliferative, therapy sensitive population to an invasive, therapy resistant population. Here, we sought to determine whether increased invasion plays a role in resistance to BRAFi in BRAF-mutant PTC and ATC. In our panel of BRAF-mutant PTC and ATC cell lines with varying sensitivity/resistance to the BRAF inhibitor dabrafenib (BRAFi), we showed that cells resistant to BRAFi exhibit a 1.8 to 2.2 fold increase (p&amp;lt;0.04) in invasion while sensitive cells do not. Using Reverse Phase Protein Array, we identified a 2.0-fold increase in the extracellular matrix protein, fibronectin (FN1), in response to BRAFi treatment. We further identified a 1.6 to 3.2 fold increase (p&amp;lt;0.02) in FN1 secretion in resistant cell lines and found that conditioned media from BRAFi-treated resistant cells promotes invasion 3.8 to 5.7-fold (p&amp;lt;0.0048). Accordingly, treatment with FN1 phenocopies BRAFi-treatment by increasing invasion 1.9 to 2.1 fold (p&amp;lt;0.04), and depletion of FN1 blocks this increase in invasion. Resistant cells with depleted FN1 also fail to exhibit a BRAFi-induced increase in secreted FN1. MAPK pathway reactivation is a common mechanism of resistance to inhibitors of the MAPK pathway, which we have shown can be blocked by dual BRAF and ERK inhibition (Hicks, HM; McKenna, LR et al. Mol Carcinog. 60(3) 2021). ERK inhibition also mitigates the increase in invasion observed in response to single-agent BRAFi (p&amp;lt;0.0014) or FN1 (p&amp;lt;0.0271) in resistant cells. We further observed that dual inhibition of BRAF and ERK slows tumor growth in vivo in a BRAFi-resistant patient-derived xenograft model (p=0.02). These data indicate that thyroid cancer cells resistant to BRAF inhibition exhibit a more invasive phenotype characterized by an increase in FN1 and a pro-invasive secretome. Dual inhibition of BRAF and ERK ablates this BRAFi-driven increase in invasion and slows tumor growth in vivo, providing a potential therapeutic strategy for BRAF-mutant thyroid cancer patients. Citation Format: Hannah M. Hicks, Veronica L. Espinoza, Sharon B. Sams, Nikita Pozdeyev, Rebecca E. Schweppe. The role of a more invasive phenotype in response to MAPK-directed therapies in thyroid cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2434.

More than FOLFOX and FOLFIRI: The Management of Metastatic Colorectal Cancer in the Era of Precision Oncology

Metastatic colorectal cancer (mCRC) is a markedly heterogeneous disease, which portends a poor prognosis, with an estimated 5-year overall survival rate of approximately 15%. The standard of care of systemic therapy remains fluoropyrimidine-based chemotherapy, with modest results, despite improvements with the combination with anti-angiogenics and anti-epidermal growth factor receptor therapy. Significant advances in cancer therapy have been observed in the past two decades. The enhanced appreciation of molecular biology in oncology has allowed for the identification of specific molecular subtypes and novel therapeutic targets. Nevertheless, meaningful precision-based advancements in the therapeutic options for mCRC have been challenging and slow to realisation. Comprehensive molecular profiling and circulating tumour DNA highlight a heterogeneous disease at the genomic, epigenomic, and transcriptomic levels, and with a low frequency of actionable alterations. In the present review, the authors describe the current and emerging predictive biomarkers in mCRC, as well as present landmark clinical trials that have allowed for evolving precision in the therapeutic management. The understanding of the benefit of immune checkpoint inhibitors in patients with high microsatellite instability cancer and in those with POLE mutations or high tumour mutational burden, the combination of BRAF with epidermal growth factor receptor inhibition in BRAF V600-mutated patients, the use of allele-specific KRAS G12C inhibitors, the promising findings of dual anti-HER2 therapy in HER2-positive mCRC, and the possibility to offer targeted therapy for patients harbouring gene fusions NTRK/ALK/ROS1 have ushered in a new era of precision oncology for mCRC, providing personalised treatments and sustaining hope for patients affected by this challenging disease.

Durable Response to Vemurafenib and Cobimetinib for the Treatment of BRAF-Mutated Metastatic Melanoma in Routine Clinical Practice.

BackgroundThe combination of BRAF and MEK inhibitors delays the onset of resistance and provides more sustained and dramatic responses in comparison with a BRAF inhibitor in monotherapy. The objective of the study was to evaluate the effectiveness of the combination therapy with vemurafenib/cobimetinib in terms of durability, and to describe differential characteristics in patients associated to durable responses in real-world settings.Patients and MethodsRetrospective, observational, cross-sectional, multicenter study involving 41 patients with advanced melanoma harboring a BRAFV600 mutation who initiated a combination therapy with vemurafenib/cobimetinib between May 2018 and March 2019. Participants were differentiated regarding the durability of the response: durable (complete response, CR, or a partial response, PR, for at least 12 months) and non-durable (stable disease, SD, progressive disease, PD, or CR/PR <12 months). Secondary endpoints included treatment adherence, labor productivity, anxiety/depression, and safety profile.ResultsDuring the combination therapy, 12 patients (29.3%) had a CR, 19 a PR (46.3%), 5 showed SD (12.2%), and 5 had PD. A total of 12 patients (29.3%) were considered as achieving a durable response and 29 (70.7%) as a non-durable one. Practically all sociodemographic and clinical characteristics were similar between patients. Body mass index was the only differential factor (with higher body mass index achieving a non-durable response). The treatment adherence was 100% in patients with durable response and 66.7% in those with non-durable.ConclusionThe combination treatment with vemurafenib/cobimetinib results in an important impact on long-term survival, leading to a steady CR in one-third of the patients.

Connective tissue panniculitis and vitiligo in a patient with stage IV melanoma achieving complete response to dabrafenib and trametinib combination therapy.

The combination of BRAF and MEK inhibitors, such as dabrafenib and trametinib, respectively, is an established treatment option for patients with advanced BRAFV600-mutated melanoma. With the wide adoption of these therapies, a range of cutaneous adverse effects has been reported. We describe the case of a 47-year-old woman with BRAFV600E-mutated stage IV melanoma treated with dabrafenib and trametinib for 30 months who presented to our attention for painful skin lesions that had been present on her limbs since the start of targeted therapy. We also observed vitiligo-like lesions on the extensor surface of both legs. Despite achieving a complete oncological response, the patient had to discontinue the treatment because of persisting fever, nausea and painful skin nodules that significantly impaired her quality of life. The recognition of cutaneous signs of efficacy of such drugs for advanced melanoma is of primary importance in order to identify patients with potential long-term clinical benefits.

Immunomodulatory Properties of BRAF and MEK Inhibitors Used for Melanoma Therapy-Paradoxical ERK Activation and Beyond.

The advent of mitogen-activated protein kinase (MAPK) inhibitors that directly inhibit tumor growth and of immune checkpoint inhibitors (ICI) that boost effector T cell responses have strongly improved the treatment of metastatic melanoma. In about half of all melanoma patients, tumor growth is driven by gain-of-function mutations of BRAF (v-rat fibrosarcoma (Raf) murine sarcoma viral oncogene homolog B), which results in constitutive ERK activation. Patients with a BRAF mutation are regularly treated with a combination of BRAF and MEK (MAPK/ERK kinase) inhibitors. Next to the antiproliferative effects of BRAF/MEKi, accumulating preclinical evidence suggests that BRAF/MEKi exert immunomodulatory functions such as paradoxical ERK activation as well as additional effects in non-tumor cells. In this review, we present the current knowledge on the immunomodulatory functions of BRAF/MEKi as well as the non-intended effects of ICI and discuss the potential synergistic effects of ICI and MAPK inhibitors in melanoma treatment.

Drug-induced colitis on BRAF and MEK inhibitors for BRAF V600E-mutated non-small cell lung cancer: a case report

SummaryIntroduction. The combination of BRAF and MEK inhibitors has deeply changed the treatment of BRAF V600-mutant non-small cell lung cancer patients. These agents demonstrated high antitumor activity as well as safe and manageable toxicity profile. Hypertension, pyrexia and increased liver enzymes are the most common adverse events. Gastrointestinal toxicities are rare, and mainly consist of mild grade vomiting and diarrhea. Case report. We report the case of 70-year-old man affected by BRAF V600-mutant NSCLC with bilateral lung and bone metastases. First-line treatment with encorafenib (450 mg once daily) and binimetinib (45 mg twice daily) was administered within a clinical trial. At the first radiological assessment, computed tomography (CT) scan showed a partial response and signs of intestinal inflammation were reported. The investigational treatment was timely withheld. The subsequent colonoscopy demonstrated the presence of ulcerative lesions at the caecal tract, and the histological diagnosis suggested a drug-induced colitis. No specific treatment was given as the patient did not report abdominal disturbances. Forty-five days after treatment interruption a new CT scan showed the resolution of bowel inflammation and investigational treatment was resumed at the same doses. The patient is still alive and free of toxicity recurrence after 11 months from treatment initiation. Conclusion. Severe gastrointestinal toxicities are uncommon with BRAF and MEK inhibitors, although cases of colitis and intestinal perforation have already been reported in literature. The pathogenesis seems to be related to the MAPK pathway inhibition performed by MEK inhibitors. These adverse events should be accounted given the potential to evolve into life-threatening conditions.

A High-throughput Approach to Identify Effective Systemic Agents for the Treatment of Anaplastic Thyroid Carcinoma.

Despite the use of aggressive multimodality treatment, most anaplastic thyroid carcinoma (ATC) patients die within a year of diagnosis. Although the combination of BRAF and MEK inhibitors has recently been approved for use in BRAF-mutated ATC, they remain effective in a minority of patients who are likely to develop drug resistance. There remains a critical clinical need for effective systemic agents for ATC with a reasonable toxicity profile to allow for rapid translational development. Twelve human thyroid cancer cell lines with comprehensive genomic characterization were used in a high-throughput screening (HTS) of 257 compounds to select agents with maximal growth inhibition. Cell proliferation, colony formation, orthotopic thyroid models, and patient-derived xenograft (PDX) models were used to validate the selected agents. Seventeen compounds were effective, and docetaxel, LBH-589, and pralatrexate were selected for additional in vitro and in vivo analysis as they have been previously approved by the US Food and Drug Administration for other cancers. Significant tumor growth inhibition (TGI) was detected in all tested models treated with LBH-589; pralatrexate demonstrated significant TGI in the orthotopic papillary thyroid carcinoma model and 2 PDX models; and docetaxel demonstrated significant TGI only in the context of mutant TP53. HTS identified classes of systemic agents that demonstrate preferential effectiveness against aggressive thyroid cancers, particularly those with mutant TP53. Preclinical validation in both orthotopic and PDX models, which are accurate in vivo models mimicking tumor microenvironment, may support initiation of early-phase clinical trials in non-BRAF mutated or refractory to BRAF/MEK inhibition ATC.

Edoxaban prevented adverse effects including pyrexia and elevation of D-dimer caused by the combination of BRAF and MEK inhibitors in a patient with BRAF-mutant melanoma.

The combination of BRAF inhibitor and MEK inhibitor is one of the first-line treatments for unresectable BRAF-mutant melanoma or as an adjuvant therapy. However, some patients who received the combination of dabrafenib and trametinib (CombiDT) or the combination of encorafenib and binimetinib (CombiEB) had adverse events (AEs) including pyrexia. We herein report a patient with BRAF-mutated melanoma who repeatedly developed elevated levels of D-dimer and pyrexia after CombiDT and CombiEB treatments. Moreover, concomitant edoxaban prevented these AEs, enabling the patient to continue receiving CombiEB.

He role of immunotherapy for the adjuvant treatment of BRAF-mutant melanoma

The introduction of anti-PD-1 drugs as an adjuvant treatment for high risk melanoma has radically changed the everyday clinical practice, with an impact on the reduction of the risk of relapse close to 50%, as observed in phase 3 clinical trials. In patients whose tumors harbor a BRAF mutation, the combination of BRAF plus MEK inhibitors is also a valuable option, with outcomes in terms of 3-year RFS similar to those observed with anti-PD-1 immunotherapy. However, numerous questions remain unanswered, particularly which is the best treatment in BRAF-mutant patients. The aim of this review was to analyze the results of randomized phase 3 clinical trials, with a focus on some hot topics and discussing the role of immunotherapy for the adjuvant treatment of BRAF-mutant melanoma.

TREATMENT OF &lt;em&gt;BRAF&lt;/em&gt;&lt;sup&gt;V600E&lt;/sup&gt; POSITIVE ANAPLASTIC THYROID CARCINOMA: CASE REPORT

Anaplastic thyroid cancer is one of the most aggressive and fatal human carcinomas. A significant experience in using various kinase inhibitors for anaplastic thyroid cancer therapy has been accumulated worldwide. The most encouraging results were obtained after using a combination of b-Raf and MEK kinase inhibitors (vemurafenib/dabrafenib and trametinib/cobimetinib, respectively) for the treatment of the unresectable BRAF V600E -positive anaplastic thyroid cancer. This drug combination makes it possible to perform surgery followed by chemoradiotherapy and other targeted therapies. Here we report a clinical case of anaplastic thyroid cancer in a 69-year-old woman, who was treated with neoadjuvant targeted therapy. The treatment was carried out on the basis of three medical institutions: the National Medical Research Radiological Centre (Moscow), the N.I. Pirogov Clinic of Advanced Medical Technologies (St. Petersburg) and the Endocrinology Research Center (Moscow). Since there is still no universal protocol for treating ATC patients, and only palliative therapy is used in most cases, we emphasized on diagnostic and treatment errors of this disease. Special attention was paid to the importance of using molecular diagnostics and modern medical imaging technologies.