BRAF-mutant Metastatic Melanoma Research Articles

Circulating tumor DNA analysis in patients with BRAF-mutated metastatic cutaneous melanoma treated with BRAF and MEK inhibitors: Analysis of the OPTIMEL study.

9541 Background: BRAF and MEK kinase inhibitors (KI) are indicated in combination for the treatment of adult patients with unresectable or metastatic melanoma (MM) harboring a BRAF V600 mutation. However, approximately half of the patients develop resistance to the treatment within a year. Circulating tumor DNA (ctDNA) has demonstrated its prognostic value for MM patients receiving specific treatment, offering potential assistance in patient follow-up. We present here the results of the prospective interventional study OPTIMEL (NCT03416933) that was conducted to investigate the relevance of ctDNA in predicting outcomes for MM patients undergoing BRAF and MEK inhibitors treatment. Methods: Thirty-five patients with histologically proven advanced cutaneous MM harboring BRAF mutations, either in a metastatic stage or cases ineligible for surgical intervention were enrolled in the study. All participants underwent treatment with BRAF and MEK inhibitors. Blood samples were systematically obtained on days 0, 15, 30, 90, 180, 270, and 365, or at the occurrence of disease progression. The assessment of mutations in the BRAF and NRAS genes in all plasma samples was conducted using the Idylla system (Biocartis, Mechelen, Belgium). Results: Out of the 35 patients initially enrolled in the study, 4 were excluded for not meeting the inclusion criteria, leaving 31 patients for the final analysis. At baseline, BRAF mutation was identified in 18 patients (58%), while it was not detected in 13 patients (42%). The presence of BRAF mutation at baseline was associated with a significantly lower progression-free survival (PFS) (HR = 3.42; CI95% [1.19;9.82]; p = 0.022). During the follow-up, BRAF mutation was detected in the plasma of 19 out of 31 patients. A BRAF variant allele frequency (vaf) below 2.3% was strongly linked to an objective response to treatment (p<0.001). The absence of BRAF variant detection during follow-up was significantly associated with better outcome (PFS 4.01 vs 12.0 months, HR = 28.5; CI95% [7.75;105.0]; p < 0.001). Moreover, PFS significantly deteriorated when BRAF vaf exceeded 4.5% (3.15 vs 12.0 months, HR = 112; CI95% [13.8;913.0]; p < 0.001). Lastly, the identification of NRAS mutation in plasma during follow-up was linked to treatment resistance and a worsened PFS (4.84 vs 10.9 months, HR = 11.6; CI95% [2.76;48.5]; p<0.001). Conclusions: This report presents the initial analysis of the OPTIMEL study. The variant allele frequency of BRAF mutations in circulating tumor DNA is indicative of the objective response to BRAF and MEK inhibitors, as well as PFS. These findings could potentially influence our approach to managing patients with MM harboring a BRAF mutation. Clinical trial information: NCT03416933 .

RICTOR/mTORC2 downregulation in BRAFV600E melanoma cells promotes resistance to BRAF/MEK inhibition.

The main drawback of BRAF/MEK inhibitors (BRAF/MEKi)-based targeted therapy in the management of BRAF-mutated cutaneous metastatic melanoma (MM) is the development of therapeutic resistance. We aimed to assess in this context the role of mTORC2, a signaling complex defined by the presence of the essential RICTOR subunit, regarded as an oncogenic driver in several tumor types, including MM. After analyzing The Cancer Genome Atlas MM patients' database to explore both overall survival and molecular signatures as a function of intra-tumor RICTOR levels, we investigated the effects of RICTOR downregulation in BRAFV600E MM cell lines on their response to BRAF/MEKi. We performed proteomic screening to identify proteins modulated by changes in RICTOR expression, and Seahorse analysis to evaluate the effects of RICTOR depletion on mitochondrial respiration. The combination of BRAFi with drugs targeting proteins and processes emerged in the proteomic screening was carried out on RICTOR-deficient cells in vitro and in a xenograft setting in vivo. Low RICTOR levels in BRAF-mutated MM correlate with a worse clinical outcome. Gene Set Enrichment Analysis of low-RICTOR tumors display gene signatures suggestive of activation of the mitochondrial Electron Transport Chain (ETC) energy production. RICTOR-deficient BRAFV600E cells are intrinsically tolerant to BRAF/MEKi and anticipate the onset of resistance to BRAFi upon prolonged drug exposure. Moreover, in drug-naïve cells we observed a decline in RICTOR expression shortly after BRAFi exposure. In RICTOR-depleted cells, both mitochondrial respiration and expression of nicotinamide phosphoribosyltransferase (NAMPT) are enhanced, and their pharmacological inhibition restores sensitivity to BRAFi. Our work unveils an unforeseen tumor-suppressing role for mTORC2 in the early adaptation phase of BRAFV600E melanoma cells to targeted therapy and identifies the NAMPT-ETC axis as a potential therapeutic vulnerability of low RICTOR tumors. Importantly, our findings indicate that the evaluation of intra-tumor RICTOR levels has a prognostic value in metastatic melanoma and may help to guide therapeutic strategies in a personalized manner.

The outcome in patients with BRAF-mutated metastatic melanoma treated with anti-programmed death receptor-1 monotherapy or targeted therapy in the real-world setting.

Immunotherapy and targeted therapy are currently two alternative backbones in the therapy of BRAF-mutated malignant melanoma. However, predictive biomarkers that would help with treatment selection are lacking. This retrospective study investigated outcomes of anti-programmed death receptor-1 monotherapy and targeted therapy in the first-line setting in patients with metastatic BRAF-mutated melanoma, focusing on clinical and laboratory parameters associated with treatment outcome. Data from 174 patients were analysed. The median progression-free survival (PFS) was 17.0 months (95% CI; 8-39) and 12.5 months (95% CI; 9-14.2) for immunotherapy and targeted therapy, respectively. The 3-year PFS rate was 39% for immunotherapy and 25% for targeted therapy. The objective response rate was 72% and 51% for targeted therapy and immunotherapy. The median overall (OS) survival for immunotherapy has not been reached and was 23.6 months (95% CI; 16.1-38.2) for targeted therapy, with a 3-year survival rate of 63% and 40%, respectively. In a univariate analysis, age < 70 years, a higher number of metastatic sites, elevated serum LDH and a neutrophil-lymphocyte ratio above the cut-off value were associated with inferior PFS regardless of the therapy received, but only serum LDH level and the presence of lung metastases remained significant predictors of PFS in a multivariate analysis. Present real-world data document the high effectiveness of immunotherapy and targeted therapy. Although targeted therapy had higher response rates, immunotherapy improved PFS and OS. While the prognostic value of LDH was confirmed, the potential use of blood cell count-derived parameters to predict outcomes needs further investigation.

Targeted therapy or immunotherapy in BRAF-mutated metastatic melanoma: a Spanish center's decade of experience.

Targeted therapies and immunotherapy are currently considered the mainstay first-line treatment for advanced BRAF-mutated melanoma. However, the impact of treatment (targeted therapy and immunotherapy) and the prognostic factors are still not clear. Medical records of 140 patients diagnosed with advanced melanoma between 2011 and 2021 were retrospectively reviewed to extract demographic, BRAF status, treatment, performance status, and survival data. ORR, PFS, and OS were compared between patients diagnosed with advanced melanoma and treated with first-line IT or BRAF/MEKi. The prognostic factors were assessed using Cox regression models. In all patients and those treated with immunotherapy, we did not find any effect of BRAF status on ORR, PFS, or OS. In patients with BRAF-mutated melanoma, ORR was 43.8% vs. 70% (P=0.04), PFS was 19.2 vs. 11.5 months (p=0.22), and OS was 33.4 vs. 16.4 months for the immunotherapy and targeted therapy groups, respectively (P=0.04). ECOG, presence of brain metastases, and high LDH level from initiation of first-line treatment were all associated with differences in PFS and OS. Patients with advanced BRAF-mutated melanoma treated with first-line immunotherapy had a significantly longer PFS and OS than those treated with first-line BRAF/MEKi; however, first-line BRAF/MEKi treatment had a significantly higher ORR than first-line immunotherapy.

The Impact of Drug-Drug Interactions on the Toxicity Profile of Combined Treatment with BRAF and MEK Inhibitors in Patients with BRAF-Mutated Metastatic Melanoma.

BRAF and MEK inhibition is a successful strategy in managing BRAF-mutant melanoma, even if the treatment-related toxicity is substantial. We analyzed the role of drug-drug interactions (DDI) on the toxicity profile of anti-BRAF/anti-MEK therapy. In this multicenter, observational, and retrospective study, DDIs were assessed using Drug-PIN software (V 2/23). The association between the Drug-PIN continuous score or the Drug-PIN traffic light and the occurrence of treatment-related toxicities and oncological outcomes was evaluated. In total, 177 patients with advanced BRAF-mutated melanoma undergoing BRAF/MEK targeted therapy were included. All grade toxicity was registered in 79% of patients. Cardiovascular toxicities occurred in 31 patients (17.5%). Further, 94 (55.9%) patients had comorbidities requiring specific pharmacological treatments. The median Drug-PIN score significantly increased when the target combination was added to the patient's home therapy (p-value < 0.0001). Cardiovascular toxicity was significantly associated with the Drug-PIN score (p-value = 0.048). The Drug-PIN traffic light (p = 0.00821) and the Drug-PIN score (p = 0.0291) were seen to be significant predictors of cardiotoxicity. Patients with low-grade vs. high-grade interactions showed a better prognosis regarding overall survival (OS) (p = 0.0045) and progression-free survival (PFS) (p = 0.012). The survival analysis of the subgroup of patients with cardiological toxicity demonstrated that patients with low-grade vs. high-grade DDIs had better outcomes in terms of OS (p = 0.0012) and a trend toward significance in PFS (p = 0.068). DDIs emerged as a critical issue for the risk of treatment-related cardiovascular toxicity. Our findings support the utility of DDI assessment in melanoma patients treated with BRAF/MEK inhibitors.

P07.03.A 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

Abstract BACKGROUND BRAF mutations are drivers of oncogenesis in a variety of tumors and they can be successfully targeted with small molecule inhibitors. In primary central nervous system tumors, BRAFV600E mutations are most frequently found in pleomorphic xanthoastrocytoma, ganglioglioma, pilocytic astrocytoma and epithelioid glioblastoma. Dabrafenib is a potent and selective inhibitor of BRAF-mutant kinase that was approved, as monotherapy or in combination with trametinib (mitogen-activated protein kinase (MAPK) kinase (MEK) inhibitor), for unresectable or metastatic BRAF-mutated melanoma, advanced non-small cell lung cancer and anaplastic thyroid cancer harboring BRAFV600E mutation. MATERIAL AND METHODS In February 2016, a 21-year-old female was admitted to our Unit for seizures. A brain magnetic resonance imaging (MRI) revealed a frontal contrast enhanced lesion. Neurosurgical resection was performed. The histological analysis diagnosed anaplastic pleomorphic xanthoastrocytoma (PXA) WHO grade III. A volumetric modulated radiotherapy course was delivered for a total dose of 59,4 Gy in 33 fractions with concomitant and adjuvant temozolomide therapy (Stupp protocol). In October 2017, a brain MRI showed relapsing disease. Six courses of chemotherapy with procarbazine, lomustine and vincristine (PCV) were administered, and then neurosurgical partial removal and carmustine wafer implantation were performed. The histological analysis confirmed BRAF V600E mutated anaplastic PXA. RESULTS In April 2019 the 24-year-old female patient with BRAF mutated anaplastic PXA started her third-line therapy with dabrafenib. The well-known tumor residue was less evident on the subsequent MRIs performed every three/four months. Given the literature data of the most effectiveness and the best control of the side effects, in August 2020 the patient was put on combined treatment with dabrafenib plus trametinib. Since December 2021 the residual tumor has not been longer visible. Last MRI evaluation, performed on January 26th 2023, showed no recurrence of the disease, four years after BRAF inhibitor treatment beginning. CONCLUSION Dabrafenib plus trametinib is a promising new therapy for patients affected by BRAFV600E-mutant glioma, with high overall response and manageable toxicity. Due to very poor prognosis, there are a few described cases of high-grade glioma (HGG) patients in third-line therapy, showing complete response and for such a long time. The emergence of optimized sequencing strategies and targeted agents, including multimodal treatment and systemic therapy with dabrafenib plus trametinib, will continue to broaden personalized therapy in HGG and to improve patient outcomes.

MEK inhibition induces expression of differentiation marker Keratin 10 in human keratinocytes

BRAF mutant metastatic melanoma was regularly treated in the past with a BRAF inhibitor (BRAFi) alone or in combination with inhibitors of the mitogen-activated protein kinase kinase (MEKi), which is still a common treatment. This combination therapy strongly reduced the occurrence of keratoacanthomas and squamous cell carcinoma, which was frequently seen when BRAFi was used as monotherapy. Here we addressed the question whether MEK inhibition counteracts squamous cell carcinoma development in part by promoting keratinocyte differentiation. Exposure of human immortalized keratinocytes to different concentrations of MEKi revealed a significant increase in the expression of differentiation-associated keratins K10 and K1 as determined by qRT-PCR and immunofluorescence staining. Taken together, the present study suggests that in a combined treatment of melanoma with BRAFi/MEKi, MEKi reduces the incidence of squamous cell carcinomas by promoting keratinocyte differentiation under combined BRAFi/MEKi treatment in melanoma. This might open further treatment perspectives for skin cancer treatment.

BI26 Treatment-induced scleroderma in a patient with metastatic melanoma

Abstract We present a 71-year-old woman who presented with sclerodermoid plaques affecting the abdomen and lower limbs, following a single cycle of nivolumab and ipilimumab 20 months prior for BRAF-mutant metastatic melanoma (pulmonary and hepatic metastases). Immunotherapy was discontinued owing to iatrogenic colitis, confirmed on flexible sigmoidoscopy, and requiring oral prednisolone, infliximab and, later, modified-release beclomethasone dipropionate. Owing to the progression of hepatic disease, she was commenced on targeted therapy with dabrafenib and trametinib. A lesional punch biopsy was performed; histological analysis demonstrated a dense dermis with mild chronic inflammatory infiltrate, in keeping with a diagnosis of scleroderma. Treatment with a combination of topical corticosteroids and vitamin D analogues improved disease from 15% body surface area (BSA) to 3% after 4 months. We performed a literature search in PubMed for articles on immunotherapy-related scleroderma published up to August 2022 and identified 18 articles that met our inclusion criteria. Scleroderma was reported in patients with melanoma, non-small-cell lung cancer, renal cell carcinoma, rectal adenocarcinoma, adenocarcinoma of the lung and large-cell neuroendocrine lung cancer treated with pembrolizumab, nivolumab, atezolizumab and ipilimumab. Latency of onset ranged from 0 to 18 months, and treatment included topical and systemic corticosteroids, mycophenolate mofetil, hydroxychloroquine, cyclophosphamide, infliximab and immunoglobulins, with varying treatment outcomes. There was no clear relationship between cancer subtype, duration of treatment and response to treatment. Furthermore, the lack of documented quantitative or semiquantitative measurements for improvement such as BSA and modified Rodnan skin score is limiting. Our case report is important in promoting the awareness of localized scleroderma as a rare side-effect of immunotherapy and highlights the various treatment options available.

Повторное применение ингибиторов BRAF и MEK у пациентов с метастатической меланомой кожи с мутацией в гене BRAF

In this paper we review the existing data and our clinical experience of repeated use of combination therapy with BRAF/MEK inhibitors (BRAFi/MEKi) in the treatment of patients with BRAF-mutated metastatic melanoma of the skin. Recent advances in medical oncology significantly increased the life expectancy of patients with metastatic and/or unresectable melanoma of the skin. However, some patients develop resistance to therapy. Retreatment after interruption or "intermediate" therapy may be of clinical benefit. Contemporary drug therapy becomes more available and there are fewer challenges to chose the first and second line therapy for patients with metastatic and/or unresectable melanoma, but there are still questions on subsequent treatment options when BRAFi/MEKi therapy had been used after the disease progression following the initial objective response. In this article, we review the definitions of “retreatment” or “rechallenge”, give the overview of the literature data, and present our clinical experience

Long-term efficacy of BRAFi/MEKi rechallenge in metastatic melanoma: Report of 9 years of clinical practice.

e21550 Background: First line BRAFi/MEKi therapy in metastatic melanoma eventually result in drug resistance and disease progression. Because drug resistance develops at least partially by epigenetic mechanisms, it may potentially be reversed after BRAFi/MEKi discontinuation. Therefore we aim to explore the clinical efficacy of BRAFi/MEKi rechallenge in 3 line treatment. Moreover the reports on the efficacy of BRAFi/MEKi after immunotherapy were contradictory, so we enrolled patients treated sequentially to explore this clinical scenario. Methods: In country-wide multicenter retrospective analysis 86 patients with metastatic BRAF-mutated melanoma were enrolled since 1/Jan/2014. Patients were treated with 1st line BRAFi/MEKi, 2nd line immunotherapy (anti-PD-1 or anti-CTLA-4) and were rechallenged with BRAFi/MEKi. Survival analyses were performed using the Kaplan-Meier method, log-rank and chi-square tests were used for comparison between groups. Data cut-off was 31/Dec/2022. Results: Median age at BRAFi/MEKi rechallenge was 50 (range: 20-81 y/o). Median overall survival (OS) from the start of the first BRAFi/MEKi therapy and from rechallenge BRAFi/MEKi treatment was 34 and 9 months, respectively; whereas median progression-free survival (PFS) was 10.5 and 4.4 months respectively. At the time of analysis 88% progressed on third line therapy and 78% patients died. Six-month, one-year, and two-year OS rates were: 99%, 93% and 70% on first line treatment; and 65%, 40% and 2% on BRAFi/MEKi rechallenge. Objective response rate and disease control rate on first line BRAFi/MEKi and rechallenge were 57% and 28%; and 91% and 64%, respectively. A lower toxicity rate was noted with BRAFi/MEKi rechallenge. The most common treatment sequence was dabrafenib/trametinib – immunotherapy – encorafenib/binimetinib. Conclusions: Rechallenge with BRAFi/MEKi after second line immunotherapy results in a clinically significant benefit in majority of eligible patients. Third line treatment should be considered for fit patients. [Table: see text]

RWD157 Healthcare Resource Utilization and Cost of Care in Patients with BRAF-Mutated Unresectable/Metastatic Melanoma in the US

The objective of this study was to assess healthcare resource utilization (HCRU) and costs associated with treatments for patients with BRAF-mutant (BRAF-m) metastatic melanoma (m-melanoma) in the US.

Patient characteristics and treatment patterns in BRAF-mutated unresectable or metastatic melanoma in the United States: A snapshot from real-world data.

e21506 Background: BRAF mutations are found in 40-60% of patients with unresectable/metastatic melanoma (m-melanoma). Recently, several new BRAF-targeted therapies (TT) have been approved, transforming the treatment landscape for patients with BRAF-mutated (BRAFm) unresectable/m-melanoma. This analysis aimed to describe patient characteristics and treatment patterns in BRAFm unresectable/m-melanoma patients receiving treatment during November 2015-June 2021. Methods: A retrospective analysis using Flatiron Health’s database was conducted. Adult patients with unresectable/m-melanoma who had evidence of the BRAF-V600 activating mutation were included. Patients were indexed at first-line (1L) therapy initiation. Treatments of interest were classified into immuno-oncology (IO) therapies and TT. All analyses were descriptive. Results: 671 unresectable/m-melanoma patients (average age: 62.7 years, 64.1% male) were included. Among them, 64.4% of patients received IO, 34.4% received TT, and 1.2% received IO+TT. In 1L, ipilimumab+nivolumab and dabrafenib+trametinib were the most common IO (50.9%) and TT (71.9%), respectively. The median duration of 1L was 8.0 months (9.7 months in IO and 6.7 months in TT). Among IO-treated patients, 28.5% had Eastern Cooperative Oncology Group (ECOG)≥1, 23.4% had elevated lactate dehydrogenase (LDH) levels, and 4.9% had 3+ metastases identified. Among TT-treated patients, 42.9% had ECOG≥1, 27.3% had elevated LDH, and 7.8% had 3+ metastases identified. Approximately one-third of the patients (n = 204) received their 1L treatment prior to being tested for BRAF mutation; the majority of whom (90.2%) received IO. 273 patients (40.7%) advanced to a second line (2L). In 2L, 14.3% of patients received the same class of therapy as in 1L, 44.7% switched from 1L IO to 2L TT, and 35.2% switched from 1L TT to 2L IO. In 2L, ipilimumab+nivolumab (50.0%) in IO and dabrafenib+trametinib (60.7%) in TT were the most common combinations. The median duration of 2L was 5.0 months (3.7 months in IO and 6.5 months in TT). Conclusions: Despite the recent availability of TT combinations for BRAFm unresectable/m-melanoma, IO is about twice as frequently prescribed than TT in 1L. One-third of the patients received treatment before BRAFm testing results were available and most of them were prescribed IO. These findings along with elevated ECOG scores, the proportion of 3+ metastases, and elevated LDH levels seen in TT patients, suggest TT is often offered to patients with a high disease burden in the current practice settings.

Abstract 1012: Detecting and intervening on rare pre-existing resistant subclones to BRAF/MEK inhibitors in metastatic melanoma

Abstract The combination of BRAF and MEK inhibitors (BRAFi/MEKi) in metastatic melanoma patients with BRAF activating mutations have resulted in dramatic responses in most patients, but unfortunately most patients progress after one year and limited subsequent treatment options are available. Although resistance mutations to BRAFi/MEKi mainly occur in the MAPK and PI3K pathways, after progression on BRAFi/MEKi drugs, targeting these mutations have been clinically unsuccessful. One possible cause of relapse is that a resistant subpopulation to BRAFi/MEKi exists prior to treatment, raising the possibility that earlier counter-resistance treatment could be administered and potentially be more successful. However, the prevalence and clinical significance of pre-existing resistance is currently unknown in melanoma. To address this, we used quantitative blocker displacement amplification (qBDA) to quantify the VAF (down to 0.01% resolution) of resistant subclones along the MAPK/PI3K pathways from FFPE biopsies on 149 metastatic melanoma patients. Due to possible intra-tumoral heterogeneity, multiple samples were taken when available per patient. Of 29 patients currently processed, 5/29 (17%) had detectable NRAS Q61L or Q61R, 5/29 (17%) had KRAS G12 or G13 mutations, and 3/29 (10.3%) had PIK3CA H1047R/Y. As expected, BRAF activating mutations were detectable in 29/29 patients, while VAF of the resistant subclones were found to be as low as 0.16%. We expect some of the putative resistance mutations to be artifacts, and all will be validated by ddPCR. To model the behavior of low-VAF resistance mutations, we conducted in vitro spike-in experiments using paired and labeled parental and BRAF/MEK inhibitor-resistant melanoma lines. Our results show that even down to 0.1%, the resistant lines can rapidly emerge as the dominant population while under drug treatment. We also tested the timing of applying a counter-resistance therapy: early vs late. Earlier intervention led to a significant delay in growth of the resistant population, as expected. However, we are currently preparing an experiment that will determine whether an earlier intervention might not simply delay resistance, but also alter its strength, at different % VAFs. We therefore anticipate mechanistic analyses of how %VAF and drug timing can optimize counter-resistance therapies. Overall, our interim data suggest a significant percentage of metastatic BRAF-mutated melanoma patients may harbor pre-existing resistant subclones, and that early treatment with counter-resistance therapy can potentially delay resistance to targeted therapy. Citation Format: Michael Nakazawa, Lauren Cheng, Mishal Ahmed, Rossana Lazcano, Khalida Wani, Omid Veiseh, Lawrence Kwong. Detecting and intervening on rare pre-existing resistant subclones to BRAF/MEK inhibitors in metastatic melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1012.

Targeting EphA2 and DDR signaling can overcome the BRAF and MEK inhibitors acquired resistance in melanoma cell lines

The BRAF and MEK inhibitors combined strategies have dramatically changed the outcome of BRAF-mutated metastatic melanoma patients. However, despite the initial promising results, the onset of primary or acquired resistance occurs in nearly half of the patients at about one year from the diagnosis. Understanding the mechanisms of resistance to these inhibitors is therefore critical for planning more effective therapeutic strategies able to improve patient outcomes. To this aim we generated BRAF and MEK inhibitors resistant melanoma cells starting from the SAN and A375 lines, both harboring the most common BRAF-V600 mutation and sensitive to these drugs. The obtained double-resistant cell lines were characterized by MTT cell proliferation, migration, invasion assays, phosphoarray and western blot analysis. Here we report that the overexpression of several Tyrosine Kinase Receptors (TKRs), such as EphA2 and DDRs, drives the resistance to these drugs and that this resistance can be overcome by treatment with ALW‑II‑41‑27 multikinase inhibitor. ALW‑II‑41‑27 blocks not only TKRs expression, but also the related downstream AKT and MAPK signaling pathways and its efficacy is documented by decreased cell viability and reduced cell invasion/migration of the resistant cells. Our results can delineate a novel promising therapeutic approach to overcoming the drug resistance occurring in BRAF-mutated metastatic melanoma.

Selected Articles from This Issue

Highlights| February 01 2023 Selected Articles from This Issue Author & Article Information Online ISSN: 1557-3265 Print ISSN: 1078-0432 ©2023 American Association for Cancer Research2023American Association for Cancer Research Clin Cancer Res (2023) 29 (3): 503. https://doi.org/10.1158/1078-0432.CCR-29-3-HI Related Content A commentary has been published: Clinical Features Associated with Outcomes and Biomarker Analysis of Dabrafenib plus Trametinib Treatment in Patients with BRAF-Mutant Melanoma Brain Metastases A commentary has been published: Safety and Efficacy of MEDI0457 plus Durvalumab in Patients with Human Papillomavirus–Associated Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma A commentary has been published: A Phase II Window of Opportunity Study of Neoadjuvant PD-L1 versus PD-L1 plus CTLA-4 Blockade for Patients with Malignant Pleural Mesothelioma View more A commentary has been published: HER2 Copy Number and Resistance Mechanisms in Patients with HER2-positive Advanced Gastric Cancer Receiving Initial Trastuzumab-based Therapy in JACOB Trial View less Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Facebook Twitter LinkedIn MailTo Tools Icon Tools Get Permissions Cite Icon Cite Search Site Article Versions Icon Versions Version of Record February 1 2023 Citation Selected Articles from This Issue. Clin Cancer Res 1 February 2023; 29 (3): 503. https://doi.org/10.1158/1078-0432.CCR-29-3-HI Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest Search Advanced Search The study from Wilmott and colleagues aimed to identify baseline clinical features associated with the outcomes of patients enrolled in the COMBI-MB phase II study of dabrafenib and trametinib treatment in patients with V600 BRAF-mutant metastatic melanoma with melanoma brain metastases (MBM). Exploratory biomarker analysis also was conducted as part of the synergistic COMBI-BRV trial (BRV116521) to identify molecular and immunological changes associated with dabrafenib in MBM and extracranial (ECM) metastases. Corticosteroid treatment was associated with reduced ICRR and PFS in COMBI-MB, similar to results with immunotherapy for MBM. Baseline corticosteroid treatment is a key factor to consider in MBM patient management and clinical trial design/interpretation. Immune checkpoint blockade (ICB) with nivolumab and ipilimumab has become standard treatment for patients with unresectable malignant pleural mesothelioma (MPM). However, the impact of neoadjuvant ICB in MPM has not yet been evaluated. Lee and colleagues report the results of a randomized, phase II,... You do not currently have access to this content.

Comparison Between First Line Target Therapy and Immunotherapy in Different Prognostic Categories of BRAF Mutant Metastatic Melanoma Patients: An Italian Melanoma Intergroup Study.

BackgroundBRAF and MEK inhibitors target therapies (TT) and AntiPD1 immunotherapies (IT) are available first-line treatments for BRAF v600 mutant metastatic melanoma patients. ECOG PS (E), baseline LDH (L), and baseline number of metastatic sites (N) are well-known clinical prognostic markers that identify different prognostic categories of patients. Direct comparison between first-line TT and IT in different prognostic categories could help in first line treatment decision.MethodsThis is a retrospective analysis conducted in 14 Italian centers on about 454 metastatic melanoma patients, divided in 3 groups: group A—patients with E = 0, L within normal range, and N less than 3; group B—patients not included in group A or C; group C—patients with E > 0, L over the normal range, and N more than 3. For each prognostic group, we compared TT and IT in terms of progression free survival (PFS), overall survival (OS), and disease control rate (DCR).ResultsIn group A, results in 140 TT and 36 IT-treated patients were, respectively, median PFS 35.5 vs 11.6 months (HR (95% CI) 1.949 (1.180–3.217) p value 0.009); median OS not reached vs 55 months (HR (95% CI) 1.195 (0.602–2.373) p value 0.610); DCR 99% vs 75% p value <0.001). In group B, results in 196 TT and 38 IT-treated patients were, respectively, median PFS 11.5 vs 5 months (HR 1.535 (1.036–2.275) p value 0.033); median OS 19 vs 20 months (HR 0.886 (0.546–1.437) p value 0.623); DCR 85% vs 47% p value <0.001). In group C, results in 41 TT and 3 IT-treated patients were, respectively, median PFS 6.4 vs 1.8 months (HR 4.860 (1.399–16) p value 0.013); median OS 9 vs 5 months (HR 3.443 (0.991–11.9) p value 0.052); DCR 66% vs 33% p value 0.612).ConclusionsIn good prognosis, group A—TT showed statistically significant better PFS than IT, also in a long-term period, suggesting that TT can be a good first line option for this patient category. It is only in group B that we observed a crossing of the survival curves after the 3rd year of observation in favor of IT. Few patients were enrolled in group C, so few conclusions can be made on it.

Treatment reality of patients with BRAF-mutant advanced/metastatic melanoma in Switzerland in the era of choice.

Cutaneous melanoma represents a major cause of cancer death in Europe. Without adequate therapy, the 5-year survival rate is 15-20% in distant metastatic disease. Evaluating the status quo of treatment standards in advanced melanoma and rationale for therapy decisions in Switzerland between January 2016 and September 2018. In this retrospective, anonymized registry, data of male and female patients with unresectable advanced/metastatic BRAF-positive cutaneous melanoma treated in first-, second- and third-line with registered substances were analyzed using descriptive statistics. Forty-one patients (56.1% male) were included providing a total of 70 treatment lines (first-line: n = 41; second-line: n = 18; and third-line: n = 11). Within the patients presenting with stage III or IV melanoma, immunotherapy with checkpoint inhibitors was more frequently administered as first-line treatment than targeted therapy (TT) (70.7% vs. 29.3%). Across all lines, patients received TT in 47.1% (predominantly combined BRAF-MEK-inhibition) and immunotherapy in 52.9% of the cases (anti-PD-1 monotherapy in 62.2% and anti-PD-1/anti-CTLA-4 combinations in 37.8%). Most commonly, the treatment type was switched from TT to immunotherapy or vice versa upon disease progression. The most frequent rationales for prescribing either TT or immunotherapy were physician's preference (40.0%) or remission pressure (28.6%), respectively. Disease progression led to treatment discontinuation more frequently than undesired events. Patients in Switzerland with unresectable advanced or metastatic BRAF-mutant melanoma predominantly receive guideline-recommended treatments. IO was used as predominant front-line therapy, with TT/immunotherapy switch being the predominant treatment principle. Sequencing studies are underway to identify the optimal treatment regimen for those patients. 32: 366-372 Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.

Efficacy and safety of anti-PD1 monotherapy or in combination with ipilimumab after BRAF/MEK inhibitors in patients with BRAF mutant metastatic melanoma

BackgroundPatients with V600BRAF mutant metastatic melanoma have higher rates of progression-free survival (PFS) and overall survival (OS) with first-line anti-PD1 (PD1]+anti-CTLA-4 (IPI) versus PD1. Whether this is also true after...

Effectiveness of immunotherapy versus BRAF/MEK inhibitors in treatment-naïve BRAF-mutant advanced melanoma: A single institution retrospective analysis.

e21515 Background: Skin cancer is the most common type of cancer in the US. Melanoma constitutes about 1% of all skin cancers, but it accounts for most of skin cancer related deaths. In 2017, 85,000 new cases of melanoma were reported while 8000 people died. BRAF is the gene encoding for B-Raf protein; a serine/threonine-protein kinase involved in cell growth and survival. Activating mutations in BRAF are present in approximately 50% of melanomas. Therapeutics in melanoma have been rapidly evolving. Currently, advanced melanoma with a mutation in the BRAF gene has two different modalities for first-line treatment; immunotherapy which mediates checkpoint inhibition versus targeted therapy with BRAF + MEK inhibitors. The aim of our study was to compare effectiveness of immunotherapy versus BRAF/MEK inhibitors as first line treatment for metastatic BRAF-mutant advanced melanoma. Methods: A retrospective study of all patients aged ≥ 18 years, diagnosed with metastatic melanoma at our center between 1/1/2011 and 05/30/2021 was carried out. Patients who had BRAF negative melanoma or other active malignancies were excluded. Our primary endpoint was difference in overall survival and progression-free survival between two treatment groups. Secondary endpoint was to compare baseline characteristics associated with treatment options. Results: A total of 308 patients were diagnosed with advanced melanoma during the study period. N = 106 (34%) were found to have BRAF mutation. Of these, 88 (83%) received single-agent or combination immunotherapy while 18 (17%) received BRAF/MEK inhibitors. In immunotherapy group, 13 (14.7%) patients received combination immunotherapy while 75 (85%) got single agent treatment. 60 (56.6%) were males. Median age was 61 (89-21) years. Mean BMI at presentation was 29.5 ± 6.8 kg while mean LDH was 407 U/L. Mean age in immunotherapy and BRAF/MEK inhibitor group was 59.5 and 54.4 years, respectively. Differences between immunotherapy and BRAF/MEK inhibitors groups were observed in duration (months) between initiation of treatment and progression of disease (10.3 vs 7.23), death at time of last follow-up (21% vs 63%), remission at time of last follow up (37% vs 16%), and progression at time of last follow up (38% vs 16%). At the time of analysis, the mean follow-up was 28 ± 23.7 months in the immunotherapy group and 24 ± 23.3 months in the BRAF/MEK inhibitor group. Overall, at a mean follow up of 27.3 ± 23.5 months, no significant difference was found between the two treatment groups in unadjusted models in terms of overall survival (p 0.67) and progression free survival (p 0.16). Conclusions: Patients receiving first-line immunotherapy showed no significant survival benefit versus those receiving BRAF/MEK inhibitor therapy. This contrasts with other studies showing survival benefits in patients receiving immunotherapy as first line agent.

The Role of Treatment Sequencing with Immune-Checkpoint Inhibitors and BRAF/MEK Inhibitors for Response and Survival of Patients with BRAFV600-Mutant Metastatic Melanoma-A Retrospective, Real-World Cohort Study.

Simple SummaryThe clinical application of kinase inhibitors and immune-checkpoint inhibitors (CPI) has substantially improved the treatment landscape of melanoma. While BRAF/MEK inhibitors allow for rapid disease control, and CPI can evoke durable tumor responses, primary and secondary resistance frequently limit treatment efficacy. Observations from preclinical trials suggest that treatment with BRAF/MEK inhibitors may enhance susceptibility towards CPI therapy and thus improve long-term tumor control. To date, little prospective data is available for the optimal sequencing of these agents in melanoma patients. In this retrospective, real-world analysis, we analyzed the role of sequential treatment with BRAF/MEK inhibitors and CPI in 135 BRAF-mutant, metastatic melanoma patients. Our results demonstrate that front-line treatment with CPI is associated with favorable tumor control and overall survival in patients with BRAF-mutant melanoma. Further, our data indicate that patients who are refractory to front-line BRAF/MEKi therapy are at higher risk of rapid disease progression compared to patients with front-line CPI treatment.The advent of immune-checkpoint inhibitors (CPI) and BRAF/MEK-directed targeted therapy (TT) has improved the treatment landscape of patients with BRAFV600-mutant metastatic melanoma. While TT allows for rapid disease control, the development of secondary TT resistance limits the duration of responses. Responses to CPI have a slower onset but can be durable in a subset of patients. To date, little prospective data is available for the optimal sequencing of these agents in melanoma patients. In this retrospective, single-center, real-world analysis, we identified 135 patients with BRAF-mutated, metastatic melanoma who received consecutive treatment with TT followed by CPI, or vice versa, as first and second-line therapy, respectively. We collected data on clinical-pathological factors, treatment duration, best overall response, progression-free survival and overall survival (OS). Our data revealed that front-line treatment with CPI, followed by TT, showed a non-significant trend towards better OS compared to front-line TT (median OS: 35.0 vs. 18.0 months, p = 0.070). This association was confirmed in a subgroup of patients without systemic pre-treatments (median OS: 41.0 vs. 14.0 months, p = 0.02). Further, we observed significantly better objective response rates to second-line treatments for patients receiving front-line CPI (18.4 vs. 37.8%, p = 0.024). Last, our results indicated that rapid disease progression was less common in patients treated with front-line CPI (27.6% vs. 16.2%) and that subsequent treatment with TT resulted in favorable survival outcomes. Our real-world data indicate that sequential treatment with front-line CPI is associated with favorable tumor control and overall survival in a subgroup of previously untreated BRAF-mutant metastatic melanoma patients.