BRAF Therapy Research Articles

Abstract 4648: Metabolic vulnerabilities of drug-resistant melanoma with therapeutic potential

Abstract Melanoma has been at the center of revolutions in both targeted BRAF therapy and immune therapy. However, the resistance to current therapeutic drugs has been a formidable obstacle to continuing benefit to patients. Overcoming resistance and new therapeutic agents and strategies are the primary goals of current cancer research. We currently found that metabolic pathways altered significantly in BRAFi-resistant melanoma. We hypothesized that BRAFi-resistant melanoma rewires its metabolic routes to reach its needs in energy and biosynthetic precursors, both essential for escaping the BRAFi attack. We found that five amino acids transporters and metabolic enzymes (ASNS, slc7a11, slc7a5, slc3a2, slc4a7) were the significant increase in resistant melanoma. Knockdown by shRNA or knockout by crispr/cas9 of these amino acids transporters or/and metabolic enzymes enhanced the sensitivity of BRAFi resistant melanoma to BRAFi. In contrast, overexpression of these amino acid transporters or/and metabolic enzymes promoted the ability of resistance of BRAFi in parent melanoma cells. Moreover, the inhibition of these amino acid transporters and metabolic enzymes by small molecular inhibitors significantly attenuated the resistance of the BRAFi-resistant melanoma whereas less affected the parent melanoma. Notably, we confirmed that blocking these amino acid transporters and metabolic enzymes by shRNA and/or small molecular inhibitors could rescue the sensitivity of resistant melanoma cells and inhibit resistant-melanoma cell growth in the preclinical mouse model in vivo. Importantly, we found that overexpression of slc7a11, slc7a5 and slc3a2 correlated with worse survival in melanoma in SK-TCGA data. Our findings uncovered the mechanism of how metabolic reprogramming fueled melanoma cell growth and proliferation for escaping drug attacks and offered a rational strategy to guide clinical treatment. The identified novel molecular proteins represented a promising therapeutic target for BRAF mutant melanoma patients with resistance to current therapy. Citation Format: Yanlin Yu, Lei Huang, Weiping Chen, Glenn Merlino. Metabolic vulnerabilities of drug-resistant melanoma with therapeutic potential [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4648.

Abstract A090: Preclinical efficacy of BDTX-4933, a brain-penetrant, orthosteric RAF inhibitor, targeting oncogenic RAF conformation shared by groups of BRAF and upstream driver mutations

Abstract Alterations in the RAS-MAPK pathway, such as mutations in NF1, RAS, and BRAF, often lead to oncogenic signaling and result in aberrant cell proliferation and tumor growth. Oncogenic BRAF mutations may be activated as either monomers or dimers, while oncogenic RAS mutations or loss-of-function mutations in NF1, a negative regulator of RAS, drive activation of RAF dimers to transduce MAPK signaling. Currently approved BRAF inhibitors are selective against monomeric BRAF mutations and largely inactive against dimeric RAF mutants. Additionally, these agents may also promote deleterious paradoxical activation of RAF in select contexts. Moreover, FDA-approved KRAS G12C mutant-selective inhibitors are ineffective for cancer patients who harbor other (non-G12C) KRAS, NRAS, and NF1 mutations which all lead to active RAF dimer. There remains a high unmet clinical need for a highly CNS penetrant RAF inhibitor that targets a broad spectrum of oncogenic RAF conformations in the context of RAF, RAS, and other upstream driver mutations. BDTX-4933 is a next generation MasterKey RAF inhibitor designed to address the shortcomings of previous generation RAF inhibitors. BDTX-4933 is an orthosteric inhibitor that potently targets the oncogenic RAF conformation shared by groups of RAF driver mutations and induces an inactive conformation of RAF. As a MasterKey inhibitor, BDTX-4933 potently inhibits a broad spectrum of BRAF mutations and active RAF dimers promoted by upstream oncogenic MAPK pathway alterations, such as KRAS, NRAS, and NF1 mutations. In vivo, once daily oral dosing of BDTX-4933 resulted in robust and sustained target engagement, inhibiting ERK phosphorylation without inducing paradoxical activation. In a mouse breadth of efficacy study with patient derived xenografts (PDX), BDTX-4933 demonstrated tumor growth inhibition and regression as a single agent across models expressing a variety of targeted BRAF or MAPK pathway oncogenic mutations. Additionally, BDTX-4933 as a single agent and in combination with a MEK inhibitor, demonstrates anti-tumor efficacy in KRAS mutant lung PDX models. In a PDX model of BRAF V600E positive tumor that progressed following BRAF and MEK combination therapy, BDTX-4933 achieved robust tumor growth regression. Furthermore, BDTX-4933 exhibits high CNS exposure leading to dose-dependent tumor growth inhibition, and survival benefit in mice implanted intracranially with xenograft BRAF mutant tumors. BDTX-4933 has a best-in-class RAF inhibitor profile to treat cancer patients harboring BRAF mutations or RAF dimer-promoting upstream genetic alterations. BDTX-4933 is currently in a Phase I clinical study in patients with solid tumor harboring sensitive BRAF and RAS alterations (NCT05786924). For more information on this active Phase 1, please contact: ClinicalTrials@bdtx.com. Citation Format: Yoon-Chi Han, Pui Yee Ng, Luisa Shin Ogawa, Shao Ning Yang, Miao Chen, Darlene Romashko, Tai-An Lin, Elizabeth Buck. Preclinical efficacy of BDTX-4933, a brain-penetrant, orthosteric RAF inhibitor, targeting oncogenic RAF conformation shared by groups of BRAF and upstream driver mutations [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A090.

153P BRAF variants and therapy outcomes in melanoma

153P BRAF variants and therapy outcomes in melanoma

A Predictive Model of Adaptive Resistance to BRAF/MEK Inhibitors in Melanoma.

The adaptive acquisition of resistance to BRAF and MEK inhibitor-based therapy is a common feature of melanoma cells and contributes to poor patient treatment outcomes. Leveraging insights from a proteomic study and publicly available transcriptomic data, we evaluated the predictive capacity of a gene panel corresponding to proteins differentially abundant between treatment-sensitive and treatment-resistant cell lines, deciphering predictors of treatment resistance and potential resistance mechanisms to BRAF/MEK inhibitor therapy in patient biopsy samples. From our analysis, a 13-gene signature panel, in both test and validation datasets, could identify treatment-resistant or progressed melanoma cases with an accuracy and sensitivity of over 70%. The dysregulation of HMOX1, ICAM, MMP2, and SPARC defined a BRAF/MEK treatment-resistant landscape, with resistant cases showing a >2-fold risk of expression of these genes. Furthermore, we utilized a combination of functional enrichment- and gene expression-derived scores to model and identify pathways, such as HMOX1-mediated mitochondrial stress response, as potential key drivers of the emergence of a BRAF/MEK inhibitor-resistant state in melanoma cells. Overall, our results highlight the utility of these genes in predicting treatment outcomes and the underlying mechanisms that can be targeted to reduce the development of resistance to BRAF/MEK targeted therapy.

Deep and lasting response and acquired resistance to BRAFV600E targeting in a low-grade ovarian cancer patient

ABSTRACT The treatment of BRAFV600E mutant melanoma has been revolutionized by BRAF inhibitors. Furthermore, the BRAF/MEK combination has shown further improvement in clinical outcomes in advanced and in adjuvant melanoma patients. In low-grade ovarian tumors, BRAF inhibitor use has been also proposed. Here we present a patient with an excellent, lasting response to BRAF therapy alone. At first progression, after more than two years on BRAF monotherapy, we could not identify any molecular mechanisms explaining resistance. After a switch to dual BRAF/MEK therapy, the patient responded. However, despite the initial response clinical the patient again progressed, this time with the appearance of a KRAS G12C mutation, which could not be overcome by BRAF/MEK therapy. We provide evidence that BRAF inhibitor alone can be highly beneficial in BRAF mutant low-grade ovarian tumors and the resistance mechanisms are similar to that of other BRAF mutant tumors, including in melanoma.

Addressing the unmet needs of patients with BRAF-mutated melanoma in Latin America: Expert perspective.

Melanoma represents an increasing public health burden with extensive unmet needs in Latin America (LA). A mutation in the BRAF gene is present in approximately 50% of all melanomas in White populations and is a target of precision medicine, with the potential to dramatically improve patient outcomes. Thus, increased access to BRAF testing and therapy is LA must be explored. At a multi-day conference, a panel of Latin American experts in oncology and dermatology were provided with questions to address the barriers limiting access to testing for BRAF mutation in patients with melanoma in LA, who may be eligible for targeted therapy to improve their prognosis. During the conference, responses were discussed and edited until a consensus on addressing the barriers was achieved. Identified challenges included ignorance of BRAF-status implications, limited human and infrastructural resources, affordability and reimbursement, fragmented care delivery, pitfalls in the sample journey, and lack of local data. Despite the clear benefits of targeted therapies for BRAF-mutated melanoma in other regions, there is no clear path to prepare LA for a sustainable personalized medicine approach to this disease. Due to melanoma's time-sensitive nature, LA must aim to provide early access to BRAF testing and consider mutational status within treatment decision making. To this end, recommendations are provided and include establishing multidisciplinary teams and melanoma referral centers and improving access to diagnosis and treatment.

BRAF v600E–mutant cancers treated with vemurafenib alone or in combination with everolimus, sorafenib, or crizotinib or with paclitaxel and carboplatin (VEM-PLUS) study

Combined BRAF + MEK inhibition is FDA approved for BRAF V600E-mutant solid tumors except for colorectal cancer. However, beyond MAPK mediated resistance several other mechanisms of resistance such as activation of CRAF, ARAF, MET, P13K/AKT/mTOR pathway exist among other complex pathways. In the VEM-PLUS study, we performed a pooled analysis of four phase one studies evaluating the safety and efficacy of vemurafenib monotherapy and vemurafenib combined with targeted therapies (sorafenib, crizotinib, or everolimus) or carboplatin plus paclitaxel in advanced solid tumors harboring BRAF V600 mutations. When vemurafenib monotherapy was compared with the combination regimens, no significant differences in OS or PFS durations were noted, except for inferior OS in the vemurafenib and paclitaxel and carboplatin trial (P = 0.011; HR, 2.4; 95% CI, 1.22–4.7) and in crossover patients (P = 0.0025; HR, 2.089; 95% CI, 1.2–3.4). Patients naïve to prior BRAF inhibitors had statistically significantly improved OS at 12.6 months compared to 10.4 months in the BRAF therapy refractory group (P = 0.024; HR, 1.69; 95% CI 1.07–2.68). The median PFS was statistically significant between both groups, with 7 months in the BRAF therapy naïve group compared to 4.7 months in the BRAF therapy refractory group (P = 0.016; HR, 1.80; 95% CI 1.11–2.91). The confirmed ORR in the vemurafenib monotherapy trial (28%) was higher than that in the combination trials. Our findings suggest that, compared with vemurafenib monotherapy, combinations of vemurafenib with cytotoxic chemotherapy or with RAF- or mTOR-targeting agents do not significantly extend the OS or PFS of patients who have solid tumors with BRAF V600E mutations. Gaining a better understanding of the molecular mechanisms of BRAF inhibitor resistance, balancing toxicity and efficacy with novel trial designs are warranted.

Ocular adverse events associated with BRAF and MEK inhibitor combination therapy: a pharmacovigilance disproportionality analysis of the FDA adverse event reporting system

ABSTRACT Background BRAF and MEK inhibitor combination therapy have significantly improved the outcome of several BRAF-mutation tumors, but it also confers the risk of drug-induced ocular adverse events (oAEs). However, very few studies focused on this risk. Methods The United States Food and Drug Administration Adverse Event Reporting System (FAERS) data from Quarter 1–2011 to Quarter 2–2022 were searched to detect signs of oAEs of three marketed BRAF and MEK inhibitor combination therapies: vemurafenib plus cobimetinib (V + C), dabrafenib plus trametinib (D + T), and encorafenib plus binimetinib (E + B). Disproportionality analyses were performed by calculating the proportional reporting ratio (PRR), χ2 (chi-square), and reporting odds ratios (RORs) with a 95% confidence interval (CI). Results A series of oAEs were identified, including 42 preferred terms, which could be classified into 8 aspects. In addition to previously reported oAEs, several unexpected oAE signals were detected. Moreover, differences in oAE profiles were found among three combination therapies (V + C, D + T, and E + B). Conclusions Our findings support an association between several oAEs and BRAF and MEK inhibitor combination therapies, including several new oAEs. In addition, oAEs profiles may vary across the treatment regimens. Further studies are needed to better quantify these oAEs.

Prediction of BRAF mutation status in glioblastoma multiforme by preoperative ring enhancement appearances on MRI.

BackgroundRing enhancement on magnetic resonance imaging (MRI) is an important characteristic of GBM. Though patients suffering from glioblastoma multiforme (GBM) with BRAF mutation (MUT BRAF) in V600E benefit from BRAF-targeted inhibitors, the relationship between ring enhancement and MUT BRAF remains elusive. The purpose of this study was to investigate the relationship between BRAF mutation status and the appearance of ring enhancement so as to guide preoperative targeted therapy for MUT BRAF GBM.MethodsPatient’s population, clinical data and characteristic ring enhancement appearances on MRI were compared between GBM with MUT BRAF and GBM with WT BRAF. A receiver operating characteristic (ROC) curve analysis was performed to evaluate the differential diagnostic significance. A nomogram was developed to predict the mutation status of BRAF. Moreover, all the variables were re-analyzed between epithelioid GBM (E-GBM) with or without MUT BRAF.ResultsCompared to GBM with WT BRAF, GBM with MUT BRAF had specific ring enhancement appearances with multiple rings, multiple located lobes, regular shape of ring, uniform thickness of ring and smaller diameter of ring. Area under the curve (AUC) of all the variables’ combination was 0.929. The nomogram was developed and validated. The re-analyzed results between E-GBM with or without MUT BRAF were similar to these above. AUC of the combination of quantity of ring, quantity of located lobe and shape of ring was 0.962.ConclusionThe characteristic ring enhancement appearances of GBM may play an important role in predicting BRAF mutation status preoperatively, especially in E-GBM. Further study with larger cases may provide more evidences to guide the pretreatment of targeted medicine for GBM patients with MUT BRAF in future.

Clinical Characteristics, Co-Mutations, and Treatment Outcomes in Advanced Non-Small-Cell Lung Cancer Patients With the BRAF-V600E Mutation.

BackgroundLimited treatment outcome data is available for advanced non-small cell lung cancer (NSCLC) patients with BRAF V600E mutations. In this multicenter study, we describe therapeutic options and survival outcomes for patients with mutated BRAF V600E.MethodThis was a retrospective study in which BRAF V600E-mutated advanced NSCLC patients were retrospectively recruited between January 2015 and December 2021 and had their clinical characteristics, co-mutations, and treatment efficacy assessed.ResultsFifty-three patients with BRAF V600E-mutant advanced NSCLC were included in the study, of which 64.2% were non-smokers, and the BRAF V600E mutation was more prevalent in men (52.8%). In addition, 96.2% of the patients had adenocarcinoma, and most (96.2%) received first-line therapy (23.5% anti-BRAF), with a progression-free survival (PFS) and overall survival (OS) of 10.0 [95% confidence interval (CI): 1.5–36.0 months] and 24.0 months [95% CI: 3.0–53.0 months], respectively. Twenty-three patients (43.4%) received second-line treatment (39.1% anti-BRAF), and PFS and OS were 5.0 [95% CI: 1.0–21.0 months] and 13.0 months [95% CI: 1.5–26.0 months], respectively. BRAF and MEK-targeted therapy (dabrafenib plus trametinib) produced longer PFS compared with that of chemotherapy with or without bevacizumab as a first-line (NA vs. 4.0 months, P = 0.025) or second-line therapy (6.0 vs. 4.6 months, P = 0.017). NSCLC patients harboring driver oncogene mutations such as BRAF V600E, EGFR, or ALK should be treated using targeted therapies. Concurrent TP53 mutations were the most common, affecting 11.3% (n = 6) of the patients, followed by EGFR 19 Del (n = 5). Patients with concurrent mutations had shorter PFS (9.0 vs. 10.0 months, P = 0.875) and OS (14.0 vs. 15.0 months, P = 0.555) than those without these mutations.ConclusionThese results suggest that combined BRAF- and MEK-targeted therapy is effective in BRAF V600E-mutated advanced NSCLC patients. Dabrafenib and trametinib re-challenge is also an option for patients with BRAF V600E-mutated NSCLC.

Molecular Dynamics Investigation of Oncogenic BRAF Mutations

BRAF is one member of the RAF serine/threonine kinase family and a key component of the RAS‐RAF‐MEK‐ERK (MAPK) signaling pathway, controlling cell growth, proliferation, differentiation, migration and survival. BRAF is the most frequently mutated kinase in human cancers, with over 200 mutations discovered, among which V600E and G469A are the most common BRAF mutations. Current therapies with ATP‐competitive inhibitors are potent against BRAFV600E, yet they display “paradoxical activation” and drug resistance toward BRAFG469Aandother non‐V600 BRAF mutants. Thus, novel BRAF therapies towards non‐V600 variants are urgently needed. However, the biochemical properties of non‐V600 BRAF mutants and the cause of drug response are unclear due to the lack of structures of BRAF mutants. In this study, we applied molecular dynamics (MD) simulations to investigate the structure, dynamics and functions of oncogenic BRAFG469A, in comparison with BRAFWT and BRAFV600E. For each BRAF type (WT or mutant), MD simulations are carried out for its monomer and dimer with or without 1 or 2 bound vemurafenib in explicit aqueous solution. Our work provides atomic information on mechanism of aberrant activation by G469A mutation, “paradoxical activation” and structural dynamics of the nucleotide pocket, activation loop, and dimer and inhibitor/BRAF interfaces. G469A mutation makes hydrophobic contact between methyl of A469 with alkyl chain of K483 in the binding pocket. This stabilizes the K483‐E501 salt‐bridge, which functions to bring αC‐helix towards the active site. Thus, G469A stabilizes the active conformation by positioning αC‐helix close to the P‐loop through increasingly stabilized salt‐bridge relative to WT and V600E. Consequently, our simulations illustrate inability of vemurafenib to disrupt active conformation of BRAFG469A by separating αC‐helix from the nucleotide binding pocket. This decreased structural fluctuation upon inhibitor binding to one protomer explains the ability of “paradoxical activation” of BRAF dimer through allosteric activation.

Biomarker testing and tissue journey among patients with metastatic non-small cell lung cancer receiving first-line therapy in The US Oncology Network

ObjectivesThe MYLUNG (Molecularly Informed Lung Cancer Treatment in a Community Cancer Network) consortium pragmatic study assessed real-world biomarker testing rates and turnaround times within a large community-based oncology network. Materials and MethodsThis retrospective observational chart review study investigated patients with mNSCLC initiating first-line (1L) systemic therapy between 01-April-2018 and 31-March-2020. Biomarker testing rates and timing relative to 1L therapy for EGFR, ALK, ROS1, BRAF, and PD-L1 were assessed, including use of next-generation sequencing (NGS). ResultsAmong 3474 adults: 74% had adenocarcinoma and 76% had a documented ECOG performance status of 0 or 1. Ninety percent had testing for at least one biomarker, and 46% received all 5 biomarker tests. Changes in testing rates from 2018 to 2020 were 71% to 71% for EGFR, 71% to 70% for ALK, 69% to 67% for ROS1, 51% to 59% for BRAF, 82% to 84% for PD-L1, and 42% to 49% for all 5 biomarkers. NGS testing increased from 33% to 45% (p < 0.0001). Median time from mNSCLC diagnosis to 1L therapy was 35 days. Median turnaround times from biomarker testing orders to results ranged from 10 to 15 days for the individual biomarkers and 18 days for NGS. ConclusionIn this real-world study, while most patients received at least one biomarker test prior to 1L, <50% received all 5 tests. NGS testing also occurred in < 50% of patients but appeared to increase over time. The next phase of MYLUNG will evaluate contemporary ordering practices and turnaround times prospectively.

Adaptive translational reprogramming of metabolism limits the response to targeted therapy in BRAFV600 melanoma

Despite the success of therapies targeting oncogenes in cancer, clinical outcomes are limited by residual disease that ultimately results in relapse. This residual disease is often characterized by non-genetic adaptive resistance, that in melanoma is characterised by altered metabolism. Here, we examine how targeted therapy reprograms metabolism in BRAF-mutant melanoma cells using a genome-wide RNA interference (RNAi) screen and global gene expression profiling. Using this systematic approach we demonstrate post-transcriptional regulation of metabolism following BRAF inhibition, involving selective mRNA transport and translation. As proof of concept we demonstrate the RNA processing kinase U2AF homology motif kinase 1 (UHMK1) associates with mRNAs encoding metabolism proteins and selectively controls their transport and translation during adaptation to BRAF-targeted therapy. UHMK1 inactivation induces cell death by disrupting therapy induced metabolic reprogramming, and importantly, delays resistance to BRAF and MEK combination therapy in multiple in vivo models. We propose selective mRNA processing and translation by UHMK1 constitutes a mechanism of non-genetic resistance to targeted therapy in melanoma by controlling metabolic plasticity induced by therapy.

Revealing innumerable occult lesions with T1-weighted 3Dblack-blood-imaging in the detection of intracranial metastatic melanoma under BRAF therapy

In the setting of melanoma, brain metastases are very common and contribute to a large number of different neurological deficits as well as death. In recent years, the general prognosis for patients with intracranial metastatic melanoma has improved due to progress in imaging and therapeutic management. The addition of a contrastenhanced T1-weighted MSDE sequence, a so-called Black-Blood - sequence, to the initial and follow up-scans is an excellent method to display intracranial metastatic melanoma. With this case report we want to demonstrate the possible big discrepancy in the number of metastases displayed by the Black-Blood-sequence compared to contrast enhanced T1-weighted imaging in the setting of BRAF-mutated intracranial metastatic melanoma. Keywords: melanoma; intracranial metastatic melanoma; CNS metastasis; black-blood-imaging; MRI.

INNV-06. BRAF AND MEK DUAL INHIBITORS THERAPY IN RECURRENT OR ANAPLASTIC PLEOMORPHIC XANTHOASTROCYTOMA (PXA)

Abstract BACKGROUND AND OBJECTIVE Recurrent and anaplastic pleomorphic xanthoastrocytoma (PXA) tumors are challenging to treat due to their rarity and lack of management consensus. About 80% of PXAs harbor BRAF gene mutation. Although the development of BRAF inhibitors has dramatically improved the outcomes for patients with BRAF V600E mutant tumors, resistance develops in the majority of cases. We hypothesize that dual BRAF/MEK inhibitors therapy can improve tumor control and patient survival without added toxicity. METHODS Medical records from 2010 to 2021 in Memorial Hermann Texas Medical Center were reviewed. Patients diagnosed with PXA who received BRAF and/or MEK inhibitors therapies were identified. The data evaluated included age, sex, treatment received, side effects, and outcomes, as well as results from blood tests, pathology, next generation sequencing and MRI. Side effects were evaluated according to the CTCAE Version 5.0. RESULTS Five patients with recurrent or anaplastic PXA were identified. The median age at diagnosis was 22 years old (range 14-66 years old), with 60% male, and 60% grade III. All patients received BRAF/MEK dual inhibitors therapy at various stages of PXA treatment. The median follow-up was 72 months (range 17-108 months). One patient (66 years old) experienced short-term disease stability for 5 months and who died from tumor related brain hemorrhage while off therapy for 9 months. Four patients experienced long-term disease control (17, 22, 94, 108 months, respectively) while three of them remain on dual therapy and one patient died from systemic PXA progression. Dual BRAF/MEK inhibitors were well tolerated with only grade 1-2 adverse effects (AE) including skin rash, fatigue, mild abdominal discomfort, diarrhea. No grade III-V AE were detected. CONCLUSION BRAF/MEK dual inhibitor can provide potential clinical benefit to PXA patients with BRAF mutations. Our study supports the concurrent use of BRAF/MEK inhibitors for best tumor control without unexpected AE.

The role of urgent BRAF testing and therapy in cardiac melanoma presenting with cardiovascular compromise.

The role of urgent BRAF testing and therapy in cardiac melanoma presenting with cardiovascular compromise.

Exploratory biomarker findings from cohort 2 of MODUL: An adaptable, phase 2, signal-seeking trial of fluoropyrimidine + bevacizumab ± atezolizumab maintenance therapy for BRAFwt metastatic colorectal cancer.

3570 Background: MODUL is an adaptable, phase 2, signal-seeking trial testing novel agents as first-line therapy for predefined subgroups of patients with metastatic colorectal cancer (mCRC). Previously reported findings demonstrated that adding atezolizumab to fluoropyrimidine (FP)/bevacizumab as first-line maintenance treatment after induction with FOLFOX + bevacizumab did not improve efficacy outcomes in BRAFwt mCRC. Given these efficacy results, exploratory assessments on tumour samples were conducted to provide insights into factors that might affect efficacy of maintenance treatment and provide guidance on appropriate therapeutic strategies for BRAFwt mCRC. Methods: In patients with BRAFwt tumours (Cohort 2), experimental treatment was FP/bevacizumab + atezolizumab. Primary efficacy endpoint: progression-free survival (PFS). Overall survival (OS) was a secondary endpoint. Archival tissue samples from 104 patients were analysed by immunohistochemistry (IHC) at HistoGeneX (PD-L1; CD8/GrB/FoxP3). SP142 antibody was used for PD-L1 IHC analysis, which evaluated PD-L1low (IC 0–1) vs PD-L1high (IC &gt; 1) in correlation with PFS and OS in the control and experimental arms. CD8/GrB/FoxP3 triplex staining was also performed to evaluate potential correlations with efficacy. Results: 445 patients with BRAFwt mCRC were randomised (2:1 ratio) to maintenance treatment in Cohort 2. Archival samples from 104 patients were analysed: FP/bevacizumab + atezolizumab (n = 82); FP/bevacizumab (n = 22). The biomarker evaluable population (BEP) for PD-L1 was n = 81 for FP/bevacizumab + atezolizumab [PD-L1low n = 35 (43%); PD-L1high n = 46 (57%)] and n = 22 for FP/bevacizumab [PD-L1low n = 16 (72%); PD-L1high n = 6 (28%)]. The BEP for CD8/GrB was n = 50 for FP/bevacizumab + atezolizumab and n = 16 for FP/bevacizumab. No difference in PFS or OS was observed in the FP/bevacizumab + atezolizumab vs FP/bevacizumab arms for PD-L1high [PFS: HR = 1.5 (95% CI 0.45−4.8), p = 0.51; OS: HR = 1.3 (95% CI 0.38−4.1), p = 0.71] or PD-L1low [PFS: HR = 0.92 (95% CI 0.47−1.8), p = 0.81; OS: HR = 0.78 (95% CI 0.4−1.5), p = 0.48]. Similar results were observed with CD8/GrBhigh [PFS: HR = 0.73 (95% CI 0.27−2.0), p = 0.55; OS: HR = 0.66 (95% CI 0.24−1.8), p = 0.44], CD8/GrBlow [PFS: HR = 1.0 (95% CI 0.42–2.5), p = 0.96; OS: HR = 0.73 (95% CI 0.3–1.8), p = 0.5], FoxP3high [PFS: HR = 0.97 (95% CI 0.37−2.5), p = 0.95; OS: HR = 0.95 (95% CI 0.36−2.5), p = 0.91] and FoxP3low [PFS: HR = 0.73 (95% CI 0.29−1.9), p = 0.53; OS: HR = 0.5 (95% CI 0.19−1.3), p = 0.18]. Conclusions: These findings suggest that PD-L1, CD8/GrB and FoxP3 might not be predictive biomarkers in BRAFwt mCRC. Further analyses are needed to further evaluate potential predictive and prognostic factors of response in this setting. Clinical trial information: NCT02291289.

Many Distinct Ways Lead to Drug Resistance in BRAF- and NRAS-Mutated Melanomas.

Advanced melanoma is a relentless tumor with a high metastatic potential. The combat of melanoma by using the targeted therapy is impeded because several major driver mutations fuel its growth (predominantly BRAF and NRAS). Both these mutated oncogenes strongly activate the MAPK (MEK/ERK) pathway. Therefore, specific inhibitors of these oncoproteins or MAPK pathway components or their combination have been used for tumor eradication. After a good initial response, resistant cells develop almost universally and need the drug for further expansion. Multiple mechanisms, sometimes very distant from the MAPK pathway, are responsible for the development of resistance. Here, we review many of the mechanisms causing resistance and leading to the dismal final outcome of mutated BRAF and NRAS therapy. Very heterogeneous events lead to drug resistance. Due to this, each individual mechanism would be in fact needed to be determined for a personalized therapy to treat patients more efficiently and causally according to molecular findings. This procedure is practically impossible in the clinic. Other approaches are therefore needed, such as combined treatment with more drugs simultaneously from the beginning of the therapy. This could eradicate tumor cells more rapidly and greatly diminish the possibility of emerging mechanisms that allow the evolution of drug resistance.

BRAF inhibitor-induced panniculitis in patients treated for stage IV metastatic melanoma: a case series

BRAF and MEK inhibitor combination therapy is the standard treatment for patients with BRAF V600E mutant metastatic melanoma. Neutrophilic panniculitis is a known rare complication of BRAF inhibitor therapy and can act as a potential mimic of melanoma metastases on 18F-FDG PET/CT. In this case series, we present three cases of BRAF inhibitor-induced panniculitis in patients being treated for BRAF-mutant metastatic melanoma and emphasize the use of ultrasound to differentiate between panniculitis lesions, which are typically ill-defined echogenic masses and subcutaneous soft tissue melanoma metastases, which present as hypoechoic vascular masses.

Cardiovascular safety of rapidly accelerated fibrosarcoma B-type and/or mitogen-activated extracellular signal-regulated kinase inhibitors: A mixed approach combining a meta-analysis and a pharmacovigilance disproportionality analysis

The risk of cardiovascular adverse events from rapidly accelerated fibrosarcoma B-type (BRAF) and mitogen-activated extracellular signal-regulated kinase (MEK) inhibitors is not fully characterized. To evaluate the cardiovascular adverse events risks related to BRAF and/or MEK inhibitors in randomized placebo-controlled clinical trials and in the real-life setting. We used two approaches. First, we conducted a systematic review and meta-analysis of randomized placebo-controlled clinical trials reporting the incidence of cardiovascular adverse events for BRAF and/or MEK inhibitors in cancer patients. Second, we performed a disproportionality analysis, using age- and sex-adjusted reporting odds ratios (arORs) and their 95% confidence intervals (CIs) from the World Health Organization's pharmacovigilance database (VigiBase®) of anticancer drug-associated reports, to investigate real-life data. MEK inhibitors increased the risk of ejection fraction decrease (odds ratio [OR] 3.35, 95% CI 1.58-7.07), peripheral oedema (OR 2.87 95% CI 1.93-4.27) and syncope (OR 6.71, 95% CI 3.00-14.99) compared with placebo in randomized placebo-controlled clinical trials. BRAF and MEK inhibitor combination therapy further increased the risk of ejection fraction decrease. In the disproportionality analysis, we found over-reporting of ejection fraction decrease (arOR 8.42, 95% CI 7.03-10.09), peripheral oedema (arOR 1.39, 95% CI 1.17-1.66), syncope (arOR 1.56, 95% CI 1.22-1.99), torsade de pointes/QT prolongation (arOR 6.13, 95% CI 5.04-7.47) and supraventricular arrhythmias (arOR 1.50, 95% CI 1.21-1.85) for BRAF and MEK inhibitors. BRAF and MEK inhibitors were not associated with hypertension in either approach. In conclusion, MEK inhibitors increase the risk of ejection fraction decrease, peripheral oedema and syncope in randomized placebo-controlled clinical trials. Real-life data confirm these findings, and suggested additional risks of torsade de pointes/QT prolongation and supraventricular arrhythmias with BRAF/MEK inhibitors.