BRAF-mutated Patients Research Articles

Clinical attributes and outcomes in metastatic non-small cell lung cancer bearing BRAF mutations treated with targeted therapy versus immunotherapy.

e21219 Background: Mutations in BRAF oncogene have been identified in about 2-4% of non-small cell lung cancer (NSCLC) patients. Combination of tyrosine kinase inhibitors (TKI), dabrafenib and trametinib has shown improved and enduring results in both first line and second line setting. Given the rarity of BRAF mutations, and the approval of TKI, the role of Immune Checkpoint Inhibitors (ICI) still needs to be ascertained. Methods: We conducted a retrospective review of 19 BRAF-mutant lung cancer patients from 2013-2020 at the University of Miami. Clinicopathologic features, and patient’s response to chemotherapy/ICI vs anti-BRAF targeted therapy (ABTT) was investigated. Duration of response (DOR) was calculated from the initiation of therapy, and Overall survival (OS) was calculated from the diagnosis of metastatic disease. OS was estimated by Kaplan-Meier method and log-rank test was used to compare groups. Hazard ratio (HR) and corresponding 95% confidence interval were estimated using Cox proportional hazards regression model. All tests were two sided and statistical significance was considered when p<0.05. Results: Total 19 patients with a median age of 63 (range 54-87) were identified from a cohort of 575 sequenced lung cancer patients (prevalence of 3.3%). 6 patients were never-smokers, 13 former/current smokers; 10 were women; 10 were Non-Hispanic White, 8 Hispanic, and 1 African American. Majority had adenocarcinoma (n=17) and non-V600E BRAF mutation (n=13)). PD-L1 expression testing (n=11) was negative in 55% (n=6 of 11), low in 9% (n=1 of 11), and high in 36% (n=4 of 11). All patients presented with metastatic disease; lung (16), bone (7), brain (5), and liver (4). 47.4% (n=9) of patients received platinum-based doublet chemotherapy as first-line (FL) treatment; 21.1% (n=4) received combined chemotherapy+ICI as FL; 5% (n=1) received ABTT as FL. Overall, 47% (n=9) received ABTT; 11.1% (n=1) as FL, 33.3% (n=3) as second line, 44.4% (n=4) as third line, and 11.1% (n=1) as fourth line. Median OS in the entire cohort was 1.86 years (95 % CI :1.26-2.32). Median DOR to ICI as first line or second line agent was 3 months (mos) (range 0.5-25mos). Median DOR to TKI in BRAFV600E cases was 13 mos (range 7-53mos), as second line agent or beyond. Among patients with BRAFV600E mutation, median OS was 4.89 years (95% CI 4.31-NA) in recipients of ABTT, and 1.68 years (95% CI not estimable) in patients who did not receive ABTT. Conclusions: In our BRAF-mutant NSCLC cohort, median DOR was greater in patients treated with ABTT, than those with ICI. ABTT treated BRAFV600E-mutant patients had longer OS, in comparison to those treated without ABTT. Our analysis highlights a potentially significant benefit of ABTT, and an unsatisfactory response with ICI, in patients harboring BRAFV600E mutation; therefore, the role of ICI in this subgroup needs further investigation.

Clinicopathologic features and impact of metastasectomy in patients with BRAF-mutant metastatic colorectal cancer.

e15547 Background: BRAF V600E mutation is associated with poor prognosis in patients with metastatic colorectal cancer (mCRC), while the non-V600E mutation mCRC patients showed better prognosis than that of V600E mutation. The clinicopathologic features between V600E and non-V600E mutation has not yet been fully evaluated. And the impact of metastasectomy for patients with BRAF-mutant mCRC was not well-known. Methods: A retrospective study was conducted to evaluate the clinical and pathological characteristics of patients with BRAF-mutant mCRC. Next generation sequencing (22-gene panel) was performed in some of the patients. Survival was also analyzed in the cohort of BRAF V600E and non-V600E mutation with or without metastasectomy. Results: Between December 2014 and August 2020, 116 patients with BRAF-mutant mCRC were enrolled, including 94 patients with BRAF V600E mutation and 22 patients with non-V600E mutation. Significant difference was observed in the prevalence of peritoneal metastasis (69.1% vs. 27.3%, P = 0.001) and lung metastasis (11.7% vs. 36.4%, P = 0.009) between BRAF V600E mutation and non-V600E mutations. In genomic profile, SMAD4 mutation (30.7% vs. 13.7%) showed higher prevalence in patients with BRAF V600E mutation than that of non-V600E mutations, while RAS mutation (18.2% vs. 6.4%) and FBXW7 mutation (13.7% vs 3.1%) had higher incidence in BRAF non-V600E mutations than that of V600E mutation. Patients with BRAF V600E mutation showed a poorer overall survival than those with non-V600E mutations (13.9 vs. 26.8 months, P = 0.038). Totally, 46 patients received metastasectomy after systemic treatment. The median survival for BRAF V600E patients with or without metastasectomy was not reach (42.3+ months) vs. 8.3 months, respectively ( P < 0.001), and for non-V600E patients with or without metastasectomy was not reach (64.2+ months) vs. 23.3 months, respectively (P < 0.001). In multivariate analysis, ECOG performance status (0-1 vs. 2) ( P = 0.001), Staging (IVa-b vs. IVc) ( P = 0.01) and metastasectomy ( P = 0.001) were independent prognostic factors of overall survival. Conclusions: BRAF V600E mutation defines a subgroup of mCRC with worse prognosis. Metastasectomy might improve the survival benefit in carefully selected BRAF-mutant mCRC patients after systemic treatment.

Factors Influencing the Adjuvant Therapy Decision: Results of a Real-World Multicenter Data Analysis of 904 Melanoma Patients.

Simple SummaryAdjuvant treatment of stage III/IV melanoma patients with immune-checkpoint inhibition or targeted therapy can significantly improve recurrence-free survival. However, it is unknown how many patients with an indication for adjuvant therapy do indeed choose to receive it and what the reasons for declining are. In patients with a BRAF mutation, it is not known whether more patients prefer targeted or immunotherapy. This study investigates the real-world situation of 904 patients from 13 German Dermatologic Cooperative Oncology Group skin cancer centers with an indication for adjuvant treatment since the approval of the corresponding drugs as adjuvant treatment. Aims of this study were to investigate the patient groups who opt for or against adjuvant treatment, respectively targeted or immunotherapy, and the reasons for refusal. Findings of this study show the current acceptance and choice of adjuvant melanoma treatment and may support patients and physicians in the therapy decision-making process.Adjuvant treatment of melanoma patients with immune-checkpoint inhibition (ICI) and targeted therapy (TT) significantly improved recurrence-free survival. This study investigates the real-world situation of 904 patients from 13 German skin cancer centers with an indication for adjuvant treatment since the approval of adjuvant ICI and TT. From adjusted log-binomial regression models, we estimated relative risks for associations between various influence factors and treatment decisions (adjuvant therapy yes/no, TT vs. ICI in BRAF mutant patients). Of these patients, 76.9% (95% CI 74–80) opted for a systemic adjuvant treatment. The probability of starting an adjuvant treatment was 26% lower in patients >65 years (RR 0.74, 95% CI 68–80). The most common reasons against adjuvant treatment given by patients were age (29.4%, 95% CI 24–38), and fear of adverse events (21.1%, 95% CI 16–28) and impaired quality of life (11.9%, 95% CI 7–16). Of all BRAF-mutated patients who opted for adjuvant treatment, 52.9% (95% CI 47–59) decided for ICI. Treatment decision for TT or ICI was barely associated with age, gender and tumor stage, but with comorbidities and affiliated center. Shortly after their approval, adjuvant treatments have been well accepted by physicians and patients. Age plays a decisive role in the decision for adjuvant treatment, while pre-existing autoimmune disease and regional differences influence the choice between TT or ICI.

BRAF-V600E testing in metastatic colorectal cancer and new, chemotherapy-free therapy options. German version

Die Therapie des metastasierten kolorektalen Karzinoms (mKRK) hat in den letzten 25 Jahren tief greifende Veränderungen erfahren. Auf die Zulassung neuerer Chemotherapeutika folgten ab 2005 die ersten zielgerichteten Therapien, die sich gegen den epidermalen Wachstumsfaktorrezeptor (EGFR) bzw. gegen Rezeptoren vaskulärer endothelialer Wachstumsfaktoren (VEGFR) richteten. Mit der fortschreitenden molekularen Charakterisierung des mKRK in den letzten 10 Jahren und der Einteilung der Erkrankung in 4 Konsensus-Subtypen zeichnet sich weiterer Wandel ab, unter anderem durch Einführung speziell entwickelter Proteinkinaseinhibitoren wie auch Immuncheckpoint-Inhibitoren in den Therapiealgorithmus.Eine angepasste molekularpathologische Testung ist heute für eine leitliniengerechte Behandlung von mKRK-Patienten unabdingbar. Neben der RAS-Testung als Voraussetzung für die Therapieentscheidung bezüglich Cetuximab und Panitumumab ist die BRAF-Testung äußerst relevant, um – im Falle des Nachweises einer BRAF-V600E-Mutation – eine Therapieentscheidung zugunsten der neu zugelassenen, chemotherapiefreien Kombination aus dem BRAF-Inhibitor Encorafenib und Cetuximab treffen zu können. Eine erweiterte Diagnostik sollte auch die Genominstabilität (Mikrosatelliten-Instabilität) einbeziehen. Insgesamt müssen immer mehr molekulare Alterationen simultan untersucht werden, sodass sich zunehmend die Verwendung des fokussierten Next Generation Sequencing empfiehlt.Diese Übersichtsarbeit beschreibt die prognostische Relevanz der BRAF-Testung im Rahmen der molekularpathologischen Diagnostik des mKRK, stellt neue Therapieoptionen zur Behandlung BRAF-mutierter mKRK-Patienten vor und erläutert, welche modernen DNA-analytischen und immunohistochemischen Verfahren zur BRAF-Diagnostik von mKRK-Patienten zur Verfügung stehen.

BRAF Gene and Melanoma: Back to the Future.

As widely acknowledged, 40–50% of all melanoma patients harbour an activating BRAF mutation (mostly BRAF V600E). The identification of the RAS–RAF–MEK–ERK (MAP kinase) signalling pathway and its targeting has represented a valuable milestone for the advanced and, more recently, for the completely resected stage III and IV melanoma therapy management. However, despite progress in BRAF-mutant melanoma treatment, the two different approaches approved so far for metastatic disease, immunotherapy and BRAF+MEK inhibitors, allow a 5-year survival of no more than 60%, and most patients relapse during treatment due to acquired mechanisms of resistance. Deep insight into BRAF gene biology is fundamental to describe the acquired resistance mechanisms (primary and secondary) and to understand the molecular pathways that are now being investigated in preclinical and clinical studies with the aim of improving outcomes in BRAF-mutant patients.

Outcome of melanoma patients with elevated LDH treated with first-line targeted therapy or PD-1-based immune checkpoint inhibition

BackgroundElevated lactate dehydrogenase (LDH) is a known predictive and prognostic factor for a poor outcome in patients with metastatic melanoma. It is unclear whether first-line targeted therapy (TT) or immune checkpoint inhibition (ICI) is more beneficial in melanoma patients with elevated LDH because prospective studies in this area are lacking. MethodsThis multicentre retrospective cohort study was conducted at 25 melanoma centres worldwide to analyse progression-free survival (PFS) and overall survival (OS) among melanoma patients with elevated LDH. The role of confounders was addressed by using inverse probability of treatment weighting. ResultsAmong 173 BRAFV600-mutant patients, PFS at 12 months in the TT group was 22% compared with 52% in the combined anti-PD-1 and anti-CTLA-4 group (HR 0.6, 95% CI 0.4–1.0, p = 0.07) and 18% in the anti-PD-1 monotherapy group (HR 1.8, 95% CI 1.2–2.8, p = 0.003). Twelve months' OS was 48% in the TT group compared with 83% in the combined anti-PD-1 and anti-CTLA-4 group (HR 0.5, 95% CI 0.3–1.0, p = 0.03) and 50% in the anti-PD-1 monotherapy group (HR 1.2, 95% CI 0.8–2.0, p = 0.37). The ORR in the TT group was 63%, compared with 55% and 20% in the combined anti-PD-1 and anti-CTLA-4 and anti-PD-1 monotherapy group, respectively. Among 314 patients receiving ICI first-line, PFS at 12 months was 33% in the anti-PD-1 group versus 38% in the combined anti-PD-1 and anti-CTLA-4 group (HR 0.8, 95% CI 0.6–1.0; p = 0.07). OS at 12 months was 54% in the anti-PD-1 group versus 66% in the combined ICI group (HR 0.7, 95% CI 0.5–1.0; p = 0.03). The ORR was 30% in the anti-PD-1 monotherapy group and 43% in the combined anti-PD-1 and anti-CTLA-4 group. Results from multivariate analysis confirmed the absence of qualitative confounding. ConclusionsAmong BRAF-mutant patients with elevated LDH, combined anti-PD-1 and anti-CTLA-4 blockade seems to be associated with prolonged OS compared with first-line TT. Among patients receiving ICI as a first-line treatment, OS appears to be longer for the combination of anti-PD-1 and anti-CTLA-4 than for anti-PD-1 alone.

Inhibition of BRAF and ERK1/2 has synergistic effects on thyroid cancer growth in vitro and in vivo.

Mutations in the BRAF gene are highly prevalent in thyroid cancer. However, the response rate of thyroid tumors to BRAF-directed therapies has been mixed. Increasingly, combination therapies inhibiting the MAPK pathway at multiple nodes have shown promise. Recently developed ERK1/2 inhibitors are of interest for use in combination therapies as they have the advantage of inhibiting the most downstream node of the MAPK pathway, therefore preventing pathway reactivation. Here, we examined the effect of combined BRAF inhibition (dabrafenib) and ERK1/2 inhibition (SCH772984) on the growth and survival of a panel of BRAF-mutant thyroid cancer cell lines using in vitro and in vivo approaches. We found that resistance due to MAPK pathway reactivation occurs quickly with single-agent BRAF inhibition, but can be prevented with combined BRAF and ERK1/2 inhibition. Combined inhibition also results in synergistic growth inhibition, decreased clonogenic survival, and enhanced induction of apoptosis in a subset of BRAF-mutant thyroid cancer cells. Finally, combined inhibition of BRAF and ERK1/2 results in enhanced inhibition of tumor growth in an anaplastic thyroid cancer in vivo model. These results provide key rationale to pursue combined BRAF and ERK1/2 inhibition as an alternative therapeutic strategy for BRAF-mutant advanced thyroid cancer patients.

Surgical series of metastatic cerebral melanoma: Clinical association of resection, BRAF-mutation status, and survival

BackgroundMajor advances in the systemic treatment of metastatic cerebral melanoma have improved patient survival. The clinical relationship between gross total resection (GTR), BRAF-mutation status, and its effects on survival in the era of targeted/immunotherapy warrants further characterization. MethodWe retrospectively reviewed survival after craniotomy for melanoma metastases in patients who also received targeted/immunotherapy and cavity radiation at four neurosurgical hospitals in Queensland, Australia from 2012 to 2019. Results152 craniotomies were performed in 138 patients (98 male, 40 female), 42% were BRAF-mutant with differences in median age for BRAF-mutant vs BRAF-wildtype (52 vs 64 years; p = 0.001), and GTR rates for BRAF-mutant vs BRAF-wildtype (85% vs 73%; p = 0.03). Median survival difference between BRAF-mutant vs BRAF-wildtype was 15.4 vs 11.9 months (p = 0.11). The longest median survival occurred in BRAF-mutant with GTR while the shortest occurred in BRAF-wildtype with STR (23 vs 4.5 months; p = 0.001). At three years, the proportion alive for GTR and BRAF-mutant vs GTR and BRAF-wildtype (47.9% vs 41.6%) was higher than STR and BRAF-mutant vs STR and BRAF-wildtype (15% vs 28.4%; p = 0.03). ConclusionBRAF-mutant patients with cerebral metastases were younger, and more likely to have a higher GTR rate with greater survival than BRAF-wildtype if GTR is achieved. Gross total resection in both groups appears to be associated with survival even in the current era of more effective systemic therapies. Subtotal resection has particularly poor survival, especially for BRAF-mutant patients.

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.

15604 Resistance to BRAF and MEK inhibitors in BRAF-mutant melanoma

The 5-year survival rate for patients diagnosed with metastatic melanoma is only 23%. Nearly half of patients diagnosed with melanoma have BRAF-mutant melanoma in which there is a driver mutation in the MAPK pathway, leading to over activation. Single-agent BRAF inhibitors had some success, but their long term efficacy is limited due to the development of resistance. Current standard of care includes a BRAF-inhibitor in combination with a MEK inhibitor in order to co-target the downstream MEK protein in the hopes of preventing reactivation of the pathway. It has been shown that this combination therapy has also met some difficulty due to the development of resistance. We generated BRAF inhibitor (dabrafenib) and MEK inhibitor (trametinib) resistant cell lines (TDR) by adding increasing concentration of the drugs to the parental cells (drug sensitive cells) for WM115 and WM983 (BRAF mutant melanoma cell lines) until they were rendered resistant. The TDR cells remained viable over increasing concentration of the inhibitor as assessed by the MTT assay. There was maintenance of p-ERK in the TDR cells, which was not observed for the parental cells under similar conditions. qPCR analysis demonstrated that TDR cells had elevated levels of the signaling molecules such as AXL, EGFR, HER3, and IGF1R. These molecules might be potential mediators of resistance to targeted therapy for BRAF-mutant melanoma. Examining potential mechanisms of resistance to BRAF and MEK inhibitors helps expand possible treatment options to aid in long-term success for BRAF-mutant melanoma patients.

The Role of BRAF in Metastatic Colorectal Carcinoma-Past, Present, and Future.

With a global incidence of 1.8 million cases, colorectal cancer represents one of the most common cancers worldwide. Despite impressive improvements in treatment efficacy through cytotoxic and biological agents, the cancer-related death burden of metastatic colorectal cancer (mCRC) is still high. mCRC is not a genetically homogenous disease and various mutations influence disease development. Up to 12% of mCRC patients harbor mutations of the signal transduction molecule BRAF, the most prominent being BRAFV600E. In mCRC, BRAFV600E mutation is a well-known negative prognostic factor, and is associated with a dismal prognosis. The currently approved treatments for BRAF-mutated mCRC patients are of little impact, and there is no treatment option superior to others. However, the gradual molecular understanding over the last decades of the extracellular signal-regulated kinase/mitogen-activated protein kinase pathway, resulted in the development of new therapeutic strategies targeting the involved molecules. Recently published and ongoing studies administering a combination of different inhibitors (e.g., BRAF, MEK, and EGFR) showed promising results and represent the new standard of care. In this review, we present, both, the molecular and clinical aspects of BRAF-mutated mCRC patients, and provide an update on the current and future treatment approaches that might direct the therapy of mCRC in a new era.

Body mass index (BMI) and outcome of metastatic melanoma patients receiving targeted therapy and immunotherapy: a multicenter international retrospective study

BackgroundObesity is a risk factor for malignancy; however, its prognostic role in patients with metastatic melanoma is controversial. We aim to investigate the prognostic role of body mass index (BMI)...

Safety and efficacy evaluation of encorafenib plus binimetinib for the treatment of advanced BRAF-mutant melanoma patients

ABSTRACT Introduction Approximately 40–50% of patients with cutaneous melanoma harbor point mutations in BRAF. BRAF and MEK inhibitors in combination are now a standard therapy for advanced BRAF V600-mutated melanoma. Nevertheless, survival rates with the combination are limited, highlighting the need for further therapeutic improvement and strategies to overcome primary and acquired resistance. Areas covered Encorafenib, a highly selective BRAF inhibitor, was developed in combination with binimetinib, a potent, selective allosteric MEK1/2 inhibitor, to improve efficacy and tolerability over other approved combo-targeted therapies. This novel combination shows peculiar pharmacodynamic properties which translate in a higher on-target potency and paradox index. Consistent survival improvements for encorafenib and binimetinib in BRAF V600-mutated melanoma have been confirmed in clinical trials, with over 4 years of median follow up. Expert opinion the favorable survival results and the attractive toxicity profile suggest that encorafenib and binimetinib combination is an intriguing standard option when targeted therapies are considered as first line treatment in BRAF mutated melanoma patients. In the near future, results from ongoing clinical trials will provide information on the use of this novel combination in specific situation, including as adjuvant treatment or as a combination strategy.

The Real-Life Data of BRAF Mutation on the Treatment of Colorectal Cancer: a TOG Study.

Colorectal cancer is the third leading diagnosis accounting for nearly 10% of all new cancers worldwide. The distinct features among BRAF mutant colorectal cancers make these tumor groups hard to treat for oncologists. The median overall survival (OS) of these types of cancers is reported to be 9 to 14 months. The study was declared on the Turkish Oncology Study Group Conference and approved. The patients' data was received from the centers who confirmed to participate. The BRAF-mutated patients were included in the study. The demographic features (age, gender, etc.), type of mutation, tumor localizations, histology, microsatellite instability (MSI) status, metastasis patterns chemotherapeutic agents and progression, and death times were recorded. Thirty-nine patients were enrolled in the study. Sixteen patients had concurrent KRAS mutations, while 7 had NRAS mutations. Most of the patients received doublet chemotherapies in combination with anti-VEGF agents in the first and second line of the treatment. There was a significant difference in OS according to the stage which showed a decreased survival in stage IV patients at the time of diagnosis. Concurrent KRAS mutation resulted in increased OS. The median OS was 47 and 24 months favoring the KRAS mutant group. The patients whose primary tumor operated had better survival when compared with other patients. The median OS of the operated group was 47 months, while the non-operated group was 24 months. Liver metastasis was related to worse prognosis at the time of diagnosis in univariate analysis. In our study we found a high concurrent RAS mutation ratio in a BRAF mutant patient group which was different from prior studies. The concurrent mutations resulted in a favorable outcome in terms of OS which is also different from the current knowledge. More prospective studies are needed especially BRAF-mutated patient population and especially with concurrent RAS mutations.

Promising Strategies for Overcoming BRAF Inhibitor Resistance Based on Known Resistance Mechanisms.

Almost 50% of metastatic melanomas harbor BRAF mutations. Since 2011, BRAF inhibitors have exhibited striking clinical benefits in BRAF-mutant melanoma patients. Unfortunately, their therapeutic effects are often temporary. The resistance mechanisms vary and can be broadly classified as MAPK reactivation-dependent and -independent. Elucidation of these resistance mechanisms provides new insights into strategies for overcoming resistance. Indeed, several alternative treatment strategies, including changes in the mode of administration, combinations of BRAF and MEK inhibitors, and immunotherapy have been verified as beneficial to BRAF inhibitor-resistant melanoma patients. In this review, we discuss promising strategies for overcoming drug resistance and highlighting the prospects for discovering strategies to counteract BRAF inhibitor resistance.

Abstract 1894: Role of IGF1R in mediating resistance to MAPK pathway inhibitors in BRAF-mutant melanoma

Abstract Melanoma is the most aggressive form of skin cancer originating in the pigment producing melanocytes of the skin. The five year survival rate for patients diagnosed with metastatic melanoma is only 23%. Around 60% of the melanomas encompass the active BRAFV600E oncoprotein, which is critical for survival and proliferation of the melanoma cells as a consequence of hyperactivation of theMAPK pathway. This opened up avenues for development of BRAF inhibitors and subsequently the development of MEK inhibitors. Co-targeting of BRAF and MEK with Dabrafenib and Trametinib respectively, results in a response rate of about 70% in patients harboring the BRAF mutation. The use of these inhibitors is limited as patients relapse on treatment typically within 6 months due to the development of acquired resistance. Recent studies have identified various resistance mechanisms including involvement of various receptor tyrosine kinases. In order to decipher novel mechanisms of resistance, we generated double resistant cell lines to BRAF and MEK inhibitor in WM115, WM983 and A375 human melanoma cell lines harboring BRAFV600 mutations using Dabrafenib and Trametinib over a course of 9-11 months. The drug resistant cell lines exhibited increased viability and maintenance of downstream p-ERK protein as compared to their drug sensitive counterparts. Receptor tyrosine kinase array revealed an increase in phosphorylated HER3, AXL, EGFR and IGF1R in the drug resistant cells versus drug sensitive cells. Quantitative PCR data revealed an upregulation of these molecules along with an increase in the expression of some of their ligands at the mRNA level. RNA-seq analysis identified IGF1R and IGF2BP2 to be upregulatedin the resistant cell lines compared to parental cell lines.IGF2BP2 is a tumor promoter and drives cancer proliferation in a variety of malignancies and is correlated with poor survival.Our next experiments are focused on testing the efficacy of IGF1R inhibitors in the drug resistant cell lines and their downstream effector signaling molecules in vitro and in vivo. Further, we aim to decipher the mechanism by which IGF2BP2 regulates the IGF1R signaling pathway in MAPK inhibitors resistant melanoma setting. Delineating the role of IGF1R in mediating resistance to BRAF and MEK inhibitors will help expand possible treatment options to aid in long-term success for BRAF-mutant melanoma patients. Citation Format: Hima Patel, Rosalin Mishra, Natasa Broit, Nour Yacoub, Long Yuan, Samar Alanazi, Nicholas Hayward, Peter Johansson, Joan T. Garrett. Role of IGF1R in mediating resistance to MAPK pathway inhibitors in BRAF-mutant melanoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1894.

Abstract 2986: NR2F1 underlies persistence of residual disease in melanoma

Abstract Despite the clinical success of targeted therapy and checkpoint inhibitors in melanoma, therapeutic responses are transient, followed by relapse that may be driven by a small subpopulation of residual or drug-tolerant cells. Understanding residual disease and metastasis mechanisms can provide clues both for developing improved versions of a drug and for guiding the selection of appropriate drug combinations for melanoma therapy. Here, we found that the well-known marker of tumor dormancy, Nuclear Receptor Subfamily 2 Group F Member 1 (NR2F1), was overexpressed in minimal disease residual cells following CDK4/6 and MEK inhibitors (CDK4/6i+MEKi) treatment in vivo. Furthermore, melanoma cells overexpressing NR2F1 were less sensitive to (CDK4/6i+MEKi) or BRAF and MEK inhibitors (BRAFi+MEKi) treatment in vitro and in vivo models, inhibiting apoptosis. Surprisingly, we did not find any evidence of decreased cell growth in our model. Using a three-dimensional tumor spheroid assay in vitro, we found the NR2F1 expression enhanced melanoma invasion following CDK4/6i+MEKi or BRAFi+MEKi treatments. The use of published RNA Seq data sets that were gathered from the GEO database and Single Cell Seq data sets from PDX melanoma samples showed that high expression of NR2F1 is enriched in the undifferentiated cell state and invasive cells, respectively. Furthermore, BRAF mutant patient sample with an acquired mutation in NRAS Q61R following BRAFi+MEKi+CDKi presented a high expression of NR2F1. Altogether, these findings suggest that NR2F1 may play a role in residual disease persistence besides known features of tumor dormancy, especially important in determining responses to dramatic changes in the environment, such as changes induced by anti-cancer therapy. Citation Format: Manoela Tiago, Jessica L. Teh, Timothy J. Purwin, Weijia Cai, Connor Hollingworth, Melisa Lopez-Anton, Julio A. Aguirre-Ghiso, Andrew E. Aplin. NR2F1 underlies persistence of residual disease in melanoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2986.

P-49 A study of first-line treatments for patients with BRAFV600E mutant metastatic colorectal cancer in a real-life setting: CAPSTAN study

The BRAF V600E mutation is associated with poor prognosis in patients with metastatic colorectal cancer (MCRC), and findings from clinical trials have largely remained inconclusive regarding the efficacy of first line treatments for BRAF-mutant mCRC patients. There is, therefore, an unmet need to document the current practices for first-line treatment of BRAF-mutant mCRC, and their effectiveness and safety in a real-world setting.

Treatment of Advanced/Metastatic Melanoma in the United States and Western Europe: Results of the CancerMPact Survey.

ContextMelanoma treatment has substantially changed over the last several years, yet little information regarding physician’s preferences around treatment exists.ObjectiveOur aim is to describe the results of the CancerMPact (CMP) survey performed in 2019 about the treatment of advanced/metastatic melanoma.MethodsCMP is a data source from Kantar, Health Division, containing data on cancer epidemiology and treatment. Once a year, Kantar performs a series of surveys with specialists in the field of interest in the United States of America (USA), Western Europe (WE), Japan, and China. The results of the survey reported in this work comprise the answers from 94 USA and 99 WE physicians about the treatment of melanoma.ResultsIn the first-line for the BRAF wild-type population, immuno-oncology (IO) drugs including nivolumab, ipilimumab or pembrolizumab (alone or in combination) were used in 80.1% of the cases in the USA and 70.6% in WE. Conventional chemotherapy or cytokine-based treatments were used in 16.4% of the USA patients and 28.2% in WE. In the second-line in the USA, 45.8% of BRAF wild-type patients received IO drugs, while 45.0% of patients received conventional chemotherapy or cytokine-based treatments. The majority of patients with BRAF mutant advanced/metastatic melanoma were treated in the first-line with BRAF-targeted therapy (61.3% USA, 71.9% WE), and few patients received conventional chemotherapy or cytokine-based treatments (11.9% USA, 12.4% WE); the most commonly used BRAF-targeted therapy was the combination of dabrafenib plus trametinib. In the second-line, BRAF mutant patients received IO drugs (45.1% USA, 53.7% WE), targeted therapy (37.6% USA, 32% WE) or conventional chemotherapy/cytokine-based treatments (14.4% USA, 11.7% WE).ConclusionThe use of IO or targeted therapy for patients with advanced/metastatic melanoma is the preferred treatment strategy by physicians in the USA and WE based on BRAF mutation status. Many patients still receive conventional chemotherapies or cytokines with unsubstantial benefit, especially in recurrent patients of BRAF wild type.

Dynamics in treatment response and disease progression of metastatic colorectal cancer (mCRC) patients with focus on BRAF status and primary tumor location: analysis of untreated RAS-wild-type mCRC patients receiving FOLFOXIRI either with or without panitumumab in the VOLFI trial (AIO KRK0109)

PurposeIn mCRC, disease dynamics may play a critical role in the understanding of long-term outcome. We evaluated depth of response (DpR), time to DpR, and post-DpR survival as relevant endpoints.MethodsWe analyzed DpR by central review of computer tomography images (change from baseline to smallest tumor diameter), early tumor shrinkage (≥ 20% reduction in tumor diameter at first reassessment), time to DpR (study randomization to DpR-image), post-DpR progression-free survival (pPFS = DpR-image to tumor progression or death), and post-DpR overall survival (pOS = DpR-image to death) with special focus on BRAF status in 66 patients and primary tumor site in 86 patients treated within the VOLFI-trial, respectively.ResultsBRAF wild-type (BRAF-WT) compared to BRAF mutant (BRAF-MT) patients had greater DpR (− 57.6% vs. − 40.8%, p = 0.013) with a comparable time to DpR [4.0 (95% CI 3.1–4.4) vs. 3.9 (95% CI 2.5–5.5) months; p = 0.8852]. pPFS was 6.5 (95% CI 4.9–8.0) versus 2.6 (95% CI 1.2–4.0) months in favor of BRAF-WT patients (HR 0.24 (95% CI 0.11–0.53); p < 0.001). This transferred into a significant difference in pOS [33.6 (95% CI 26.0–41.3) vs. 5.4 (95% CI 5.0–5.9) months; HR 0.27 (95% CI 0.13–0.55); p < 0.001]. Similar observations were made for patients stratified for primary tumor site.ConclusionsBRAF-MT patients derive a less profound treatment response compared to BRAF-WT patients. The difference in outcome according to BRAF status is evident after achievement of DpR with BRAF-MT patients hardly deriving any further disease control beyond DpR. Our observations hint towards an aggressive tumor evolution in BRAF-MT tumors, which may already be molecularly detectable at the time of DpR.