ALBERT

Description: Background: Solid tumor patients are at a heightened risk for developing therapy-related myeloid neoplasms (tMN). Recent studies show evidence of somatic mutations in leukemia-associated genes in normal healthy individuals, referred to as clonal hematopoiesis (CH). We and others have shown that clonal hematopoiesis (CH) is also frequent in cancer patients. A detailed characterization of the relationship between exposure to specific oncologic regimens, the molecular features of CH presentation and how these relate to tMN risk is warranted to inform treatment decisions, early detection and prevention strategies. Methods: To determine the relationship between CH and oncologic therapy, we performed a systematic interrogation of CH in a cohort of 17,478 solid tumor patients with clinical, outcome and molecular profiling by MSK-IMPACT. MSK-IMPACT is a targeted panel of cancer-associated mutations used to screen tumor samples against a blood control sample. Mutation detection was performed on blood derived sequencing data (median coverage at 600x) using the matched tumor as a comparator and accounted for background sequencing error rates. Results: Overall, 40% of the 17,478 patients were treatment naïve prior to IMPACT testing, 37% had received chemotherapy alone, 17% had received radiation therapy and 18% had received both. CH was identified in 4013 (23%) of patients, median VAF was 4% (range=1-80%). The vast majority (76%) had a single mutation whereas 9% had two and 5% had three or more. The number of mutations correlated with clone size (p-value=

Description: Langerhans Cell Histiocytosis (LCH) and Erdheim-Chester Disease (ECD) are systemic histiocytic disorders characterized by infiltration of histiocytes in multiple tissues of the body leading to organ compromise. Although the underlying etiology of these conditions has long been enigmatic, recent investigations have determined that LCH and ECD are clonal disorders of myeloid-derived precursor cells with a high frequency of BRAFV600E mutations (40-60% of patients). Moreover, treatment of BRAF-mutant LCH and ECD patients with the BRAF inhibitor vemurafenib has demonstrated dramatic efficacy. The above data underline the importance of accurately identifying BRAF mutational status in patients with systemic LCH and ECD. Unfortunately, the scant histiocyte content and marked stromal contamination, which are a hallmark of these disorders, make mutation detection in tissue biopsies challenging. Moreover,the propensity of histiocytic lesions to involve difficult to biopsy locations frequently necessitates the use of bone biopsies further limiting the availability of suitable tumor material for BRAF genotyping. We therefore initiated a prospective, blinded, multicenter study of BRAFV600E mutation detection in the cell-free DNA (cfDNA) from plasma and urine of histiocytosis patients to determine the sensitivity/specificity of cfDNA mutation detection compared with tissue biopsy and to track disease burden serially with therapy. Between January 2013 and June 2014, 30 consecutive patients with ECD (n=25) and LCH (n=5) were enrolled from Memorial Sloan Kettering Cancer Center and MD Anderson Cancer Center. Initial BRAF tissue mutation testing on tissue biopsies was performed by a variety of methods as part of routine care in CLIA-certified molecular diagnostic laboratories. We applied a droplet-digitial PCR assay (RainDrop ddPCR) for quantitative detection of the BRAFV600E mutation in plasma and urine cell-free cfDNA in all patients. Of 30 patients enrolled, initial tissue BRAFV600E genotyping identified 15 patients to be mutant, 6 patients as wildtype, and 9 as indeterminate. There was 100% concordance between tissue and urinary cfDNA genotype in samples from treatment naïve patients (sensitivity 92.9%, specificity 100%, positive predictive value 100%, negative predictive value 85.7% compared to tissue biopsy detection). Urinary cfDNA analysis identified 5 patients as being BRAFV600E mutant that were not known to have the BRAF mutation previously (Figure A). Subsequent tissue biopsy was performed in 2 of these patients and identified the BRAFV600E mutation, allowing both patients to enroll in an ongoing phase II study of vemurafenib. Results from plasma cfDNA for identifying the BRAFV600E mutation were comparable to urinary cfDNA results Next examining serial samples during therapy, a significant decrease in the cfDNA BRAFV600E:BRAF wildtype ratio was seen with therapy compared with pretreatment samples (p

Description: Background: Whole-genome sequencing has identified a 4-6% incidence of BRAF mutations in multiple myeloma (MM). We undertook a histology-independent, "basket" study of VEM in BRAF V600m-positive cancers (NCT01524978). Six disease cohorts were prespecified; remaining tumors were classified in a 7th "all-comers" cohort. Here we present preliminary efficacy and safety data for the MM cohort. Methods: A multicenter, Simon, 2-stage adaptive design in patients with relapsed refractory BRAF V600m-positive MM who were receiving VEM (960 mg bid) until disease progression (PD) or unacceptable toxicity was used. Primary end point is investigator-assessed response rate (RR) at week 8 by International Myeloma Working Group criteria. Secondary objectives include overall RR, clinical benefit rate, duration of response, progression-free survival, overall survival, and safety. Stage 1 was complete after the 7th patient received a minimum of 8 weeks of treatment, died, or withdrew early from the study. Results: Eight patients had been enrolled in the MM cohort at the time of the data cutoff (December 3, 2014). Data are presented on patients in stage 1. Twelve patients were screened, of which 4 patients did not meet eligibility criteria. Of the 8 patients enrolled in the study, 6 were men and 2 were women, with a median age of 64 years (range, 55-68). High-risk features were seen in 3 patients by cytogenetics and fluorescence in situ hybridization (FISH). Prior treatment included immunomodulators (IMiDs) in 100% of patients, proteasome inhibitors in 75%, and chemotherapy (melphalan, bendamustine, cytoxan, doxorubicin, etoposide, and cisplatin) in 87.5%. Patients had received between 2 and 7 lines of treatment before enrolling in the BASKET trial, and 5 were refractory to IMiDs or proteasome inhibitors, or both. Median duration of treatment was 3.3 months (range, 1-5) at the time of data cutoff; 3 patients continue to be treated and 5 patients discontinued study drug. Response data were available for 7 patients at the end of 2 cycles. One patient achieved partial response (PR); 4 patients had stable disease; 1 patient had progressive disease; and 1 patient response was reported as not evaluable (objective response rate [ORR] week 8, 14%; 95% confidence interval [CI], 0.4-57.9). Of the patients enrolled, 71% (95% CI, 29.0-96.3) had clinical benefit with single-agent VEM. Responses occurred beyond 2 cycles: 1 patient went on to achieve very good PR (after cutoff date, January 2015). Three patients experienced disease progression between study days 57 and 85, and 1 of these patients died as a result of progressive disease. Single-agent VEM was well tolerated, with a safety profile similar to that observed in melanoma patients. Seven patients (88%) had at least 1 adverse event (AE) of grade 3 or 4, and 3 patients (38%) had at least 1 serious AE, including sepsis and lower respiratory tract infection, that was attributable to the underlying disease. Toxicity was manageable, and 1 patient discontinued treatment because of lower respiratory tract infection and skin lesions. Dose modification was necessary in 5 of 8 patients because of toxicity. Conclusions: This is the first mutation-specific clinical trial in MM. VEM has promising activity in patients with BRAF V600m-positive MM despite these patients being heavily pretreated. Because obvious clinical benefit for patients has been observed, the decision to recruit additional patients was made, and recruitment is ongoing. Updated efficacy results from all patients currently participating in the study will be presented. Disclosures Raje: Amgen: Consultancy; Celgene: Consultancy; Astra Zeneca: Research Funding; Eli Lilly: Research Funding; BMS: Consultancy; Roche: Consultancy; Takeda: Consultancy; Onyx: Consultancy. Off Label Use: Vemurafenib is a potent inhibitor of BRAF mutated at codon 600 (BRAFV600). Here we explored the efficacy of vemurafenib in multiple myeloma patients with BRAFV600 mutations.. Chau:Roche: Research Funding. Hyman:Chugai Pharma: Consultancy; Biotherapeutics: Consultancy; Atara: Consultancy, Honoraria. Ribrag:Gilead: Membership on an entity's Board of Directors or advisory committees; Esai: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmamar: Honoraria, Membership on an entity's Board of Directors or advisory committees. Blay:roche: Research Funding. Tabernero:Taiho: Consultancy; Millennium: Consultancy; Merck: Consultancy; Amgen: Consultancy; Imclone: Consultancy; Chugai: Consultancy; Merck Serono: Consultancy; Boehringer Ingelheim: Consultancy; Eli Lilly: Consultancy; Celgene: Consultancy; Sanofi: Consultancy; Roche: Consultancy; Novartis: Consultancy; Symphgen: Consultancy. Wolf:Roche: Consultancy, Equity Ownership, Honoraria, Research Funding. Sirzen:F. Hoffmann-La Roche: Employment, Equity Ownership. Faris:Merrimack Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Roche: Research Funding; N-of-One-Therapeutics: Consultancy. Kaiser:Bristol-Myers Squibb: Consultancy; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Honoraria; Chugai: Consultancy. Veronese:F. Hoffmann-La Roche: Employment. Makrutzki:F. Hoffmann-La Roche: Employment. Lasserre:F. Hoffmann-La Roche: Employment, Other: Unspecified, Patents & Royalties. Puzanov:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Baselga:Roche: Consultancy.

Description: Background: Recent genomic studies have identified somatic mutations in leukemia genes in asymptomatic individuals without known hematologic disease. These mutations lead to clonal expansion of hematopoietic cells, in the absence of clinically overt hematologic transformation. This entity is thought to be analogous to other precursor conditions such as monoclonal gammopathy of undetermined significance (MGUS) and monoclonal B-cell lymphocytosis (MBL); consistent with this notion, a subset of patients with clonal hematopoiesis can subsequently develop myeloid malignancies, including myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). However, the incidence of clonal hematopoiesis in patients with solid tumors has not been extensively studied. Moreover, most genomic profiling platforms used to identify somatic mutations in epithelial tumors use blood as the matched normal control, which may lead to the identification of clonal hematopoiesis in a subset of cancer patients. We therefore sought to assess for clonal hematopoiesis in patients with solid tumors seen at Memorial Sloan Kettering Cancer Center (MSKCC) who were profiled using paired tumor/blood sequencing which is primarily designed to identify tumor-specific mutations. Methods: The study population included patients at MSKCC who were consented on protocol NCT01775072, “Tumor genomic profiling in patients evaluated for targeted cancer therapy.” All patients had tumor and blood genomic profiling sequenced using the MSK-IMPACT hybridization capture-based next-generation sequencing assay, which encompasses all protein-coding exons of 410 cancer-associated genes. For assessment of the incidence and distribution of blood mutations, 3,964 patients consented were evaluated. Patients with known active hematologic malignancies at time of sequencing were excluded from analyses. For comparisons regarding clinical correlations, 2,146 patients were included for whom detailed chart review has been performed. We investigated for the presence of “hotspot” mutations, collected from COSMIC database (v71), in matched blood DNA. Mutations were scored as present in the normal blood if they were detected in more than 8 reads with a variant allele frequency (VAF) greater than 2% which was at least twice the VAF seen in tumor. For cases where at least one mutation exceeded these thresholds, we reduced the VAF threshold in blood to 1% to detect secondary events. Mutations where VAF in the normal blood and the tumor sample were both greater than 30% were excluded as likely germline events. Results: Clonal hematopoiesis was identified in 108/3,964 solid tumor patients who had paired tumor/blood sequencing (2.7% of all patients); 7 patients had 2 unique mutations. DNMT3A mutations were most frequent, occurring in 34% of patients with clonal hematopoiesis (Figure 1). 107/115 mutations (93%) were in known leukemia-associated genes. We collected and analyzed detailed clinical parameters for 2,146 patients, including 42 patients (2.0%) with clonal hematopoiesis. The mean age at the time of testing was 62.1 years in patients with clonal hematopoiesis and 57.2 years in patients without evidence of clonal hematopoiesis (p = 0.015). When comparing baseline blood parameters, there were no statistically significant differences between the two groups. 62% of patients with clonal hematopoiesis had previous radiation therapy compared to 45% of patients without clonal mutations in their blood (p = 0.046). There was no statistically significant difference in the proportion of patients who had received previous chemotherapy (71% of patients in each group). On prospective follow up of patients with clonal hematopoiesis, no patients have progressed to develop overt MDS or AML, though median follow up was limited (median 11.7 months, range 5.5-16.7 months). Conclusions: Clonal hematopoiesis in solid tumor patients without known hematologic disease is common and is associated with increasing age and prior radiation therapy. In our cohort, no patients with clonal hematopoiesis progressed to overt MDS or AML though follow up is limited. Ongoing prospective observation of these patients is imperative to determine the clinical impact of these mutations after ongoing exposure to cytotoxic therapy. Further data including updated clinical and genomic correlates will be presented. Reference: Cheng DT et al. J Mol Diagn 2015 May; 17(3): 251-64. Figure 1. Figure 1. Disclosures Hyman: Chugai Pharma: Consultancy; Biotherapeutics: Consultancy; Atara: Consultancy, Honoraria. Levine:Loxo Oncology: Membership on an entity's Board of Directors or advisory committees; CTI BioPharma: Membership on an entity's Board of Directors or advisory committees; Foundation Medicine: Consultancy.

Description: Histiocytic neoplasms are clonal, hematopoietic disorders characterized by an accumulation of abnormal monocyte-derived dendritic cells or macrophages in Langerhans Cell (LCH) and non-Langerhans (non-LCH) histiocytoses, respectively. The discovery of the BRAF V600E mutation in ~50% of patients with LCH and the non-LCH Erdheim-Chester Disease (ECD) provided the first molecular target in these patients and novel insights into the pathogenesis of these disorders. However, recurrent mutations in the majority of the ~50% of BRAF V600E-wild type patients with non-LCH are unknown. Moreover, recurrent mutations outside of the MAP kinase pathway are undefined throughout histiocytic neoplasms. To address these issues, we performed whole exome sequencing (WES) of frozen biopsies from 24 patients with LCH (n=10) or ECD (n=14) paired with peripheral blood mononuclear cells. 13/24 patients also underwent RNA sequencing (RNA-seq). All mutations in activating kinases were validated by droplet-digital PCR, while targeted-capture next-generation sequencing validated all others. Both adult (n=18; n=2 with LCH) and pediatric cases (n=9; n=8 with LCH) were included. Using combined WES/RNA-seq, activating kinase alterations were identified in 100% of patients. In LCH, 60% and 40% had BRAF V600E and MAP2K1 mutations, respectively. In non-LCH 51%, 14%, 14%, and 7% were BRAFV600E, ARAF, MAP2K1, and NRAS mutant (Fig1A). Overall, a mean of 7 non-synonymous mutations per adult patient was identified (range 1-22) compared with 5 mutations per pediatric patient (range 4-9; p =ns). Mutations affecting diverse cellular processes were found to co-exist with kinase mutations including mutations in epigenetic modifiers and the p38/MAPK pathway. In addition to kinase point mutations, RNA-seq identified recurrent, in-frame kinase fusions-a first for these disorders. All identified fusions were validated using FISH and RT-PCR. This includes novel fusions in BRAF (RNF11-BRAF and CLIP2-BRAF), as well as therapeutically important fusions in ALK (2 separate KIF5B-ALK fusions) and NTRK1 (LMNA-NTRK1;Fig1B). Expression of each fusion in Ba/F3 cells conferred cytokine-independent growth. Importantly, the BRAF fusions were found to be sensitive to MEK inhibition but resistant to vemurafenib while the ALK fusions conferred sensitivity to the ALK inhibitors crizotinib or alectinib. We next interrogated a validation cohort of 37 BRAF V600E-wild type, non-LCH, formalin-fixed, paraffin-embedded tissue samples using targeted mutational profiling for MAP2K1, ARAF, NRAS, KRAS, and PIK3CA. This revealed activating mutations in MAP2K1 (32%; n=12), NRAS (16%; n=6), KRAS (11%; n=4), PIK3CA (8%; n=3), and ARAF (3%; n=1). Three of the investigated non-LCH patients with refractory disease and progressive organ dysfunction were treated with targeted therapies based on the discovery of novel kinase alterations described above. Treatment of 2 refractory MAP2K1- mutant, non-LCH patients with MEK inhibitors (trametinib or cobimetinib) resulted in dramatic clinical improvement (Fig1C). Both patients have been maintained on MEK inhibitor single-agent therapy with a sustained clinical response for 〉100 days. Further evidence of effective targeted inhibition was found in a refractory ECD patient carrying an ARAF S214A mutation. This patient failed to respond to 3 lines of prior therapies and suffered near blindness due to disease infiltration in the retina and optic nerves. Given a recent report of complete response to sorafenib in a lung cancer patient with an ARAF S214C mutation, we initiated sorafenib. Within 12 weeks, there was improvement in the patientÕs eyesight and decreased infiltrative disease, coinciding with 〉50% decrease in mutant ARAF DNA in plasma cell-free DNA. Whole exome and transcriptome sequencing identified activating kinase mutations or translocations in all patients with the common downstream effect of activating the MAPK pathway. The preliminary, dramatic, clinical efficacy observed with use of MEK and RAF inhibitors in MAP2K1 - and ARAF-mutated, non-LCH patients further supports the central role of targeting the MAPK pathway in these tumors. The discovery of the discussed mutations and fusions in diverse kinases provides critical new insights into the genetic events central to a spectrum of adult and pediatric histiocytic neoplasms. Figure 1. Figure 1. Disclosures Off Label Use: This abstract describes use of MEK inhibitors (both tremetinib and cobimetinib) as well as sorafenib for MEK1 and ARAF mutant histiocytosis. . Stephens:Foundation Medicine, Inc.: Employment, Equity Ownership. Miller:Foundation Medicine, Inc.: Employment, Equity Ownership. Ross:Foundation Medicine Inc.: Employment. Ali:Foundation Medicine Inc.: Employment. Hyman:Chugai Pharma: Consultancy; Biotherapeutics: Consultancy; Atara: Consultancy, Honoraria.

Description: Background: ECD and LCH are rare disorders for which no approved therapies are available. BRAFV600E mutations have been observed in 50% of patients with LCH and in 50-60% of patients with ECD. Here we present data from a planned Week 16 analysis of patients with ECD/LCH who were enrolled in the VE-BASKET study (ClinicalTrials.gov identifier NCT01524978). Methods: This open-label, Simon 2-stage adaptive-design, phase 2 study included patients with BRAFV600E-mutant ECD and LCH. Patients received vemurafenib (960 mg bid) until disease progression or unacceptable toxicity. The primary endpoint was investigator-assessed response rate at Week 8; secondary endpoints included best overall response rate, clinical benefit rate, progression-free survival (PFS), and overall survival (OS). For a subset of patients (n=15), metabolic response by 18F-FDG-PET was assessed; five target lesions were selected and their maximal standardized uptake value (SUVmax), normalized for body weight (BW), was compared with background (liver) SUV. Data cut-off was 2 October 2015. Results: 26 patients (22 with ECD and 4 with LCH; median age 61y) were enrolled. Seven patients (27%) had one prior therapy, six (23%) had two prior therapies, four (15%) had ≥3 prior therapies, and nine (35%) had no prior systemic therapy. Six patients were in follow-up at data cut-off; 16 were on treatment. Best overall response (according to RECIST v1.1) in 25 patients with measurable disease at baseline was 60% (95% CI 38.7-78.9%) with complete response (CR) in two patients (8%) and partial response (PR) in 13 patients (52%) (Figure). Responses were seen in patients with ECD (1 CR, 10 PRs) and LCH (1 CR, 3 PRs). After a median treatment exposure of 14.2 months (range 4.2-22.5 months), median OS and PFS have not been reached. All of the 15 patients assessed by 18F-FDG-PET showed a response: 12 patients had a complete metabolic response (normalization of all lesions' SUVmax-BW to background SUV) and three had a partial metabolic response (〉50% decrease in sum of baseline SUVmax of all target lesions) (Figure). Overall, safety data were consistent with prior studies of vemurafenib. Arthralgia (n=17; 65%), fatigue (n=15; 58%), rash macropapular (n=14; 54%), alopecia (n=14; 54%), skin papilloma (n=14; 54%), prolonged QT (n=12; 46%), and palmar-plantar erythrodysesthesia syndrome (n=12; 46%) were the most common all-grade adverse events (AEs). Seventeen patients had serious AEs, including 10 with squamous cell carcinoma of the skin. Seven patients discontinued vemurafenib due to AEs. Conclusion: These data, which represent the only prospective clinical trial data of BRAF inhibition in histiocytosis to date, reveal that vemurafenib has potent single-agent activity in patients with ECD/LCH. Moreover, vemurafenib treatment had remarkable durability of response in histiocytosis, such that no evidence of resistance has been encountered following a median of 14.2 months of treatment. These results are distinct from vemurafenib use in other solid or hematologic malignancies. Figure Figure. Disclosures Subbiah: Abbvie: Research Funding; Nanocarrier: Research Funding; GlaxoSmithKline: Research Funding; Roche/Genentech: Research Funding; Bayer: Research Funding; Novartis: Research Funding. Blay:F. Hoffmann-La Roche: Consultancy, Research Funding; MDS: Research Funding; Lilly: Research Funding; Bayer: Consultancy, Research Funding; Pharmamar: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Puzanov:Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Immunocore: Consultancy. Wolf:F. Hoffmann-La Roche Ltd.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Clovis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; MSD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Boehringer-Ingelheim: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Ulaner:GE Healthcare: Research Funding; Genentech: Research Funding; Blue Earth Diagnostics: Research Funding; Susan Komen Foundation: Research Funding; Department of Defense: Research Funding; National Institutes of Health: Research Funding; Zevacor: Honoraria. Lacouture:Quintiles: Consultancy; Boehringer Ingelheim: Consultancy; AstraZeneca: Consultancy; Genentech: Consultancy; Foamix: Consultancy; Infinity: Consultancy; Janssen: Consultancy; Novartis: Consultancy; Berg: Research Funding; Bristol Myers Squibb: Research Funding. Robson:F. Hoffmann-La Roche Ltd: Employment. Makrutzki:F. Hoffmann-La Roche Ltd: Employment.

Description: Background: Clonal hematopoiesis (CH) as evidenced by recurrent somatic mutations in leukemia-associated genes has been demonstrated to predict increased risk for subsequent hematologic cancers and decreased overall survival (OS) in large, population-based studies. We examined the incidence and clinical implications of CH in a large cohort of patients with advanced, non-hematologic cancers to examine whether individual mutations carried unique phenotypes with respect to effect on hematologic parameters and association with prior toxic exposures. Methods: We analyzed deep coverage targeted next-generation sequencing data of 410 cancer genes in paired tumor and blood samples from 7,200 patients with non-hematologic cancers. We called mutations in the blood and genotyped them in the matched tumor and required them to be supported by at least 8 reads and present at twice the variant allele frequency (VAF) or greater in blood cells compared to the tumor. Mutations were scored as hematopoietic in origin if they were detected with a VAF greater than 2% for a selected panel of leukemia genes and 5% for other genes. When at least one mutation exceeded these thresholds, we reduced the VAF threshold in blood to 1% to detect subsequent events for leukemia genes and 3% for non-leukemia genes. Mutations where VAF in blood and tumor were both greater than 35% were excluded as likely germline events except in cases where the blood-associated variants were seen in the blood at 〉35% for mutations reported in COSMIC on at least 10 occasions.Common SNPs were excluded. We excluded patients with concurrent hematologic malignancies.We examined whether different mutations harbored unique phenotypes in regard to their effect on hematologic parameters and associations with prior toxic exposuresin a subset of 5,145 patients. Results: CH was identified in 23.4% of patients. CH was associated with increased age (p

Description: Background: The systemic histiocytic disorders Erdheim-Chester disease (ECD) and Langerhans cell histiocytosis (LCH) are rare hematologic malignancies with heterogenous clinical courses and prognoses that share a common primary event: the pathologic accumulation and infiltration of cells thought to be of the monocyte/macrophage lineage in affected tissue. The recent discovery of BRAFV600E mutations in a high proportion (50-60%) of patients with LCH/ECD has provided pivotal insight into the cause and potential management of these disorders. The VE-BASKET study (ClinicalTrials.gov identifier, NCT01524978) was designed to explore the efficacy and safety of vemurafenib, a selective oral inhibitor of mutated BRAFV600 kinase, in non–melanoma, non–papillary thyroid cancers harboring BRAFV600 mutations. The preliminary efficacy data in adult patients with ECD/LCH are presented herein. Methods: Simon 2-stage adaptive-design, open-label, multicenter, multinational, phase 2 study of vemurafenib in patients with cancer harboring BRAFV600 mutations. The primary objective was to evaluate the efficacy of vemurafenib in patients with BRAFV600 mutation–positive cancers at week 8 by investigator-assessed response rate using RECIST version 1.1. Tumor assessment was performed by computed tomography, magnetic resonance imaging, or physical examination every 8 weeks. Patients without RECIST v1.1 measurable disease were followed up by use of positron emission tomography; these response data will be presented separately. Data cutoff was March 18, 2014. Results: Fifteen patients with ECD/LCH (6 male, 9 female) have been enrolled. Median age is 67 years (range, 35-83). Eleven of 15 patients (73%) received at least 1 prior therapy. Median duration of vemurafenib treatment was 94 days (range, 6-478). Maximal percentage change from baseline in target lesion diameter sum and best overall response are shown in Figure 1A. To date, in 11 patients assessed by RECIST v1.1, overall response rate was 36.4% (95% CI, 10.9-69.2) and clinical benefit rate was 90.9% (95% CI, 58.7-99.8). No patient experienced progression while taking vemurafenib. Best overall responses by RECIST 1.1 are as follows: 1 (9.1%) complete, 3 (27.3%) partial, 6 (54.6%) stable, 0 progressive, and 1 (9.1%) not evaluable. Three patients (20%) discontinued treatment because of adverse events (AEs; grade 3 gastric infection, grade 3 arthralgia, and grade 4 alanine transaminase level elevation); 12 patients are still receiving treatment. Thirteen patients (87%) had at least 1 grade 3 or 4 AE—most commonly skin squamous cell carcinoma (40%)—and actinic keratosis, keratoacanthoma, maculopapular rash, arthralgia, and dehydration (each 13%). No patient died during the study. Two representative patient vignettes are presented herein. Patient 1 is a 68-year-old woman with extensive ECD involving the brain, bones, and retroperitoneum. She previously received high-dose methotrexate and underwent stenting for disease-related renal artery stenosis that resulted in an emergency hypertensive event and renal failure, transiently requiring hemodialysis. At the time of enrollment, this patient had severe gait instability and dysarthria and was unable to perform activities of daily living (ADLs). After 8 weeks of vemurafenib therapy, she achieved partial response (Figure 1B), is ambulating with minimal assistance, and is independent with ADLs. She continues therapy. Patient 2 is a 77-year-old woman with LCH previously treated with vinblastine, methotrexate, an AKT inhibitor, and cladribine. At the time of enrollment she had debilitating cutaneous involvement that required long-term administration of narcotics and resulted in recurrent infection. After 4 weeks of vemurafenib therapy, the patient achieved complete response, including total resolution of skin lesions (Figure 1C). Subsequent biopsy also confirmed complete pathologic response and complete absence of the BRAFV600E mutant protein by immunohistochemistry using the VE1 antibody (Figure 1D). The patient continues therapy. Conclusion: There are no approved therapies for adult patients with multisystem histiocytic disorders. The magnitude and durability of response to vemurafenib in patients with multisystemic BRAFV600-mutated ECD and LCH are encouraging. Updated results will be presented at the American Society of Hematology annual meeting. Figure 1 Figure 1. Disclosures Hyman: Chugai Pharma: Consultancy; Atara Biotherapeutics: Consultancy. Off Label Use: Vemurafenib is a BRAF inhibitor currently approved for treatment of patients with unresectable or metastatic melanoma with BRAF V600E mutation as detected by an FDA-approved test. The data included in this abstract is a subgroup analysis of VE-BASKET, a phase 2 study of vemurafenib in non-melanoma cancer patients harboring BRAFV600 mutations in order to explore the efficacy of vemurafenib in other cancer populations. Subbiah:MD Anderson Cancer Center: Employment. Blay:University Lyon I: Employment; Centre Leon Berard: Employment. Sirzen:F. Hoffmann-La Roche: Employment, Equity Ownership. Veronese:F. Hoffmann-La Roche: Employment. Laserre:F. Hoffmann-La Roche: Employment. Baselga:Roche: Consultancy.