bluuebunny/crossref_metadata_2025_split huggingface dataset:
Whole exome and whole transcriptome sequencing in melanoma patients to identify mechanisms of resistance to combined RAF/MEK inhibition.
Authors: Wagle Nikhil , Van Allen Eliezer Mendel , Frederick Dennie T. , Cooper Zachary A. , Farlow Deborah Norman , Treacy Daniel , Goetz Eva M. , Johannessen Cory M. , Carter Scott L. , Taylor-Weiner Amaro , Hodis Eran , Lawrence Donald P. , Sullivan Ryan J. , Getz Gad , Gabriel Stacey B. , Flaherty Keith , Wargo Jennifer Ann , Garraway Levi A. 
Published: March 2020

9015 Background: The RAF inhibitors vemurafenib and dabrafenib (D) and the MEK inhibitor trametinib (T) improve survival as monotherapies in BRAF-mutant melanoma. Since clinical mechanisms of resistance (MoR) result in MAPK pathway reactivation, recent efforts have focused on combined targeting of RAF and MEK. The combination of D and T (D/T) increased progression-free survival and response rate compared with D alone (Flaherty et al, NEJM, 2012). The MoR to this combination remain unknown. Methods: To look for clinical MoR to combined RAF/MEK inhibition, we performed whole exome (WES) and whole transcriptome sequencing (RNASeq) on tumors from 4 patients (pts) with acquired resistance and 1 pt with intrinsic resistance to D/T. Pre-treatment and post-resistance tumors from all pts were analyzed for point mutations, insertions/deletions, copy number alterations, alternatively spliced transcripts, rearrangements, and expression changes. Results: In 2 of 4 pts with acquired resistance, WES identified mutations in MEK1 and MEK2 that were undetectable in the pre-treatment tumors. In the 3rd pt, RNASeq identified an alternatively spliced isoform of BRAF lacking exons 2-10, also undetectable in the pre-treatment tumor. In the 4th pt, no obvious MoR were seen, though multiple alterations were enriched in the post-resistance tumor. The pt with intrinsic resistance had several alterations in genes that conferred resistance to RAF/MEK inhibition when overexpressed in BRAF-mutant cell lines. Integration of WES and RNASeq data also identified several co-existing alterations that may synergize to increase resistance. Conclusions: Analysis of combined WES and RNASeq data from pt samples provides a more complete picture of clinical MoR to MAPK-targeted therapy. Post-resistance tumors from 3 of 4 pts with acquired resistance to D/T had alterations in MAPK genes not detectable in the pre-treatment tumors, suggesting that resistance involves reactivation of the MAPK pathway despite combined RAF/MEK inhibition. Alternative dosing of current agents, more potent RAF/MEK inhibitors, and/or inhibition of the downstream kinase ERK may be needed for durable control of BRAF-mutant melanoma.
Comparison of BRAF inhibitor (BRAFi)-induced cutaneous squamous cell carcinoma (cuSCC) and secondary malignancies in BRAF mutation-positive metastatic melanoma (MM) patients (pts) treated with dabrafenib (D) as monotherapy or in combination with MEK1/2 inhibitor (MEKi) trametinib (T).
Authors: Cebon Jonathan S. , Flaherty Keith , Weber Jeffrey S. , Kim Kevin , Infante Jeffrey R. , Daud Adil , Hamid Omid , Kefford Richard , Schuchter Lynn Mara , Sosman Jeffrey Alan , Sznol Mario , Sharfman William Howard , Gonzalez Rene , Andrews Miles Cameron , Dronca Roxana Stefania , Long Georgina , Little Shonda M , Sun Peng , Patel Kiran , McWilliams Robert R. 
Published: March 2020

9016 Background: The MAP kinase (MAPK) pathway is of critical importance for keratinocyte proliferation and maturation and is essential for epidermal homeostasis. Occurrence of hyperproliferative skin lesions including keratoacanthomas (KA) and cuSCC are considered a class effect of BRAFi [Anforth 2012, Chu 2012, Mattei 2012]. These effects, as well as promotion of pre-existing RAS-driven malignancies, may be caused by paradoxical activation of the MAPK pathway downstream of BRAF in wild-type BRAF cells. As MEK inhibition blocks downstream MAPK signaling, it was hypothesized that addition of a MEKi to a BRAFi would abrogate these effects [Su, 2012]. Methods: This 4-part phase I/II study enrolled 365 BRAFV600E/Kmutated MM pts in Parts B-D. In part C, 162 pts (BRAFi and MEKi treatment-naïve, ≥ 18 yrs; ECOG PS <2; RECIST measurable disease) were randomized to D monotherapy 150mg BID (D mono) vs. the combination of D (150 mg BID) and T (1 mg or 2 mg QD). Primary endpoints included safety and efficacy. Occurrence of cuSCC (including KA) across three arms in Part C and secondary malignancies with D+T across all Parts are provided below. Results: The difference in incidence of cuSCC between D mono and the D+T (150/1) was statistically significant, whereas the difference in incidence between D mono and D+T (150/2) was not. The median time to onset of cuSCC was 30 days in D mono compared to 282 and 152 days with D+T (150/1 and 150/2, respectively). Of 365 pts who received D+T, 2 (<1%) cases of new cancers (colorectal and gliobastoma) and 2 (<1%) cases of new primary malignant melanoma were reported. Conclusions: These data support the experimental hypothesis that the occurrence of cuSCC (including KA) can be substantially reduced and delayed by the addition of a MEKi to BRAFi therapy. Clinical trial information: NCT01072175. [Table: see text]
Identification of changing melanocytic lesions in patients on BRAF inhibitor therapy.
Authors: Yagerman Sarah , Flores Eileen , Marghoob Ashfaq A. , Lacouture Mario E. 
Published: March 2020

9018 Background: Patients treated with BRAF inhibitors (BRAFi) have been observed to develop new primary melanomas. In addition, these patients often develop new nevi and involuting nevi. It remains a challenge to detect clinically subtle and histopathologically early melanomas in a background of such increased nevus volatility. In this study, we sought to quantify and describe the new, changing, and involuting melanocytic lesions observed in these patients. Methods: A retrospective chart and image analysis was conducted for all BRAFi treated patients referred to the Dermatology service at Memorial Sloan-Kettering Cancer Center. Initial overview and follow-up images were compared in MIRROR Body Mapping image system, DermaGraphiX software (Canfield Imaging Systems, Fairfield, NJ). A total count of new, changing, and involuting melanocytic lesions was determined in four anatomic areas: upper back, lower back, chest, and abdomen. Dermoscopy images of all changing lesions that were biopsied were evaluated for dermoscopic pattern and for the presence or absence of any melanoma specific features. Results: Average photography follow-up was 261 days (n=21). The average number of combined new and changing melanocytic lesions was 13.1, 16.4, 9.5, and 6.1 for the upper back, lower back, chest, and abdomen respectively. The average number of involuting melanocytic lesions was 8.0, 4.0, 4.3, and 3.4 for the upper back, lower back, chest, and abdomen respectively. Of all new and changed lesions, 38 were biopsied revealing 31 benign melanocytic lesions and 7 melanomas (18% of lesions biopsied). All 7 melanomas revealed at least one melanoma specific structure, with the most significant dermoscopic discriminate being negative network. Conclusions: Given the setting of highly volatile melanocytic changes in BRAFi treated patients and that 18% of biopsied lesions were melanomas; we propose the use of total body photography and dermoscopy as a method for the identification and monitoring of secondary atypical pigmented lesions.
Gene expression profile of primary cutaneous melanomas to distinguish between low and high risk of metastasis.
Authors: Lawson David H. , Russell Maria , Wilkinson Jeffrey , Amaria Rodabe Navroze , Gonzalez Rene , Gerami Pedram , Lyle Stephen , Jackson Gilchrist L. , Greisinger Anthony , Johnson Clare , Oelschlager Kristen M. , Stone John F , Maetzold Derek , Cook Robert W. , Delman Keith A. 
Published: March 2020

9022 Background: Wide variability exists in metastatic rates of primary cutaneous melanoma (CM), even within TNM stage groupings. We developed an RT-PCR based gene expression profile (GEP) test to predict distant metastases in early stage CM. Methods: RNA was isolated from formalin-fixed, paraffin embedded biopsies or wide excisions of primary CM from patients with stage 1-4 CM (87% stage 1-2) converted to cDNA and analyzed using RT-PCR. All analyses were done using JMP Genomics and WinSTAT. Radial Basis Machine (RBM) modeling was used to predict metastasis-free survival (MFS) for the training set of 149 samples. Independent validation was performed on an additional 107 CM samples. RBM reports a binary Class 1 (low risk) and Class 2 (high risk). Results: Analysis of the training set resulted in a model with 85% receiver operating characteristic (ROC) and sensitivity of 82%. Prediction of metastatic risk for the validation set resulted in a 90% ROC and sensitivity of 89%. 30 of 33 stage 1-3 cases with a known metastatic event were accurately called Class 2. Kaplan-Meier analysis showed 5-year MFS rates of 88% and 25% for predicted Class 1 and Class 2, respectively, in the training set (p<0.0001, overall MFS=60%). Similarly, MFS was 95% and 26% for Class 1 and Class 2, respectively, in the independent validation set (p<0.0001, overall MFS=67%). Univariate Cox regression analysis of the validation set revealed that GEP, AJCC stage, Breslow thickness, and ulceration were each predictors of metastatic risk (HR=27.2, 11.4, 3.0, and 11.6, respectively, p<0.002 for each). Multivariate analysis showed GEP and AJCC stage were independent predictors of risk (HR=8.4 and 6.4 respectively, p<0.007 for both). Conclusions: This GEP signature provides an accurate stratification of metastatic risk in the training and validation samples independent of all other histologic factors. This test may serve as a prognostic tool for outcomes in patients with melanoma and for stratifying patients for clinical trials.
A phase II study of the multitargeted kinase inhibitor lenvatinib in patients with advanced BRAF wild-type melanoma.
Authors: O'Day Steven , Gonzalez Rene , Kim Kevin , Chmielowski Bartosz , Kefford Richard , Long Georgina , Loquai Carmen , Cowey Charles Lance , Hauschild Axel , Hainsworth John D. , Hersey Peter , Boyle Frances , Evans T. R. Jeffry , Hamid Omid , Meneses Nicole , Andresen Corina , Ren Min , O'Brien James P. , Flaherty Keith 
Published: March 2020

9026 Background: Lenvatinib is an oral receptor tyrosine kinase inhibitor targeting VEGFR1-3, FGFR1-4, RET, KIT, and PDGFRβ. Melanoma responses in the phase I study led to this multicenter phase II trial of lenvatinib in separate cohorts of BRAF mutant and BRAF wild-type (wt) melanoma to provide an estimate of efficacy and to identify molecular correlates of clinical benefit. Primary analyses of clinical outcomes for the BRAF wt cohort are reported here; the BRAF mutant cohort will be presented at a later date. Methods: Eligible patients (pts) had stage IV or unresectable stage III BRAF wt melanoma with ≥1 prior treatment (26/96 [27%] pts received ≥3 treatments) and no prior VEGF-targeted therapy. Lenvatinib 24 mg once daily with dose reduction for toxicity was administered until disease progression or unmanageable toxicities. Primary endpoint was response rate by independent review (IRR) using RECIST 1.1. Archival tumor tissue and baseline and posttreatment serum samples were collected for molecular analysis. Results: 93 pts were treated (median [m] age: 64 y; male: 69%; 95% AJCC stage IV). Confirmed partial responses (PRs) were observed in 8 pts (9%) with a clinical benefit rate (CR+PR+durable SD ≥23 wks) of 32% by IRR. mPFS was 3.7 mos (95% CI, 2.5-4.0) by IRR and mOS was 9.5 mos (95% CI, 8.3-12.9); 46% pts required dose reduction for management of toxicity; 12% were withdrawn from therapy due to toxicity. Treatment-related adverse events reported in ≥20% pts included hypertension 59% (34% Gr 3/4), fatigue 58% (16% Gr 3/4), nausea 44% (3% Gr 3/4), diarrhea 43% (2% Gr 3/4), decreased appetite 38%, vomiting 29% (2% Gr 3), dysphonia 27%, and proteinuria and headache 26% each (4% and 1% Gr 3/4). Serum biomarker analysis showed baseline levels of serum angiogenic factors, such as angiopoietin-2, correlated with OS. More extensive biomarker analyses are reported in an accompanying abstract. Conclusions: Lenvatinib administered to pts with advanced BRAF wt melanoma was associated with frequent but manageable toxicity. Clinical benefit was seen in some pts. Predictive biomarkers for response to lenvatinib, such as the serum level of angiogenic factors, may be useful for future clinical trials. Clinical trial information: NCT01136967.
Lenvatinib combined with dacarbazine versus dacarbazine alone as first-line treatment in patients with stage IV melanoma.
Authors: Maio Michele , Hassel Jessica Cecile , Del Vecchio Michele , Testori Alessandro , Ascierto Paolo Antonio , Marshall Ernie , Glen Hiliary , Lorigan Paul , Meek Elaine , Liou Song , Hodge Jeff Paul , Bologna Fabrina , Dave Harish P. 
Published: March 2020

9027 Background: Lenvatinib (E7080; LEN) is an oral, receptor tyrosine kinase inhibitor targeting VEGFR1-3, FGFR1-4, RET, KIT and PDGFRβ . In a phase I study qd dosing of >/= 20mg LEN demonstrated PRs and prolonged SD in patients (pts) with advanced melanoma. Dacarbazine (DTIC) upregulates the proangiogenic factor VEGF and has been shown to confer resistance in melanoma cell lines (Lev, JCO 2004; 22:2092-2100). Treatment of melanoma pts with LEN + DTIC may potentiate the therapeutic effects of DTIC. Methods: This was a phase II study in pts with metastatic melanoma randomized 1:1 to receive LEN (20 mg QD) + DTIC (1000 mg/m2 Q 21 d) or DTIC (1000 mg/m2Q 21 d). Pts were stratified by LDH level and stage IV subclass. Eligible pts were ECOG PS 0/1 and had no prior systemic therapies. BRAF status was determined from circulating tumor DNA. The primary endpoint was PFS by independent assessment. Results: In a modified ITT analysis,a total of 78 of 81 pts were evaluable for efficacy; 59% were male, 59% were Stage IV M1c, 22% had elevated LDH, 29% had prior adjuvant therapy and 49% BRAF wild-type (wt). Most common AEs in the LEN + DTIC arm were hypertension (48%), nausea (38%), constipation (33%), and diarrhea (31%). Most common Grade 3/4 AEs in LEN + DTIC were hypertension (26%) and neutropenia (10%). There were no deaths due to an AE. Median PFS increased in LEN + DTIC compared to DTIC alone (see Table). An improvement in median PFS was observed in BRAFwt pts on the combination. Conclusions: A 2.7-fold increase in the median PFS was observed in pts administered LEN + DTIC compared to single agent DTIC. A 2.5 fold increase in the median PFS was observed in the combination arm in pts with BRAFwt melanoma. The AE profile observed with the LEN + DTIC was consistent with observed LEN monotherapy studies. These data suggest further evaluation of LEN + DTIC in BRAFwt melanoma is warranted. Clinical trial information: NCT01133977. [Table: see text]
Phase II study of low-dose peginterferon alfa-2b antiangiogenic therapy in patients with metastatic melanoma overexpressing basic fibroblast growth factor: An Eastern Cooperative Oncology Group study (E2602).
Authors: Go Ronald S. , Lee Sandra J. , Shin Donghoon , Callister Steven M , Jobe Dean A , Conry Robert Martin , Tarhini Ahmad A. , Kirkwood John M. 
Published: March 2020

9038 Background: FGF-2 plays an important role in the pathogenesis and progression of melanoma. In particular, FGF-2 and its receptor are expressed in melanoma cells. We investigated the use of graded dosages Peg-IFN in patients with stage IV melanoma overexpressing FGF-2. Primary objective: suppression of plasma FGF-2 to normal levels (< 7.5 pg/mL). Secondary objectives: clinical efficacy of Peg-IFN and its association with angiogenic factor levels (FGF-2 and vascular endothelial growth factor /VEGF). Methods: Patients were eligible if they had stage IV melanoma from any primary site. Prior systemic therapies (< 4) were allowed including IFN. Plasma FGF-2 was measured at baseline (Step 1) and patients with levels > 15 pg/mL allowed to receive study treatment (Step 2). Peg-IFN was given weekly at starting dose of 0.5 mcg/kg/wk with increments every 3 weeks (maximum dose: 5 mcg/kg/wk) based on serial FGF-2 levels. Results: 207 patients entered into Step 1 and 45 (22%) overexpressed FGF-2 with a median level of 22 pg/dL (range, 15-216). 29 eligible patients enrolled into Step 2 and received treatment. The median age was 64 years and most had > 2 prior therapies. FGF-2 decreased in 28 (97%) patients with suppression to normal level in 10 (35%). The median time to FGF-2 suppression was 30 days (range, 14-116). The best clinical responses were PR (7%) and stable disease (17%). The median PFS and OS were 2.0 and 9.7 months, respectively. Patients who achieved FGF-2 suppression were more likely to have a response or stable disease compared to those who did not (50% vs 11%; P=.03). Landmark analysis at 63 days showed similar OS between those who achieved FGF-2 suppression and those who did not (7.8 vs 7.7 months; P=.31). VEGF decreased in 27 patients (93%) during treatment and the levels paralleled those of FGF-2 over time. We did not find a compensatory rise in VEGF level among those with FGF-2 suppression. Conclusions: Graded dose Peg-IFN suppresses FGF-2 and has activity against metastatic refractory melanoma. Complete suppression of plasma FGF-2 was observed in 35% of the patients and correlated with clinical response but not OS. Clinical trial information: NCT00049530.
Open-label, multicenter safety study of vemurafenib in patients with BRAFV600 mutation–positive metastatic melanoma.
Authors: Larkin James M. G. , Del Vecchio Michele , Ascierto Paolo Antonio , Schachter Jacob , Garbe Claus , Neyns Bart , Mandala Mario , Lorigan Paul , Miller Wilson H , Guminski Alexander David , Berking Carola , Rutkowski Piotr , Queirolo Paola , Hauschild Axel , Arance Ana Maria , Brown Michael Paul , Mitchell Lada , Veronese Maria Luisa , Blank Christian U. 
Published: March 2020

9046 Background: Vemurafenib (VEM), a BRAF kinase inhibitor, has demonstrated high response rates and improved progression-free and overall survival in pts with BRAFV600mutation–positive metastatic melanoma (mM). We present interim results from predefined subgroups from a large multicenter, open-label safety study of VEM in pts with mM (NCT01307397). Methods: Pts with BRAFV600mutation–positive histologically confirmed mM received VEM (960 mg BID) as first-line therapy or subsequent to previous therapies. Assessments for safety and efficacy were made every 28 days. Results: As of Feb 29, 2012, 2,265 pts have received VEM. Pts had a median age of 54.0 (13-95) yrs and median time since diagnosis of mM of 6.2 (0-351.9) mos. 59% had received prior systemic therapy. Median time of exposure to VEM as of the cut-off date was 3 (0.03-11.24) mos for the overall population and majority of subgroups, and approximately 2.5 mos for pts with ECOG ≥2 and age ≥75 yrs. 1537 (68%) pts were still receiving VEM at the cut-off date. 728 (32%) pts discontinued, most frequently because of PD (538/728 pts; 74%). Adverse events (AEs) were reported for 87% of all patients, with arthralgia (32%) and rash (26%) the most frequent. The incidences of AEs in the subgroups are summarized (Table). Although efficacy analyses are limited by the short duration of follow-up, six-month OS rate was 76% (95% CI 72-79%) and median PFS was 4.1 mos (95% CI 3.9-4.5 mos). Postbaseline tumor assessments were available for 63% and 30% of pts at wk 8 and 16, respectively. At wk 8 CR: 2%, PR: 57%, SD: 30%, PD: 6%. At wk 16 CR: 3%, PR: 46%, SD: 31%, PD: 15%. Conclusions: Although the overall safety profile of VEM in this study was consistent with previous clinical data, interim analyses of subgroups suggest that very elderly pts may be at higher risk of G3 AEs. Clinical trial information: NCT01307397. [Table: see text]
Pharmacodynamic effect of ipilimumab on absolute lymphocyte count (ALC) and association with overall survival in patients with advanced melanoma.
Authors: Postow Michael Andrew , Chasalow Scott D. , Yuan Jianda , Kuk Deborah , Panageas Katherine S. , Cheng Michael , Shahabi Vafa , Berman David Mark , Wolchok Jedd D. 
Published: March 2020

9052 Background: Ipilimumab (Ipi) is a fully human monoclonal antibody that augments antitumor T-cell responses. Ipi has been shown to improve overall survival (OS) in 2 phase (ph) III trials of advanced melanoma, as monotherapy at 3 mg/kg in previously treated patients (pts) (MDX010-20) or at 10 mg/kg with dacarbazine in previously untreated pts (CA184-024). In preclinical and clinical studies, inhibition of CTLA-4 by Ipi resulted in increases in activation and proliferation of peripheral T cells and increases in ALC. Baseline ALC may be a prognostic biomarker in several cancer types. The current analyses aim to increase understanding of changes in ALC with Ipi treatment and association of these changes with OS. Methods: Data were from 6 studies of Ipi with chemotherapy (CT) (ph I 078; N=59) or without CT (ph III MDX010-20; ph II trials 004, 007, 008, and 022; N=1203), and Ipi monotherapy in an Expanded Access Program (N=117) or with commercially available Ipi (N=71) or BRAF inhibitors (N=39). ALC was measured at baseline, prior to each dose during induction (weeks 1, 4, 7, and 10) and at the end of induction (week 13). Cox proportional hazards models were used to estimate and test associations between ALC measures and OS. Results: In all studies, mean ALC increased significantly over time in pts who received Ipi, with or without CT (P<.0001 to P=.03). There was no significant mean increase in ALC in pts who received gp100 or BRAF-inhibitor monotherapy. In study MDX010-20, pts with a greater rate of change in ALC from baseline to week 7 tended to have longer OS (P=.0003). A similar association was found between OS and ALC ≥1000/µL after 2 Ipi doses. However, pts in MDX010-20 had an OS benefit from Ipi relative to gp100, regardless of rate of change in ALC (P=.14). Conclusions: In these analyses, consistent with inhibition of CTLA-4, Ipi induced an increase in mean ALC, even with the addition of CT. A positive association between rate of ALC increase and OS was observed, but this was not specifically predictive of OS benefit from Ipi. Therefore, ALC cannot currently be used to guide clinical management with Ipi. However, further prospective investigation may be warranted.