bluuebunny/crossref_metadata_2025_split huggingface dataset:
Changes in the quality of life of advanced melanoma patients after 12 weeks of treatment with ipilimumab compared to gp100 in a phase III clinical trial.
Authors: Harvey Becca , Lee Dawn , Gaudin Anne-Francoise , Gueron Beatrice , Bregman Bruno , Lebbé Céleste , Borget Isabelle 
Published: March 2020

9084 Background: This study analyses health-related quality of life (HRQL) outcomes for ipilimumab (ipi) with and without gp100 and gp100 alone during the 12 week treatment (T) induction period compared to baseline. The aim of this study was to express the HRQL as proportions of patients experiencing changes during the induction period, when most of the immune-related adverse events (ir-AE) on ipi occur. Methods: Data from the MDX010-20 trial, including 676 previously treated patients (pts) with unresectable stage III or IV melanoma, was analysed. Differences between ipi with/without gp100 and gp100 alone in terms of HRQL 12 weeks after randomisation according to the EORTC QLQ-C30 were searched for. The sample consisted of 388 pts (ipi: 83; ipi + gp100: 227; gp100: 78) completing both baseline and week (W)12 questionnaires. Ordinal regression was performed for these pts to determine a T effect on W12 scores (in ordered categories) whilst adjusting for key covariates. Fisher’s Exact Test was used to detect differences between Ts for each EORTC domain when considering mean change in scores, categorised as “clinically worse” (≤-10 on functional domains, ≥10 on symptoms), “stable” (>-10 to <10) and “clinically improved” (≥10 on functional domains, ≤-10 on symptoms). Results: There were no significant differences for any domain score between the 3 T arms at W12. The odds of attaining high HRQL scores at W12 were heavily dependent on the baseline scores; baseline scores explained most of the variability as per regression analysis. There was no significant difference between the 3 T arms in terms of pts showing a clinically significant reduction or improvement in HRQL. HRQL remained globally stable from baseline to W12, in > 50% of pts for most domains. Conclusions: Ipi with/without gp100 does not have a significant negative HRQL impact in stage III-IV melanoma during the T induction phase relative to gp100 alone after adjustment for differences in baseline scores. The lower rate of pts showing HQRL reduction and the absence of difference with gp100 suggest that ir-AE have little impact on HRQL. Further HRQL studies are needed, as efficacy benefits of ipi continue after W12.
Use of tumor exome analysis to reveal neo-antigen-specific T-cell reactivity in ipilimumab-responsive melanoma.
Authors: van Rooij Nienke , Haanen John B. A. G. , van Buren Marit , Philips Daisy , Toebes Mireille , Heemskerk Bianca , van Dijk Laura , Behjati Sam , Stratton Michael R. , Kerkhoven Ron M , Kesmir Can , Kvistborg Pia , Schumacher Ton 
Published: March 2020

9085 Background: Evidence for T cell mediated regression of human cancer in particular melanoma following immunotherapy is strong. Anti-CTLA4 treatment has been approved for treatment of metastatic melanoma and blockade of PD-1 has shown encouraging results. However, it is unknown which T cell reactivities are involved in cancer regression. Reactivity against non-mutated tumor self-antigens has been analyzed in patients treated with Ipilimumab or with autologous TILs, but the size of these responses are modest. Therefore, T cell recognition of patient-specific mutant epitopes may be a potentially important component. Animal model data recently suggested that analysis of T cell reactivity against patient-specific neo-antigens may be feasible through exploitation of cancer genome data. However, human data have thus far been lacking. Methods: To address this we have used MHC class I peptide exchange technology allowing production of very large collections of pMHC complexes, together with a pMHC "combinatorial coding" strategy for parallel detection of dozens of different T cell populations within a single sample. Results: From a melanoma patient responding to ipilimumab treatment, we identified tumor specific mutations via exome sequencing of tumor material. The exome contained 1,075 non-synonymous mutations. Possible MHC epitopes covering these mutations were predicted based on; 1) predicted to bind the patient’s MHC; 2) predicted to be cleaved by the proteasome; 3) genes of which the mutated peptides arose had evidence of RNA expression. The analysis yielded 1,952 epitopes restricted to the HLA-A and HLA-B. To screen for T cell reactivity against these epitopes we used the pMHC combinatorial coding approach. We found T cell reactivity against 2 neo-antigens, including a dominant T cell response against a mutant epitope of the ATR gene product. Analysis of PBMC samples collected before and during Ipilimumab therapy showed that this particular response increased strongly after treatment from 0.06% to 0.28% of CD8 T cells after being stable in magnitude for 10 months. Conclusions: These data provide the first demonstration of cancer exome-guided analysis to dissect the effects of melanoma immunotherapy.
Gamma knife stereotactic radio-surgery and BRAF inhibition in metastatic melanoma.
Authors: Wilson Melissa , Lee John Y , Alonso-Basanta Michelle , Xu Wei , McGettigan Suzanne , Schuchter Lynn Mara , Amaravadi Ravi K. , Gangadhar Tara C. 
Published: March 2020

9088 Background: Gamma knife radio-surgery (GK) is an effective approach to treating brain metastases in patients with metastatic melanoma. BRAF inhibition with vemurafenib produces a median progression free survival (PFS) of 7 months, but low central spinal fluid penetration may limit its effectiveness in patients who develop brain metastases. We report long term follow-up of patients with BRAF mutant melanoma treated with vemurafenib and GK. Methods: Demographics and clinical outcomes were characterized for 18 BRAF mutant melanoma patients with brain metastases treated between 2007 and 2012 with GK and with vemurafenib (vem) for >1 month. Results: The median age at starting vem was 51 yrs (range 34-76). 61% of the patients were women. Patients were treated with a median of 1 prior therapy (range 0-3). 7/18 patients (39%) had brain involvement prior to starting vem. 16/18 patients (89%) had stage M1c disease at the time of starting vem. Patients were treated with vem for a median of 8.4 months (range 2.1 to 27 months), had a median survival of 15.7 months after starting vem (range 4.2-29.4), and a median survival after GK of 7.8 months (range 1.2-21.1). Patients underwent GK to a median of 3 lesions (range 1-6). In total, 8/18 patients (44%) were treated with WBRT. 7/18 patients underwent craniotomies, 2 of which were for progression in lesions treated with GK, and 4 of which were also among the patients treated with WBRT. In 7/18 patients treated with GK for new brain progression after starting vem, vem was continued after GK for a median duration of 4.1 months (range 1.3 to 15.8). In these 7 patients that had vem and GK and continued vem, the median overall survival after starting vem was 19.9 months (range 6.7 to 29.3). Of these 7 patients, 4 required whole brain radiation therapy (WBRT); 3 have not required any additional brain directed therapy, including 2 patients who continue on vemurafenib at the time of analysis. 5/18 patients were treated with more than 1 round of GK, 3 of which were subsequently treated with WBRT. Conclusions: Despite the brain being a common site of progression on vemurafenib therapy, long term survival can be achieved in some cases by continuing vem after GK therapy.
Activity of cabozantinib in metastatic uveal melanoma: Updated results from a phase II randomized discontinuation trial (RDT).
Authors: Daud Adil , Kluger Harriet M. , Edelman Gerald , Gordon Michael S. , Schimmoller Frauke , Weitzman Aaron , Samuel Thomas A. , Moussa Ali H. , Flaherty Keith , Shapiro Geoffrey 
Published: March 2020

9094 Background: MET and VEGF signaling are implicated in angiogenesis, invasion, and metastasis, and upregulation of MET as a consequence of GNAQ/GNA11 mutation has been implicated in uveal melanoma. Historical rates of median overall survival (OS) in patients (pts) with metastatic uveal melanoma range from 6-9 months (mos). A RDT evaluated activity and safety of cabozantinib, a MET and VEGFR2 inhibitor, in 9 tumor types including a metastatic melanoma cohort where 55% and 5% of pts experienced objective tumor regression and confirmed partial response, respectively (J. Clin. Oncol. 30, 2012 (suppl; abstr. 8531)). Here we report on the longer term followup of metastatic uveal melanoma pts enrolled to this cohort. Methods: Eligible pts were required to have progressive measurable disease per RECIST. Pts received cabozantinib at 100 mg po qd over a 12 wk Lead-in stage. Tumor response (mRECIST) was assessed q6 wks. Treatment ≥ wk 12 was based on response: pts with PR continued open-label cabozantinib, pts with SD were randomized to cabozantinib vs placebo, and pts with PD discontinued. Pts were followed for overall survival. Results: 23 of 77 pts enrolled in the melanoma cohort had the uveal subtype. Median age was 65 yrs; median prior regimens was 1 (range 0-5). Tumor mutation status was determined for 10/23 pts. 9/10 harbored either a GNAQ or GNA11 mutation, while GNA11 status was unknown for one pt. Pts had substantial tumor burden; median sum of the longest diameter of target lesions was 11.9 cm (range, 2-37.2). Median follow-up was 26.5 mos. (range 21.7-33.8). Median PFS from Study Day 1 was 4.8 mos. The estimate of PFS at month 6 (PFS6) was 41% and median OS was 12.6 mos. Most common Grade 3/4 AEs were HTN (13%), abdominal pain (9%), hypokalaemia (9%), hyperbilirubinaemia (9%) and increased lipase (9%). Conclusions: Cabozantinib is active in pts with metastatic uveal melanoma. Treatment with cabozantinib is associated with encouraging progression-free and overall survival. The safety profile of cabozantinib was comparable to that of other VEGFR TKIs. A randomized Phase 2 study is planned comparing cabozantinib to temozolomide plus dacarbazine in pts with uveal melanoma. Clinical trial information: NCT00940225.
Detection of DDR2 mutations in malignant melanoma: A potentially targetable feature of advanced stage disease.
Authors: Wang Yongbao , Billouin-Frazier Shere S , Windham Justin P , Jones Daniel 
Published: March 2020

9100 Background: The discoidin domain receptor tyrosine kinase 2 (DDR2) gene is mutated in a subset of non-small cell carcinoma of the lung. In lung cancer, targeting of DDR2 with the inhibitor dasatinib has been shown to inhibit DDR2-mutated cell line growth. Responses to dasatinib in DDR2-mutated lung tumors are currently being investigated in clinical trials. We investigated whether somatic DDR2 mutations also occur in melanomas using a set of different clinical subtypes bearing a variety of melanoma-associated molecular alterations. Methods: DNA was extracted from macrodissected FFPE sections of 168 melanomas and subjected to next-generation sequencing using a custom-designed 36-amplicon panel including the coding regions of DDR2 and exons 11 and 15 of BRAF. PCR products were prepared by Access Array, sequenced on the Ion Torrent PGM, and analyzed using Sequence Pilot software. All DDR2 mutations were confirmed by bidirectional Sanger sequencing. Relative expression analysis of the DDR2 gene was performed using RT-PCR on RNA extracted from FFPE sections, with levels normalized to ABL1 and GAPDH. Results: Heterozygous DDR2 point mutations were identified in 3.4% of BRAF-mutated melanoma (n=117) but not in any cases that lacked BRAF mutations (n = 51). All DDR2-mutated melanomas were advanced stage with lymph node and/or extensive soft tissue involvement and included both BRAF V600K and V600E cases. In contrast to the range of mutation sites reported in lung cancers, DDR2 mutations in melanoma (I488S, F574C, S667F and L701F) were at highly evolutionarily conserved positions in the kinase domain. The mutations are expected to be disruptive and may therefore modulate kinase activity. DDR2 transcripts were expressed in tumor cells in all mutated cases. Conclusions: DDR2 mutations in advanced stage melanoma may provide a targetable genetic feature for tyrosine kinase inhibitors such as dasatinib. The invariant association of DDR2 mutation with activating BRAF mutations suggests synergy in transformation between these distinct signaling pathways.
Systematic review and indirect treatment comparison (ITC) of dabrafenib (Dab) and trametinib (Tram) versus first-line (1L) treatments for metastatic melanoma (MM).
Authors: Srivastava Kunal , Pathak Purnima , Amonkar Mayur , Stapelkamp Ceilidh , Swann R. Suzanne , Casey Michelle , Rana Cheena 
Published: March 2020

e20012 Background: In PhIII randomized controlled trials (RCTs), Dab and Tram have shown significant improvement in the primary endpoint of progression-free survival (PFS) as monotherapies vs dacarbazine (DTIC) in 1L patients (pts) with BRAF V600E+ MM. Overall survival (OS) in these studies was confounded by crossover of DTIC pts to active treatment (trt) upon disease progression. This study compares PFS and OS for Dab and Tram with other 1L MM trts. Methods: Embase, MEDLINE, CCTR, and conferences were systematically searched through 10/2012 for relevant RCTs. Comparators were DTIC, vemurafenib (Vem), and ipilimumab (Ipi). Using random-effects network meta-analysis, Dab and Tram were compared directly (D) vs DTIC and indirectly (I) vs Vem and DTIC+Ipi. Results: 48 studies (147 publications) met inclusion criteria; 4studies (1,603 pts) contributed data to current network meta-analysis.Both Dab and Tram showed statistically significant reduction in the risk of progression directly vs DTIC and indirectly vs DTIC+Ipi and comparable PFS indirectly vs Vem (no statistically significant difference). Dab and Tram also demonstrated a statistically nonsignificant but numerically lower hazard of death directly vs DTIC and indirectly vs Vem and DTIC+Ipi. Conclusions: Using ITC, 1L trt of MM with Dab and Tram monotherapies was statistically significantly better than DTIC and DTIC+Ipi for PFS, with comparable efficacy to Vem for PFS and OS. Results must be interpreted cautiously given methodological assumptions and immature OS data for Dab and Tram. H2H studies remain gold standard for comparing trts. [Table: see text]
Patterns of pharmaceutical therapy in advanced melanoma.
Authors: Bilitou Aikaterini , Zhao Zhongyun , Barber Beth L. , Clapton Genevieve Sian , Saltman Deborah 
Published: March 2020

e20014 Background: Since 2011, two therapies that provide novel approaches to the treatment of advanced (unresectable or metastatic) melanoma have been introduced to the market: ipilimumab for second line and vemurafenib for BRAF mutation-positive melanoma. It is not known how the new drugs influence treatment; this study investigated current treatment patterns in advanced melanoma. Methods: A clinician-validated, web-based survey was administered between August and November 2012 to clinicians who treat advanced melanoma in France, Germany, Italy, Spain, and the UK. Respondents were asked about their treatment of patients in the previous 12 months, including treatment modalities and pharmaceutical therapies used, and factors that affect treatment choice. Results: 150 oncologists and dermatologists completed the survey, 30 in each country. Pharmaceutical therapy was more commonly used than other treatment modalities and varied by stage of disease. A high proportion of patients with late stage of disease were treated with pharmaceutical therapy in Germany (85% in M1B) and France (83% in M1C). Among the countries, 51% (Italy) to 87% (France) of respondents test BRAF mutation status. In patients with wild-type BRAF tumors, dacarbazine, which has not been shown to provide any overall survival benefit, was the most commonly used drug for first-line therapy in all countries. In mutated BRAF tumors, vemurafenib was the most commonly used drug in first line therapy in 3 of 5 countries. There was no standard of care in second line for either patients with wild-type or mutated-BRAFtumors; therapies used included fotemustine, temozolomide, interferon, paclitaxel, and ipilimumab. Conclusions: Treatment options for patients with advanced melanoma are limited, particularly for patients with wild-type BRAF disease. In second line, there does not appear to be an established standard of care: a range of treatments are used, including several not indicated for melanoma.
Bortezomib and interferon alpha-2b in metastatic melanoma.
Authors: Markowitz Joseph , Luedke Eric A , Grignol Valerie P , Hade Erinn , Paul Bonnie K. , Mundy-Bosse Bethany L. , Dao Thao-Vi , Kondalasula Sri Vidya , Lesinski Gregory B. , Olencki Thomas , Kendra Kari Lynn , Carson William Edgar 
Published: March 2020

e20018 Background: Preclinical studies revealed that bortezomib and interferon-α (IFN-α ) induce synergistic apoptosis in human melanoma cells. Combined treatment with bortezomib and IFN-α led to significant survival increases in a melanoma murine model. A phase I study is presented to determine the safety, tolerability and dose-limiting toxicity of bortezomib when administered in combination with interferon-alpha-2b (IFN-α) to patients with metastatic melanoma. Methods: Metastatic melanoma patients with ECOG status ≤ 2 were treated on a 5 week cycle. IFN-α (5 MU/m2) was administered subcutaneously (s.c.) on days 1, 3, and 5 of week one. During weeks 2-4 bortezomib was administered intravenously on day 1 along with IFNEα (5 MU/m2 s.c.) on days 1, 3, and 5. There was no treatment during week 5. After the first cycle, bortezomib was administered intravenously on day 1 of the weekly cycle along with IFNEα on days 1, 3, and 5. Bortezomib does levels were 1.0, 1.3, or 1.6 mg/m2 to cohorts of three patients. Results: 16 patients (8 men, 8 women, median age 58.5 (34-82) years) were treated. The most common metastatic disease sites included the lung, subcutaneous nodules, lymph nodes, and soft tissue. Other sites included: brain, skin, viscera, and bone. Grade 3 toxicities most frequently included fatigue, vomiting, and diarrhea. Syncope, depression, hypokalemia, motor neuropathy, and dyspnea were also observed. Grade 4 toxicities included fatigue and lymphopenia. There were 1 PR, 7 SD, and 8 PD. Median PFS and OS were 2.5 months (95% CI: 1.4-3.7) and 10.3 months (95% CI: 5.5-12.8), respectively. Bortezomib did not limit the ability of IFN-α to induce STAT1 phosphorylation in PBMCs. Levels of proEangiogenic cytokines (VEGF and IL-8) were higher in melanoma patients than in normal controls. Levels of VEGF, IL-8 and IL-6 all decreased during week 2 in the patient who experienced a PR. Bioplex cytokine analysis revealed decreases in IL-8 and VEGF in melanoma patients. Conclusions: Bortezomib and IFN-α represents a novel immune based treatment for melanoma. This combination reduces levels of pro-angiogenic factors in melanoma patients, is generally well tolerated, and can be safely administered to melanoma patients including those patients with treated CNS metastases. Clinical trial information: NCT01462773.
Efficacy and cost of nab-paclitaxel (nab-P) in metastatic melanoma (mM).
Authors: Agarwala Sanjiv S , Whiting Scott , Binder Gary , Hersh Evan 
Published: March 2020

e20033 Background: A recent phase III trial of nab-paclitaxel (nab-P, 130 nm albumin-bound paclitaxel) vs dacarbazine (DTIC) in mM demonstrated a significant improvement in progression-free survival (PFS). An economic analysis was applied to the results of this trial. Methods: Chemotherapy naive stage IV mM patients received nab-P 150 mg/m2 on days 1, 8, and 15 every 4 weeks or DTIC 1000 mg/m2 every 3 weeks. 529 patients were randomized to nab-P (n = 264) or DTIC (n = 265). The primary endpoint was independently assessed PFS, with overall survival (OS) as a secondary endpoint. Costs of nab-P and DTIC were taken from published 2013 Medicare reimbursement rates. A literature review identified costs for expected adverse events (AE), administration, and recently approved mM treatments. Results: In the intent-to-treat population, median PFS was 4.8 and 2.5 months in the nab-P and DTIC arms, respectively (HR: 0.792; P = 0.044). Median OS at the time of an interim analysis was 12.8 months with nab-P and 10.7 months with DTIC (HR: 0.831; P = 0.094; determination of ultimate statistical significance is pending full analysis at study conclusion). The most common grade ≥3 treatment-related AEs were neuropathy (nab-P: 25% vs DTIC: 0%) and neutropenia (nab-P: 20% vs DTIC: 10%). Grade 4 neutropenia rates were similar between arms (nab-P: 3% vs DTIC: 4%). Median time to neuropathy improvement by >1 grade was 28 days. Median treatment duration was 3 months with nab-P vs 2.1 months with DTIC. Incremental costs per patient were $23,359 ($24,663 for nab-P vs $1,304 for DTIC) including drug, infusion, and AE management costs. These costs compare favorably to incremental costs of over $50,000 for newly approved therapies with similar median OS gains vsDTIC. Conclusions: nab-P is the only chemotherapy in a phase III trial to demonstrate a significant and clinically meaningful delay in disease progression over dacarbazine. Total costs are attractive in the context of other agents recently approved for mM. Further analysis is merited when final OS is available. Clinical trial information: NCT00864253.
Differential clinical associations of BRAF and NRAS mutations among histologic types of cutaneous melanomas.
Authors: Stockman David , Tetzlaff Michael T. , Al-Zaid Tariq , Torres-Cabala Carlos A. , Bucheit Amanda Dawn , Lazar Alexander J. F. , Sui Dawen , Jakob John Andrew , Bassett Roland , Prieto Victor G. , Davies Michael A. , Curry Jonathan L. 
Published: March 2020

e20034 Background: Previous studies have investigated whether BRAF and NRAS mutation status in melanoma correlate with histologic parameters and overall survival (OS), but evaluation of mutation groups irrespective of specific mutation among histologic types of melanoma has led to variability in the reproducibility of results. We tested the hypothesis that different histologic types of melanoma (nodular [NM] and superficial spreading [SSM]) have distinct clinical associations with specific BRAF and NRAS mutations. Methods: Primary tumor histology, BRAF/NRAS mutation status, and clinical outcomes were collected for 195 patients (pts) with stage III or IV disease. Clinical associations with specific mutations were determined separately for patients with NM (n=105) and SSM (n=90) histologic types of primary cutaneous melanomas. Results: Mutational status in NM: 69 BRAF (66%), 19 NRAS (18%), & 17 wild-type (WT;16%). Specific BRAF mutations in NM: V600E 50 (75%), V600K 13 (19%), V600R 4 (6%). Specific NRAS mutations in NM: Q61K 6 (32%), Q61L 2 (11%), Q61R 8 (42%); other 3 (16%). Mutation status in SSM: 45 BRAF (50%), 24 NRAS (27%), 21 WT (23%). Specific BRAF mutations in SSM: V600E 32 (71%), V600K 12 (24%), V600R 0. Specific NRAS mutations in SSM: Q61K 2 (8%), Q61L 5 (21%), Q61R 12 (50%). The distribution of specific BRAF (p=0.21) and NRAS (p=0.29) mutations between NM and SSM was not significantly different. Among NM pts, pts with activating NRAS mutations had shorter OS from the diagnosis of Stage IV melanoma than WT (HR 3.42, p=0.02) and BRAF (HR 2.40, p=0.009). There was no significant difference for BRAF pts vs WT (HR 1.43, p=0.47). Among SSM patients, neither NRAS (HR 1.3, p=0.53) nor BRAF(HR 0.54, p=0.16) were significantly associated with OS compared to WT. Comparison of patients with BRAF V600E vs V600K showed significant association for OS from stage 4 in SSM pts (HR 0.24, p=0.01), but not in NM pts (HR 0.64, p=0.36). Conclusions: The prognostic significance of BRAF and NRAS mutations on OS from stage IV differed for pts with NM and SSM primaries. Further investigation of the histologic types of melanoma with specific BRAF and NRAS mutations in a larger series is necessary to validate these apparent impacts on patient outcomes.