Benefit from temozolomide (TMZ) chemotherapy in the treatment of isocitrate dehydrogenase (IDH)-wildtype glioblastoma is essentially limited to patients with O6-methylguanine DNA methyltransferase (MGMT) promoter-methylated tumors. Recent studies suggest that the impact of the MGMT status on chemosensitivity may be modulated by telomerase reverse transcriptase (TERT) promoter hotspot mutations.
MGMT promoter methylation and TERT promoter mutation status were assessed in an exploratory prospective cohort of IDH-wildtype glioblastoma patients of the German Glioma Network (GGN) (n=298) and validated in a retrospective cohort from Düsseldorf, Germany, and Zurich, Switzerland (n=302).
In the GGN discovery cohort of patients with MGMT promoter-unmethylated tumors, TERT promoter mutation showed a trend towards inferior outcome (p=0.085). TERT promoter mutations were not associated with improved outcome in patients with MGMT promoter-methylated tumors. The same patterns were seen when the analysis was restricted to patients intended to be treated with TMZ. Different TERT promoter hotspot mutations were not associated with distinct outcomes. These results were confirmed in the retrospective validation cohort.
Analysis of two independent cohorts of glioblastoma patients, including the prospective GGN cohort, did not confirm previous data suggesting that TERT promoter mutations confer an enhanced benefit from TMZ in patients with MGMT promoter-methylated glioblastoma. Thus, diagnostic testing for TERT promoter mutations may not be required for prediction of TMZ sensitivity in IDH-wildtype glioblastoma patients.
The authors.
German Cancer Aid.
M. Weller: Honoraria (self), Advisory/Consultancy, Research grant/Funding (self): AbbVie; Research grant/Funding (self): Adastra; Research grant/Funding (self): Dracen; Honoraria (self), Advisory/Consultancy, Research grant/Funding (self): Merck; Honoraria (self), Advisory/Consultancy, Research grant/Funding (self): Sharp & Dohme (MSD); Honoraria (self), Advisory/Consultancy, Research grant/Funding (self): Merck (EMD); Research grant/Funding (self): Novocure; Honoraria (self), Advisory/Consultancy: Medack; Honoraria (self), Advisory/Consultancy: Basilea; Honoraria (self), Advisory/Consultancy: Bristol-Myers Squibb (BMS); Honoraria (self), Advisory/Consultancy: Celgene; Honoraria (self), Advisory/Consultancy: Nerviano Medical Sciences; Honoraria (self), Advisory/Consultancy: Orbus; Honoraria (self), Advisory/Consultancy: Roche; Honoraria (self), Advisory/Consultancy: Tocagen. P. Roth: Honoraria (self), Advisory/Consultancy: Bristol-Myers Squibb; Honoraria (self), Advisory/Consultancy: Debiopharm; Honoraria (self), Advisory/Consultancy: Medac, Merck; Honoraria (self), Advisory/Consultancy: MSD; Honoraria (self), Advisory/Consultancy: Novocure; Honoraria (self), Advisory/Consultancy: QED; Honoraria (self), Advisory/Consultancy: Roche. T. Pietsch: Honoraria (self): Chugai; Honoraria (self): Mayo Clinic. M. Sabel: Honoraria (self): Novocure; Honoraria (self): Integra. G. Reifenberger: Honoraria (self), Advisory/Consultancy: AbbVie. All other authors have declared no conflicts of interest.
MGMT methylation (MGMTmet) status represents an important prognostic factor for glioblastoma (GBM) patients (PTS). Quantitative pyrosequencing approach has proven to be feasible for MGMTmet testing but its value is still unclear. We performed a large, multicentre, retrospective study to identify the association between MGMTmet values and clinical outcome.
From 9 Italian centres, we collected consecutive GBM PTS with assessment of MGMTmet by pyrosequencing approach evaluating CpGislands from 75 to 84. Other inclusion criteria were: histological diagnosis of GBM, ECOG PS≤2, therapy with RT+TMZ. Kaplan-Meier method was used to estimate the survival curves, time-dependent ROC curve for defining the optimal cut-off value of mean percentage of MGMTmet in terms of 2y-OS, Cox regression for multivariable analysis, and restricted cubic spline to investigate the non-linear association between methylation values and OS.
681 PTS were enrolled; median age was 60 ys; ECOG PS was 0 in 292, 1 in 306, 2 in 83; 391 (58%) had a complete resection. 8% received a second surgery. IDH was mutated in 6%. 2y-OS was 31.6%, median OS 17.4 ms. Median MGMTmet was 3.5% (IQR 0-22%). ROC curve identified a cutoff of 15% of MGMTmet in terms of 2y-OS (sens 78% spec 57% AUC=0.67). 2y-OS was 19.7% and 53.7% for MGMTmet< and ≥15%, respectively (p<0.0001). At multivariable analysis, MGMTmet<15% was associated with impaired survival (HR 2.7 95% CI 2.1-3.4 p<0.00001), adjusting for age, PS, type of surgery and second surgery. A non-linear association between MGMTmet and survival was identified (p<0.0001), with lower values of MGMTmet associated with lower survival; indeed, estimated median OS was lowest (14 ms 2ys-OS 17.4%) with MGMTmet of 4%, 21ms (2yr-OS 40.9%) with MGMTmet of 20%, 27ms (2yr-OS 40.9%) when MGMTmet was 40%, then leveled around 30ms (2yr-OS 54.5-59.8%) when MGMTmet was>40%.
This study represents one of the largest trials analyzing MGMTmet by pyrosequencing approach. Lower values of MGMTmet were associated with impaired survival and the relationship was non-linear. Noteworthy, we identified a strong prognostic value of MGMTmet which could be used as stratification factor in prospective clinical trials.
Giuseppe Lombardi.
Has not received any funding.
All authors have declared no conflicts of interest.
Edema is a hallmark of inflammation. Therefore, we explored the correlation of the peritumoral edema with tumor-infiltrating lymphocyte (TIL) density in newly diagnosed glioblastoma.
133 patients (60.9% male; 39.1% female) with histologically verified newly diagnosed glioblastoma were included in this study. The volume of peritumoral non-enhancing T2-hyperintense signal abnormalities was measured to quantify edema and non-enhancing tumor tissue. CD3+, CD8+ and PD-1+ TIL densities were analyzed using immunohistochemistry and tissue phenomics software.
Median perifocal edema volume was 84200 mm3 (range: 442.4 – 254700). Median TIL densities were 74.7 cells/mm2 for CD3+ (range: 3.1 – 1071.4), 29.6 cells/mm2 for CD8+ (range: 3.0 – 290.3) and 13.6 cells/mm2 for PD-1+ TILs (range: 1.6 – 141.5). Strong correlation between CD3+ and CD8+ TIL densities was observed (Spearman’s r = 0.784, p < 0.001), furthermore PD-1+ TIL density correlated with CD3+ (r = 0.591, p < 0.001) and CD8+ (r = 0.532, p < 0.001) TIL densities. Larger than median perifocal edema volume correlated with higher CD8+ (p = 0.036) and tendentially higher PD-1+ TIL densities (p = 0.199), but not with CD3+ TIL density (p = 0.883). Among 84 patients with known methylguanine methyltransferase (MGMT) promoter methylation status, 33 (39.3%) patients with MGMT promoter hypermethylation had less perifocal edema than their unmethylated counterparts (n = 51/84, 60.7%; median: 84200 mm3 vs. 122400 mm3; p = 0.047), while there was no significant difference in CD3+, CD8+ and PD-1+ TIL density according to MGMT promoter methylation status.
Peritumoral non-enhancing T2-hyperintense signal abnormality volumes correlate with the density of intra-tumoral cytotoxic T cells in newly diagnosed glioblastoma and may serve as “immuno-radiomic” surrogate parameter.
The authors.
Roche (unrestricted grant), Medical University of Vienna (research budget).
M. Preusser: Honoraria (self), Advisory/Consultancy: Bayer; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Bristol-Myers Squibb; Honoraria (self), Advisory/Consultancy: Novartis; Honoraria (self), Advisory/Consultancy: Gerson Lehrman Group (GLG); Honoraria (self), Advisory/Consultancy: CMC Contrast; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): GlaxoSmithKline; Honoraria (self), Advisory/Consultancy: Mundipharma; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Roche; Honoraria (self), Advisory/Consultancy: BMJ Journals; Honoraria (self), Advisory/Consultancy: MedMedia; Honoraria (self), Advisory/Consultancy: AstraZeneca; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): AbbVie; Honoraria (self), Advisory/Consultancy: Lilly; Honoraria (self), Advisory/Consultancy: Medahead; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Daiichi Sankyo; Honoraria (self), Advisory/Consultancy: Sanofi; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Merck Sharp & Dohme; Honoraria (self), Advisory/Consultancy: Tocagen; Research grant/Funding (institution): Boehringer Ingelheim; Research grant/Funding (institution): Novocure. A.S. Berghoff: Honoraria (self), Advisory/Consultancy, Research grant/Funding (self): Daiichi Sankyo; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Roche; Honoraria (self), Advisory/Consultancy: Bristol-Myers Squibb; Honoraria (self), Advisory/Consultancy: Merck; Travel/Accommodation/Expenses: Amgen; Travel/Accommodation/Expenses: AbbVie. All other authors have declared no conflicts of interest.
Precise clinical characterization and prognostic assessments in brain metastases (BM) patients are important to guide individualized treatment decisions and clinical trial development.
6001 patients with newly diagnosed BM treated between 1986-2020 were identified from the Vienna Brain Metastasis Registry.
Frequency of the primary tumor did not shift over the observation period with lung cancer being the most frequency source of BM (50.5%) followed by breast cancer (16.0%), melanoma (11.1%), colorectal cancer (5.8%), renal cell carcinoma (5.5%) and BM of unknown primary (2.5%). A rising incidence of BM diagnosed by screening in absence of neurological symptoms was found (p<0.001; 1986-1999:15.3%; 2000-2009:25.5%; 2010-2020:31.4%). A significant change in initial BM treatment approaches was observed during the decades (p<0.001): 36.8% of the patients received stereotactic radiosurgery (SRS) between 1986-1999, while 56.3% between 2000-2009. Furthermore, an increase in systemic treatment (1986-1999: 0.4%; 2010-2020: 2.4%) and a decrease in neurosurgical resection (1986-1999: 39.3%; 2010-2020: 20.4%) as initial BM treatment approaches were observed. Patients diagnosed with BM between 1986-1999 presented with an unfavorable median overall survival (5 months) compared to patients diagnosed between 2000-2009 and 2010-2020 (7 months, each; p<0.005). Furthermore, the diagnostic- specific graded prognostic assessment (DS-GPA) (Hazard ratio [HR] 1.42; p<0.001), and the GPA for lung cancer using molecular markers (Lung-molGPA) (HR 1.67; p<0.001) and for melanoma using molecular markers (Melanoma-molGPA (HR 1.46; p=0.011) showed statistically significant correlation with overall survival.
For BM patients, treatment patterns have changed towards increased use of SRS as well as systemic therapies, and survival times have improved over time. Furthermore, our data confirm refinement of BM-specific prognostic scores by incorporation of molecular data.
The authors.
Has not received any funding.
A. Starzer: Travel/Accommodation/Expenses: PharmaMar. M. Preusser: Honoraria (self): Bayer; Honoraria (self): Bristol-Myers Squibb; Honoraria (self): Novartis; Honoraria (self): Gerson Lehramt Group; Honoraria (self): CMC Contrast; Honoraria (self): GlaxoSmithKline; Honoraria (self): Munidpharma; Honoraria (self): Roche; Honoraria (self): AstraZeneca; Honoraria (self): AbbVie; Honoraria (self): Lilly; Honoraria (self): Medadhead; Honoraria (self): Daiichi Sankyo; Honoraria (self): Merck Sharp & Dome. A.S. Berghoff: Honoraria (self), Advisory/Consultancy, Research grant/Funding (self): Daiichi Sanyo; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Roche ; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Bristol-Myers Squibb; Honoraria (self), Advisory/Consultancy: Merck; Travel/Accommodation/Expenses: Amgen; Travel/Accommodation/Expenses: AbbVie. All other authors have declared no conflicts of interest.
Pts with
Full analysis set (FAS) comprised 16 pts with baseline CNS metastases per BICR (measurable or non-measurable), with 5 tumour types (8 NSCLC; 4 thyroid; 2 sarcoma; 1 salivary; 1 breast). Of these 16 pts, 8 had measurable CNS metastases (measurable set) and were evaluable for response. IC outcomes for FAS and measurable set are summarised (Table). IC ORRs were high in the FAS (50.0%) and measurable set (62.5%). IC efficacy was evident regardless of prior brain radiotherapy. In the safety population, neurotoxicity profile was similar in pts with (n=176) and without (n=328) baseline CNS metastases (per investigator), including cognitive disorders (6.3% and 6.4% respectively).
Entrectinib shows durable IC activity in pts with IC, intracranial; NE, not estimable.*As per RECIST v1.1 non-measurable CNS disease could only be categorised as CR, non-CR/non-PD, or PD.†IC PFS events occurred in 4 pts (2 PD, 2 deaths).‡IC PFS events occurred in 10 pts (3 PD, 7 deaths).
Intracranial outcomes Pts with Measurable set (n=8) Full analysis set* (n=16) IC ORR, n (%) 5 (62.5) 8 (50.0) CR 1 (12.5) 4 (25.0) PR 4 (50.0) 4 (25.0) SD, n (%) 1 (12.5) 1 (6.3) PD, n (%) 1 (12.5) 1 (6.3) Non-CR/non-PD, n (%) 0 5 (31.3) Missing/unevaluable, n (%) 1 (12.5) 1 (6.3) Median IC DoR in responders (95% CI) NE (5.0–NE) 8.0 (6.7–NE) Median IC PFS (95% CI) 10.1 (2.8–NE)† 8.9 (5.9–14.3)‡
ALKA-372-001 (EudraCT 2012-000148-88); STARTRK-1 (NCT02097810); STARTRK-2 (NCT02568267).
Third-party medical writing assistance, under the direction of the authors, was provided by Lewis Cawkwell, PhD, of Gardiner-Caldwell Communications, and was funded by F. Hoffmann-La Roche Ltd.
F. Hoffmann-La Roche Ltd.
F. Hoffmann-La Roche Ltd.
T. John: Honoraria (self): AZ, Roche, Merck, MSD; Advisory/Consultancy: BMS, AstraZeneca, Boehringer Ingelheim, Takeda, Pfizer, Novartis, Merck, Ignyta, and Roche. C-H. Chiu: Honoraria (self): Pfizer, AstraZeneca/MedImmune, Boehringer Ingelheim, Bristol-Myers Squibb, Chugai Pharmaceutical, Eli Lilly, MSD, Novartis, Ono Pharmaceutical, and Roche; Advisory/Consultancy: AstraZeneca/MedImmune, Boehringer Ingelheim, Bristol-Myers Squibb, Chugai Pharmaceutical, MSD, Novartis, Ono Pharmaceutical, and Roche. B.C. Cho: Advisory/Consultancy: Novartis, AstraZeneca, Boehringer Ingelheim, Roche, BMS, Ono, Yuhan, Pfizer, Eli Lilly, Janssen, Takeda, MSD, Janssen, Medpacto, Blueprint med-icines, Kanaph Therapeutic Inc; Research grant/Funding (institution): Novartis, Bayer, AstraZeneca, Mogam Institute, Dong-A ST, Champions Oncology, Janssen, Yuhan, Ono, Dizal Pharma, MSD, AbbVie, Medpacto, GI-Innovation, Eli Lilly, Blueprint medicines; Shareholder/Stockholder/Stock options: TheraCanVac Inc, Gencurix Inc, Bridgebio Therapeutics, Kanaph Therapeutic Inc; Licensing/Royalties: Champions Oncology; Officer/Board of Directors: Daan biotherapeutics. M. Fakih: Honoraria (self): Amgen; Advisory/Consultancy: Array, Amgen, Pfizer, and Bayer Pharmaceuticals; Speaker Bureau/Expert testimony: Amgen, Guardant360; Research grant/Funding (institution): Amgen, AstraZeneca, Novartis. A.F. Farago: Honoraria (self): Dava Oncology, Clinical Care Options, Medical Learning Institute, Medscape, PeerView, Research to Practice; Advisory/Consultancy: Bayer, Loxo Oncology, Inc., Genentech, Roche, Bristol-Myers Squibb, AstraZeneca, AbbVie, PharmaMar, Boehringer Ingelheim, Merck, H3 Biomedicine, Pfizer, Syros; Research grant/Funding (self): Bayer, Loxo Oncology, Inc., Genentech, Roche, Bristol-Myers Squibb, AstraZeneca, AbbVie, PharmaMar, Merck, Ignyta, Amgen, Novartis. G.D. Demetri: Honoraria (self): M.J. Hennessey/OncLive, Medscape, AACR/ASCO; Advisory/Consultancy: Roche, Ignyta, Genentech, Bayer, EMD-Serono, Loxo Oncology, Daiichi Sankyo, WCG/Arsenal Capital, Blueprint Medicines, Merrimack Pharmaceuticals, PharmaMar, Pfizer, Novartis, Epizyme, AbbVie, GlaxoSmithKline, Janssen, Mirati, Sanofi, ICON PLC, Ziopharm, Research grant/Funding (institution): Roche, Ignyta, Bayer, Loxo Oncology, Daiichi Sankyo, Janssen, Pfizer, Novartis, Epizyme, AbbVie; Travel/Accommodation/Expenses: Epizyme, Roche; Shareholder/Stockholder/Stock options: Blueprint Medicines, G1 Therapeutics, Caris Life Sciences, Bessor Pharmaceuticals, Erasca Pharmaceuticals, Champions Oncology, Translate BIO, Relay Therapeutics, Caprion HistoGeneX; Licensing/Royalties: Novartis to Dana-Farber Cancer Institute; Officer/Board of Directors, Board of Directors Member: Blueprint Medicines, Translate BIO; Non-remunerated activity/ies: Alexandria Real Estate Equities; Advisory/Consultancy: Polaris Pharmaceuticals, Medscape, Relay Therapeutics, Caprion/HistoGeneX, McCann Health. K. Goto: Honoraria (self): Astellas Pharma Inc.; AstraZeneca; Boehringer Ingelheim; Bristol-Myers Squibb; Chugai Pharma; Daiichi Sankyo Co., Ltd.; Guardant Health Inc.; IQVIA Services Japan K.K.;Janssen Pharmaceutical K.K.; Kyowa Hakko Kirin Co., Ltd; Life Technologies; Lilly; MSD; Advisory/Consultancy: Amgen Inc; Otsuka Pharma; Research grant/Funding (institution): Amgen Inc; Astellas Pharma; AstraZeneca; Boehringer Ingelheim; Bristol-Myers Squibb; Chugai Pharma; Daiichi Sankyo; Eisai; Ignyta; Janssen; Kyowa Hakko Kirin; Life Technologies; Lilly; Loxo; Medical & Biological Laboratories Co., Ltd; Merck Serono; MSD; Honoraria (self): Nippon Kayaku; Novartis; Ono Pharmaceutical; Otsuka Pharmaceutica; Pfizer; Taiho Pharmaceutical; Takeda; Research grant/Funding (institution): Novartis; Ono Pharmaceutical; Pfizer; Riken Genesis; Sumitomo Dainippon; Sysmex Corporation; Taiho Pharmaceutical; Takeda; Xcoo. R.C. Doebele: Advisory/Consultancy: Ignyta, Genentech/Roche, Loxo Oncology, Bayer, Eli Lilly, AstraZeneca, Pfizer, Blueprint Medicines, Anchiano, and Rain Therapeutics; Research grant/Funding (institution): Ignyta, Loxo, Mirati, Pfizer, Eli Lilly, and Strategia; Travel/Accommodation/Expenses: Ignyta, Genentech/Roche, Eli Lilly, Pfizer, Blueprint Medicines, and Rain Therapeutics; Shareholder/Stockholder/Stock options: Rain Therapeutics; Licensing/Royalties, Patent and biologic material licensing fees: Ignyta, Loxo, Abbott Molecular, Genentech/Roche, Chugai, Foundation Medicine, Black Diamond, and Rain Therapeutics, Voronoi, Pearl River, Ariad. S. Siena: Advisory/Consultancy: Amgen, Bayer, BMS, CheckMab, Celgene, Daiichi Sankyo, Incyte, Merck, Novartis, Roche, and Seattle Genetics. A. Drilon: Honoraria (institution): Ignyta/Roche/Genentech, Loxo, Bayer, lilly, TP Therapeutics, AstraZeneca, Pfizer, Blueprint, Takeda, Ariad, Millennium, Helsinn, BeiGene, BerGenBio, Hengrui, Exelixis, Tyra, Verastem, MORE Health, AbbVie, 14ner/Elevation Oncology, Axis, Peerview Institute,; Research grant/Funding (self): Foundation Medicine; Research grant/Funding (institution): Pfizer, Exelixis, Taiho, Teva, GlaxoSmithKline and PharmaMar; Licensing/Royalties: Wolters Kluwer; Honoraria (institution): OncLive, Paradigm Medical Communications, Remedica Ltd, ArcherDX, Foundation Medicine, PeerVoice, Research to Practice, Medscapem, WebMD. M.R. Patel: Advisory/Consultancy: Nektar Therapeutics; Research grant/Funding (self): Merck, Vyriad and Fate Therapeutics. S.V. Liu: Advisory/Consultancy: AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Catalyst, Celgene, G1 Therapeutics, Genentech/Roche, Guardant Health, Inivata, Janssen, Lilly, Loxo, MSD, Pfizer, PharmaMar, Regeneron, Takeda; Research grant/Funding (institution): Alkermes, AstraZeneca, Bayer, Blueprint, Bristol-Myers Squibb, Corvus, Genentech, Lilly, Lycera, Merck, Merus, Molecular Partners, Pfizer, Rain, RAPT, Spectrum, Turning Point Therapeutics; Travel/Accommodation/Expenses: AstraZeneca, Genentech/Roche, MSD. M-J. Ahn: Honoraria (self): AstraZeneca, Lilly, Takeda, Roche, MSD; Advisory/Consultancy: AstraZeneca, Lilly, Takeda, Roche, MSD, Merck, Boehringer Ingelheim, Ono Pharmaceutical, Bristol-Myers Squibb, Alpha Pharmaceutical, and Progeneer. L. Bazhenova: Advisory/Consultancy: Genentech, BeyondSpring Pharma, AstraZeneca, BI, Takeda, Blueprint, Novartis; Research grant/Funding (self): BeyondSpring Pharma; Shareholder/Stockholder/Stock options: Epic Sciences. T.R. Overbeck: Advisory/Consultancy: AstraZeneca, BMS, Boehringer Ingelheim, Eli Lilly, Medac, MSD, Novartis, Roche/Genentech, Sanofi-Aventis, Tesaro/GSK; Travel/Accommodation/Expenses: AstraZeneca, Roche/Genentech. J. Nieva: Honoraria (self): AstraZeneca, Fujirebio, Western Oncolytics; Research grant/Funding (institution): Merck; Shareholder/Stockholder/Stock options: Epic Sciences, Cansera, Quantgene; Licensing/Royalties: Cansera. S-W. Kim: Advisory/Consultancy: AstraZeneca, Boering-Ingelheim, Lilly, Novartis; Speaker Bureau/Expert testimony: Boehringer Ingelheim; Research grant/Funding (self): AstraZeneca. L. Veronese: Full/Part-time employment: F. Hoffmann-La Roche Ltd. B-M. Day: Full/Part-time employment: Genentech. F. De Braud: Advisory/Consultancy: Bristol-Myers Squibb, Eli Lilly, Roche, Amgen, AstraZeneca, Istituto Gentili, Fondazione Internazionale Menarini, Octomet Oncology, Novartis, Merck Sharp & Dohme, Ignyta, Bayer, Noema, ACCMED, Dephaforum, Nadirex, Biotechspert, Pfizer, Speaker Bureau/Expert testimony: Bristol-Myers Squibb, Roche, Merck Sharp & Dohme, Ignyta,Dephaforum, prIME Oncology, Pfizer, Biotechespert; Research grant/Funding (institution): Roche, Novartis, Merck Sharp & Dohme, Bristol-Myers Squibb, Pfizer, Kymab, Celgene, Tesaro; Travel/Accommodation/Expenses: Bristol-Myers Squibb, Roche, Celgene, Amgen; Advisory/Consultancy: Tiziana Life Sciences, Pierre Fabre.