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An adaptive, biomarker directed platform study in metastatic urothelial cancer (BISCAY) with durvalumab in combination with targeted therapies
Annals of Oncology 30 (Supplement 5): v356–v402, 2019 doi:10.1093/annonc/mdz249
GENITOURINARY TUMOURS, NON-PROSTATE 901O
EV-103: Initial results of enfortumab vedotin plus pembrolizumab for locally advanced or metastatic urothelial carcinoma
Background: Platinum-based chemotherapy remains the standard of care for patients (pts) with locally advanced or metastatic urothelial carcinoma (la/mUC). Despite the use of first-line (1L) PD-1/PD-1L inhibitors, 71–76% of pts who are cisplatin-ineligible do not respond. EV is an antibody-drug conjugate targeting Nectin-4, which is highly expressed in mUC. EV monotherapy data are encouraging; combination therapy may provide additional benefit. Here, we report initial data on a cohort of cis-ineligible pts receiving 1L EV þ pembrolizumab. Methods: This phase 1b study (NCT03288545) evaluated the safety/activity of EV þ pembrolizumab. In the dose-escalation cohort, 1L or 2L pts received 1.0 or 1.25 mg/kg EV þ 200 mg pembrolizumab. Cohort A pts received the recommended dose of 1.25 mg/kg EV þ pembrolizumab as 1L therapy. In each 21-day cycle, EV was administered on Days 1 and 8 and pembrolizumab on Day 1. The primary endpoint was safety/ tolerability; key secondary objectives: recommended EV dose, antitumor activity, DCR, DOR, PFS, and OS. Results: As of 20 Feb 2019, 29 la/mUC pts (median 68 [51–90] y; 31% liver metastasis, 17% ECOG 2) have been treated with EV (1.25 mg/kg) þ pembrolizumab in the 1L setting and completed at least 2 post-baseline scans or discontinued treatment. The most common treatment-emergent adverse events (AE) were fatigue (66%, 14% Grade 3), decreased appetite (52%, 0% Grade 3), alopecia (45%), and diarrhea (41%, 3% Grade 3). Among AE of clinical interest, rash of any type occurred in 45% of pts (14% Grade 3), peripheral neuropathy of any type in 52% (3% Grade 3), and 17% experienced immune-mediated events that required systemic steroid treatment (10% Grade 3). Overall, 2 pts (7%) discontinued treatment with EV þ pembrolizumab due to AE (lipase increase,multi-organ failure). Preliminary confirmed ORR per RECIST 1.1 was 62% by investigators, including a 14% CR rate. The DCR was 90%. Conclusions: In 1L cis-ineligible pts with la/mUC, EV þ pembrolizumab demonstrates encouraging efficacy with a tolerable and manageable safety profile. Further evaluation of this combination is warranted. Updated data, including responses pending confirmation, will be available at the meeting. Clinical trial identification: NCT03288545. Editorial acknowledgement: Heather Brignull, PhD of Seattle Genetics. Legal entity responsible for the study: Seattle Genetics, Inc. Funding: Seattle Genetics, Inc. Astellas Pharma, Inc, and Merck. Disclosure: C.J. Hoimes: Advisory / Consultancy, Speaker Bureau / Expert testimony: Bristol-Myers Squibb; Advisory / Consultancy: Eisai; Advisory / Consultancy: Foundation Medicine; Advisory / Consultancy, Speaker Bureau / Expert testimony: Genentech; Advisory / Consultancy, Research grant / Funding (institution): Merck; Advisory / Consultancy: Prometheus Labs; Honoraria (self), Advisory / Consultancy: Seattle Genetics. J.E. Rosenberg: Advisory / Consultancy: Adicet Bio; Advisory / Consultancy, Research grant / Funding (institution): Agensys; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution): Bayer; Advisory / Consultancy: BioClin Therapeutics; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Bristol-Myers Squibb; Advisory / Consultancy: EMD Serono; Advisory / Consultancy: Fortress Biotech; Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: Genentech; Advisory / Consultancy: Inovio Pharma; Honoraria (self): Eli Lilly; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Merck; Advisory / Consultancy: Pharmacyclics; Advisory / Consultancy: QED Therapeutics; Advisory / Consultancy: Sanofi; Advisory / Consultancy, Research grant / Funding (institution): Seattle Genetics; Advisory / Consultancy: Sensei Biotherapeutics; Advisory / Consultancy: Western Oncolytics; Shareholder / Stockholder / Stock options: Illumina; Honoraria (self): Chugai Pharma. S. Srinivas: Advisory / Consultancy: Roche; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Genentech; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Exelixis; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Seattle Genetics. D.P. Petrylak: Advisory / Consultancy, Research grant / Funding (institution): Astellas; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution): Bayer; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Bellicum Pharm; Advisory / Consultancy, Research grant / Funding (institution): Dendreon; Advisory / Consultancy: Exelixis; Advisory / Consultancy: Ferring; Advisory / Consultancy, Research grant / Funding (institution): Johnson & Johnson; Advisory / Consultancy, Research grant / Funding (self): Eli Lilly; Advisory / Consultancy, Research grant / Funding
902O
An adaptive, biomarker directed platform study in metastatic urothelial cancer (BISCAY) with durvalumab in combination with targeted therapies
T. Powles1, A. Balar2, G. Gravis3, R. Jones4, A. Ravaud5, J. Florence6, P. Grivas7, D.P. Petrylak8, M. Galsky9, J. Carles10, S. Sridhar11, H-T. Arkenau12, D. Carroll13, J. DeCesare14, F. Mercier14, D. Hodgson15, J. Stone13, J. Cosaert14, D. Landers16 1 Genitourinary Oncology, Barts Cancer Institute, London, UK, 2Oncology, NYU Langone, New York, NY, USA, 3Medical Oncology, Institute Paoli Calmettes, Marseille, France, 4 Beatson West of Scotland Cancer Centre, University of Glasgow, Glasgow, UK, 5Medical Oncology, CHU Bordeaux Hopital St. Andre´, Bordeaux, France, 6Oncologie Medicale, Centre Francois Balesse, Caen, France, 7Hematology Oncology, University of Washington Seattle Cancer Care Alliance, Seattle, WA, USA, 8Medical Oncology, Yale Cancer Center, New Haven, CT, USA, 9Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai Hospital, New York, NY, USA, 10Medical Oncology Department, Vall d’Hebron University Hospital, Barcelona, Spain, 11Medical Oncology, Princess Margaret Hospital, Toronto, ON, Canada, 12SCRI, Sarah Cannon Research Institute, London, UK, 13 IMED Biotech Unit, AstraZeneca, Cambridge, UK, 14IMED Biotech Unit, AstraZeneca, Melbourn, UK, 15IMED Biotech Unit, AstraZeneca, Boston, MA, USA, 16IMED Biotech Unit, AstraZeneca, Macclesfield, UK Background: Durvalumab (D), a PD-L1 inhibitor with efficacy in platinum refractory advanced urothelial cancer (UC), was investigated by combining with targeted therapy inhibitors (FGFR1,2,3, PARP, TORC 1 þ 2) with a PD-L1 monotherapy arm (D alone) as a non-randomized control. An FGFRi monotherapy arm was also included. Methods: Platinum refractory, immuno-therapy naı¨ve UC patients were allocated, depending on tumour DNA alterations determined by next generation sequencing (NGS), to: arm A (randomisation of D þ FGFRi AZD4547 vs AZD4547 monotherapy: for FGFR mutations/fusions), arm B (D þ PARPi olaparib: for BRCA1/2, ATM and HRR gene alterations (GA) and unselected patients), arm E (D þ mTORi vistusertib:
C European Society for Medical Oncology 2019. Published by Oxford University Press on behalf of the European Society for Medical Oncology. V
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C.J. Hoimes1, J.E. Rosenberg2, S. Srinivas3, D.P. Petrylak4, M. Milowsky5, J.R. Merchan6, M.A. Bilen7, S. Gupta8, A-S. Carret9, N. Yuan9, A. Melhem-Bertrandt10, T. Flaig11 1 Medical Oncology, Case Western Reserve University/University Hospitals, Cleveland, OH, USA, 2Medical Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA, 3Medical Center, Stanford University, Palo Alto, CA, USA, 4Medical Oncology, Yale Cancer Center, New Haven, CT, USA, 5Medical Oncology, University of North Carolina, Chapel Hill, NC, USA, 6Hematology and Oncology, University of Miami, Miami, FL, USA, 7 Oncology, Emory University Winship Cancer Institute, Atlanta, GA, USA, 8Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA, 9Clinical Development, Seattle Genetics, Bothell, WA, USA, 10Clinical Development, Astellas Pharma USA, Northbrook, IL, USA, 11School of Medicine, University of Colorado Cancer Center Anschutz Cancer Pavilion, Aurora, CO, USA
(institution): Millennium; Advisory / Consultancy: Medivation; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Advisory / Consultancy, Research grant / Funding (institution): Roche; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Sanofi; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Tyme; Advisory / Consultancy, Research grant / Funding (institution): Seattle Genetics; Research grant / Funding (institution): Agensys; Speaker Bureau / Expert testimony: Celgene; Research grant / Funding (institution): Clovis Oncology; Research grant / Funding (institution): Genentech. M. Milowsky: Research grant / Funding (institution): Mirati Therapeutics; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Cerulean Pharm; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Seattle Genetics; Research grant / Funding (institution): Acerta Pharma; Research grant / Funding (institution): BioClin Therapeutics; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): X4 Pharma; Research grant / Funding (institution): MedImmune; Research grant / Funding (institution): Incyte; Research grant / Funding (institution): Innocrin Pharma; Research grant / Funding (institution): Inovio Pharmaceuticals. J.R. Merchan: Research grant / Funding (institution): Seattle Genetics; Advisory / Consultancy: Exelixis; Research grant / Funding (institution): Rexahn; Research grant / Funding (institution): Eli Lilly; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Tocagen; Research grant / Funding (institution): Agensys; Research grant / Funding (institution): Tracon. M.A. Bilen: Advisory / Consultancy: Exelixis; Advisory / Consultancy, Research grant / Funding (institution): Nektar; Advisory / Consultancy: Genomic Health; Advisory / Consultancy, Research grant / Funding (institution): Seattle Genetics; Advisory / Consultancy: Sanofi; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Genentech/Roche; Research grant / Funding (institution): Incyte; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Tricon Pharmaceuticals; Research grant / Funding (institution): Peleton; Research grant / Funding (institution): Pfizer. S. Gupta: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Genentech; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Seattle Genetics; Research grant / Funding (institution): Astellas; Research grant / Funding (institution): Medivation; Research grant / Funding (institution): Innocrin Pharma; Research grant / Funding (institution): MedImmune; Research grant / Funding (institution): Merck. A. Carret: Honoraria (self), Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Full / Part-time employment: Seattle Genetics. N. Yuan: Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Full / Part-time employment: Seattle Genetics. A. Melhem-Bertrandt: Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Full / Part-time employment: Astellas. T. Flaig: Advisory / Consultancy: GTX; Leadership role, Shareholder / Stockholder / Stock options, Officer / Board of Directors: Aurora Oncology; Honoraria (self): BN ImmunoTherapeutics; Research grant / Funding (institution): Agensys; Research grant / Funding (institution): Aragon Pharma; Research grant / Funding (institution): Astellas; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Bavarian Nordic; Research grant / Funding (institution): Dendreon; Research grant / Funding (institution): Exelisix; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): GTx; Research grant / Funding (institution): Janssen; Research grant / Funding (institution): La RochePosay; Research grant / Funding (institution): Eli Lilly; Research grant / Funding (institution): Medivation; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Seattle Genetics; Research grant / Funding (institution): Pfizer.
abstracts
Annals of Oncology
Table: 902O
N PD-L1þve TMB high > 10M/MB ORR (RECIST1.1) 80% CI Discontinued due to AE
AZD4547 (A)
AZD4547 þ Vistusertib þ durvalumab durvalumab durvalumab (D) (A) (E)
15 27% 20% 20% 7.6%; 39% 20%
21 33% 5% 29% 16%; 45% 33%
29 38% 38% 21% 11%; 34% 38%
29 41% 17% 28% 17%; 41% 10%
Conclusions: Combination treatments with durvalumab are tolerated. Clinical activity was seen in all arms of the study including both biomarker-selected and unselected individuals. Clinical trial identification: NCT02546661; 11-Sep-2015. Legal entity responsible for the study: AstraZeneca AB, 151 85 So¨dert€alje, Sweden. Funding: AstraZeneca. Disclosure: T. Powles: Honoraria (self): AstraZeneca, Roche, MSD, Pfizer, Novartis, Seattle Genetics, Ipsen; Research grant / Funding (institution): AstraZeneca, Roche, MSD. A. Balar: Honoraria (self): AstraZeneca; Roche-Genentech; Merck; Advisory / Consultancy: AstraZeneca, Genentech/Roche, Merck, Incyte, Seattle Genetics, DragonFly, Nektar; Research grant / Funding (institution): Merck, Genentech/Roche, Seattle Genetics, Bristol-Myers Squibb, AstraZeneca, Nektar; Shareholder / Stockholder / Stock options: EpiVax Oncology. G. Gravis: Travel / Accommodation / Expenses: BMS; Pfizer; Janssen; Ipsen. R. Jones: Honoraria (self): AstraZeneca; MSD; Merck Serono; Roche; BMS; Janssen; Astellas; Honoraria (institution): AstraZeneca, Janssen, Astellas; Advisory / Consultancy: AstraZeneca; MSD; Roche; BMS; Pfizer; Janssen; Astellas; Research grant / Funding (institution): Roche; Pfizer; AstraZeneca; Travel / Accommodation / Expenses: BMS; MSD; Astellas. A. Ravaud: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Pfizer; BMS; AstraZeneca; Roche; MSD; Ipsen; Research grant / Funding (institution): Pfizer. J. Florence: Advisory / Consultancy: Roche; Ipsen; AstraZeneca; Janssen; Tesaro; BMS; Pfizer; Novartis; Sanofi; Astellas; Research grant / Funding (institution): Astellas; Travel / Accommodation / Expenses: Roche; Ipsen; AstraZeneca; Janssen; Tesaro; BMS. P. Grivas: Advisory / Consultancy: Merck & Co; Genentech; Dendreon; Bayer; Pfizer; Bristol-Myers Squibb; Exelixis; AstraZeneca; Biocept; Clovis Oncology; EMD Serono; Seattle Genetics; Foundation Medicine; Driver Inc.; QED Therapeutics; Heron Therapeutics; Janssen; Speaker Bureau / Expert testimony: Genentech; Bristol-Myers Squibb;; Travel / Accommodation / Expenses: AstraZeneca; Clovis Oncology; Research grant / Funding (institution): Merck & Co.; Genentech; Bayer; Mirati; Oncogenex; AstraZeneca; Pfizer; Clovis Oncology; Bavarian Nordic; Immunomedics. D.P. Petrylak: Advisory / Consultancy: Ada Cap (Advanced Accelerator Applications), Amgen, Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myer Squibb, Clovis, Eli Lilly, Exelixis, Incyte, Janssen, Pfizer, Pharmacyclics, Roche Laboratories, Seattle Genetics, Urogen; Research grant / Funding (institution): Ada Cap (Advanced Accelerator Applications), Astellas, AstraZeneca, Bayer, Bristol-Myers Squibb, Clovis, Eli Lilly, Endocyte, Genentech, Innocrin, MedImmune, Merck, Novartis, Pfizer, Progenics, Roche Laboratories, Sanofi Aventis, Seattle Genetics; Shareholder / Stockholder / Stock options: Bellicum, Tyme. M. Galsky: Advisory / Consultancy: AstraZeneca, BMS, Genentech, Merck, Pfizer, Dracen, Dragonfly Therapeutics, Astellas, Seattle Genetics, Janssen; Research grant / Funding (institution): AstraZeneca, BMS, Merck, Dendreon, Roche-Genentech. J. Carles: Advisory / Consultancy: Bayer; Johnson & Johnson; Bristol-Myers Squibb; Astellas Pharma; Pfizer; Sanofi; MSD Oncology; Roche; AstraZeneca; Speaker Bureau / Expert testimony: Bayer; Johnson & Johnson; Asofarma; Astellas Pharma; Research grant / Funding (institution): AB Science, Aragon Pharmaceuticals, Arog Pharmaceuticals, INC, Astellas Pharma, AstraZeneca AB, Aveo Pharmaceuticals INC, Bayer AG, Blueprint Medicines Corporation, BN Immunotherapeutics INC, Boehringer Ingelheim Espa~ na, S.A., Bristol-Myers Squibb Intern. S. Sridhar: Advisory / Consultancy: AstraZeneca, Roche, Merck, BMS, Bayer, Janssen, Astellas. H. Arkenau: Leadership role: Sarah Cannon Research Institute; Research grant / Funding (self): AstraZeneca; Roche; BMS; Novartis; GSK; Servier; Astellas; Array; Iovance; Cytomx; Research grant / Funding (institution): Sarah Cannon Research Institute; Travel / Accommodation / Expenses: Iovance. D. Carroll: Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca; Spouse / Financial dependant: Azeria Therapeutics. J. DeCesare: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. F. Mercier: Full / Part-time employment: AstraZeneca; Shareholder / Stockholder / Stock options: Stat Process sarl (Paris, France) - CRO; Health Data Process (Alicante, Spain) - CRO. D. Hodgson: Shareholder / Stockholder / Stock options, Non-remunerated activity/ies: AstraZeneca. J. Stone: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca; Shareholder / Stockholder / Stock options: GSK. J. Cosaert: Full / Part-time employment: AstraZeneca. D. Landers:
Volume 30 | Supplement 5 | October 2019
Research grant / Funding (institution): Clinical Experimental Pharmacology Group, CRUK Manchester Institute, Manchester, UK; AstraZeneca; Full / Part-time employment: AstraZeneca.
903O
Redefining the IGCCCG classification in advanced non-seminoma
S. Gillessen1, L. Collette2, G. Daugaard3, R. de Wit4, A. Tryakin5, C. Albany6, O. Stahl7, K. Fizazi8, J.A. Gietema9, U.F.F. De Giorgi10, A.R. Hansen11, D. Feldman12, F. Cafferty13, T. Tandstad14, X. Garcia del Muro15, R.A. Huddart16, C.J. Sweeney17, D.Y.C. Heng18, N. Sauve2, J. Beyer19 1 Department of Oncology/Hematology, The Christie NHS Foundation Trust, Manchester, UK, 2Statistics, EORTC - European Organisation for Research and Treatment of Cancer, Brussels, Belgium, 3Oncology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark, 4Oncology, Erasmus MC Daniel den Hoed Cancer Center, Rotterdam, Netherlands, 5Oncology, N. N. Blokhin Russian Cancer Research Center, Moscow, Russian Federation, 6Oncology, Indiana University, Indianapolis, IN, USA, 7Oncology, Skane University Hospital, Lund, Sweden, 8Cancer Medicine, Gustave Roussy, Villejuif, France, 9Medical Oncology, University Hospital Groningen (UMCG), Groningen, Netherlands, 10Medical Oncology Department, Istituto Tumori della Romagna I.R.S.T., Meldola, Italy, 11Medical Oncology, Princess Margaret Cancer Centre, Toronto, ON, Canada, 12Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA, 13Institute of Clinical Trials & Methodology, Medical Research Council, London, UK, 14Oncology, St Olav’s University Hospital, Trondheim, Norway, 15Medical Oncology, ICO - Institut Catala d’Oncologia Hospital Duran i Reynals, Hospitalet de Llobregat, Spain, 16Radiotherapy and Imaging, Royal Marsden Hospital Institute of Cancer Research, Sutton, UK, 17Medical Oncology, Dana Farber Cancer Institute, Boston, MA, USA, 18Oncology, University of Calgary, Calgary, AB, Canada, 19Medical Oncology, University Hospital Zu¨rich, Zurich, Switzerland Background: The International Germ Cell Cancer Collaborative Group (IGCCCG) has been the reference classification for assessing prognosis in men with advanced nonseminomatous germ-cell tumors (NSGCT) for more than 20 years and it relied on 5202 cases treated between 1975 and 1990. Methods: An international consortium (30 centers/groups) contributed data on 9530 advanced NSGCT patients treated with cisplatin/etoposide based first line chemotherapy between 1990 and 2013 in prospective cohorts or clinical trials. Updated 5-year progression-free (PFS) and overall survival (OS) rates were calculated. A subset of 4874 patients with complete information on components of IGCCCG, age and lung metastases were split into training (3536) and validation sets (1338). Prognostic factors for PFS were identified in the training set (alpha¼0.05) by Cox model, including (transformed) continuous factors and interactions. Results: Compared to the 1997 IGCCCG figures, the contemporary 5-year PFS was unchanged for good and intermediate, but significantly improved for poor risk patients; whereas 5-year OS was substantially better for all risk groups (Table). The subgroup with complete data was unbiased. Besides traditional IGCCCG components, we identified older age and lung metastases as negative determinants of PFS. A nomogram including AFP, HCG (both continuous), LDH>2.5xnormal, mediastinal primary, non-pulmonary visceral metastases, age (linear) and lung metastases, with several interactions was built. Its c-index was 0.745 in the training set compared to 0.701 for the 1997 IGCCCG.
Table: 903O 5-year PFS 5-year PFS 5-year OS 5-year OS IGCCCG 1997 contemporary IGCCCG 1997 contemporary Good 89 (87 – 91%) 90 (89 - 91%) Intermediate 75 (71 – 79%) 78 (76 - 80%) Poor 41 (35 – 47%) 54 (52 - 56%)
91 (89 - 93%) 96 (95 - 97%) 79 (75 - 83%) 89 (88 - 91%) 48 (42 - 54%) 67 (65 - 69%)
Conclusions: In this modern series, PFS improved for poor risk patients, while OS improved in all IGCCCG risk groups. A new prognostic model including older age and presence of lung metastases as additional negative factors is proposed. Independent validation and comparison to the IGCCCG 1997 are being conducted and will tell if the model can identify patient subgroups who may require intensified treatment. Legal entity responsible for the study: The International Germ Cell Cancer Collaborative Group (IGCCCG). Funding: Swiss Cancer Foundation. Disclosure: S. Gillessen: Advisory / Consultancy: AAA International, Active Biotech, Amgen, Astellas Pharma, Bayer, Bristol-Myers Squibb, CellSearch, Clovis, CureVac, Dendreon, ESSA Pharmaceuticals, Ferring, Innocrin Pharmaceuticals, Janssen Cilag, MaxiVAX SA, Millennium, Nectar, Novartis, Orion, Pfizer,; Licensing / Royalties: Co-inventor on patent application (WO 2009138392 A1) for a method for biomarker discover (granted in China, Europe, Japan and the US). R. de Wit: Honoraria (self): Merck, Sanofi, Bayer, Janssen, Roche and Clovis. R.A. Huddart: Honoraria (self): Janssen; Advisory / Consultancy, Research grant / Funding (self), Travel / Accommodation / Expenses: MSD; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Roche; Advisory / Consultancy: Bristol-Myers Squibb; Research
doi:10.1093/annonc/mdz249 | v357
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enriched for TSC1/2 and RICTOR GA). Arm D (D only) followed by Arm F (D þ STAT3 mRNA ASO danvatirsen) for patients without “actionable” GA. Primary objectives included safety and tolerability. Key secondary objectives included assessment of ORR and OS rate. Efficacy analysis was explored based on PD-L1 expression and tumour mutational burden (TMB). Results: As of March 2019, of 393 patients’ whose tumours were screened with NGS, 154 started study drug and had a baseline tumor assessment. Confirmed responses were assessed according to RECIST 1.1 and ranged from 20% to 29% (Table). TMB and PDL1 were inconsistent across arms (e.g. 38% TMB high for Arm E vs 5% in Arm A combination and 17% in Arm D). D monotherapy (n ¼ 29) had an ORR of 28% [80% CI 17% - 41%] with 12% [80% CI 3.2% - 28%] and 45% [80% CI 24% - 63%] of patients alive and progression free and alive at 12 months, respectively. Complete responses were not prominent in any study arm. Arms A, D and E completed earlier than arms B and F. Data will be updated based on additional follow-up.
GENITOURINARY TUMOURS, NON-PROSTATE 901O
EV-103: Initial results of enfortumab vedotin plus pembrolizumab for locally advanced or metastatic urothelial carcinoma
Background: Platinum-based chemotherapy remains the standard of care for patients (pts) with locally advanced or metastatic urothelial carcinoma (la/mUC). Despite the use of first-line (1L) PD-1/PD-1L inhibitors, 71–76% of pts who are cisplatin-ineligible do not respond. EV is an antibody-drug conjugate targeting Nectin-4, which is highly expressed in mUC. EV monotherapy data are encouraging; combination therapy may provide additional benefit. Here, we report initial data on a cohort of cis-ineligible pts receiving 1L EV þ pembrolizumab. Methods: This phase 1b study (NCT03288545) evaluated the safety/activity of EV þ pembrolizumab. In the dose-escalation cohort, 1L or 2L pts received 1.0 or 1.25 mg/kg EV þ 200 mg pembrolizumab. Cohort A pts received the recommended dose of 1.25 mg/kg EV þ pembrolizumab as 1L therapy. In each 21-day cycle, EV was administered on Days 1 and 8 and pembrolizumab on Day 1. The primary endpoint was safety/ tolerability; key secondary objectives: recommended EV dose, antitumor activity, DCR, DOR, PFS, and OS. Results: As of 20 Feb 2019, 29 la/mUC pts (median 68 [51–90] y; 31% liver metastasis, 17% ECOG 2) have been treated with EV (1.25 mg/kg) þ pembrolizumab in the 1L setting and completed at least 2 post-baseline scans or discontinued treatment. The most common treatment-emergent adverse events (AE) were fatigue (66%, 14% Grade 3), decreased appetite (52%, 0% Grade 3), alopecia (45%), and diarrhea (41%, 3% Grade 3). Among AE of clinical interest, rash of any type occurred in 45% of pts (14% Grade 3), peripheral neuropathy of any type in 52% (3% Grade 3), and 17% experienced immune-mediated events that required systemic steroid treatment (10% Grade 3). Overall, 2 pts (7%) discontinued treatment with EV þ pembrolizumab due to AE (lipase increase,multi-organ failure). Preliminary confirmed ORR per RECIST 1.1 was 62% by investigators, including a 14% CR rate. The DCR was 90%. Conclusions: In 1L cis-ineligible pts with la/mUC, EV þ pembrolizumab demonstrates encouraging efficacy with a tolerable and manageable safety profile. Further evaluation of this combination is warranted. Updated data, including responses pending confirmation, will be available at the meeting. Clinical trial identification: NCT03288545. Editorial acknowledgement: Heather Brignull, PhD of Seattle Genetics. Legal entity responsible for the study: Seattle Genetics, Inc. Funding: Seattle Genetics, Inc. Astellas Pharma, Inc, and Merck. Disclosure: C.J. Hoimes: Advisory / Consultancy, Speaker Bureau / Expert testimony: Bristol-Myers Squibb; Advisory / Consultancy: Eisai; Advisory / Consultancy: Foundation Medicine; Advisory / Consultancy, Speaker Bureau / Expert testimony: Genentech; Advisory / Consultancy, Research grant / Funding (institution): Merck; Advisory / Consultancy: Prometheus Labs; Honoraria (self), Advisory / Consultancy: Seattle Genetics. J.E. Rosenberg: Advisory / Consultancy: Adicet Bio; Advisory / Consultancy, Research grant / Funding (institution): Agensys; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution): Bayer; Advisory / Consultancy: BioClin Therapeutics; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Bristol-Myers Squibb; Advisory / Consultancy: EMD Serono; Advisory / Consultancy: Fortress Biotech; Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: Genentech; Advisory / Consultancy: Inovio Pharma; Honoraria (self): Eli Lilly; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Merck; Advisory / Consultancy: Pharmacyclics; Advisory / Consultancy: QED Therapeutics; Advisory / Consultancy: Sanofi; Advisory / Consultancy, Research grant / Funding (institution): Seattle Genetics; Advisory / Consultancy: Sensei Biotherapeutics; Advisory / Consultancy: Western Oncolytics; Shareholder / Stockholder / Stock options: Illumina; Honoraria (self): Chugai Pharma. S. Srinivas: Advisory / Consultancy: Roche; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Genentech; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Exelixis; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Seattle Genetics. D.P. Petrylak: Advisory / Consultancy, Research grant / Funding (institution): Astellas; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution): Bayer; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Bellicum Pharm; Advisory / Consultancy, Research grant / Funding (institution): Dendreon; Advisory / Consultancy: Exelixis; Advisory / Consultancy: Ferring; Advisory / Consultancy, Research grant / Funding (institution): Johnson & Johnson; Advisory / Consultancy, Research grant / Funding (self): Eli Lilly; Advisory / Consultancy, Research grant / Funding
902O
An adaptive, biomarker directed platform study in metastatic urothelial cancer (BISCAY) with durvalumab in combination with targeted therapies
T. Powles1, A. Balar2, G. Gravis3, R. Jones4, A. Ravaud5, J. Florence6, P. Grivas7, D.P. Petrylak8, M. Galsky9, J. Carles10, S. Sridhar11, H-T. Arkenau12, D. Carroll13, J. DeCesare14, F. Mercier14, D. Hodgson15, J. Stone13, J. Cosaert14, D. Landers16 1 Genitourinary Oncology, Barts Cancer Institute, London, UK, 2Oncology, NYU Langone, New York, NY, USA, 3Medical Oncology, Institute Paoli Calmettes, Marseille, France, 4 Beatson West of Scotland Cancer Centre, University of Glasgow, Glasgow, UK, 5Medical Oncology, CHU Bordeaux Hopital St. Andre´, Bordeaux, France, 6Oncologie Medicale, Centre Francois Balesse, Caen, France, 7Hematology Oncology, University of Washington Seattle Cancer Care Alliance, Seattle, WA, USA, 8Medical Oncology, Yale Cancer Center, New Haven, CT, USA, 9Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai Hospital, New York, NY, USA, 10Medical Oncology Department, Vall d’Hebron University Hospital, Barcelona, Spain, 11Medical Oncology, Princess Margaret Hospital, Toronto, ON, Canada, 12SCRI, Sarah Cannon Research Institute, London, UK, 13 IMED Biotech Unit, AstraZeneca, Cambridge, UK, 14IMED Biotech Unit, AstraZeneca, Melbourn, UK, 15IMED Biotech Unit, AstraZeneca, Boston, MA, USA, 16IMED Biotech Unit, AstraZeneca, Macclesfield, UK Background: Durvalumab (D), a PD-L1 inhibitor with efficacy in platinum refractory advanced urothelial cancer (UC), was investigated by combining with targeted therapy inhibitors (FGFR1,2,3, PARP, TORC 1 þ 2) with a PD-L1 monotherapy arm (D alone) as a non-randomized control. An FGFRi monotherapy arm was also included. Methods: Platinum refractory, immuno-therapy naı¨ve UC patients were allocated, depending on tumour DNA alterations determined by next generation sequencing (NGS), to: arm A (randomisation of D þ FGFRi AZD4547 vs AZD4547 monotherapy: for FGFR mutations/fusions), arm B (D þ PARPi olaparib: for BRCA1/2, ATM and HRR gene alterations (GA) and unselected patients), arm E (D þ mTORi vistusertib:
C European Society for Medical Oncology 2019. Published by Oxford University Press on behalf of the European Society for Medical Oncology. V
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C.J. Hoimes1, J.E. Rosenberg2, S. Srinivas3, D.P. Petrylak4, M. Milowsky5, J.R. Merchan6, M.A. Bilen7, S. Gupta8, A-S. Carret9, N. Yuan9, A. Melhem-Bertrandt10, T. Flaig11 1 Medical Oncology, Case Western Reserve University/University Hospitals, Cleveland, OH, USA, 2Medical Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA, 3Medical Center, Stanford University, Palo Alto, CA, USA, 4Medical Oncology, Yale Cancer Center, New Haven, CT, USA, 5Medical Oncology, University of North Carolina, Chapel Hill, NC, USA, 6Hematology and Oncology, University of Miami, Miami, FL, USA, 7 Oncology, Emory University Winship Cancer Institute, Atlanta, GA, USA, 8Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA, 9Clinical Development, Seattle Genetics, Bothell, WA, USA, 10Clinical Development, Astellas Pharma USA, Northbrook, IL, USA, 11School of Medicine, University of Colorado Cancer Center Anschutz Cancer Pavilion, Aurora, CO, USA
(institution): Millennium; Advisory / Consultancy: Medivation; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Advisory / Consultancy, Research grant / Funding (institution): Roche; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Sanofi; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Tyme; Advisory / Consultancy, Research grant / Funding (institution): Seattle Genetics; Research grant / Funding (institution): Agensys; Speaker Bureau / Expert testimony: Celgene; Research grant / Funding (institution): Clovis Oncology; Research grant / Funding (institution): Genentech. M. Milowsky: Research grant / Funding (institution): Mirati Therapeutics; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Cerulean Pharm; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Seattle Genetics; Research grant / Funding (institution): Acerta Pharma; Research grant / Funding (institution): BioClin Therapeutics; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): X4 Pharma; Research grant / Funding (institution): MedImmune; Research grant / Funding (institution): Incyte; Research grant / Funding (institution): Innocrin Pharma; Research grant / Funding (institution): Inovio Pharmaceuticals. J.R. Merchan: Research grant / Funding (institution): Seattle Genetics; Advisory / Consultancy: Exelixis; Research grant / Funding (institution): Rexahn; Research grant / Funding (institution): Eli Lilly; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Tocagen; Research grant / Funding (institution): Agensys; Research grant / Funding (institution): Tracon. M.A. Bilen: Advisory / Consultancy: Exelixis; Advisory / Consultancy, Research grant / Funding (institution): Nektar; Advisory / Consultancy: Genomic Health; Advisory / Consultancy, Research grant / Funding (institution): Seattle Genetics; Advisory / Consultancy: Sanofi; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Genentech/Roche; Research grant / Funding (institution): Incyte; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Tricon Pharmaceuticals; Research grant / Funding (institution): Peleton; Research grant / Funding (institution): Pfizer. S. Gupta: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Genentech; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Seattle Genetics; Research grant / Funding (institution): Astellas; Research grant / Funding (institution): Medivation; Research grant / Funding (institution): Innocrin Pharma; Research grant / Funding (institution): MedImmune; Research grant / Funding (institution): Merck. A. Carret: Honoraria (self), Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Full / Part-time employment: Seattle Genetics. N. Yuan: Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Full / Part-time employment: Seattle Genetics. A. Melhem-Bertrandt: Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Full / Part-time employment: Astellas. T. Flaig: Advisory / Consultancy: GTX; Leadership role, Shareholder / Stockholder / Stock options, Officer / Board of Directors: Aurora Oncology; Honoraria (self): BN ImmunoTherapeutics; Research grant / Funding (institution): Agensys; Research grant / Funding (institution): Aragon Pharma; Research grant / Funding (institution): Astellas; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Bavarian Nordic; Research grant / Funding (institution): Dendreon; Research grant / Funding (institution): Exelisix; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): GTx; Research grant / Funding (institution): Janssen; Research grant / Funding (institution): La RochePosay; Research grant / Funding (institution): Eli Lilly; Research grant / Funding (institution): Medivation; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Seattle Genetics; Research grant / Funding (institution): Pfizer.
abstracts
Annals of Oncology
Table: 902O
N PD-L1þve TMB high > 10M/MB ORR (RECIST1.1) 80% CI Discontinued due to AE
AZD4547 (A)
AZD4547 þ Vistusertib þ durvalumab durvalumab durvalumab (D) (A) (E)
15 27% 20% 20% 7.6%; 39% 20%
21 33% 5% 29% 16%; 45% 33%
29 38% 38% 21% 11%; 34% 38%
29 41% 17% 28% 17%; 41% 10%
Conclusions: Combination treatments with durvalumab are tolerated. Clinical activity was seen in all arms of the study including both biomarker-selected and unselected individuals. Clinical trial identification: NCT02546661; 11-Sep-2015. Legal entity responsible for the study: AstraZeneca AB, 151 85 So¨dert€alje, Sweden. Funding: AstraZeneca. Disclosure: T. Powles: Honoraria (self): AstraZeneca, Roche, MSD, Pfizer, Novartis, Seattle Genetics, Ipsen; Research grant / Funding (institution): AstraZeneca, Roche, MSD. A. Balar: Honoraria (self): AstraZeneca; Roche-Genentech; Merck; Advisory / Consultancy: AstraZeneca, Genentech/Roche, Merck, Incyte, Seattle Genetics, DragonFly, Nektar; Research grant / Funding (institution): Merck, Genentech/Roche, Seattle Genetics, Bristol-Myers Squibb, AstraZeneca, Nektar; Shareholder / Stockholder / Stock options: EpiVax Oncology. G. Gravis: Travel / Accommodation / Expenses: BMS; Pfizer; Janssen; Ipsen. R. Jones: Honoraria (self): AstraZeneca; MSD; Merck Serono; Roche; BMS; Janssen; Astellas; Honoraria (institution): AstraZeneca, Janssen, Astellas; Advisory / Consultancy: AstraZeneca; MSD; Roche; BMS; Pfizer; Janssen; Astellas; Research grant / Funding (institution): Roche; Pfizer; AstraZeneca; Travel / Accommodation / Expenses: BMS; MSD; Astellas. A. Ravaud: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Pfizer; BMS; AstraZeneca; Roche; MSD; Ipsen; Research grant / Funding (institution): Pfizer. J. Florence: Advisory / Consultancy: Roche; Ipsen; AstraZeneca; Janssen; Tesaro; BMS; Pfizer; Novartis; Sanofi; Astellas; Research grant / Funding (institution): Astellas; Travel / Accommodation / Expenses: Roche; Ipsen; AstraZeneca; Janssen; Tesaro; BMS. P. Grivas: Advisory / Consultancy: Merck & Co; Genentech; Dendreon; Bayer; Pfizer; Bristol-Myers Squibb; Exelixis; AstraZeneca; Biocept; Clovis Oncology; EMD Serono; Seattle Genetics; Foundation Medicine; Driver Inc.; QED Therapeutics; Heron Therapeutics; Janssen; Speaker Bureau / Expert testimony: Genentech; Bristol-Myers Squibb;; Travel / Accommodation / Expenses: AstraZeneca; Clovis Oncology; Research grant / Funding (institution): Merck & Co.; Genentech; Bayer; Mirati; Oncogenex; AstraZeneca; Pfizer; Clovis Oncology; Bavarian Nordic; Immunomedics. D.P. Petrylak: Advisory / Consultancy: Ada Cap (Advanced Accelerator Applications), Amgen, Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myer Squibb, Clovis, Eli Lilly, Exelixis, Incyte, Janssen, Pfizer, Pharmacyclics, Roche Laboratories, Seattle Genetics, Urogen; Research grant / Funding (institution): Ada Cap (Advanced Accelerator Applications), Astellas, AstraZeneca, Bayer, Bristol-Myers Squibb, Clovis, Eli Lilly, Endocyte, Genentech, Innocrin, MedImmune, Merck, Novartis, Pfizer, Progenics, Roche Laboratories, Sanofi Aventis, Seattle Genetics; Shareholder / Stockholder / Stock options: Bellicum, Tyme. M. Galsky: Advisory / Consultancy: AstraZeneca, BMS, Genentech, Merck, Pfizer, Dracen, Dragonfly Therapeutics, Astellas, Seattle Genetics, Janssen; Research grant / Funding (institution): AstraZeneca, BMS, Merck, Dendreon, Roche-Genentech. J. Carles: Advisory / Consultancy: Bayer; Johnson & Johnson; Bristol-Myers Squibb; Astellas Pharma; Pfizer; Sanofi; MSD Oncology; Roche; AstraZeneca; Speaker Bureau / Expert testimony: Bayer; Johnson & Johnson; Asofarma; Astellas Pharma; Research grant / Funding (institution): AB Science, Aragon Pharmaceuticals, Arog Pharmaceuticals, INC, Astellas Pharma, AstraZeneca AB, Aveo Pharmaceuticals INC, Bayer AG, Blueprint Medicines Corporation, BN Immunotherapeutics INC, Boehringer Ingelheim Espa~ na, S.A., Bristol-Myers Squibb Intern. S. Sridhar: Advisory / Consultancy: AstraZeneca, Roche, Merck, BMS, Bayer, Janssen, Astellas. H. Arkenau: Leadership role: Sarah Cannon Research Institute; Research grant / Funding (self): AstraZeneca; Roche; BMS; Novartis; GSK; Servier; Astellas; Array; Iovance; Cytomx; Research grant / Funding (institution): Sarah Cannon Research Institute; Travel / Accommodation / Expenses: Iovance. D. Carroll: Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca; Spouse / Financial dependant: Azeria Therapeutics. J. DeCesare: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. F. Mercier: Full / Part-time employment: AstraZeneca; Shareholder / Stockholder / Stock options: Stat Process sarl (Paris, France) - CRO; Health Data Process (Alicante, Spain) - CRO. D. Hodgson: Shareholder / Stockholder / Stock options, Non-remunerated activity/ies: AstraZeneca. J. Stone: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca; Shareholder / Stockholder / Stock options: GSK. J. Cosaert: Full / Part-time employment: AstraZeneca. D. Landers:
Volume 30 | Supplement 5 | October 2019
Research grant / Funding (institution): Clinical Experimental Pharmacology Group, CRUK Manchester Institute, Manchester, UK; AstraZeneca; Full / Part-time employment: AstraZeneca.
903O
Redefining the IGCCCG classification in advanced non-seminoma
S. Gillessen1, L. Collette2, G. Daugaard3, R. de Wit4, A. Tryakin5, C. Albany6, O. Stahl7, K. Fizazi8, J.A. Gietema9, U.F.F. De Giorgi10, A.R. Hansen11, D. Feldman12, F. Cafferty13, T. Tandstad14, X. Garcia del Muro15, R.A. Huddart16, C.J. Sweeney17, D.Y.C. Heng18, N. Sauve2, J. Beyer19 1 Department of Oncology/Hematology, The Christie NHS Foundation Trust, Manchester, UK, 2Statistics, EORTC - European Organisation for Research and Treatment of Cancer, Brussels, Belgium, 3Oncology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark, 4Oncology, Erasmus MC Daniel den Hoed Cancer Center, Rotterdam, Netherlands, 5Oncology, N. N. Blokhin Russian Cancer Research Center, Moscow, Russian Federation, 6Oncology, Indiana University, Indianapolis, IN, USA, 7Oncology, Skane University Hospital, Lund, Sweden, 8Cancer Medicine, Gustave Roussy, Villejuif, France, 9Medical Oncology, University Hospital Groningen (UMCG), Groningen, Netherlands, 10Medical Oncology Department, Istituto Tumori della Romagna I.R.S.T., Meldola, Italy, 11Medical Oncology, Princess Margaret Cancer Centre, Toronto, ON, Canada, 12Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA, 13Institute of Clinical Trials & Methodology, Medical Research Council, London, UK, 14Oncology, St Olav’s University Hospital, Trondheim, Norway, 15Medical Oncology, ICO - Institut Catala d’Oncologia Hospital Duran i Reynals, Hospitalet de Llobregat, Spain, 16Radiotherapy and Imaging, Royal Marsden Hospital Institute of Cancer Research, Sutton, UK, 17Medical Oncology, Dana Farber Cancer Institute, Boston, MA, USA, 18Oncology, University of Calgary, Calgary, AB, Canada, 19Medical Oncology, University Hospital Zu¨rich, Zurich, Switzerland Background: The International Germ Cell Cancer Collaborative Group (IGCCCG) has been the reference classification for assessing prognosis in men with advanced nonseminomatous germ-cell tumors (NSGCT) for more than 20 years and it relied on 5202 cases treated between 1975 and 1990. Methods: An international consortium (30 centers/groups) contributed data on 9530 advanced NSGCT patients treated with cisplatin/etoposide based first line chemotherapy between 1990 and 2013 in prospective cohorts or clinical trials. Updated 5-year progression-free (PFS) and overall survival (OS) rates were calculated. A subset of 4874 patients with complete information on components of IGCCCG, age and lung metastases were split into training (3536) and validation sets (1338). Prognostic factors for PFS were identified in the training set (alpha¼0.05) by Cox model, including (transformed) continuous factors and interactions. Results: Compared to the 1997 IGCCCG figures, the contemporary 5-year PFS was unchanged for good and intermediate, but significantly improved for poor risk patients; whereas 5-year OS was substantially better for all risk groups (Table). The subgroup with complete data was unbiased. Besides traditional IGCCCG components, we identified older age and lung metastases as negative determinants of PFS. A nomogram including AFP, HCG (both continuous), LDH>2.5xnormal, mediastinal primary, non-pulmonary visceral metastases, age (linear) and lung metastases, with several interactions was built. Its c-index was 0.745 in the training set compared to 0.701 for the 1997 IGCCCG.
Table: 903O 5-year PFS 5-year PFS 5-year OS 5-year OS IGCCCG 1997 contemporary IGCCCG 1997 contemporary Good 89 (87 – 91%) 90 (89 - 91%) Intermediate 75 (71 – 79%) 78 (76 - 80%) Poor 41 (35 – 47%) 54 (52 - 56%)
91 (89 - 93%) 96 (95 - 97%) 79 (75 - 83%) 89 (88 - 91%) 48 (42 - 54%) 67 (65 - 69%)
Conclusions: In this modern series, PFS improved for poor risk patients, while OS improved in all IGCCCG risk groups. A new prognostic model including older age and presence of lung metastases as additional negative factors is proposed. Independent validation and comparison to the IGCCCG 1997 are being conducted and will tell if the model can identify patient subgroups who may require intensified treatment. Legal entity responsible for the study: The International Germ Cell Cancer Collaborative Group (IGCCCG). Funding: Swiss Cancer Foundation. Disclosure: S. Gillessen: Advisory / Consultancy: AAA International, Active Biotech, Amgen, Astellas Pharma, Bayer, Bristol-Myers Squibb, CellSearch, Clovis, CureVac, Dendreon, ESSA Pharmaceuticals, Ferring, Innocrin Pharmaceuticals, Janssen Cilag, MaxiVAX SA, Millennium, Nectar, Novartis, Orion, Pfizer,; Licensing / Royalties: Co-inventor on patent application (WO 2009138392 A1) for a method for biomarker discover (granted in China, Europe, Japan and the US). R. de Wit: Honoraria (self): Merck, Sanofi, Bayer, Janssen, Roche and Clovis. R.A. Huddart: Honoraria (self): Janssen; Advisory / Consultancy, Research grant / Funding (self), Travel / Accommodation / Expenses: MSD; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Roche; Advisory / Consultancy: Bristol-Myers Squibb; Research
doi:10.1093/annonc/mdz249 | v357
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enriched for TSC1/2 and RICTOR GA). Arm D (D only) followed by Arm F (D þ STAT3 mRNA ASO danvatirsen) for patients without “actionable” GA. Primary objectives included safety and tolerability. Key secondary objectives included assessment of ORR and OS rate. Efficacy analysis was explored based on PD-L1 expression and tumour mutational burden (TMB). Results: As of March 2019, of 393 patients’ whose tumours were screened with NGS, 154 started study drug and had a baseline tumor assessment. Confirmed responses were assessed according to RECIST 1.1 and ranged from 20% to 29% (Table). TMB and PDL1 were inconsistent across arms (e.g. 38% TMB high for Arm E vs 5% in Arm A combination and 17% in Arm D). D monotherapy (n ¼ 29) had an ORR of 28% [80% CI 17% - 41%] with 12% [80% CI 3.2% - 28%] and 45% [80% CI 24% - 63%] of patients alive and progression free and alive at 12 months, respectively. Complete responses were not prominent in any study arm. Arms A, D and E completed earlier than arms B and F. Data will be updated based on additional follow-up.