Optimizing treatment for metastatic bladder cancer in chemotherapy-resistant urothelial carcinoma Moran Gadot M.D SHEBA Medical Center ISRAEL
Disclosures none
All (eligible) patients should get chemotherapy for 1 st line Treatment
Who is chemotherapy resistant? Patient who developed disease progression During chemotherapy Tx Within 12 month from completing neo-adjuvant chemotherapy Within 12 month from completing firs line chemotherapy (Cis ineligible= chemotherapy resistant?)
Subsequent systemic treatment- Post Platinum
Considerations for subsequent therapy ECOG Previous treatment and response to treatment Clinical trial Local treatment Genomics? Biomarkers? Health and Drug Basket
Subsequent treatment Immunotherapy chemotherapy Targeted therapy Pembrolizumab Nab-paclitaxel Paclitaxel Ramucirumab (+Docetaxel) Atezolizumab Docetaxel Gemcitabine Erdafitinib (FGFRi) Nivolumab Pemetrexed Vinflunine (Europe) Enfortumab Vedotin (nectin 4 i) Durvalumab Ifosfamid MTX Avelumab Oxaliplatin CT dublet DDMVAC
Immunotherapy
Presented By Thomas Powles at 2018 ASCO Annual Meeting Changes to PD-L1 and CD8 expression with therapy
chemotherapy FGFR CDK Immunotherapy RR chemotherapy
2 nd line CT after failure of platinum salt: single-agent ph II trials Author & year of publ. Agent N (evaluable) ORR (%) PFS (mo) OS (mo) Pronzato, 1997 20 5 NR 0.8 Ifosfamide Witte,1997 58 20 2.2 5.1 Mc Caffrey, 1997 30 13 NR 9.0 Docetaxel Choueiri, 2012 (1 arm out of 2) 75 (72) 7 1.6 7.0 Papamichael, 1997 14 7 NR NR Vaughn, 2002 Paclitaxel 31 10 2.2 7.2 Joly, 2009 45 (37) 9 3 7.0 Lorusso, 1998 35 (31) 23 3.8 5.0 Gemcitabine Albers, 2002 30 (28) 11 4.9 8.7 Witte, 1998 Topotecan 44 9 1.4 5.1 Dodd, 2000 Pyrazoloacridine 14 0 NR 9.0 Roth, 2002 Piritrexim 35 (27) 7 2.1 7.0 Moore, 2003 Oxaliplatin 18 6 NR NR Dreicer, 2007 Epothilone B 45 (42) 12 2.7 8 Sweeney, 2006 Galsky, 2007 Crevera-Grau, ASCO 2012 Pemetrexed 45 13 44 28 8 NR 2.9 NR 4.1 9.6 NR 7.2 Sridhar, ASCO GU 2011 Nab-paclitaxel 48 32 6 10.8 J Lee, ASCO GU 2011 Paclitaxel PM 34 21 2.7 6.5 Loriot, ASCO 2012 Pralatrexate 30 3.3 (conf.) 4.0 9.3 No compound tested in phase III, no further development
Targeted therapy
RANGE trial- Docetaxel +/- Ramucirumab Phase III post platinum N-530 pep PFS 4.1 vs 2.8 months HR 0.76 ORR 24.5 vs 14% trend for OS benefit Powles et al. Lancet. 2017;390(10109):2266
Erdafitinib- FGFRi First Results From the Primary Analysis Population <br />of the Phase 2 Study of Erdafitinib <br />(JNJ-42756493) in Patients With Metastatic or Surgically Unresectable Urothelial Carcinoma and FGFR Alterations Presented By Arlene Siefker-Radtke at 2018 ASCO Annual Meeting
The FGFR Landscape in Cancer: Analysis of 4,853 Tumors by Next-Generation Sequencing T Helsten et al.ccr-14-3212 January 2016
FGFR Alterations Are Common in Cancer Presented By Arlene Siefker-Radtke at 2018 ASCO Annual Meeting
Response to Erdafitinib in a Patient With Liver Metastases Presented By Arlene Siefker-Radtke at 2018 ASCO Annual Meeting
Responses <br />to Erdafitinib <br />Were Maintained Presented By Arlene Siefker-Radtke at 2018 ASCO Annual Meeting
The SHEBA Medical Center experience Based on two early phase clinical trials with two investigational products: n=12 Best response- two drugs combined * FGFR Inhibitor INCB 054828 - ( INCB ) * Pan FGFR kinase inhibitor BGJ398 ( Novartis ) 30% 10% 20% 20% Median time on drug 1.6 month (range 5 days to 13.3 months) 20% PR clinical PR SD mixed PD
Presented By Andrea Necchi at 2018 ASCO Annual Meeting
Enfortumab Vedotin- anti nectin 4 Updated Results From the Enfortumab Vedotin Phase 1 (EV-101) Study in Patients With Metastatic Urothelial Cancer Presented By Jonathan Rosenberg at 2018 ASCO Annual Meeting
Enfortumab Vedotin is an Antibody Drug Conjugate (ADC) that Targets Nectin-4 Presented By Evan Yu at 2018 ASCO Annual Meeting
Enfortumab Vedotin Phase 1 Updated Efficacy Results Presented By Evan Yu at 2018 ASCO Annual Meeting
Enfortumab Vedotin Phase 1 Safety Results Presented By Evan Yu at 2018 ASCO Annual Meeting
Duration of Response Presented By Jonathan Rosenberg at 2018 ASCO Annual Meeting
HER2/neu, an Oldie but Goodie Presented By Evan Yu at 2018 ASCO Annual Meeting
DNA Repair Genes and Homologous Recombination Deficiency Presented By Evan Yu at 2018 ASCO Annual Meeting
Ongoing clinical trials Immunotherapy doublet Targeted therapies Combinations: Immunotherapy-chemotherapy Immunotherapy-targeted therapy
conclusion We can maximize treatment after chemotherapy failure! Genomics- Molecular stratification of treatment Clinical trials! Thank you!