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2L Advanced Urothelial Carcinoma:New Options and Sequencing
Vinicius Carrera, M.D
@vini_carrera
Disclosures
• De acordo com a resolução do Conselho Federal de Medicina nº 1595/2000 e Resolução da Diretoria Colegiada da ANVISAnº 96/2008, eu declaro que:
• Pesquisa Clínica – Como investigador: BMS, Janssen
• Apresentações científicas – Como palestrante: Bayer, Janssen, Novartis, AstraZeneca, MSD
• Atividades de Consultoria – Como membro de Advisory Boards: Roche, Janssen
Declaro não ter ações em bolsa de valores das empresas supracitadas. Meus pré-requisitos para participar destas atividadessão o intercâmbio científico, a autonomia do pensamento científico, independência de opiniãoe liberdade de expressão.
2019 2L Advanced Urothelial Cancer Review
Agenda
1
2
3
4
5
Overview
Checkpoint Inhibitors
FGFR inhibitors
Antibody-drug Conjugates
Combination and/or sequencing
Overview
911
1011
28
6,9 7 7,28,7
9,6
0
5
10
15
20
25
30
Vinflunine Docetaxel Paclitaxel Gemcitabine Pemetrexed
EFFICACY OUTCOMES OF 2L CHEMOTHERAPY
ORR OS
Second-line chemotherapy for advanced and metastatic urothelial carcinoma – Vinflunine and beyond: A comprehensive review of the current literature. J Urol. 2016 Feb;195(2):254-63
O.S: 7 to 9 months
Long-term survival of phase III trial ofvinflunine
Long-term survival results of a randomized phase III trial of vinflunine plus best supportive care versus best supportive care alone in advancedurothelial carcinoma patients after failure of platinum-based chemotherapy. Ann Oncol. 2013 Jun;24(6):1466-72
OS: 6.9 vs 4.6 (2.3 m) P=NS
Negative
Nivolumab Avelumab
Durvalumab
Pembrolizumab
Atezolizumab
Checkpoint Inhibitors
Atezo: IMvigor210; Nivolumab Checkmate 275; Pembro KEYNOTE-045; Avelumab JAVELIN; Durva S1108
21,1
15
19,617,8 18,2
10,39 8,7
18,2
13,7
0
5
10
15
20
25
Pembrolizumab Atezolizumab Nivolumab Durvalumab Avelumab
Checkpoint Inhibitors Approved for use in UC
ORR OS
1. Rosenberg JE et al. Lancet 2016;387:1909–1920; 2. Sharma P et al. Lancet Oncol2017;18:312–322; 3. BellmuntJ et al. N EnglJ Med 2017 2017;376:1015–1026; 4. ApoloAB et al. ESMO 2017. Abst856P; 5. Powles T et al. JAMA Oncol. doi:10.1001/jamaoncol.2017.2411. 6. PowlesT et al The Lancet 2018 Table adapted from GrivasP. ASCO 2017.
Response Rate
KN-045 long-term safety and efficacy
Randomized phase III KEYNOTE-045 trial of pembrolizumab versus paclitaxel, docetaxel, or vinflunine in recurrentadvanced urothelial cancer: results of >2 years of follow-up. Ann Oncol. 2019 May 3
mFUP: 27.7 months
1 year OS: 44.2 vs 26.9%
2 year OS: 29.8 vs 14.3%
Duration of response:Not reached vs 4.4 months
1
2
3
4
5
Overview
Checkpoint Inhibitors
FGFR inhibitors
Antibody-drug Conjugates
Combination and/or sequencing
FGFR inhibitors
Erdafitinib in Locally Advanced or Metastatic Urothelial Carcinoma. N Engl J Med. 2019 Jul 25;381(4):338-348
BLC2001 Study Design
FGFR alteration ~ 20% of advancedurothelial carcinoma
FGFR2 ou 3 fusion 25%
FGFR3 mut 75%
Erdafitinib in Locally Advanced or Metastatic Urothelial Carcinoma. N Engl J Med. 2019 Jul 25;381(4):338-348
BLC-2001
43%
79%
53%
Erdafitinib
ASCO 2018
Efficacy Outcomes
Erdafitinib in Locally Advanced or Metastatic Urothelial Carcinoma. N Engl J Med. 2019 Jul 25;381(4):338-348
N=99 ORR=40%
PFS 5.5 M
OS 13.8 M
Response to prior treatment with IO
Erdafitinib in Locally Advanced or Metastatic Urothelial Carcinoma. N Engl J Med. 2019 Jul 25;381(4):338-348
59%
49%
16%
Most common treatment-related AE
55%
37%
TRAEs of Clinical Importance or SpecialInterest
73%
52%
21%
Antibody-drug Conjugates
1
2
3
4
5
Overview
Checkpoint Inhibitors
FGFR inhibitors
Antibody-drug Conjugates
Combination and/or sequencing
Enfortumab Vedotin
Targets Nectin-4, a protein highlyexpressed in UC
ASCO 2019
EV-201: Phase 2 Enfortumab Vedotin
ASCO 2019
Pivotal Trial of Enfortumab Vedotin in Urothelial Carcinoma After Platinum and Anti-ProgrammedDeath 1/Programmed Death Ligand 1 Therapy. J Clin Oncol. 2019 Jul 29:JCO1901140.
EV-201: Phase 2 Enfortumab Vedotin
ASCO 2019Pivotal Trial of Enfortumab Vedotin in Urothelial Carcinoma After Platinum and Anti-Programmed Death 1/Programmed Death Ligand 1 Therapy. J Clin Oncol. 2019 Jul 29:JCO1901140.
Waterfall plot of the best percentage of changefrombaseline.
84%
PR=44% CR=12%N=125
09/2019: FDA Granted Priority Review for Enfortumab Vedotin
2 factorsOS 3.8m
PFS 5.8 m
EV-201: Phase 2 Enfortumab Vedotin
Pivotal Trial of Enfortumab Vedotin in Urothelial Carcinoma After Platinum and Anti-Programmed Death 1/ProgrammedDeath Ligand 1 Therapy. J Clin Oncol. 2019 Jul 29:JCO1901140.
Summary of Adverse Events in Patients Receiving Enfortumab Vedotin2 factorsOS 3.8m
PFS 5.8 m
Sacituzumab Govitecan (SG)
ASCO GU 2019
Trop-2 is an epithelial cellsurface antigen highlyexpressed in UC
EnfortumabVedotin
Targets Nectin-4, a protein highlyexpressed in UC
Sacituzumab Ph I/II Single-Arm Basket Study in Advanced Epithelial Cancers (mUC Cohort)
ASCO GU 2019
Sacituzumab Ph I/II Single-Arm Basket Study in Advanced Epithelial Cancers (mUC Cohort)
ASCO GU 2019
• Heavily pretreated mUC cohort (median of 2 prior therapies, range: 1–6)
• Prior platinum and CPIs don’t decrease response rate
31%
Sacituzumab Govitecan: Ph 2 TROPHY-U-01
ESMO 2019
Annals of Oncology (2019) 30 (suppl_5): v851-v934. 10.1093/annonc/mdz394
Open-label, ph2, N=100
Sacituzumab Govitecan: Ph 2 TROPHY-U-01
ESMO 2019
Annals of Oncology (2019) 30 (suppl_5): v851-v934. 10.1093/annonc/mdz394
Patients With Objective Responses
ESMO 2019
Annals of Oncology (2019) 30 (suppl_5): v851-v934. 10.1093/annonc/mdz394
ORR 29%
Case: Retroperitoneal Lymph Node Metastasis
ESMO 2019
Annals of Oncology (2019) 30 (suppl_5): v851-v934. 10.1093/annonc/mdz394
Combination and/or sequencing
1
2
3
4
5
Overview
Checkpoint Inhibitors
FGFR inhibitors
Antibody-drug Conjugates
Combination and/or Sequencing
FIERCE-22: Ph 2 Vofatamab + pembro post-chemo
Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019) 4511-4511.
Study Design
Elegibility: mUCprogressing afterplatinum-base chemo, PDL1 naive
ASCO 2019
FIERCE-22: Ph 2 Vofatamab + pembro post-chemo
ASCO 2019
Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019) 4511-4511.
FIERCE-22: Ph 2 Vofatamab + pembro post-chemo
ASCO 2019
Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019) 4511-4511.
ORR 36%FGFR3 WT 33%FGFR3 mut/fus 43%
Nivo + Ipi 3Checkmate 032
Sharma P, Siefker-Radtke A, de Braud F, et al. Nivolumab alone and with ipilimumab in previously treated metastatic urothelial carcinoma: CheckMate 032 nivolumab1 mg/kg plus ipilimumab 3 mg/kg expansion cohort results. J Clin Oncol. 2019;37(19):1608-1616
ORR 38%
Take Home Message
Which CPI Should Be Used After Progression onPlatinum-Based Chemo in mUC
OS gainPhase 3Level 1 data
No OS gainPh 3
No Ph 3 No Ph3 No Ph3
Pembro Atezo Nivo Durva Avelu
2L
What Treatment Options Are Available AfterDisease Progression on Platinum-Based Chemo
BLC2001 Study Design40% response rate – approved in Brazil
Targeted Therapies in Advanced UrothelialCancer (FGFR, Antibody-drug Conjugates)
Sequencing after Platinum-based Chemo
Pembro
Clinical trial
Erdafitinib Chemo
Ph3 DataLevel 1
If FGRF driven tumor
If FGFR neg or after Erda
If Clinical Trial Non available,Chemo
