Developmental Therapeutics for Genitourinary Malignancies

Transcription

1 Developmental Therapeutics for Genitourinary Malignancies Russell Szmulewitz, MD April 2018

2 Disclosure Information 23 rd Annual Developmental Therapeutics Symposium Name of Speaker I have the following financial relationships to disclose: Advisory Board Consultant for: Pfizer, Bayer, Amgen, Abbvie, Janssen, Merck, Astellas Grant/Research support (University of Chicago) from: Abbvie, Astellas, Incyte, Janssen, Bayer, Novartis Intellectual Property: Co-inventor on patent for dual androgen and glucocorticoid receptor blockade in prostate cancer licensed to Corcept Therapeutics - or - I will discuss the following investigational use in my presentation: Mifepristone for prostate cancer, afatanib for urothelial cancer, enfortumab vedotin for urothelial cancer, nivolumab/rucaparib for prostate cancer 2

3 Outline Evolving standard of care in prostate cancer Highlight of PCCC trials Urothelial cancer: now what? Highlight of PCCC/UCM trials Renal cancer

4 Clinical States of PC Prognosis 10Y+ ~9Y 1 4-5Y+ 2,3 ~3Y 4,5 ~1.5Y 6 ~1Y 7,8 Clinically Localized Disease Noncastrate Non- Castrate Rising PSA Castration-resistant Clinical Metastases: Noncastrate Nonmetastatic CRPC (nmcrpc) 40mo MFS 9 Castration- Resistant Metastatic (mcrpc): 1 st Line mcrpc: 2nd Line mcrpc: 3rd Line mcrpc: 4th Line Szmulewitz, Crook et al, NEJM, 2012 [NCIC PR07] 2. Sweeney et al, NEJM, 2015 [CHAARTED] 3. Fizazi et al, NEJM, 2017 [LATITUDE] 4. Ryan et al, Lanc Onc, 2015 [COU-302] 5. Scher et al, NEJM, 2012 [AFFIRM] 6. debono et al, Lancet, 2010 [TROPIC] 7. Smith et al, JCO, 2016 [COMET-I] 8. Mateo et al, NEJM, 2015 [TOPARP] 9. Smith et al, NEJM, 2018 [SPARTAN] Modified from Scher, ASCO

5 Androgen Receptor (AR) Signaling is Critical for the Development and Progression of Prostate Cancer Feldman et al

6 Abiraterone Acetate: COU-AA-302 Ryan, Lancet Onc, 2015; Ryan, NEJM,

7 Enzalutamide phase III-asymptomatic Szmulewitz, 2017 Beer, T et al. N Engl J Med,

8 Abiraterone in CSPC Latitude (Fizazi et al, NEJM, 2017) High risk=metastatic, 2/3 of-gs 8-10, 3 or more bone lesions, measurable visceral disease) STAMPEDE (James, NEJM, 2017)- 5mg pred Mixed cohort Szmulewitz, 2017 Szmulewitz APAO

9 Latitude Median OS: NR vs [Note: median OS for CHAARTED high volume control was 32mo] Median PFS: 33 vs 14.8 months Szmulewitz,

10 Key Questions and Opportunities How do we maximize efficiency and resources for these expensive therapies? Taking advantage of pharmacology Predictive biomarkers (e.g. ARv7) How can we improve on these new standards based on biology? Are there other therapeutic targets besides the AR, microtubules? What about immunotherapy? 12

11 Maximizing the meds we have Szmulewitz These oral medications are expensive Abiraterone acetate oral bioavailability ~5 fold increase with food vs. fasting Pharmacodynamic/Pharmacokinetic randomized trial of abiraterone 250mg/d with food vs. 1000mg/d fasting [NCT ] Primary endpoint-psa change at 12 weeks Secondary endpoints-pk, adrenal androgen levels, med adherence N=72 Accrued completely through PCCC 13

12 Szmulewitz et al, JCO,

13 Classes of resistance to AR-targeted Sustained AR signaling (mutation, splicing) Alternative nuclear hormone signaling(e.g. GR) Non-endocrine survival mechanisms PI3K JAK/STAT Parp1/DNA damage stem cell genes MYC upregulation 15

14 A phase I/II trial of enzalutamide plus the glucocorticoid receptor antagonist mifepristone for patients with mcrpc [DoD PC121149, NCT ] Primary endpoint: PSA-PFS Correlatives (PCF support): CTC GR expression, gene expression, ctdna Open through PCCC (Decatur, NorthShore, Karmanos, UCM): N=29 randomized, N=24 in lead in 16

15 DNA damage as an immunotherapy sensitizer: Nivolumab + Rucaparib mcrpc willing to undergo 2 biopsies Primary endpoint: Feasibility Correlatives: Multiple immune Rucaparib + Nivolumab mcrpc or mec Randomization Rucaparib Biopsy Nivolumab 4 weeks Biopsy Biopsy Biopsy Opening through PCCC 2018 Rucaparib + Nivolumab Progression PI: Patnaik Funding Support from BMS and Clovis 17

16 Urothelial Cancer 18

17 Urothelial Cancer: Immunotherapy Revolution (2 nd Line) Atezolizumab Nivolumab Pembrolizumab Avelumab Durvalumab Target PD-L1 PD-1 PD-1 PD-L1 PD-L1 Phase Phase II single arm Phase II single arm Phase III Randomized trial # of patients Dose/schedule 1200 mg every 3 weeks 3 mg/kg every 2 weeks 200 mg every 3 weeks Phase 1b 241 (153 patients with 6 mo f/u) 10 mg/kg every 2 weeks Phase I/II 191 (103 eligible for efficacy analysis) 10 mg/kg every 2 weeks ORR 15% 19.6% 21.1% 17.6% 20.4% Duration of response 84% of responses ongoing at median follow up of 11.7 months 77% of responses ongoing at median follow up of 7 months 72% of responses ongoing at median follow-up of 14.1 months 89% of responses ongoing at median follow up of 7.3 months 81% of responses lasting 6 months Median OS (months) Median PFS (months) Rate of Grade 3/4 AEs Not reached (6- month OS 54.5%) 14.1 months % 18% 13.5% (15% G3-5) 7.5% 6.8% From R. Sweis 19

18 Urothelial Cancer Key Questions What is the appropriate sequence of immunotherapy/chemotherapy? Gem/Cis-atezo sequencing (UC IRB ) First line therapy for cis-ineligible? Gem/Carbo/Atezo 3 arm (IRB ) Rogaratinib (FGFRi)+atezo (IRB ) Immunotherapy combinations? Multiple through DT program Pembro+epacadostat (IRB ) Targeted therapy? 20

19 ErbB family alterations are common in UC EGFR amp 11% HER2 amp 7% ERBB3 mutations 11% Afatinib is a novel oral irreversible TKI of the ErbB receptor family 21

20 Patients allowed on study regardless of ERBB status 5/6 (83.3%) with HER2 and/or ERBB3 alterations achieved PFS3, versus 0/15 without alterations (P<0.001) Median time to progression/discontinuation of afatinib was 6.6 mo in pts with alterations, vs 1.4 mo in patients without alterations (P<0.001) Phase II expansion for biomarker+ open through PCCC and activating sites. Choudhury et al., JCO (2016) 22

21 Enfortumab Vedotin Drug-immuno conjugate targeting Nectin-4 Nectin-4 near universal expression in muc Phase I expansion (Petrylak et al ASCO 2017): 53% ORR in refractory UC Phase II for refractory muc open at UCM (IRB ) 23

22 Conclusions Standard of care evolving for mpc biomarker driven studies to target resistance, improve immunotherapy Exciting time for DT in urothelial carcinoma immunotherapy incorporation/improvement molecularly targeted therapies 24