Treatment of Advanced Bladder Cancer, Where We've Been and How to Move Forward Maha Hussain, MD, FACP Professor of Medicine & Urology Co-Leader Prostate/GU Oncology Program Associate Director for Clinical Research University of Michigan Comprehensive Cancer Center
Updated Disclosure Federal/Foundation funding: NCI, PCF, SU2C Research support (contracts with UM): Astellas/Medivation, Pfizer, Genentech, Consulting: Synthone, J&J
Track Record - 1 M1 Bladder Cancer 1980 2014 + Author Treatment RR OS (m) p-value Toxic Death Von der Masse (2000, 2005) Sternberg (2001) Siefker-Radtke (2002) MVAC 46% 15.2 NS 3% Gemcitabine,Cisplatin 49% 14.0 1% MVAC 50% 14.1 NS 4% HD-MVAC & G-CSF 62% 14.5 3% MVAC 59% 12.5 NS 9% Cisplatin, IFN, &5-FU 42% 12.5 Bamias (2004) MVAC 54% 14.2 0.026 2% Docetaxel, Cisplatin 37% 9.3 1% Dreicer (2004) MVAC 36% 15.4 NS 2% Carboplatin, paclitaxel 28% 13.8 3%
Bellmunt et al, JCO2012 EORTC 30987 / SWOG: Paclitaxel/ Gemcitabine/Cisplatin vs Gemcitabine/Cisplatin
Track Record - 2 Bladder Cancer Second Line Chemotherapy * Trial Regimen Response rate TTP (months) Lorusso 1998 Gemcitabine 22.5% 3.8 5 Albers 2002 Gemcitabine 11% 4.9 8.7 Vaughn 2002 Paclitaxel 10% 2.2 7.2 Pronzato1997 Ifosfamide 5% NR NR Witte1997 Ifosfamide 20% 2.5 5.5 McCaffrey 1997 Docetaxel 13% NR 9 Culine 2006 Vinflunine 18% 3.0 (PFS) 6.6 Sweeny 2006 Pemetrexed 28% 2.9 9.6 Dreicer 2007 Epothilone B 12% 2.7 (PFS) 8 * Includes only published trials of 20 or more patients. NR: not reported TTP: Time to progression PFS: Progression free survival Median survival (months)
Vinflunine + Best Supportive Care vs BSC as 2nd line therapy after a platinum-containing regimen in advanced TCC: OS ITT (n = 370) Bellmunt J et al. JCO 2009;27:4454-4461
Track Record - 3 Not fit for Cisplatin EORTC30986: Gemcitabine/carboplatin vs methotrexate/carboplatin/vinblastine % 100 90 80 70 60 50 40 30 20 10 8.1 months (95%CI: 6.1, 10.3) 9.3 months (95%CI: 7.6, 11.3) HR=0.94 (95%CI: 0.72, 1.22) p=0.64 0 (years) 0 1 2 3 4 5 6 7 8 O N Number of patients at risk : Treatment 108 119 37 13 7 3 1 1 1 M-CAVI 110 119 44 15 5 2 2 1 1 GC M. De Santis et al phase III 30986 ASCO 2010
1980 2014 + So Where are We? Advanced urothelial cancer is responsive to first line combination chemotherapy (CR rates of 15-30%) BUT responses are NOT durable, cures are rare & median survival has not been impacted in decades While suboptimal cisplatin based therapy is the current standard for cisplatin eligible pts No best standard 1st line therapy for pts who are not cisplatin candidates (significant proportion of the pts population) No standard second line therapy for M1 pts in the USA (Vinflunine approved in Europe) There are ZERO FDA approved systemic agents in the last 20 years
Selected Agents Tested or Undergoing Testing in Clinical Trials Cytotoxic Agents Eribuline (E7389) Nab-Paclitaxel Irinotecan Targeted Agents Angiogenesis Inhibitors Sunitinib, Pazopanib Bevacizumab IMC1121b IMC-18F1 Vandetanib EGF/HER-2 Inhibitors Trastuzamab, Cetuximab, Lapatinib, Gefitinib, Afatinib Others OGX-427, Cabozantinib, sorafinib, Lenalidomide, Ipilimumab, tamoxifen, Bortezomib, Everolimus, vorinostat, ALT801, cabozantinib, TRC105, FGFR-I
Clinical Research: Challenges, Priorities & Opportunities in Advanced Urothelial Cancer Glaring deficiency: Investment in research & drug development is still lagging at all levels We still use a one size fit all treatment approaches (No predictive biomarkers) Priorities/Opportunities: Maximize therapeutic efficacy / opportunity for cure in MIBC & M1 disease Where / how best to develop new agents / combinations Define appropriate second line therapy Special populations (age, comorbidities)
Challenges for Drug Development in the Era of Targeted Therapies & Precision Medicine Re-define definitions of diseases Morphology OR Molecular Profile How to define a relevant target? Is it biologically relevant? Where is the marker to be measured & what expression rate is meaningful What about tumor heterogeneity What disease context Greater efficacy in selected population Small patient populations (Feasibility/cost) Alternative study designs and Endpoints Endpoints and Outcome surrogates/designs to be validated Unselected vs enriched, biomarker/target stratified Adaptive Modified from R. Pazdur
What Pathway /Target /Agent to select & How best to test Oncogene/Tumor Suppressor Gene Alterations Alteration Function Change Clinical Association Frequency p53 suppressor gene Mut / Del Increased risk of disease progression/ recurrence, decreased survival in some studies but not all Rb gene suppressor gene Mut/ Del More aggressive disease, progression of disease, decreased survival 29-52% 34-37% EGFR Oncogene Overexpress Tumor grade, stage, progression and survival 35-86% Her2/neu Oncogene Overexpress Higher stage, progression, greater incidence metastasis. Mixed effect on survival 26-74% VEGF Angiogenic factor Overexpress Grade, stage, recurrence unknown PDGF Angiogenic factor Overexpress Invasion, grade, progression, recurrence unknown Cox-2 Angiogenic factor Overexpress Invasion 31% p21 p27 Cell cycle regulator Cell cycle regulator Decreased expression Decreased expression E-cadherin Cell adhesion Decreased expression CD 44 Cell adhesion Decreased expression Urokinase type PA Cell adhesion Elevated expression Decreased survival Grade, progression, decreased survival Invasion, progression, grade, stage, metastasis, survival Stage, survival Invasion, metastasis, progression, survival unknown unknown unknown unknown unknown
Issues to Consider -1 How successful are we in selecting and targeting solid tumors? Tumor Breast Breast GIST NSCLC Melanoma Colorectal Target ER (IHC) Her-2 (IHC/FISH) C-Kit (IHC/ RT- PCR) ALK B-RAF Wildtype K- ras % Pt 65-70 20-25 90 expression Drug Tamoxifen /AI Trastuzum ab 70-75 mutations Imatinib 3-7 40-60 35-40 Crizotini b Vemurafen ib Cetuximab RR (%) 50-60 15-26 45-70 55-60 48-52 10-12
Issues To Consider 2 Importance of Understanding the Biological Context Tumor Angiogenesis: Therapeutic Implications Folkman et al, NEJM 1971
Targeting VEGF Pathway in Breast & Prostate Cancer Advanced Prostate Cancer: Negative Phase III Trials VEGF/Angiogenesis Taxotere +/- Bevacizumab Docetaxel +/- aflibercept Docetaxel +/- Lenalidomide Sunitinib Advanced Breast Cancer: Negative Phase III Trials for Survival Bevacizumab Sunitinib: Sunitinib combination therapy may also have resulted in AEs that yield an unfavorable riskbenefit ratio Bergh et al, JCO 2012
Randomized, phase 2 trial of maintenance sunitinib versus placebo after response to chemotherapy in patients with advanced urothelial carcinoma Median PFS sunitinib: 2.9 months (95% CI: 2.4-6.3 m) vs 2.7 months for placebo (95% CI, 2.5 months-7.2 months) The median OS sunitinib: 10.5 m (95% CI: 8.1-13.8 m) vs 10.3 m for placebo (95%CI, 6.8-18.1 m). Grivas et al, Cancer 2013
CALGB/SWOG: Randomized Phase III Study of Gemcitabine and Cisplatin +/-Bevacizumab in Patients with Advanced UC Decreased hazard rate for death by 24%, Increase OS from 13.8 to 18.63 months, 87% power, two-sided alpha = 0.05
Issues to Consider - 3 Disease/pathway appropriate predictive biomarkers & Feasibility of a priori biomarker testing in advanced bladder cancer
Gemcitabine/Cisplatin +/- Cetuximab in advanced Urothelial Carcinoma Hussain et al, Cancer 2014
Trastuzumab, Paclitaxel, Carboplatin, Gemcitabine In Advanced Her-2/neu Positive Urothelial Carcinoma Method HER-2 Status N=109 Number of Positive Patients Percentage Positive Any Method 57 52.3% IHC (2+ or 3+) 53 48.6% FISH (>2.0) 15 13.8% Serum (>16.0) 13 11.9% Any 2 out of 3 21 19.3% All 3 criteria 3 2.8% Hussain et al, J Clin Oncol. 2007
Issues to Consider - 4 May be we should be Not so Precise nor very Personal
Inhibition of PD-L1 by MPDL3280A<br />leads to clinical activity in<br />patients with metastatic urothelial bladder cancer (UBC) Presented By Thomas Powles at 2014 ASCO Annual Meeting
MPDL3280A: Summary of ORR in UBC <br />Efficacy-evaluable population with UBC in Phase I expansion Presented By Thomas Powles at 2014 ASCO Annual Meeting
Drug Development Overarching Objectives: Impact Standards of Care & Aim for Cure Appropriate Phase III/ registrational studies FDA Approval Adjuvant Identification of active & safe combinations Neoadjuvant Identification of active drugs Discovery Biology Cost: Patients, Decades & $$$$$$$
Transformative Science: Provide right care at the right time, for the right price Metastatic UC is a complex smart cancer Therapy development MUST focus on: Totality of disease biology: Comprehensive molecular understanding of disease states Thorough validation of candidate targets/pathways/ biomarkers Understand the biological context & rate-limiting / cooperative interactions Multi-targeted approaches: aiming at cytotoxic impact The best cancer cell is a dead one Clinical trials: Scientifically / clinically relevant, statistically sound, feasible to complete