Case-Based Discussion: Muscle Invasive Bladder Cancer Se Seth P. . - PowerPoint PPT Presentation

Case-Based Discussion: Muscle Invasive Bladder Cancer Se Seth P. . Lerner MD; Gu Gui Go Godoy MD, , MPH; Jennifer Taylor MD, , MPH; A. Edward Yen, MD Urologic Oncology & GU Medical Oncology 13 September 2019

Case 1 • 57 yo male with gross hematuria – Normal renal function, former smoker • TURBT - T1HG, multifocal CIS No re-resection; Urologist recommends BCG Patient seeks second opinion Re-resection • TURBT - T2Tis with multifocal LVI Next steps? • Neoadjuvant chemotherapy and radical cystectomy treatment of choice

Case 2 Urothelial NOS • 66 yo healthy male • Remote history of colon cancer – Chemo, XRT and Low anterior resection • T2Nx tumor high anterior wall and dome – Urothelial carcinoma with “extensive” Urothelial with squamous features but no lymphovascular Squamous invasion Next steps? • Neoadjuvant GC/Celecoxib x 4

Integrated Treatment Options • Pre-operative irradiation No role with contemporary radical cystectomy for urothelial Ca • Peri-operative chemotherapy – Neo-adjuvant – Adjuvant – Until recently only 11.6% receive – mostly adjuvant – Today up to 50% of patients receiving • SWG S1011 56% (88% cisplatin-based) Level I evidence only supports cisplatin based combination therapy

SWOG 8710: Overall Survival by Treatment Arm No. Pts. Median 100 No. %5 Yr p Value Survival Survival ARM Pts . Dead (log-rank, 1-sided) Percent Surviving % Control 154 96 43.2 mos 42.1% 0.044 MVAC 153 90 74.7 mos 57.2% 80% 60% 40% 0 24 48 72 96 120 144 168 20% Months 0%

Neoadjuvant Chemotherapy Improves pCR (P0) rate CTx + cyst cyst alone MRC/International (CMV) 32.5% 12.3% SWOG (MVAC) 38% 15% Nordic II (MTX/Cisplatin) 1 26.4% 11.5 MSKCC (GC) 26% NA MSKCC (M-VAC) 28% NA Columbia (MVAC) 31% NA Columbia (GC) 25% NA CCF (GC) 2 7% NA International consortium 3 NA 5.1%

Risk Factors for Extravesical and Occult Metastatic Disease Higher risk of relapse: 3-D mass on EUA • Prostatic stroma, vaginal wall involvement (T4a) • LVI - increased risk of occult nodal involvement • Hydronephrosis - Increased risk of extra-vesical extension • Micropapillary tumor vonRundstedt, et al Bladder Cancer 3:35, 2017 • Small cell neuroendocrine tumor • Culp , et al, J Urol 191:40, 2014

SWOG 8710 Neoadjuvant M-VAC- Benefit cT2 vs. cT3-T4a Pts with cT2 also benefit from neoadjuvant chemotherapy Median survival cT2 105 vs. 75 mos cT3-4a 65 vs. 24 mos Grossman, et al NEJM 349:859, 2003

Low Risk Patients Benefit from NAC Mayo Clinic 1980-2016 • RC for cT2-4N0; n = 1931 • Low risk (n = 1025; 104 with NAC) • NAC in LR patients was associated with greater odds of pT0 (OR 3.05; p < 0.001) and < pT2 (OR 2.53; p < 0.001) disease, but was not significantly associated with CSS ( p = 0.31) “These data support offering NAC to all eligible MIBC patients irrespective of risk classification, and may aid in informed discussion of treatment sequencing for LR patients.” Bhindi et al. Eur Urol 72 (5): 660, 2017

Neo-adjuvant Chemotherapy Meta Analysis 5% Survival Advantage Cisplatin alone Cisplatin combo • Individual patient data from 6 randomized trials • 9% survival benefit with platinum based combination chemotherapy Vale, et al Eur Urol 48:202, 2005

Guidelines – AUA, EAU, ASCO • Neoadjuvant chemotherapy with cis-platin based multi-agent regimen standard of care • AUA: Strong Recommendation; Evidence Level: Grade B • M-VAC/CMV only regimens tested in Phase III trials **Common use of GC based on patients with metastatic disease and has not been evaluated in Phase III neoadjuvant trials

Case 3 • 75 yo male with gross hematuria – Current smoker (100 pk-yrs), CAD, CKD (eGFR 48) • TURBT – T2 Urothelial cancer

Eligibility for Cisplatin-Based Therapy • Renal function Based on GFR / Creatinine clearance • GFR > 60 : standard dosing • GFR 50-60: consider split-dosing, extra hydration • GFR <50: rarely eligible • Hearing Loss • Cis toxicity manifests as sensorineural hearing loss with tinnitus • Peripheral neuropathy • Functional status: ECOG 0-1 An estimated 40-50% of patients not eligible for cisplatin Dash et al. Cancer 2006;107:506-13

Carboplatin In Neoadjvuant Regimens • Carboplatin is active in UC but no neoadjuvant studies have demonstrated equivalence to cisplatin or cisplatin based regimens • Carboplatin combinations have shown activity in small trials 1,2 • Carboplatin/gemcitabine showed worse rates of complete pathologic response and downstaging and worse 2 yr survival compared to ddMVAC and GC in a large retrospective study 3 • Carboplatin may be inferior to cisplatin based regimens in the advanced setting 4 1. Hussain et al. J Clin Oncol. 2001;19(9):2527. 2. Mertens et al. J Urol. 2012 Oct;188(4):1108-13. Epub 2012 Aug 15. 3. Peyton, et al. JAMA Oncol. 2018;4(11):1535-1542 4. Bellmunt et al. Cancer. 1997 Nov 15; 80(10):1966-72.

2019 NCCN Guidelines • “Neoadjuvant chemotherapy followed by radical cystectomy is a category 1 recommendation based on high level data supporting its use. Patients with hearing loss or neuropathy, poor performance status, or renal insufficiency may not be eligible for cisplatin-based chemotherapy. If neoadjuvant cisplatin-based chemotherapy cannot be given, neoadjuvant chemotherapy is not recommended. Cystectomy alone is an appropriate option for these patients.”

Future Treatment Paradigm for MIBC (?) TCGA (n=412) Luminal Basal/Squamous KRT20+, GATA3+, FOXA1+ KRT5,6,14+, GATA3-, FOXA1- Luminal-papillary Luminal-infiltrated Luminal Basal/Squamous Neuronal FGFR3 mut, fusion, amp Low purity UPKs Female SOX2 Papillary histology EMT markers (TWIST1, ZEB1) KRT20 Squamous differentiation DLX6 SHH+ miR-200 family SNX31 Basal keratin markers MSI1 Low CIS Medium CD274 (PD-L1), CTLA-4 High CD274 (PD-L1), PLEKHG4B Myofibroblast markers CTLA4 E2F3/SOX4 amp ‘p53-like’ Immune infiltrates High cell cycle Low risk Anti-PD-L1, PD-1, CTLA-4 Targeted therapy? Anti-PD-L1, PD-1, CTLA-4 Etoposide/Cisplatin NAC NAC* Cisplatin-based NAC** Cisplatin-based NAC FGFR3 inhibitors ** Low response rate * Low likelihood of response based on preliminary data (Seiler et al. 2017) Robertson, et al Cell, 2018

Expression Subtypes and Response to Neoadjuvant Chemotherapy (NAC) Seiler et al, Eur Urol 72:544, 2017

Slide 4 Presented By Andrea Necchi at 2018 ASCO Annual Meeting

Pathologic Response to Pembrolizumab Necchi; et al JCO 36, 3353, 2018

Take-Away: Non-Metastatic MIBC • Cultivate relationships with medical oncologist and radiation oncologist • Multidisciplinary discussion of every patient with newly diagnosed MIBC • Be aware of cooperative group or other clinical trials available for your patients There may (will?) be a time when not all patients will be advised to undergo radical cystectomy and we will have confidence in alternate treatment plans

Case 4 • 72 yo male with gross hematuria • Agent Orange exposure, former smoker (80 pk-yrs), Htn • TURBT – T2 Urothelial cancer *Axial image of metastatic disease

Advanced Urothelial Carcinoma (UC) • 12 th most common cancer worldwide 1 • 199,922 worldwide deaths yearly (2018) • 8 th most common cause of cancer deaths in US men • US, 2017: 17, 670 deaths from bladder cancer 2 • Prognosis with firstline combination chemotherapy with platinum: 14-15 months 3 • Prognosis after failure of platinum 1. Bray et al. CA CANCER J CLIN 2018;68:394–424 combination: 4-7 months 4 2. ACS Facts & Figures, 2019 3. Von der Maase et al. J Clin Onc 2005 4. Bellmunt J et al. J Clin Onc 2009.

PD-1 and PD-L1 Pathway • PD1: Programmed Death 1 • receptor expressed primarily on activated T cells 1,2 • inhibitory action when bound • PD-L1: Ligand to PD1 • an immune ‘checkpoint’, in tumor cells and tumor microenvironment 1,2 • PD-L1 <binds> PD-1 >>> down-regulates T cell function >>> cancer can evade immune surveillance 1,2 • Blockade of PD-1/ PD-L1 pathway has been shown to improve overall survival in multiple solid tumors 3, 4 1. Keir ME et al. Annual Rev Immunol. 2008; 26:677-704 2. Pardoll DM. Nat Rev Cancer. 2012; 12: 252-264. 3. Brown et al. J Immunol. 2003 4. Latchman et al. Nat Immunol. 2001.

First Checkpoint Inhibitor (CPI) Trials In Advanced UC Trial N Median PD-L1 status ECOG PS Histology ≥ 2 prior GFR < 60 Age systemic ml/min therapies KEYNOTE-012 1 33 70 Only positive (>1% 72.7% 91% 51.5% n/a Cohort C (UC) (44-85) IHC+) patients PS1 pure UC (Pembro-) NCT01375842 2 92 66 PD-L1+ >> all 60% PS1 N/A 72% 41% Urothelial Cancer (36-89) comers (52.8% IC2/3) Cohort (Atezo-) • Pembrolizumab: humanized IgG4 kappa mAb to PD-1 Atezolizumab: humanized mAb IgG1 with selective PD-L1 binding • • Primary endpoints: safety and antitumor activity • Trial patients with UC were heavily pretreated with advanced disease and poor risk 1. Plimack E. 2015 ASCO Annual Meeting presentation 2. Petrylak D. 2015 ASCO Annual Meeting presentation

Initial Findings: CPI • Treatment with checkpoint inhibition in UC patients was safe and tolerable • Treatment with checkpoint inhibition showed activity in a heavily pretreated population with advanced disease • Responses seen even in patients without high levels of PD-L1 expression