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

• 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” squamous features but no lymphovascular invasion

Next steps?

• Neoadjuvant GC/Celecoxib x 4

Urothelial NOS Urothelial with Squamous

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

100 % 80% 60% 40% 20% 0%

0 24 48 72 96 120 144 168

Months Percent Surviving

ARM No. Pts.

• No. Pts.

Dead Median Survival %5 Yr Survival p Value

(log-rank, 1-sided)

Control 154 96 43.2mos 42.1% MVAC 153 90 74.7mos 57.2%

0.044

SWOG 8710: Overall Survival by Treatment Arm

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 consortium3 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
• Small cell neuroendocrine tumor

Culp , et al, J Urol 191:40, 2014 vonRundstedt, et al Bladder Cancer 3:35, 2017

SWOG 8710 Neoadjuvant M-VAC- Benefit cT2 vs. cT3-T4a

Grossman, et al NEJM 349:859, 2003

Median survival cT2 105 vs. 75 mos cT3-4a 65 vs. 24 mos

Pts with cT2 also benefit from neoadjuvant chemotherapy

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.”

Low Risk Patients Benefit from NAC

Bhindi et al. Eur Urol 72 (5): 660, 2017

Vale, et al Eur Urol 48:202, 2005

Neo-adjuvant Chemotherapy Meta Analysis 5% Survival Advantage

• Individual patient data from 6 randomized trials
• 9% survival benefit with platinum based combination chemotherapy

Cisplatin alone Cisplatin combo

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 trials1,2
• 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 (?)

Luminal

KRT20+, GATA3+, FOXA1+

Basal/Squamous

KRT5,6,14+, GATA3-, FOXA1-

Basal/Squamous Neuronal

FGFR3 mut, fusion, amp Papillary histology SHH+ Low CIS Low purity EMT markers (TWIST1, ZEB1) miR-200 family Medium CD274 (PD-L1), CTLA-4 Myofibroblast markers ‘p53-like’ UPKs KRT20 SNX31 SOX2 DLX6 MSI1 PLEKHG4B E2F3/SOX4 amp High cell cycle Female Squamous differentiation Basal keratin markers High CD274 (PD-L1), CTLA4 Immune infiltrates Low risk NAC* FGFR3 inhibitors Anti-PD-L1, PD-1, CTLA-4 Cisplatin-based NAC** Targeted therapy? Anti-PD-L1, PD-1, CTLA-4 Cisplatin-based NAC Etoposide/Cisplatin NAC

Luminal-papillary Luminal-infiltrated Luminal

** Low response rate * Low likelihood of response based on preliminary data (Seiler et al. 2017)

Robertson, et al Cell, 2018

TCGA (n=412)

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
• ncologist
• 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)

• 12th most common cancer worldwide1
• 199,922 worldwide deaths yearly (2018)
• 8th 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

combination: 4-7 months 4

1. Bray et al. CA CANCER J CLIN 2018;68:394–424 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 microenvironment1,2

• PD-L1 <binds> PD-1 >>>

down-regulates T cell function >>> cancer can evade immune surveillance1,2

• 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

• 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

Trial N Median Age PD-L1 status ECOG PS Histology ≥ 2 prior systemic therapies GFR < 60 ml/min KEYNOTE-0121 Cohort C (UC) (Pembro-) 33 70 (44-85) Only positive (>1% IHC+) patients 72.7% PS1 91% pure UC 51.5% n/a NCT013758422 Urothelial Cancer Cohort (Atezo-) 92 66 (36-89) PD-L1+ >> all comers (52.8% IC2/3) 60% PS1 N/A 72% 41%

• 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

First CPI Trials In Metastatic UC

Phase 2 and 3 trials in patients who were cisplatin ineligible or platinum-relapsed/refractory

• IMvigor 210, cohort 1 (phase 2): 1st line Atezolizumab in cisplatin-ineligible, metastatic patients
• IMvigor 210, cohort 2 (phase 2): Atezolizumab for post-platinum progressive disease
• Imvigor211 (phase 3): Atezolizumab for post-platinum progressive disease
• Checkmate 275 (phase 2): Nivolumab for post platinum progressive disease
• KEYNOTE-045 (phase 3): Pembrolizumab for post platinum progressive disease
• KEYNOTE-052 (phase 2): Pembrolizumab for cisplatin-ineligible patients
• JAVELIN Solid Tumor Study (phase1b): Avelumab for cisplatin-ineligible
• Study 1108 (phase 1/2): Durvalumab for cisplatin-ineligible patients

Cisplatin-Ineligible Patients

• Several studies in first-line therapy for cisplatin-ineligible pts with

mUC

• IMvigor 210, cohort 1: Atezolizumab, phase 2
• n=119 (70% with CKD, 20% ECOG 2)
• KEYNOTE-052: Pembrolizumab, phase 2
• N=370 (43% CKD, 45% ECOG 2)

IMVigor 210: Antitumor Activity

Better reduction in tumor burden with higher PD-L1 expression

IC 0 group IC 1 group IC 2/3 group

Rosenberg JE et al. Lancet 2016; 387: 1909-20

IMVIGOR 210 Update

• Atezolizumab: cisplatin-ineligible (n=119) and second-line N+/M+

(n=310)

• Median follow up: 29 and 33
• Cohort 1: ORR 24%, CR 8%
• Median follow up 23 months
• Late responses seen (>6 mos)
• Median DOR not reached
• Median OS: 16.3 months, 1 yr OS 58%, 2 yr OS 41%
• Cohort 2: ORR 16%, CR 7%
• Median follow up 33 months
• Median OS 7.9 months, 1yr OS 37%, 2 yr OS 23%

DURABLE and TOLERABLE treatment for advanced disease.

• Balar. ASCO 2018

KEYNOTE 052: 1st line Pembrolizumab for Cisplatin-Ineligible

• n=370
• median age 74yrs, 10% over 85yrs, 42% ECOG 2, 85% visceral disease
• Updated results: median follow up 11.5 months
• Overall Response 28.9%
• 8.1% complete / 20.8% partial
• nearly 50% in patients with PDL1 (+) staining
• Response Duration not reached
• 82% >6mos and 68% >12 mos
• Median Survival 11.5 months
• 1yr OS 47.5%
• PDL1 positive: ORR 47.3%, mOS 18.5 months

Vuky et al. Ab#4524, ASCO 2018.

KEYNOTE-045: Pembrolizumab vs 2nd line Chemotherapy

Bellmunt J. N Engl J Med 2017;376:1015; Fradet et al, Ab #4521, ASCO 2018.

Second-Line after platinum-based chemotherapy. Phase 3 chemo vs. Pembro Updated median follow up 27.7 mos ORR 11% (chemo) vs. 21% (Pembro) Overall Survival: Median 7.3 mos (chemo) vs. 10.3 mos (Pembro) Response duration 4.4 (chemo) vs. NR (Pembro)

Outcomes of CPI Trials For UC

Trial Phase N ORR (%) CR (%) Highest PDL1 dep RR (%) Median OS, mos Rate of AEs > Grade 3, % 2nd line Atezolizumab1,2 2 310 16 7 27 7.9 16% Nivolumab3,4 2 270 20.7 6.7 25.8 8.6 18% Avelumab5 1 249 17 3 24 8.2 8% Durvalumab6 1/2 191 17.8 3 27.6 18.2 6.8% Pembrolizumab Vs chemo7 3 542 21.1 11.0 9.3 2.9 20.3 (vs 6.7) 10.3 7.4* 16.5 50.2 Cis-Ineligible Pembrolizumab8 2 370 28.9 8.1 yes 11.5 16% Atezolizumab2 2 119 24% 8% yes 16.3 16%

• 1. Balar et al. Lancet 2017; 389:67-76. 2. Balar ASCO 2018. 3. Siefker-Radtke ASCO 2019. 4. Sharma et al. Lancet Oncol 2017: 18:312-22. 5. Patel et al. Lancet

Oncol 2018; 19: 51–64. 6. Baldini et al. Onco Targets Ther. 2019; 12: 2505–2512. 7. Fradet et al. Annals of Oncology 30: 970–976, 2019. 8. Balar et al Lancet Oncol 2017:18: 1483-92.

*60% of chemotherapy pts alive received CPI

Adverse Events

• Treatment-related toxicities
• fatigue, nausea, pruritis, arthralgias, fever, diarrhea, infusion reactions
• <20% with grade 3 AEs
• Immune-related toxicities
• pneumonitis, transaminitis, rash
• Approximately 20%, mostly grade 1/2
• Grade 3 immune related AE very rare but can be lethal
• in Imvigor 210, 22% pts received steroids to manage AE
• Compared to chemotherapy, less treatment related AE and less

discontinuations

FDA Approval

• Five checkpoint inhibitors are FDA-approved for second-line treatment of

metastatic UC

• Atezolizumab (Tecentriq) – FIRST approved, 2016
• Nivolumab (Opdivo) – 2/2017
• Avelumab (Bavencio) – 5/2017
• Pembrolizumab (Keytruda) – 5/2017
• Durvalumab (Infinzi) – 5/2017
• Two checkpoint inhibitors are FDA-approved for 1stline in cisplatin-ineligible

patients

• Atezolizumab
• Pembrolizumab

https://www.cancer.gov/about-cancer/treatment/drugs/bladder

Future Directions

• Frontline combinations
• IMvigor 130 (phase 3) : 3 arms: platinum+ gemcitabine +atezolizumab vs

atezolizumab vs chemo

• Checkmate 901(phase 3): nivo/ipi ànivo vs platinum/gemcitabine
• Cisplatin-eligible only pts: cis/gem +nivoànivo
• DANUBE (phase 3): durvalumab+tremelimumab vs chemo 1st line
• KEYNOTE 361 (phase 3): chemo+pembro vs pembro vs chemo

Future Directions

• Maintenance after platinum combination
• HCRN GU14-182 (phase 2): Switch maintenance with pembrolizumab

improved PFS; OS results not mature

• JAVELIN 100 (phase 3): Switch maintenance avelumab after platinum

response

Other Future Directions

• Neoadjuvant and adjuvant immunotherapy trials
• Immunotherapy with chemoradiation
• Immunotherapy with new targeted agents
• Immunotherapy in non-muscle invasive bladder cancer

Take-Away: Metastatic MIBC

• Since the first approval of a checkpoint inhibitor in bladder cancer,

treatment landscape of bladder cancer has changed dramatically and will continue

• Five checkpoint inhibitors are approved for second-line therapy in

metastatic UC

• Atezolizumab and Pembrolizumab approved for first-line therapy in

metastatic UC cases ineligible for cisplatin if high PDL1 expression or unfit for any platinum

Additional SPL slides

Neoadjuvant Chemotherapy - Future

• Currently one size fits all
• Prognostic biomarkers
• Predictive biomarkers

– COXEN – DNA damage repair genes – Expression subtypes

• Precision medicine

SWOG S1314 COXEN Validation Neoadjuvant Chemotherapy Trial

Selection Criteria SWOG 8710 (T2-T4a N0M0, cisplatin eligible)

C Y S T E C T O M Y

Randomize to chemo n=184 Gem-Cis DD-MVAC

Assessment

To characterize the relationship of MVAC- and GC-specific COXEN scores in terms of pT0 rate

Biomarker validation and Biomarker discovery

Tumor Sample TURBT

Collection

Tissue, blood, urine

Molecular Analysis

Gene expression Sequencing microRNA SNP

Collection

Tissue (>P0), blood, urine

Molecular Analysis

Gene expression Sequencing microRNA SNP Cystectomy Pathology

Discovery

Activated July 1, 2014 Completed enrollment 12/17

S1314: Favorable GC score and (pT0 + ≤ pT1) response in pooled arms (n=167)

Pathologic Response GC score in pooled treatment arms Favorable Not favorable pT0 18 (42%) 37 (30%) Downstaged ≤ pT1 10 (23%) 22 (18%) Non-responders 15 (35%) 65 (52%) Total 43 (100%) 124 (100%)

GC Score – Predictive Properties in Combined Arms Sensitivity Specificity

PPV NPV

pT0 + downstaging 28/87 = 32% 95% CI: (23%, 43%) 65/80 = 81% 95% CI: (71%, 89%)

28/43 = 65% 95% CI: (49%, 79%) 65/124 = 52% 95% CI: (43%, 61%)

Flaig, et al ASCO 2019

DNA Damage Repair Pathway Alterations Predict NAC Response

Van Allen et al, Cancer Discovery 4:1140, 2014 Plimack, et al Eur Urol 68:959, 2015

DNA damage repair genes

Phase II ddGC NAC ATM, FANC, RB-1 and NAC Response

Iyer, et al JCO 36:1949-1956, 2018

ERCC2 ERCC5 BRCA1 BRCA2 RAD51C ATR RECQL 4 ATM FANCC

Modified DDR gene panel

Deleterious alterations in one or more of these genes will allow patients to be potentially eligible for the bladder-sparing arm of the study

271 patients 59 patients 187 patients WES Mutation signature of DDR impairment Novel alterations associated with response ChemoRT

2500

Primary Endpoint: 3-year recurrence-free survival in bladder sparing group

A031701: A phase II study of dose-dense Gemcitabine plus Cisplatin in patients with muscle-invasive bladder cancer with bladder preservation for those patients whose tumors harbor deleterious DNA damage response (DDR) gene alterations

MDA_basal MDA_p53 MDA_luminal Lum−Pap Neuronal BS Lum−Inf Lum GSM1709080 GSM1709072 GSM1709066 GSM1709091 GSM1709073 GSM1709096 GSM1709084 GSM1709097 GSM1709083 GSM1709088 GSM1709069 GSM1709101 GSM1709102 GSM1709092 GSM1709076 GSM1709085 GSM1709093 GSM1709082 GSM1709070 GSM1709086 GSM1709094 GSM1709074 GSM1709079 GSM1709098 GSM1709081 GSM1709100 GSM1709089 GSM1709087 GSM1709071 GSM1709068 GSM1709095 GSM1709078 GSM1709067 GSM1709090 GSM1709099 GSM1709103 GSM1709075 GSM1709077 Sample TCGA Clusters

Single−sample classification: GSE69795

+ + + + + + + + + + + + + + + + + + + + + + +

Log−rank P= 0.17

0.00 0.25 0.50 0.75 1.00 20 40 60 Survival time (months) Survival probability

TCGA Clusters BS_13_2 Luminal−Inf_8_4 Luminal−Pap_15_7

Choi et al: DDMVAC+ bevacizumab Confidential do not publish K=5 TCGA MDA