RECENT DEVELOPMENTS in Muscle Invasive Bladder Cancer

Transcription

1 RECENT DEVELOPMENTS in Muscle Invasive Bladder Cancer IX CIS and EURASIA ONCOLOGY and RADOLOGY CONGRESS, ONCOUROLOGY SESSION 16 June 2016 Richard E Greenberg, MD, FACS Chief Urologic Oncology, Fox Chase Cancer Center Professor of Urology, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania, USA

2 Fox Chase Cancer Center Philadelphia, PA., USA

3 Epidemiology 75,000 new cases and 16,000 deaths in 2014 Number increased > 50% in the US ( ) 3-4 times more common in men Whites twice as often as AA Highest incidence in the Northeast US and least in Hawaii and Utah Median age at diagnosis: 69 in men and 71 in women Int J Cancer. 2001;91(4):575.

4 Risk factors 50% of all cases caused by smoking for both men and women (HR 3.89 and 4.65) 20% of all cases has occupational exposure: aromatic amines, benzidine and their derivatives (metal workers, painters, rubber industry, leather workers, electrical workers, miners, cement workers, transport operators) 5 fold increase was observed in subjects who worked for > 10 years as hairdressers or barbers in LA Chronic cystitis (squamous cell) Schistosoma haematobium, Foley FAMILIAL: HEREDITARY NONPOLYPOSIS COLORECTAL CANCER (LYNCH II) Iatrogenic: Radiation (controversial) Cyclophosphamide (4.5-fold increased risk of bladder cancer ) Phenacetin (increased risk of TCC renal pelvis) Pioglitazone (Actos)

5 Clinical Presentation & Diagnosis Hematuria (intermittent, gross, painless, and present throughout micturition) 12% incidence of bladder cancer ( Urol. 2000;163(2):524). Pain advanced disease Voiding symptoms (irritative or obstructive) DIAGNOSIS: UA Urine cytology (false-positive results are rare) Cystoscopy => the gold standard (often multifocal the entire urothelium needs to be evaluated if a tumor is found) Imaging ( CT urogram) For patients with confirmed muscle-invasive bladder cancer, CT CAP is the optimal form of staging, including CT urogram for complete radiologic evaluation of the upper urinary tracts

6 Pathology Urothelial TCC (low-grade and high-grade) 90% BLADDER (94%) RENAL PELVIS (5%) URETER (1%) Multicentric and bilateral (up to 10%) Up to 50% of upper tract Ca will develop bladder Ca Squamous (5%) Adenocarcinoma (1-2% ) Small cell Sarcomas

7 Bladder Cancer o non-muscle-invasive or superficial (NMIBC) 70% - 75% of patients (i.e., stage Ta, Tis, or T1) In the absence of muscularis propria in the specimen, data suggests that 20-40% of patients will have either residual tumor and/or unrecognized muscle invasive disease => repeated biopsy is mandatory! (Guidelines) o muscle-invasive (MIBC) o metastatic

8 NMIBC

9 Treatment options for NMIBC Standard treatment options: o TUR with fulguration recurrence after initial resection around 80% o TUR with fulguration followed by intravesical chemotherapy epirubicin, mitomycin C, thiotepa, pirarubicin reduced the odds of recurrence by 39% o TUR with fulguration followed by intravesical chemotherapy followed by BCG an induction phase of six weekly treatments followed by three weekly treatment every 3 months CR rates of about 70%, Decreasing the need for salvage cystectomy No survival advantage Risk factors for recurrence and progression are: o High-grade o CIS o Tumor > 3 cm o Multiple tumors o History of prior bladder cancer

10 MIBC

11 Treatment for MIBC (stage II - III) 1. Neoadjuvant chemo, followed by radical cystectomy 2. Radical cystectomy (? +/- adjuvant chemo or RT) 3. EBRT plus concomitant chemo 4. EBRT alone

12 Neoadjuvant Chemotherapy BA trial (Medical Research Council and the EORTC) J Clin Oncol 29 (16): , patients with T2 T4a disease randomized to - definitive treatment (surgery or RT) - 3 cycles of neoadjuvant cisplatin, vinblastine, and methotrexate RESULTS: - Median follow-up of 8.0 years OS was significantly greater (HR 0.84, P =.037). - The survival benefit 6% absolute increase SWOG study NEJM 349 (9): , patients with stage T2 to stage T4a a) 3 cycles of neoadjuvant MVAC b) cystectomy RESULTS: - 5-year OS was 57% vs 43% (two-sided P value =.06). - No deaths were associated with neoadjuvant chemotherapy and preoperative chemotherapy did not prevent cystectomy - 38% had a pathologic CR - 85% of those achieving a pathologic CR were alive at 5 years

13 Neoadjuvant chemo Meta-analysis (Lancet 361 (9373): , 2003) 2,688 pts, 10 randomized trials of neoadjuvant chemo cisplatin-based chemotherapy was associated with a significant 13% relative reduction in the risk of death and resulted in an improvement in 5-year survival from 45% to 50% (P =.016) Meta-analysis (A. J Urol 171 (2 Pt 1): 561-9, 2004) 2605 pts, 11 randomized controlled trials eight trials that used multiagent, cisplatin-based chemotherapy, neoadjuvant chemotherapy was associated with a 6.5% absolute benefit in 5-year OS (50% vs. 56.5%; P =.006)

14 Neoadjuvant Chemotherapy is Standard of Care for MIBC Magnitude of benefit similar to adjuvant 5FU therapy for CRC, which is widely accepted International Standard of Care (Level 1) Bajorin et al, JCO, Eur Urol 48, 202 (Aug, 2005).

15 yet underutilized National database query only 11.6% of stage III patients received perioperative chemotherapy Survey of 14 academic centers only 35% received perioperative chemotherapy Of these, 30% neoadjuvant, 60% adjuvant Of the neoadjuvant patients, only 65% received cisplatin Commonly cited reason is time (delay to surgery) and perceived toxicity David et al. J Urol, 2007 Feifer. GU ASCO 2011

16 von der Maase et al. J Clin Oncol, 2000 What is standard neoadjuvant chemotherapy? Cisplatin based Prospective neoadjuvant studies used conventional MVAC or CMV regimens Data in the metastatic setting showed similar outcomes with GC vs. conventional MVAC, but less neutropenic fever/sepsis with GC. In practice GC is more commonly used, despite lack of prospective neoadjuvant data NCCN guidelines currently list GC, CMV or accelerated/dose dense MVAC as options Conventional MVAC is no longer recommended

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18 Phase II Clinical Trial of Neoadjuvant AMVAC in MIBC Hypothesis: AMVAC will yield similar pt0 rate to standard MVAC with shorter time to surgery and less toxicity Primary Objective To asses the rate of complete response (pt0) at surgery Secondary Objectives Toxicity, Overall Survival, Correlative Studies Inclusion Clinical stage: T2-T4a, cn0-n1 Candidate for surgery PS 0 or 1 EF normal CrCl > 50 ml/min (measured or calculated) Exclusion Any 100% non urothelial histology Any component of small cell carcinoma Previous systemic chemotherapy Neuropathy > Gr 1

19 Pathologic Response T3, T4, N+ 35% T0 38% T2 13% T1 8% Tis Ta 8%

20 Summary Collective experience in the neoadjuvant and metastatic setting shows AMVAC to be safe Q2 week administration is efficient, minimizing delays to surgery Optimal number of cycles is not defined, but 3 and 4 have both been explored with pt0 results similar to historical controls. Neoadjuvant AMVAC is now our standard of care at FCCC, becoming more common at other centers

21 Radical cystectomy Radical cystectomy with pelvic lymph node dissection oincludes removal of the bladder, perivesical tissues, prostate, and seminal vesicles in men and removal of the uterus, tubes, ovaries, anterior vaginal wall, and urethra in women operioperative mortality rate of 2% to 3% oearly complications (any complication within 3 months of surgery)=> 28% ofive-year OS = 50% to 60%

22 Results of radical cystectomy Stage Recurrence-Free Overall Survival 5 y. 10y. 5 y. 10y. T2 N N T3a N N T3b N N T4a N N Stein et al JCO 2001;19:666

23 Results of radical cystectomy Stage Recurrence-Free /Overall Survival 5 years Organ-confined (<pt2pno) 73% 62% non-organ-confined (>pt2pno) 56% 49% Positiv lymph nodes (pt1-4, pn+) 33% 24% Madersbacher et al JCO 2003;21:690

24 Adjuvant chemotherapy Eight randomized trials have compared chemo with observation after definitive therapy, only 4 completed accrual Only 2 showed benefit from adjuvant chemo (each trial enrolled fewer than 100 patients) Not standard of care Could be considered for node positive disease, lymphovascular invasion, positive margins in pts who are candidates for cisplatin-based chemotherapy

25 EBRT alone frail, elderly patients or those medically unfit best results are seen in patients with solitary lesions and without carcinoma in situ or hydronephrosis local recurrence after RT alone is up to 70% (inferior results compared to cystectomy) 5 year OS from 20 40% not considered an acceptable alternative to radical cystectomy in otherwise healthy patients

26 Tri-modal Bladder-sparing protocol TURBT (maximally resect the tumor) Synchronous Therapy: RT + chemotherapy (cisplatin, paclitacel, fluorouracil, mitomycin C) Cystoscopy after 40 Gy no tumor + tumor Consolidation: RT + CT (completed to a dose of about 65 Gy) cystectomy

27 Results of bladder-sparing therapy and cystectomy Bladder-sparing n Pat. 5y. OS 5y. Survival therapy % with Bladder % Houssett NA Sauer Shipley Shipley Rodel Cystectomy Dalbagni NA Stein NA

28 Bladder-sparing protocol T2: 5y / 10y OS: 74% / 66% T3-T4a: 5y / 10y OS: 53% / 52% Shiply et al. Urology 2002;60:62

29 Combined-modality treatment and organ preservation in invasive bladder cancer Rödel et al. JCO 2002;20: pts with T1 high-risk, T1-4, N0-1 - between 1982 and Transurethral resection a) RT (n=126) b) RCT (n=289) 2. RT median 54 Gy, CT cisplatin week 1 and 5 (25 mg/m2/d on 5 consecutive days) in 145 pts; carboplatin (65 mg/m2/d on 5 consecutive days) in 95 pts (Cr Cl < 60) or cisplatin (20 mg/m2/d on consecutive days) and 5-fluorouracil (5- FU) (600 mg/m2/d; 120-hour continuous infusion) was applied to 49 patients.) 3. Restaging-TUR after 6 weeks RESULTS: Complete remission 72% Local control after CR 64% (10 y.) Distant metastasis 35% (10 y.) Disease-specific survival 42% (10 y.) Preservation of bladder >80%

30 Disease-specific survival for patients after salvage cystectomy 50% 45% 21% 18% Rödel et al. JCO 2002;20:3061

31 Randomized trials that directly compare the bladder-preserving chemoradiation therapy approach with radical cystectomy have not been performed; the relative effectiveness of these two treatments is unknown

32 TUR alone Additional surgical bladder preservation techniques Radical endoscopic resection Higher rates of recurrence than radical surgery or multimodal treatments Focal lesions. No hydro, negative resection bed biopsy, no UT TUR plus systemic chemotherapy Cisplatin based neoadjuvant ot adjuvant protocol Reserved fpr patients refusing standard therapy Partial cystectomy(2-3% of MIBC ) Limited disease inpatients medically unfit for radical surgery Solitary tumor amenable to complete resection No CIS

33 Metastatic disease the median survival is about 15 months 5 year survival rate is about 15 % A poor performance status (Karnofsky < 80), the presence of visceral (ie, pulmonary, liver, bone) metastases correlate with shortened survival The presence of these unfavorable features was associated with a median survival of 4 months

34 Front line therapy A cisplatin-based combination chemotherapy regimen is the preferred initial therapy Cisplatin-based combination chemotherapy results in superior survival when compared with single-agent cisplatin Cisplatin-based regimens: MVAC Methotrexate, vinblastine, doxorubicin, and cisplatin GC Gemcitabine plus cisplatin PCG Paclitaxel, gemcitabine, and cisplatin

35 MVAC MVAC is a standard first-line option 269 patients with advanced urothelial carcinoma randomly assigned to treatment with either MVAC or single-agent cisplatin. Results: 1. improvement in the ORR: 39 vs. 12% 2. increase in PFS: 10 vs. 4 months 3. improvement in OS: 13 vs. 11 months J Clin Oncol. 1992;10(7):1066.

36 GC A phase III trial 405 patients were randomly assigned to either GC or MVAC RESULTS: Similar ORR (49 vs. 36%). Similar time to progression (7 months in each arm). Similar OS (14 vs. 15 months). Similar quality of life, though patients experienced less weight loss, a better performance status, and less fatigue. Less serious (grade 3/4) toxicity, including neutropenia (71 vs. 82%), neutropenic sepsis (2 vs. 14%), and mucositis (1 vs. 22%) Alternate dosing schedules with the GC regimen have used a threeweek instead of four-week schedule J Clin Oncol. 2000;18(17):3068.

37 PCG European Organization for the Research and Treatment of Cancer Study (EORTC 30987) o 626 patients with advanced urothelial carcinoma and randomly assigned them to treatment with GC or PGC for a maximum of six cycles. o A median follow-up of 4.6 years o RESULTS: - An increase in the ORR (56 vs 44%, p = 0.003). - A trend towards an improvement in PFS (8.3 vs. 7.6 months) - A trend towards longer OS (15.8 vs months, P = 0.075) - Increased incidence of serious (grade 3/4) toxicity, including neutropenia (65 vs. 51%), fatigue (15 vs. 11%), and infections (18 vs 14 %) - These results suggest that PGC is a treatment option for patients with metastatic urothelial carcinoma J Clin Oncol. 2012;30(10):1107.

38 Carboplatin + Gemcitabine EORTC patients with impaired renal function (GFR <60 but >30 ml/min) and/or a poor performance status ( ECOG 2) were randomly assigned to Carbo/Gem or methotrexate, carboplatin, plus vinblastine (MCAVI). RESULTS: ORR (41 vs. 30%) that did not reach statistical significance. No difference in median OS (9 vs. 8 months) No difference in median PFS (6 vs. 4 months) Less serious (grade 3/4) toxicity overall (9 vs. 21%), including neutropenia (52 vs. 63% percent) and febrile neutropenia (5 vs. 15%). Option for patients with impaired renal function or a poor performance status (ECOG 2)

39 Cisplatin contraindications ECOG 2 or greater or Karnofsky 60 to 70 or less Cr clearance < 60 ml/min A hearing loss (measured at audiometry) of 25 db at two contiguous frequencies Grade 2 or greater neuropathy NYHA class III or greater CHF

40 Non platinum regimens Paclitaxel plus gemcitabine appears to be more active than docetaxel plus gemcitabine: Paclitaxel plus gemcitabine ORR 54 70% and median OS of months Toxicity with this combination is primarily hematologic, although severe pulmonary toxicity was reported J Clin Oncol. 2005;23(6):1185. Docetaxel plus gemcitabine: ORR % and median OS of months Cancer. 2003;98(9):1863; Br J Cancer. 2005;92(4):645.

41 Second line chemotherapy response rates < 20% no one regimen is considered to be the standard second-line therapy Ifosfamide, oxaliplatin, pacitaxel, docetaxel, gemcitabine

42 Treatment of muc Advanced UC is a uniformly fatal disease after failure of platinum chemotherapy Median survival is short Durable responses are not routinely observed in this patient population Grade 3-4 toxicities are high with 2L chemotherapy Difficult to treat patient population Vinflunine is the only approved agent in the EU, but has no survival benefit compared with BSC in the intent-to-treat population Vinflunine was tested in a pure 2L population ORR of 8.6% (vs 0% for BSC) 1 No single-agent therapy has been observed to improve median OS mos Vinflunine + BSC: 6.9 mo BSC: 4.6 mo BSC, best supportive care; VFL, vinflunine; 2L, second-line. Reference: 1. Bellmunt et al. J Clin Oncol

43 Immune Checkpoint Inhibition in Urothelial Cancer

44 Atezolizumab (MPDL3280A): A Humanized Anti-PDL1 Antibody Atezolizumab (anti-pdl1) T cell Tumor cell T cell Atezolizumab (anti-pdl1) Signaling through programmed deathligand 1 (PD-L1), which is expressed in many cancers including muc, can inhibit antitumor immune responses Atezolizumab can enhance T-cell priming and reinvigorate suppressed immune cells by inhibiting binding of PD-L1 to PD-1 and B7.1 By leaving the PD-L2/PD-1 interaction intact, atezolizumab has the potential to preserve peripheral immune homeostasis 1,2 Dendritic cell References: 1. Akbari et al. Mucosal Immunol Matsumoto et al. Biochem Biophys Res Commun

45 IMvigor 210: Phase II Study Locally advanced or metastatic cancer of the bladder, renal pelvis, ureter or urethra Predominant transitional cell histology Progression during or following platinum No restriction on number of prior lines of therapy Creatinine clearance 30 ml/min ECOG PS 0-1 Tumor tissue evaluable for PD-L1 testing a Atezolizumab 1200 mg IV q3 weeks until loss of clinical benefit Response assessment q9 weeks (q12 weeks after 54 weeks) Co-primary Endpoints ORR (confirmed) per RECIST v.1.1 (central independent review) Investigator-assessed ORR per modified RECIST Primary endpoints met if null hypothesis (ORR of 10%) rejected at significance level (α) of 5% Key Secondary Endpoints PFS, DOR, OS, Safety a PD-L1 prospectively assessed by central laboratory. Patients and investigators blinded to PD-L1 IHC status. Trial Identifier: NCT

46 Screened (n = 486) Enrolled (n = 316) Received treatment (N = 311) Still on therapy (n = 88) Discontinued treatment (n = 223) Progression of disease (n = 196) Adverse event (n = 11) Withdrawal by subject (n = 8) Death (n = 3) Other (n = 2) Physician decision (n = 2) Non-compliance (n = 1) Excluded (n = 170 a ) Brain metastasis (n = 26) ECOG PS2 (n = 22) Inadequate hematologic/end organ function (n = 18) Life expectancy < 12 wk (n = 15) Informed consent form not signed (n = 14) No measurable disease (n = 13) Inadequate tissue (n = 7) Other (e.g. autoimmune disease, prior therapy, abnormal laboratory results; n = 53) Treated patients b : Europe 26.4% United States/Canada 73.4% Safety/efficacy evaluable (N = 311) a Includes re-screened patients. b Excludes 1 patient with unknown site.

47 PD-L1 Immune Cell Expression and Prevalence IHC Status of Treated Patients in IMvigor 210 Study (N = 311) 5% 1 but < 5% < 1% IC2/3 IC1 IC0 IC2/3 32% n = 100 IC0 33% n = 103 IC1 35% n = 108 IMvigor 210 enrolled an all-comer population VENTANA PD-L1 (SP142) CDx Assay was used to prospectively measure tumor-infiltrating immune cell (IC) PD-L1 expression based on 3 IHC scoring levels Images at 10x magnification.

48 Baseline Characteristics Characteristic N = 311 Age, median (range) 66 y (32-91 y) Male 78% Bladder primary tumor 75% Creatinine Clearance < 60 ml/min 35% ECOG PS 1 62% Hemoglobin 10 g/dl 22% Metastatic sites at baseline Visceral a 78% Liver 31% Prior systemic regimen setting Metastatic 78% 2 regimens for metastatic disease 20% 3 regimens for metastatic disease 20% No significant differences in baseline demographics between PD-L1 subgroups a Visceral metastasis defined as liver, lung, bone, any non-lymph node or soft tissue metastasis. Data cutoff May 5, 2015.

49 RECIST v1.1 Criteria by Independent Review a PD-L1 subgroup n CR (%) ORR (%) 95% CI P value b IC2/ % 27% 19, 37 <.0001 IC1/2/ % 18% 13, All 311 4% 15% 11, IC % 10% 5, 18 N/A c IC % 9% 4, 16 N/A c IMvigor 210 met its co-primary endpoints in all subgroups tested ORR by independent review (RECIST v1.1) and investigator (mrecist) were concordant Early response data are likely to mature in subsequent analyses a Objective response evaluable population: all treated patients had measurable disease at baseline per investigator-assessed RECIST v1.1. = c No formal hypothesis testing conducted. Data cutoff May 5, Follow up 24 weeks. b P-value for H o : ORR 10% versus H a : ORR 10%, where 10% ORR is historical control, α

50 Mean SLD Reduction from Baseline, % 51/85 (60%) a Efficacy: Changes in Target Lesions by PD-L1 Subgroup PD-L1 status IC2/3 ORR b 27% aaa 38/88 (43%) 0 IC1 10% aa 27/85 (32%) 0 IC0 9% -100 PD SD PR CR Unknown 111/258 (43%) patients with tumor assessments had SLD reduction SLD, sum of longest diameters. a > 100% increase. b Per confirmed RECIST v1.1 (independent review). Data cutoff May 5, Follow up 24 weeks. Patients without post-baseline tumor assessments not included. Several patients with CR had < 100% reduction due to lymph node target lesions. All lymph nodes returned to normal size per RECIST v1.1.

51 Efficacy: Subgroup Analyses ORR, % (95% CI) a Subgroup IC2/3 All Prior systemic regimens, metastatic setting b 1 26% (12, 43) 12% (7, 19) 2 39% (17, 64) 18% (9, 30) 3 20% (6, 44) 13% (6, 24) Metastatic sites at baseline Visceral 17% (9, 28) 10% (6, 14) Liver 15% (4, 34) 6% (2, 13) Lymph node only 38% (19, 59) 33% (20, 49) ECOG PS 1 19% (10, 31) 10% (6, 15) Hemoglobin < 10 g/dl 21% (7, 42) 9% (3,18) Median DOR not yet reached in any of the subgroup populations a Per RECIST v1.1 (independent review). b In patients with 0 prior regimens, ORR (95% CI) was 26% (11, 46) in IC2/3 patients (n = 27) and 20% (11, 31) in all-comer patients (n = 70). Data cutoff May 5, Follow up 24 weeks.

52 Progression-Free Survival Survival Progression-Free Survival IC2/3 n = 100 IC0/1 n = 211 All N = 311 Median PFS, a mo (95% CI) 2.1 (2.1, 4.1) 2.1 (2.0, 2.1) 2.1 (2.1, 2.1) IC2/3 IC0/1 + Censored a Per RECIST v1.1 (independent review). Data cutoff May 5, Follow up 24 weeks Time, months No. at Risk IC2/3: IC0/1:

53 Overall Survival Preliminary Analyses of Overall Survival Survival IC2/3 n = 100 IC0/1 n = 211 All N = 311 Median OS, mo (95% CI) NR (7.6, NE) 6.7 (5.7, 8.0) 7.9 (6.7, NE) 100 Median follow up: 7 mo (range, 0-11 mo) IC2/3 IC0/1 + Censored Time, months No. at Risk IC2/3: IC0/1: NR, not reached; NE, not estimable. Data cutoff May 5, Follow up 24 weeks.

54 Conclusions IMvigor 210 met its co-primary endpoints in IC2/3, IC1/2/3 and all-comer subgroups, demonstrating significant improvement over a historical 10% ORR Durable responses were seen in a heavily pretreated population with muc that progressed on platinum-based chemotherapy Median duration of response was not reached in any IC or prognostic subgroup (e.g. liver metastases at baseline) Higher PD-L1 IC status was associated with higher ORR Overall survival data are immature at this time Atezolizumab was well tolerated with a low rate of treatmentrelated Grade 3-4 toxicities and no treatment-related renal toxicity No treatment-related deaths were observed Atezolizumab has the potential to change the standard of care in metastatic urothelial carcinoma

55 PD-1 Pathway and Immune Surveillance Programmed cell death receptor 1 (PD-1) is a negative co-stimulatory receptor expressed primarily on activated T cells 1,2 Binding of PD-1 to its ligands PD-L1 and PD-L2 inhibits effector T-cell function 1,2,3 Expression of PD-L1 on tumor cells and macrophages can suppress immune surveillance and permit neoplastic growth 1,2,3 1. Keir ME et al. Annu Rev Immunol. 2008;26: Pardoll DM. Nat Rev Cancer. 2012;12: Hirano F et al. Cancer Res. 2005;65:

56 Pembrolizumab Phase I: PFS and OS

57 PD-1/L1 Blocking Antibodies in Clinical Development in Urothelial Cancer Company Agent Target Bristol-Myers Squibb Nivolumab PD-1 Merck Pembrolizumab (MK-3475) PD-1 Genentech/Roche Atezolizumab (MPDL3280A) PD-L1 Medimmune/AZ Durvalumab (MEDI4736) PD-L1 Merck Serono/Pfizer Avelumab (MSB C) PD-L1

58 2 nd line and beyond 1 st line Ongoing Trials with Checkpoint Inhibitors Bladder Cancer Non-muscleinvasive bladder cancer Muscle-invasive bladder cancer Metastatic bladder cancer Low grade High grade Neoadjuvant Adjuvant Cisplatin-eligible Cisplatin-ineligible In development Pembrolizumab/ BCG In development Trimodality Atezolizumab (Ph III) Maintenance Pembrolizumab (Ph II) Atezolizumab (Ph II) BCG-refractory In development Pembrolizumab (Ph II) Avelumab (Ph III) Pembrolizumab (Ph II) Cisplatin-refractory Pembrolizumab (Ph III) Atezolizumab (Ph III) Nivolumab (Ph II) Adapted from: Fakhrejahani F et al. Curr Opin Urol 2015;25:

59 Take home messages Absence of muscularis propria in the biopsy specimen => repeated biopsy is needed! Neoadjuvant chemo, followed by radical cystectomy is standard of care NCCN: GC, CMV or accelerated/dose dense MVAC as options Optimal number of cycles is not defined, but 3 and 4 have both been explored with pt0 results similar to historical controls Adjuvant chemo => considered for node positive disease, lymphovascular invasion, positive margins Front line regimens for metastatic disease: AMVAC, GC or PGC No standard second-line chemotherapy: Ifosfamide, oxaliplatin, pacitaxel, docetaxel, AND CLINICAL TRIALS Checkpoint inhibitors are now approved for second line Rx:ATEOILIZUMAB Research ongoing with adjuvant check point inhibitors

60 What takes me home