Treatment of muscle invasive bladder cancer. ie: pt2. N. Mottet

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1 Treatment of muscle invasive bladder cancer ie: pt2 N. Mottet

2 Disclosures Astellas BMS Pierre Fabre Sanofi

3 MIBC: really undertreated MIBC in the US (national database). Gray Eur Urol 2013 Patients seen: N = median age: 72 years

4 Neoadjuvant chemotherapy (NAC) A MUST in all the guidelines published (Gr A) At least the following EAU ESMO NCCN Only limitation: patients fit enough to receive cisplatin

5 Neoadjuvant chemotherapy ABC. Eur Urol 2005 N = (RCT, local treatment ± neoadjuvant chemotherapy). back to individual data 822 deaths / 1406 if neoadj CT deaths / 1403 control Absolute + 5% OS (5 years). No difference age / sexe / N / T / PS Cisplatine alone When used OS identical SWOG MRC/EORTC Polychemotherapy with CisPlatine Global

6 Neoadjuvant chemotherapy ABC. Eur Urol 2005 OS HR: 0,86 (0,77 0,95). p = 0,003

7 Griffiths J Clin Oncol 2011 Median follow up: 8 years 17% > 70 years OS MRC / EORTC trial Complete population ITT HR: 0.84 ( ). P = 0.037

8 Bladder response with MV(A)C Treatment and source n pt0 5-y surv. pt0 5-y surv. (all pt) Comment MVAC Grossman, NEJM 2003 CMV Hall, ASCO 2002 Meta-analysis 7 trials, Winquist, J Urol 2004 Accelerated MVAC Plimack, J Clin Oncol % 57% % 87% 50% % - 55% 44 38% pt0 not translated into survival pt0 - rate only independent predictive factor of OS in 4 trials

9 Bladder response with Gem/Cis Treatment and source n pt0 Comment Gem/Cis Dash, Cancer % retrospective Gem/Cis Weight, Cancer % Lack of dose density and excessive delay of radical cystectomy! Gem/Cis Yuh, J Urol % (47% <pt2) pooled analysis of 7 studies Gem/Cis MVAC Lee, Adv in Urol % 22% (<pt2: 35% vs 49%) retrospective analysis, (87 neoadj chemo)

10 Very selected population NAC without cystectomy Deserves a clinical trial OS Herr 2008 Immediate cystect. Cystect. at relapse All pt0 after NAC Meyer J Urol 2014 OS based on TTT modality Sternberg 2003

11 Patients refusing cystectomy after NAC Herr, Eur Urol 2008 Sternberg, Cancer 2003 Meyer, J Urol 2014 CR (ct0) after NAC. (MVAC) N= 63 N= 37 N=25 5-year survival 64% 68% DSS 88% Intact bladder 54% 51% 72% Relapse in bladder Muscle invasive Non muscle invasive 64% 35% 52% 28% 24% Relapse metastatic n.r. 24% - Alive with intact bladder n.r. 38% -

12 Adjuvant chemotherapy Leow Eur Urol 2014 N = 945 patients 9 RCT Relative 23% OS benefit (almost significant)

13 Adjuvant chemotherapy Leow Eur Urol 2014 N = 945 patients (9 RCT) NOT based on individual data Benefit mainly in pn+

14 Adjuvant chemotherapy: EORTC Sternberg Lancet Oncol 2015 N = 284 patients (out of 660 planned) pt3-4, or pn1-3 M0 4 GC / DD MVAC / MVAC OR deferred CT at relapse (6 cycles) pn0 OS Modified HR for "meta-analyse": 0.77 ( ) Sternberg Lancet Oncol 2015 pn+

15 MIBC: Standard of care Witjes. EAU guidelines 2016

16 MIBC: Standard of care Witjes. EAU guidelines 2016

17 Radio-chemotherapy better than RX alone Numerous phase I/II studies: feasible and safe Three phase III studies: benefit in terms of local control RT vs RT + Cisplatin (NCIC) RT vs RT + Nicotinamide/Carbogen (BCON) R-CON CDDP Hoskin PJ, J Clin Oncol 2010 P = 0.34 Coppin CM, J Clin Oncol 1996

18 Radio-chemotherapy better than RX alone N = 360 (median age: 72 years) James NEJM 2012 T2-4, N0. PS 2, GFR 25 ml/min, liver function < 1.5 upper limit Rx : RX + 5FU 500 mg/sqm/day [D1-5 / 16-20] + MMC: 12 mg/sqm D1

19 Radio-chemotherapy with TURB Combined analysis 6 RTOG protocols Mak JCO 2014 N = 468 T2-4a N0. All included Cisplatine (several dosages / schedules) Median age: 66 years (36% > 70 years)

20 Radio-chemotherapy with TURB Best results if T2, complete TUR-B, single lesion NO hydronephrosis NO CIS NO tumour invasion into stroma of the prostate Well functioning bladder Otherwise only an alternative to cystectomy (relative efficacy?)

21 Radio-chemotherapy: a real alternative? OS Rene. Current Oncology 2009

22 Effective alternatives Systematic revue (Ploussard Eur Urol 2014) Requires patients fit enough to receive these drugs

23 Radio-chemotherapy for inoperable / unresectable disease Reference Treatment Pts (N) Atasoy, 2014 (retrospective) De Santis, 2014 (Phase I) Higano, 2008 (Pilot Phase II) Hussain, 2001 (Phase II) RT (63 Gy) + Gem. (75 mg/m 2 weekly) RT (55.5 Gy / 30 fractions) + Gem. (40 mg/m 2 twice-weekly over 6 wks) RT (40+16 Gy) + 5FU (5FU 1000mg/m² d1-4) RT (50+10 Gy) + Cis/5FU (Cis 75 mg/m 2, d1 and 5FU 1000 mg/m 2 d1-4y, q 4wks; 2 cycles concomitant, 2 cycles after RT) Response 26 CR: 62.5 % 5-year local PFS: 40.6% DSS: 59.5% OS: 58.5 % 28 2-y DFS with intact bladder: 38% 2-y locoregional failure: 32% 9 (32%) distant mets 6 (21%) deaths disease related 37 CR 49% PFS 13 mos OS 20 mos 5y OS 30% 53 ORR: 51% CRR: 49% OS (56 pts): 27 mos 5-year survival: 32% 5-year OS: 45% (pts refusing surgery) Patient Characteristic unfit muscle-invasive bladder cancer pts ineligible for surgery, due to local tumor extension, age, co-morbidities, refusal; ct2-t4, cn0-1, M0 Assigned inoperable by treating physician ct2-t4, N+ medically or surgically inoperable (21% + 34%), or refused cystectomy (45%)

24 M1: Prognostic factors of OS in first-line therapy Agents MVAC Gem/Cis MVAC vs Gem/Cis Gem/Cis/ Ptx (Ptx)/Cis/ 5-FU Author Bajorin 1999 Stadler 2002 von der Masse 2005 Bellmunt 2002 Lin 2007 Trials - 3 phase II 1 phase III 1 phase I/II 2 phase II Patients PS Visceral metastasis Alkaline phosphatase

25 Metastatic disease Survival prediction Bajorin factors (MVA) KPS 80 Visceral mets Hb < N First model

26 MVAC: Methotrexate, Vinblastine, Adriamycin, Cisplatin An established systemic therapy regimen Author Treatment N RR/CR (%) Median OS (months) Survival-rate P value (Median survival) Loehrer, J Clin Oncol 1992 Logothetis, J Clin Oncol 1990 MVAC / % Cisplatin / % (5-year) MVAC 65 65/ NR CISCA 55 46/ < 0.05 Bamias, J Clin Oncol 2004 MVAC+ G-CSF DC+ G-CSF / % / % (2-year) (0.089 adjusted) Sternberg, J Clin Oncol 2001 MVAC / % HD-MVAC / % (2-year) Necchi, Clin Genitourin Cancer 2013 Mod-MVAC / (5-year) NA Overall: RR: 50% - CR: 20% - median survival: 14 months

27 GC vs MVAC GC ± Paclitaxel GC: 14.0 months MVAC: 15.2 months HR: 1.09 ( ) ORR: 55.5 vs 43.6% Median PFS (mos): 8.3 (PCG) vs 7.6 (CG) Median OS (mos): 15.8 (PCG) vs 12.7 (CG) von der Maase H, J Clin Oncol 2005 Bellmunt J, J Clin Oncol 2012

28 Limited Advances Achieved in 20 years Author Treatment N RR (%) MDS (mo) Best arm Loehrer Logothetis Von der Maase Sternberg Bamias Dreicer Bellmunt Bamias M-VAC CDDP M-VAC CISCA M-VAC GC DD-MVAC M-VAC M-VAC DC M-VAC CT PCG GC DD MVAC DD CG MVAC M-VAC M-VAC ~ GC DD-M-VAC ~ M-VAC M-VAC Underpowered PCG ~ GC P=0.03 (primary bladder) Premature closure NS Bellmunt, Semin Oncol. 2012

29 Long term survival exist with Cisplatin Author N median f-up Median 5-year Treatment arm (ITT) (yrs) survival (mos) (%) Sternberg, 2006 MVAC DD-MVAC von der Maase, 2005 MVAC Gem/Cis visc mets no visc mets >

30 Senior adults Some important points to consider Senior adults Have a decreased bone marrow reserve. primary GCSF Prophylaxis / Primary dose reductions / Schedule adaptations? Are under-represented in clinical trials Crome Drugs Aging 2011, Pallis Ann Oncol 2011, Hutchins N Engl J Med 1999 Neuropathy Risk associated with cumulative dose (platinum, taxanes) Worsens in 30% after treatment is discontinued

31 Consensus definition of unfit patients for clinical trials Galsky et al. J Clin Oncol. 2011; 29:

32 Unfit for cisplatin 50% of patients with MIBC: ineligible for Cisplatine Dash Cancer 2006, Nogue-Aliguer Cancer 2003, Balducci Oncologist 2000, De Santis Curr Opin Urol 2007 No standard chemotherapy for this patient group. EORTC definition of fit and unfit for cisplatin fit GFR 60 ml/min and PS 0-1 unfit GFR < 60 ml/min and /or PS 2

33 How to make the patient fit for cisplatin? Creatinine clearance: measurement? Calculation: formula? (under-estimation in pts > 65 y ). At least MDR! EDTA clearance if needed? Raj, JCO 2006 Dash, Cancer 2006 Consider... i.v. hydration (but no cosmetics ) Ureter-stenting Percutaneous nephrostomy

34 Cisplatin-ineligible pts: EORTC EORTC Cisplatin-based chemotherapy- naive patients with measurable disease and impaired renal function (GFR >30 but <60 ml/min) and/or performance status 2 GC Gemcitabine 1000 mg/m 2 on days 1 and 8 Carboplatin [AUC] 4.5 for 21 days M-CAVI Methotrexate 30mg/m 2 on days 1, 15, and 22 Carboplatin AUC 4.5 on day 1 Vinblastine 3 mg/m 2 on days 1, 15, and 22 for 28 days endpoints of response and severe acute toxicity (SAT) were evaluated with respect to treatment group, renal function, PS, and Bajorin risk groups.

35 EORTC 30986: results ITT analysis (n=238) De Santis J Clin Oncol 2011 OS no statistically significant difference HR 0.94 ( ) 9.3 mos [GCa] / 8.1 mos [M-CAVI] Less adverse effects with GC (9.3%) / 21.2% (M-CAVI)) BUT if: PS 2 and GFR < 60 / Bajorin risk group 2 Less toxic death with GC (1.7%) / 3.4% (M-CAVI) median OS: 5.5 mos 20% only 1 cycle Monotherapy / best supportive care better

36 Vinflunine: an alternative? Randomised phase II De Santis An Oncol 2014 Vinflunine 280 or 250 mg/m 2 Gemcitabine* 1000 or 750 mg/m 2 D1 and D8 (Gem) OR Vinflunine 280 or 250 mg/m 2 + Carboplatine AUC 4.5 VFL + GEM VFL + CBDCA VFL + GEM or CBDCA N = Best RR / Confirmed ORR [%] Duration of confirmed ORR [N/median, months] 52.9% / 44.1% 15 / 8.2 mo 42.9% / 28.6% 10 / 7.7 mo 47.8% / 36.2% Disease control [n, (%)] 26 (76.5%) 27 (77.1%) 53 (76.8%) [95% CI] Duration of DC [median, months] 7.2 mo 8.3

37 EAU Guidelines: 1 st line Witjes. EAU guidelines 2016

38 Second line A challenge for anticancer agents Multiple small phase II mainly single agents High variability of response Heterogeneity of population Gemcitabine active..... But already used in first line Cisplatin rechalenge if relapse > 6-12 months

39 Second line CT after Cisplatin Prognostic factors Bellmunt J Clin Oncol. 2010

40 Second line CT after Cisplatin Prognostic factors: delay matters Sonpavde. Eur Urol 2013 MULTIVARIABLE Performance status Liver metastases ECOG 1 vs ECOG ( ) Yes vs no 1.54 ( ) Anemia <10 vs 10 g/dl 1.59 ( ) Time since last chemotherapy MULTIVARIABLE MODEL 2 Performance status Continuous (log scale) ECOG 1 vs ECOG ( ) 1.79 ( ) Liver metastases Yes vs no 1.54 ( ) Anemia <10 vs 10 g/dl 1.60 ( ) Time since last chemotherapy <3 mo vs 3 mo 0.63 ( ) < < < < < < < <0.00 1

41 Second line CT after Cisplatin Urothelial cancer Progression following first - line Ctx with Cisplatin

42 Second line CT after Cisplatin Bellmunt Ann Oncol 2013 OS ITT Population (N=370) OS Eligible Population (N=357) P= >2 months, maintained at > 3.5 yr FU

43 EAU Guidelines: 2 nd line Witjes. EAU guidelines 2016

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45 The future... soon Practical impact (neoadjuvant DD MVAC) (Siefker-Radtke. ASCO GU 2015) Better results for the basal type (pt0 / survival) 5 years OS: basal 77% / p53 57% / luminal 57% p = Bone mets: only in the p53 subgroup

46 The future... PD1 / PDL-1 inhibitors: of real interest

47 Predictive factor for PD1 / PDL1 response Still unclear / Adaptative / Evolutive expression Linked to PD1 expression Petrylak ASCO 2015 But still responses if IC: 0/1 Depends also where IC considered Pembrolizamub. Plimack. ASCO 2015 tumors cells only / T cells + T associated inflammatory cells

48 Promising new CT agent Eribulin (extract from see sponge) Phase II Quinn ASCO 2015 All pretreated. N = % RC / 27% PR / 36.7% SD / ORR: 34/7% Median OS: 9.5 months (Vinflunine: median OS: 6.9 months)

49 2016 Finally real advances in muscle invasive bladder cancer?