nccn bladder cancer guidelines for the treatment of bladder cancer

nccn bladder cancer guidelines for the treatment of bladder cancer

1. Bladder Cancer Primer Min Yuen Teo, MD Assistant Attending Genitourinary Oncology 07/05/2023

2. Bladder Cancer DMT Medical Oncology Dean Bajorin Jonathan Rosenberg Gopa Iyer Samuel Funt Min Yuen Teo David Aggen Radiation Oncology Marisa Kollmeier Urology Bernard Bochner Harry Herr Guido Dalbagni Timothy Donahue Sherri Donat Alvin Goh Eugene Cha Eugene Pietzak

3. Topics to cover Epidemiology Presentation and Diagnosis Staging – and how we look at bladder cancer Treatment Non-muscle invasive bladder ca Muscle-invasive bladder ca Metastatic bladder ca

4. Epidemiology In the United States, more than 81,000 patients are diagnosed with bladder cancer annually (6 th most common; 4 th most common in men), with ~17,000 cases bladder-cancer-related mortality. 11 th most common cancer worldwide ~70-75% of cases affect men Median age of diagnosis ~73 years old Tobacco exposure is most common etiology in USA Schistosomiasis in Egypt usually squamous cell carcinomas Aromatic amines found in paint, rubber, petroleum products, certain dyes Arsenic (well water)

5. Hematuria Voiding symptoms Pain Constitutional symptoms Clinical Presentation

6. Urinalysis Urine cytology Cystoscopy Transurethral resection of bladder tumor (TURBT) Urinary tract imaging Imaging for metastatic disease Diagnosis

7. Urinalysis Urine cytology Cystoscopy Transurethral resection of bladder tumor (TURBT) Urinary tract imaging Imaging for metastatic disease Diagnosis

8. How to look at “bladder cancer” Anatomic Location : Bladder Urethra Upper tract Renal pelvis Ureter Histology: Urothelial carcinoma NOS NOS + variant histology Non-UC / Variant histologies Small cell Adenocarcinoma (urachal, non-urachal) Squamous cell carcinoma Plasmacytoid Etc Disease Stage: Non-muscle invasive Muscle-invasive Advanced Locally advanced Metastatic

9. Bladder cancer staging

10. Bladder cancer staging ~10% advanced disease at diagnosis ~30% with invasive disease (MIBC) ~60% with superficial disease (NMIBC) Pattern of disease presentation: De novo Recurrence Progression

11. Bladder cancer staging

12. Bladder cancer staging

13. Not all bladder cancers are built alike ~10% advanced disease at diagnosis ~30% with invasive disease (MIBC) T2-T4a N0 ~60% with superficial disease (NMIBC) Ta, Tis, T1 Pattern of disease presentation: De novo Recurrence Progression

14. Bladder cancer staging IMPORTANT DIAGNOSTIC POINT: TUR specimens NEED to show Muscularis propria

15. Stein et al, J Clin Oncol 2001 T- and N- statuses correlate with clinical outcomes

16. Management of bladder cancer Non-muscle invasive bladder ca (Ta, Tis, T1)  TUR +/- intravesical therapies Muscle invasive bladder ca (T2+ N0)  definitive local therapy +/- neoadjuvant cisplatin-based chemotherapy Local/regional m etastas is (T4 or N+)  chemotherapy +/- local therapy Metastatic disease  Systemic Therapy

17. Non-muscle invasive bladder cancer

18. BCG (or cystectomy) Management of NMIBC

19. Management of NMIBC

20. Localized Bladder (MIBC T2 – 4a N0) Definitive local therapy +/- perioperative chemotherapy Cisplatin-based chemotherapy; no substitution of carboplatin for cisplatin Evaluation for neoadjuvant cisplatin-based chemotherapy ECOG ≥2 Impaired renal function ( CrCl > 60 mL/min) Grade ≥ 2 Hearing Loss: Impaired hearing (25 decibels across two contiguous frequencies) Grade ≥ 2 Neuropathy: Moderate symptoms limiting instrumental ADLs (NYHA III – IV heart failure)

21. MIBC Radical Cystectomy Radiotherapy +Neoadjuvant chemotherapy +Concurrent chemotherapy Management of MIBC

22. James et al, NEJM 2012 Radiation +/- concurrent chemotherapy

23. MIBC Radical Cystectomy Radiotherapy +Neoadjuvant chemotherapy +Concurrent chemotherapy Management of MIBC

24. Cystectomy vs. Neoadjuvant Chemo + Cystectomy

25. Cystectomy vs. Neoadjuvant Chemo + Cystectomy

26. MIBC Radical Cystectomy Radiotherapy +Neoadjuvant chemotherapy +Concurrent chemotherapy Management of MIBC +Adjuvant Systemic Therapy

27. Adjuvant cisplatin-based chemotherapy – updated meta-analysis Leow et al, Eur Urol 2014

28. Adjuvant cisplatin-based chemotherapy – updated meta-analysis Leow et al, Eur Urol 2014

29. Statistical Plan #1: 5-year OS 35% -> 42% (HR 0.826) N required=1344 Statistical Plan #2: HR 0.76 N required=660 Statistical Plan #3: N enrolled=284 5-year OS 50% -> 65% HR 0.62

30. Primary EP: OS mOS 6.74 vs. 4.60 years 5yr-OS 53.6% vs. 47.7% Secondary EP: PFS mPFS 3.11 vs. 0.99 years 5yr-OS 47.6% vs. 31.8% Sternberg et al, Lancet Oncol 2015 Clinical outcomes

31. CheckMate 274 (NCT02632409) Placebo Nivolumab R High risk of recurrence originating in the bladder, ureter or renal pelvis Surgical resection (radical cystectomy or nephroureterectomy) Co-primary endpoints: DFS in pts with ≥1% PD-L1 and all patients; N=640 AMBASSADOR (NCT03244384) Observation Pembrolizumab R High risk of recurrence originating in the bladder, ureter or renal pelvis Surgical resection (radical cystectomy or nephroureterectomy) Co-primary endpoints: DFS and OS; N=739 IMvigor010 (NCT02450331) Observation Atezolizumab R High risk of recurrence originating in the bladder, ureter or renal pelvis Surgical resection (e.g. radical cystectomy or nephroureterectomy) Primary endpoint: DFS; N=700 Adjuvant IO trials in high risk patients following RC

32. CHECKMATE 274 Bajorin et al, NEJM 2021 Adjuvant

33. CHECKMATE 274 Bajorin et al, NEJM 2021

34. CHECKMATE 274 Bajorin et al, NEJM 2021

35. Adjuvant nivolumab in high-risk UC FDA approved based on DFS benefit High-risk T2 or greater disease at RC following neoadjuvant chemotherapy T3 or greater disease at RC in patients who did not receive neoadjuvant chemotherapy

36. NMIBC MIBC Advanced Cis-Eligible Cis- Inligible NAC -> RC ChemoRT RC ChemoRT Cisplatin-based chemo Carbo-based chemo Pembrolizumab Pembrolizumab Nivolumab Enfortumab Vedotin Sacituzumab Govitecan Erdafitinib (FGFR3mt) Docetaxel/Paclitaxel/Vinflunine 1L 2L and Beyond Current Therapeutic Landscape Enfortumab Vedotin + Pembrolizumab Adjuvant Nivo Adjuvant Nivo Maintenance Avelumab Maintenance Avelumab *”BLADDER CANCER” in the metastatic discussion encompasses Upper tract disease Urothelial cancer with or without variant histology EXCLUDES non-UC tumors

37. GC vs. MVAC in Advanced/Metastatic Bladder OS PFS GC MVAC ORR 54.3% 55.0% SD 33.5% 32.5% PR 37.2% 33.8% CR 12.2% 11.9% Von der Maase JCO 2001

38. GC vs. MVAC in Advanced/Metastatic Bladder – Carbo for cis-ineligible OS PFS mOS 9.3 vs 8.1 months mPFS 5.8 vs 4.1 months De Santis et al, JCO 2012

39. [Up until last year…] Approved Anti-PD-1/PD-L1 Therapies Anti-PD-1 Pembrolizumab Nivolumab Anti-PD-L1 Atezolizumab Durvalumab Avelumab

40. Currently Approved Anti-PD-1/PD-L1 Therapies Anti-PD-1 Pembrolizumab Nivolumab Anti-PD-L1 Atezolizumab Durvalumab Avelumab* ONLY as maintenance therapy

41. JAVELIN Bladder 100 study design (NCT02603432) Presented By Thomas Powles at TBD

42. OS in the overall population Presented By Thomas Powles at TBD

43. PFS by independent radiology review in the overall population Presented By Thomas Powles at TBD

44. Pembrolizumab Improves OS vs. Chemo Post Platinum

45. Antibody-drug conjugates: a new class of therapeutic agents for metastatic urothelial cancers Heath et al, Nat Rev Urol 2021; Powles et al, NEJM 2021; Tagawa et al, ASCO 2019 Antibody Payload Target

46. Sacituzumab Govitecan 46 CPI therapy (includes anti - PD-1/anti-PD-L1 – based therapies). CPI, immune checkpoint inhibitor; DOR, duration of response; mUC, metastatic urothelial cancer; ORR, objective response rate; OS, overall survival; PD-1, programmed death-1; PD-L1, programmed death-ligand 1; PFS, progression-free survival; pts, patients; SG, sacituzumab govitecan. EudraCT Number: 2018-001167-23; ClinicalTrials.gov Number: NCT03547973; IMMU-132-06 study. 1. Petylak , DP et al. J Clin Oncol. 2020;38(suppl), abstract 5027. Cohort 1 (100 pts): pts with mUC who progressed after prior platinum-based and CPI-based therapies Cohort 2 (40 pts): pts with mUC ineligible for platinum-based therapy and who progressed after prior CPI-based therapies 1 Continue treatment until loss of clinical benefit or unacceptable toxicity Days 1 and 8, every 21 days Primary objective: ORR by central review Secondary objectives: Safety/tolerability DOR PFS OS SG 10 mg/kg Cohort 3 (up to 61 pts): mUC CPI-naïve pts who progressed after prior platinum-based therapies SG days 1 and 8, every 21 days Pembrolizumab 200 mg day 1, every 21 days TROPHY-U-01 Cohort 1 Final Results

47. Demographic and Baseline Characteristics 47 Characteristic N=113 Age, median (range), y 66 (33 – 90) ≥75, n (%), y 26 (23) Male, n (%) 88 (78) Race, n (%) White 84 (74) Black 3 (3) Asian 3 (3) Other 1 (1) Not reported 22 (20) ECOG PS, n (%) 32 (28) 1 81 (72) Visceral metastatic sites, n (%) a 70 (62) Lung/Pleura 45 (40) Liver 32 (28) Other 13 (12) Characteristic N=113 Prior anticancer regimens, median (range), n 3.0 (1 – 8) Median duration of last anticancer regimen (range), mos 2.8 (0 – 36) Lines of prior metastatic regimens, n (%) 1 22 (20) 2 30 (27) ≥3 56 (50) Prior platinum therapy, n (%) Cisplatin 81 (72) Carboplatin 39 (35) Bellmunt risk factors , n (%) b 14 (12) 1 61 (54) 2 31 (27) 3 7 (6) TROPHY-U-01 Cohort 1 Final Results a Visceral metastases included only target and non-target lesions (metastatic sites are not mutually exclusive). b Risk factors are ECOG PS >0, presence of liver metastases, and hemoglobin <10 g/dL. ECOG PS, Eastern Cooperative Oncology Group performance status; mos, months.

48. Response Assessments a Endpoint Cohort 1 (N=113) ORR, n (%) [95% CI] 31 (27) [19, 37] CR, n (%) 6 (5) PR, n (%) 25 (22) Median duration of response, mos [95% CI] (Range) 5.9 [4.70, 8.60] (1.4 –11.7 ) Median time to onset of response, mos (Range) 1.6 (1.2–5.5) a Assessments were per Blinded Independent Review Assessment, RECIST 1.1. CI, confidence interval; CR, complete response; ORR, objective response rate; PR, partial response; TTR, time to response. 48 TROPHY-U-01 Cohort 1 Final Results ORR, median DOR, and median TTR values were consistent with investigator assessments

49. 49 Survival Outcomes a OS, overall survival; PFS, progression-free survival. a Median follow-up time was 6.3 months, defined as time from informed consent date to death date, end of study date or data cutoff date, whichever occurs first. Orange hash marks indicate data censoring. 1 2 3 4 5 8 9 1 11 1 2 13 14 1.0 0.8 0.4 0.2 0.0 0.6 Probability of Progression - Free Survival Median PFS (95% CI): 5.4 (3.5, 6.9) Censored 10 3 8 1 6 5 1 48 Month s 2 3 7 6 3 2 1 No. of Subjects at Risk 113 35 28 6 7 Probability of Overall Survival . . 2 . 4 . 6 . 8 1 . Median OS (95% CI): 10.5 (8.2, 12.3) 113 107 103 90 81 76 61 51 41 31 23 16 11 5 4 1 0 Censored 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 No. of Subjects at Risk TROPHY-U-01 Cohort 1 Final Results

50. EV301 Enfortumab Vedotin

51. Powles et al, NEJM 2021 Median f/u 11.1 months Median OS: 12.88 mo with EV vs 8.97 mo with chemo (HR 0.70, p=0.001) ORR: 40.6% vs 17.9%, p<0.001 EV301 Median PFS: 5.55 vs 3.71 mo , p<0.001

52. Hoimes et al, JCO 2023 When EV meets Pembrolizumab…

53. EV +/- Pembro O’Donnell et al, JCO 2023

54. Genomic Landscape of MIBC (Urothelial TCGA) (n=412) Potential roles of targeted therapy in mUC

55. BLC2001 phase II trial: Erdafitinib in mUC Loriot et al, NEJM 2019

56. Confirmed ORR: 40% (3% CR) 39.4% stable disease Median time to response: 1.4 months Median duration of response: 5.6 months 35% response rate in liver metastases 59% ORR in post-immunotherapy patients (IO response rate 5%) BLC2001 Loriot et al, NEJM 2019

57. Majority of events were grade 1/2 Few patients (n = 7) discontinued because of AEs of special interest All AEs of special interest were managed with supportive therapies, dose interruption, and/or modification CSR is a known class effect of inhibitors of the MAPK pathway CSR rarely led to discontinuation (n = 3), and no patient had retinal vein or artery occlusion Siefker -Radtke et al, ASCO 2018 Renouf DJ, et al. J Clin Oncol . 2012;30:3277-3286 Stjepanovic N, et al. Ann Oncol. 2016;27:998-1005 BLC2001

58. mOS 12.1 vs 7.8 months HR 0.64 (p=0.005) mPFS 5.6 vs 2.7 months HR 0.58 (p=0.0002) Loriot et al, ASCO 2023

59. NMIBC MIBC Advanced Cis-Eligible Cis- Inligible NAC -> RC ChemoRT RC ChemoRT Cisplatin-based chemo Carbo-based chemo Pembrolizumab Pembrolizumab Nivolumab Enfortumab Vedotin Sacituzumab Govitecan Erdafitinib (FGFR3mt) Docetaxel/Paclitaxel/Vinflunine 1L 2L and Beyond Current Therapeutic Landscape Enfortumab Vedotin + Pembrolizumab Adjuvant Nivo Adjuvant Nivo Maintenance Avelumab Maintenance Avelumab *”BLADDER CANCER” in the metastatic discussion encompasses Upper tract disease Urothelial cancer with or without variant histology EXCLUDES non-UC tumors

60. Management of bladder cancer TUR is diagnostic and therapeutic – MUST HAVE MUSCULARIS PROPRIA for adequate staging Non-muscle invasive bladder ca (Ta, Tis, T1)  TUR +/- intravesical therapies Muscle invasive bladder ca (T2+ N0)  definitive local therapy +/- neoadjuvant cisplatin-based chemotherapy Local/regional m etastas is (T4 or N+)  chemotherapy +/- local therapy Metastatic disease  Systemic Therapy