The Rationale for Immunotherapy as an Adjuvant Treatment for Locally Advanced BC

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1 The Rationale for Immunotherapy as an Adjuvant Treatment for Locally Advanced BC Seth P. Lerner, MD, FACS Professor, Scott Department of Urology Beth and Dave Swalm Chair in Urologic Oncology Baylor College of Medicine 4 th FOIU July 3-5, 2018

2 Financial and Other Disclosures Off-label use of drugs, devices, or other agents: none Data from IRB-approved human research is presented I have the following financial interests or relationships to disclose: FKD Roche/Genentech JBL Viventia BioCancell, Nucleix, QED, UroGen UroGen, Vaxiion Disclosure code S S S S C C 2

3 Guidelines Adjuvant Therapy AUA: Patients with RC path pt3/t4and/or N+ who have not received cisplatin-based NAC should be offered adjuvant cisplatin- based chemotherapy. (Moderate Recommendation; Evidence Level: Grade C) EAU and ASCO: Data are not convincing enough to give an unequivocal recommendation for the use of immediate adjuvant chemotherapy as compared to chemotherapy at the time of relapse (1A) NCCN: Consider if pt3-4, Tany N+, if no NAC given (2B) 3

4 Rationale for Adjuvant Therapy Clinical understaging Perceived low utilization of neoadjuvant chemotherapy (NAC) Non-cisplatin eligible don t receive NAC Non-responders to NAC decreased OS Peri-operative morbidity may limit use of adjuvant chemotherapy

5 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 vonrundstedt, et al Bladder Cancer in press Culp, et al, J Urol 191:40, 2014

6 NAC Utilization Randomized 613 patients No Neoadjuvant Neoadjuvant Total Randomized 267 (44%) 346 (56%) Patients RANDOMIZED ARM Extended LND 133 (44%) 169 (56%) (302/49%) Standard LND 134 (43%) 177 (57%) (311/51%) AGE (years) Median SEX Males 204 (76%) 281 (81%) Females 63 (24%) 65 (19%) CLINICAL STAGE ct2 (431/70%) 215 (81%) 216 (62%) ct3-4a (182/30%) 52 (19%) 130 (38%) NEOADJUVANT CHEMOTHERAPY Cisplatin Based (88%) Carboplatin Based (6%) Other (6%)

7 Cisplatin Eligibility Galsky, et al Lancet Oncology 12:211-14, 2011

8 Impact of Response to NAC Secondary analysis of SWOG /144 (44%) treated with NAC < pt2 46 (30%) pt0 Path stage T0, Tis, Ta, T1 and < T2N0 with best survival Sonpavde, et al Cancer 115:4104, 2015

9 Contemporary Morbidity and Mortality MSKCC 1,145 patients % 1 complication 83% grade 2-5 (modified Clavien) 57% within 90 days of surgery 26% re-admission Post operative morbidity may limit up to 30% of patients from undergoing adjuvant chemotherapy 1 Donat, et al Eur Urol 55:177, 2009

10 Adjuvant Therapy - Unmet Need Residual invasive cancer after radical cystectomy without NAC pt3-4 Nany or Tany N+ Residual invasive cancer after radical cystectomy with NAC pt2-4a Nany or Tany N+ Cisplatin ineligible Level of evidence supporting adjuvant chemotherapy not as high as for NAC

11 Why Immunotherapy? Efficacy demonstrated in both cisplatin eligible and ineligible locally advanced unresectable or metastatic urothelial cancer 5 checkpoint inhibitors approved in bladder cancer 3 adjuvant Phase III CPI trials ongoing Total expected accrual (800, 640, 739 = 2179) Imvigor 010 Atezolizumab (NCT ) Checkmate 274 Nivolumab (NCT ) AMBASSADOR Alliance - Pembrolizumab (NCT )

12 Urothelial carcinoma-specific antitumor T-cell immunity cycle Tumors maintain an immunosuppressive via PD-L1/PD-1 binding Inhibiting: T-cell migration Proliferation secretion of cytotoxic mediators Kim JW, Tomita Y, Trepel J, Apolo AB. Curr Opin Oncol Siefker-Radtke AO, Apolo AB, Bivalacqua TJ, Spiess PE, Black PC. J Urol Nov 4

13 Initial Second-line Phase I/II studies with Checkpoint Blockade in Metastatic Urothelial Carcinoma: Summary of ORR Atezolizumab Pembrolizumab Avelumab Powles,et al., Nature. 2014;515: Plimack ER, et al. Lancet Oncol 2017 Feb;18(2): Apolo, A. B., et al. (2017) J Clin Oncol 1;35(19): Nivolumab Durvalumab Sharma, P., et al. (2016). Lancet Oncol 17: Massard, C., et al. (2016). J Clin Oncol 34(26): Presented by: Andrea B. Apolo

14 Pembrolizumab Phase III Randomized Study KEYNOTE-045 Study Design (NCT ) Key Eligibility Criteria Urothelial carcinoma of the renal pelvis, ureter, bladder, or urethra Transitional cell predominant PD after 1-2 lines of platinum-based chemo or recurrence within 12 mo of perioperative platinum-based therapy ECOG PS 0-2 Provision of tumor sample for biomarker assessment R (1:1) N = 542 N = 270 N = 272 Pembrolizumab 200 mg IV Q3W for 2 years Paclitaxel 175 mg/m 2 Q3W OR Docetaxel 75 mg/m 2 Q3W OR Vinflunine 320 mg/m 2 Q3W Stratification Factors ECOG PS (0/1 vs 2) Hemoglobin level (<10 vs 10 g/dl) Liver metastases (yes vs no) Time from last chemotherapy dose (<3 vs 3 mo) Key End Points Primary: OS and PFS in total and PD-L1 CPS 10% populations Secondary: ORR and DOR in total and PD-L1 CPS 10% populations; safety in total population Bellmunt J., et al., NEJM 2017; 376: CPS = combined positive score.

15 O S, % Pembrolizumab Phase III Randomized Study Overall Survival: Total Events, n HR (95% CI) Pembro ( ) Chemo % 30.7% Median (95% CI) 10.3 mo ( ) 7.4 mo ( ) No. at risk Time, months P Bellmunt J., et al., NEJM 2017; 376: Data cutoff date: Sep 7, 2016.

16 P F S, % Pembrolizumab Phase III Randomized Study Progression-Free Survival: Total Events, n HR (95% CI) Pembro ( ) 0.42 Chemo % 26.8% 16.8% 6.2% Median (95% CI) 2.1 mo ( ) 3.3 mo ( ) P No. at risk Time, months Bellmunt J., et al., NEJM 2017; 376: Assessed per RECIST v1.1 by blinded, independent central review. Data cutoff date: Sep 7, 2016.

17 Incidence, % Pembrolizumab Phase III Randomized Study Treatment-Related AEs With Incidence 10% Grade Pembrolizumab Chemotherapy Bellmunt J., et al., NEJM 2017; 376: Alopecia occurred in 37.6% of patients in the chemotherapy arm.

18 INTERGROUP: Phase III randomized Adjuvant study of pembrolizumab in muscle invasive and locally advanced urothelial carcinoma (AMBASSADOR ) versus observation Co-primary Eligibility MIBC or UTUC h/o cystectomy or nephrectomy within 16 weeks pt2-4anx or ptxn+ post neoadjuvant chemotherapy OR pt3-4nx or pn+ post surgery with no chemotherapy Stratify PDL1 +/- Neoadjuvant chemotherapy yes/no Pathologic stage: pt2/3/4an0 vs pt4bnx orn1-3 R A N D O M I Z E N=739 Pembrolizumab 200mg q3w 1 year Observation O V E R A L L S U R V I V A L D I S E A S E F R E E S U R V I V A L 1:1 PI: Andrea B. Apolo

19 adjuvant Adjuvant Chemotherapy in MIBC Atezolizumab muscle-invasive TCC of the bladder or the upper urinary tract 19 clinicaltrials.gov; assessed Feb 2018

20 Dept. of Urology adjuvant Adjuvant Chemotherapy in MIBC Nivolumab Estimated Primary Completion Date: Oct clinicaltrials.gov; assessed Jan 2018

21 Conclusions Patients with residual muscle invasive cancer and or resected lymph node metastasis are at high risk for progression There is no FDA or EMA approved adjuvant therapy At best only 50-60% of patients may be eligible for and receive neoadjuvant cisplatin based chemotherapy

22 Conclusions Checkpoint inhibitors have demonstrated efficacy and are approved for use in locally advanced and metastatic urothelial cancer Toxicity profile acceptable Three Phase III randomized trials are ongoing that will define the role for immunotherapy in the adjuvant setting post radical cystectomy