Oral Communications & Posters

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1 Carcinoma uroteliale: Current and future directions of treatment of Muscle-Invasive Bladder cancer/ Multimodality approach of bladder cancer Oral Communications & Posters CRISTINA MASINI Oncologia Medica IRCCS-Arcispedale S.Maria Nuova Reggio Emilia

2 Neoadjuvant treatment OUTLINE 1) Efficacy of standard chemotherapy: Abstract #520, #446 2) Efficacy of new combination of chemotherapy: Abstract #468 3) Ongoing trials with new molecules: Abstract #TPS533, #TPS534, #TPS535, #TPS528 4) Markers to guide treatment: Abstract #TPS537, #416 Outcomes of different histopathologicals subtype 1) Small cell bladder cancer: Abstract #452 2) Plasmocytoid urothelial carcinoma: Abstract #522 3) Micropapillary urothelial carcinoma: Abstract #439

3 Neoadjuvant treatment OUTLINE 1) Efficacy of standard chemotherapy: Abstract #520, #446 2) Efficacy of new combination of chemotherapy: Abstract #468 3) Ongoing trials with new molecules: Abstract #TPS533, #TPS534, #TPS535, #TPS528 4) Markers to guide treatment: Abstract #TPS537, #416 Outcomes of different histopathologicals subtype 1) Small cell bladder cancer: Abstract #452 2) Plasmocytoid urothelial carcinoma: Abstract #522 3) Micropapillary urothelial carcinoma: Abstract #439

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5 Abs 520 pcr is associated with a favorable prognosis Conditional survival is an anlytic technique that estimates a pt s dynamic prognosis given that they have already survived for a particular period of time after treatment The aim of the study is to investigate whether the difference in prognosis of pts with CR and RD is sustained After 4 years MIBC pts with RD after NAC have worse conditional survival up to years 3 post-rc relative to those with CR, but this differece diminishes after 4 years These findings inform pt counseling, surveillance intensity and novel adjuvant approaches for pts with RD

6 Abs Retrospective review of MIBC from 2005 to 2016 who received NAC - GFR was calculated using MDRD and CG formula

7 Neoadjuvant treatment OUTLINE 1) Efficacy of standard chemotherapy: Abstract #520, #446 2) Efficacy of new combination of chemotherapy: Abstract #468 3) Ongoing trials with new molecules: Abstract #TPS533, #TPS534, #TPS535, #TPS528 4) Markers to guide treatment: Abstract #TPS537, #416 Outcomes of different histopathologicals subtype 1) Small cell bladder cancer: Abstract #452 2) Plasmocytoid urothelial carcinoma: Abstract #522 3) Micropapillary urothelial carcinoma: Abstract #439

8 Abs A single arm phase II trial designed with 80% power to detect an ORR of > 35% - 27 pts with histologically confirmed primary TCC of the urinary bladder ct2-t4 N0 M0 - ORR was 61.5%, pcr 34.6%, 34.6% had evidence of residual MI-TCC at radical cystectomy - Median PFS and OS have not been met at the time of this report - Disease progression during NAC 7/27 pts and a further 6/27 (22%) subsequent to completion of this trial - 7/27 had died (25.9%) with median time from progression to death of 2.3 months, demostrating the aggressive nature of MI-TCC in the absence of a chemotherapy response Conclusions: 1)This regimen of chemotherpy was found to be extremely well tolerated and dose intensity was maintained for a very high proportion of pts 1)Benefit from NAC may be observed even when pcr is not achieved 1)Stable or improved QoL was oserved during chemotherapy in over half (10/19, 53%) of pts who completed the standardised EORTC QLQ-C30 questionnaire at baseline and throughout chemotherapy. In addition, negative changes in Global QoL scores were numerically small and again demonstrate the excellent tolerability of Cisplatin and cabazitaxel regimen

9 Neoadjuvant treatment OUTLINE 1) Efficacy of standard chemotherapy: Abstract #520, #446 2) Efficacy of new combination of chemotherapy: Abstract #468 3) Ongoing trials with new molecules: Abstract #TPS533, #TPS534, #TPS535, #TPS528 4) Markers to guide treatment: abstract #TPS537, #416 Outcomes of different histopathologicals subtype 1) Small cell bladder cancer: Abstract #452 2) Plasmocytoid urothelial carcinoma: Abstract #522 3) Micropapillary urothelial carcinoma: Abstract #439

10 Abstract TPS533 Primary endpoint: pathologic complete response (pcr) In the first stage (49 pts) 6 pcr and 13 in the whole study population

11 Abs TPS534 Primary endpoint: pathologic complete response (pcr) In the first stage (49 pts) 6 pcr and 13 in the whole study population

12 Abs TPS535

13 Abs TPS528

14 Neoadjuvant treatment OUTLINE 1) Efficacy of standard chemotherapy: Abstract #520, #446 2) Efficacy of new combination of chemotherapy: Abstract #468 3) Ongoing trials with new molecules: Abstract #TPS533, #TPS534, #TPS535, #TPS528 4) Markers to guide treatment: Abstract #TPS537, #416 Outcomes of different histopathologicals subtype 1) Small cell bladder cancer: Abstract #452 2) Plasmocytoid urothelial carcinoma: Abstract #522 3) Micropapillary urothelial carcinoma: Abstract #439

15 Molecular Predictors of Response <br />to Neoadjuvant Chemotherapy Presented By Peter Black at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care

16 Molecular subtypes: basal vs. luminal Presented By Peter Black at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care

17 GSC: Hybrid Subtyping Presented By Peter Black at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care

18 Presented By Peter Black at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care

19 Coxen - CO-eXpression ExtrapolatioN Presented By Peter Black at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care

20 SWOG S1314 Coxen Clinical Trial Presented By Peter Black at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care

21 Mutations in ATM, RB1, FANCC Presented By Peter Black at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care

22 Where does this leave us? Presented By Peter Black at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care

23 Abs TPS537 We hypothesize that -AMVAC followed by chemoradiotion is particularly effective in a subgroup with the aforementioned molecular signature and -pts who have a CR at the time of cystectomy or those who go on to active surveillance due to no visible disease and the presence of genomic alterations, will have detectable mutations in urinary cell-free DNA prior to NAC but will no longer have those mutations detectable after NAC

24 Abs bladder cancer pts treated with cistectomy between april 2004 and may We conduct an immunohistochemical examination of PD-L1 expression using SP142 assay PD-L1 expression was scored at three diagnostic levels (0/1/2) % of pts had previously undergone NAC % of pts had recurring disease and 33.3% died - In neoadjuvant (+) group the 5-year DFS rate was 65% for PD-L1 (-) pts and 31.7% for PD- L1 (+) pts (p=0.006) - In neoadjuvant (+) group the 5-year CSS rate was 69.6% for PD-L1 (-) pts and 48.1% for PD-L1 (+) pts - Dispite the small study size, our data suggest that post-chemotherapy PD-L1 expression is associated with poor prognosis in pts receivng NAC who had previously undergone cystectomy

25 Atezolizumab vs Chemotherapy in Platinum-Treated Locally Advanced or Metastatic Urothelial Carcinoma: Immune Biomarkers, Tumor Mutational Burden and Clinical Outcomes From the Phase III IMvigor211 Study Presented By Thomas Powles at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care

26 OS by PD-L1 IC Status Presented By Thomas Powles at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care

27 OUTLINE Neoadjuvant treatment 1) Efficacy of standard chemotherapy: Abstract #520, #446 2) Efficacy of new combination of chemotherapy: Abstract #468 3) Ongoing trials with new molecules: Abstract #TPS533, #TPS534, #TPS535, #TPS528 4) Markers to guide treatment: Abstract #TPS537, #416 Outcomes of different histopathologicals subtypes 1) Small cell bladder cancer: Abstract #452 2) Plasmocytoid urothelial carcinoma: Abstract #522 3) Micropapillary urothelial carcinoma: Abstract #439

28 Abs 452 Small cell bladder cancer is a rare subtype representing about 1% of bladder cancers. DLL3 is a Notch patwhay protein that is overexpressed in small cell and neuroendocrine malignancies Prior analyses found that increased DLL3 protein expression and small cell% predict worse outcomes Assessment of gene and protein expression of other neuroendocrine markers (ASCL1 and CD56) can add additional prognostic value in small cell bladder carcinoma Conclusions: Most SCBC tumors express CD56, ASCL1 and DLL3 and increased protein expression of CD56 and DLL3 and poor prognostic factors associated with shorter OS and PFS Low concurrent protein expression of both CD56 and DLL3 is a positive prosgnostic marker associated with improved OS and PFS Strong correlation of mrna and protein expression for both CD56 and DLL3 indicated that regulation of expression of these proteins occurs at the transcriptional level, and suggest that gene expression of these proteins can be included in a prognostic gene expression signature

29 Abs Plasmacytoid urothelial carcinoma (PUC) is a histologic variant with an aggressive natural history - It is associated with higher rates of positive ureteral margin, positive surgical margin and nodal involvement as well as a diffuse pattern of growth - They are genomically characterized by truncating somatic alterations in the CDH1 gene - The pre-operative chemotherapy in PUC remains controversial and poorly-defined This study aims to: Describe our institutional experience in managment of non-metastatic PUC Define their clinicopathologic features at diagnosis Determine their response to pre-operative chemotherapy Consecutive cases of PUC of the bladder diagnosed between 2000 and 2017 A separate cohort of urothelial cancer treated with NAC Cisplatin plus Gemcitabine was used as comparator for clinical outcomes.

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31 Abs Micropapilalry UC remains a rare histologic variant of urothelial carcinoma a very aggressive phenotype with poor outcomes - Between 1997 to pts were identified, 82 pts had cistectomy - 19/82 pts had received NAC - 61/102 pts had recurrent or de-novo metastatic disease (most with nodal/regional recurrence) - 31/82 pts had recurrence post surgery - 21 pts received adjuvant CHT. 3 adjuvant RT

32 In conclusion 1) Neoadjuvant treatment is a cornerstone of therapy in muscle-invasive bladder cancer. Today the combination of cisplatin plus gemcitabine remains the best strategy but new, less toxic and more intelligent agents are under study. 2) We need to identify the response to available treatments of emerging histopathologicals subtype of bladder cancer. 3) We need biomarkers to predict response to neoadjuvant treatment for urothelial carcinoma.