GENITOURINARY CANCERS ASCO Poster review

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1 GENITOURINARY CANCERS ASCO Poster review Francesco Massari Oncologia Medica Azienda Ospedaliero Universitaria di Bologna Policlinico S. Orsola-Malpighi AIOM POST-ASCO REVIEW: Updates and news from the Annual Meeting in Chicago - Milano,

2 Disclosures No pertinent C.O.I. with this presentation Advisory Boards/Honoraria/Consultant for: Astellas BMS Janssen Merk Pfizer Roche

3 Prostate: 92 Kidney: 48 Urothelial: 37 Testis : 10 Penis: 1 GENITOURINARY 188 Poster

4 Urothelial Cancer

5 Novel therapeutic strategies for advanced bladder cancer Abstract #4512: BMS , an indoleamine 2,3-dioxygenase 1 inhibitor (IDO1i), in combination with nivolumab (NIVO): Updated safety across all tumor cohorts and efficacy in pts with advanced bladder cancer (advbc). Abstract #4513: Rogaratinib in patients with advanced urothelial carcinomas prescreened for tumor FGFR mrna expression and effects of mutations in the FGFR signaling pathway. Tabernero J et al., J Clin Oncol 36, 2018 (suppl; abstr 4512) Joerger M et al., J Clin Oncol 36, 2018 (suppl; abstr 4513)

6 Novel therapeutic strategies for advanced bladder cancer Abstract #4512: BMS , an indoleamine 2,3-dioxygenase 1 inhibitor (IDO1i), in combination with nivolumab (NIVO): Updated safety across all tumor cohorts and efficacy in pts with advanced bladder cancer (advbc). Abstract #4513: Rogaratinib in patients with advanced urothelial carcinomas prescreened for tumor FGFR mrna expression and effects of mutations in the FGFR signaling pathway. Tabernero J et al., J Clin Oncol 36, 2018 (suppl; abstr 4512) Joerger M et al., J Clin Oncol 36, 2018 (suppl; abstr 4513)

Study Design Phase 1/2a, open label, dose escalation, cohort-expansion Safety, tolerability, efficacy of BMS-986205 alone or combined with NIVO in advanced cancer Dose escalation methods previously

7 Study Design Phase 1/2a, open label, dose escalation, cohort-expansion Safety, tolerability, efficacy of BMS alone or combined with NIVO in advanced cancer Dose escalation methods previously described Expansion: BMS mg or 200 mg QD + NIVO 240 mg Q2W or 480 Q4W Advanced bladder cancer: 100 or 200 mg QD + NIVO 240 mg Q2W Tabernero J et al., J Clin Oncol 36, 2018 (suppl; abstr 4512)

8 Baseline characteristics in all Patients Tabernero J et al., J Clin Oncol 36, 2018 (suppl; abstr 4512)

9 Bladder cancer expansion cohort Safety Tabernero J et al., J Clin Oncol 36, 2018 (suppl; abstr 4512)

10 Bladder cancer expansion cohort Activity Tabernero J et al., J Clin Oncol 36, 2018 (suppl; abstr 4512)

11 BMS Nivolumab Open questions Is this practice changing routine day-to-day practice right now? NO Strengths: robust mechanistic rationale, very well designed/conducted, phase II dose identified (100 mg) Weakness: small sample size

12 Novel therapeutic strategies for advanced bladder cancer Abstract #4512: BMS , an indoleamine 2,3-dioxygenase 1 inhibitor (IDO1i), in combination with nivolumab (NIVO): Updated safety across all tumor cohorts and efficacy in pts with advanced bladder cancer (advbc). Abstract #4513: Rogaratinib in patients with advanced urothelial carcinomas prescreened for tumor FGFR mrna expression and effects of mutations in the FGFR signaling pathway. Tabernero J et al., J Clin Oncol 36, 2018 (suppl; abstr 4512) Joerger M et al., J Clin Oncol 36, 2018 (suppl; abstr 4513)

Fibroblast Growth Factor Receptor (FGFR) Pathway Activating mutations common (80-85%) in low grade and early stage bladder tumors FGFR3 mutations/fusions (20% in advanced UC) more common in high

13 Fibroblast Growth Factor Receptor (FGFR) Pathway Activating mutations common (80-85%) in low grade and early stage bladder tumors FGFR3 mutations/fusions (20% in advanced UC) more common in high grade invasive tumors and upper tract UC Putative driving role in tumorigenesis and chemotherapy/immunotherapy resistance Pharmacologic inhibition has cytostatic effect with G0 or G1 arrest. Massari F et al. Expert Rev Anticancer Ther Nov 14:1-3

Prevalence of FGFR1-3 mrna overexpression and FGFR3 gene mutations Phase 1 expansion cohort of late-stage muscle invasive UC FFPE tumor tissue FGFR1-3 mrna overexpression screened by

14 Prevalence of FGFR1-3 mrna overexpression and FGFR3 gene mutations Phase 1 expansion cohort of late-stage muscle invasive UC FFPE tumor tissue FGFR1-3 mrna overexpression screened by RNA ISH and by NanoString ncounter FGFR1-3 mrna positive patients treated with ROGARATINIB 800 mg BID (continuous 21-day cycle) Joerger M et al., J Clin Oncol 36, 2018 (suppl; abstr 4513)

Rogaratinib Efficacy ORR 24% (1 CR, 11 PR); 49% SD; DCR 73% No Patient with response had mutations in either PIK3CA or RAS-encoding genes, but 7 of 14 patients with PD had mutations in either genes

15 Rogaratinib Efficacy ORR 24% (1 CR, 11 PR); 49% SD; DCR 73% No Patient with response had mutations in either PIK3CA or RAS-encoding genes, but 7 of 14 patients with PD had mutations in either genes UC patients with wilde-type PIK3CA/RAS ORR 33% 7/11 responders showed FGFR3 mrna overexpression without FGFR3 gene mutations/translocation Joerger M et al., J Clin Oncol 36, 2018 (suppl; abstr 4513)

16 Rogaratinib Toxicity Joerger M et al., J Clin Oncol 36, 2018 (suppl; abstr 4513)

17 Rogaratinib : What did we learn? Treatment with Rogaratinib demonstrated clinical benefit in UC tumors with FGFR3 mrna overexpression but without FGFR3 gene mutation The use of mrna-based screening identified additional rogaratinib-sensitive patients with UC with FGFR1 mrna overexpression Rogaratinib treatment in patients with advance UC with FGFR overexpression resulted in a manageable safety profile and encouraging efficacy, including in patients refractory to prior immuno-oncology treatment, but not in those harbouring PIK3CA or RAS mutations Joerger M et al., J Clin Oncol 36, 2018 (suppl; abstr 4513)

18 Prostate Cancer

19 Prostate cancer poster Abstract #LBA5009: Abi Race: A prospective, multicenter study of black (B) and white (W) patients (pts) with metastatic castrate resistant prostate cancer (mcrpc) treated with abiraterone acetate and prednisone (AAP). Abstract #5015: Phase 2 randomized cross-over trial of abiraterone + prednisone (ABI+P) vs enzalutamide (ENZ) for patients (pts) with metastatic castration resistant prostate cancer (mcprc): Results for 2ndline therapy. George DJ et al., J Clin Oncol 36, 2018 (suppl; abstr LBA5009) Khalaf D et al., J Clin Oncol 36, 2018 (suppl; abstr 5015)

20 Prostate cancer poster Abstract #LBA5009: Abi Race: A prospective, multicenter study of black (B) and white (W) patients (pts) with metastatic castrate resistant prostate cancer (mcrpc) treated with abiraterone acetate and prednisone (AAP). Abstract #5015: Phase 2 randomized cross-over trial of abiraterone + prednisone (ABI+P) vs enzalutamide (ENZ) for patients (pts) with metastatic castration resistant prostate cancer (mcprc): Results for 2ndline therapy. George DJ et al., J Clin Oncol 36, 2018 (suppl; abstr LBA5009) Khalaf D et al., J Clin Oncol 36, 2018 (suppl; abstr 5015)

21 Abi Race: mcrpc outcomes by race Black men have 2.5 times likelihood of dying from prostate cancer but are underrepresented in clinical trials 2-5% of recent mcrpc RCT patients were black Subgroup analyses impossible by race due to low numbers COU-302 data suggest possible higher PSA 90 rates and longer median rpfs for black man Side effect profiles may different by race George DJ et al., J Clin Oncol 36, 2018 (suppl; abstr LBA5009)

22 Abi Race: mcrpc outcomes by race Do prostate cancer specific and side effect outcomes differ by race during treatment with abiraterone? Is it feasible to enroll a prostate cancer clinical trial including 50% black men?

23 Abi Race Trial Design Non-comparative pilot open-label, parallel arm study of AP in 100 men (50 B, 50 W) with mcrcpc, self-identified race George DJ et al., J Clin Oncol 36, 2018 (suppl; abstr LBA5009)

24 Abi Race Radiographic Progression Free Survival rpfs Similar by Race George DJ et al., J Clin Oncol 36, 2018 (suppl; abstr LBA5009)

25 Abi Race PSA-Progression Free Survival Longer PSA PFS by Race George DJ et al., J Clin Oncol 36, 2018 (suppl; abstr LBA5009)

26 Abi Race Toxicity Profile (any grade) George DJ et al., J Clin Oncol 36, 2018 (suppl; abstr LBA5009)

27 Abi Race Different Genotypic Clusters (SNP Analysis) George DJ et al., J Clin Oncol 36, 2018 (suppl; abstr LBA5009)

28 Abi Race: What did we learn? Inclusion of representative number of black men in mcrpc clinical trials is feasible PSA response may differ by race during treatment with abiraterone despite similar rpfs Further studies including more patients are required to confirm it. Adverse events rates may vary by race Could germline SNP differences in androgen transport genes and others be driving differences in outcomes and toxicity profiles? George DJ et al., J Clin Oncol 36, 2018 (suppl; abstr LBA5009)

29 Prostate cancer poster Abstract #LBA5009: Abi Race: A prospective, multicenter study of black (B) and white (W) patients (pts) with metastatic castrate resistant prostate cancer (mcrpc) treated with abiraterone acetate and prednisone (AAP). Abstract #5015: Phase 2 randomized cross-over trial of abiraterone + prednisone (ABI+P) vs enzalutamide (ENZ) for patients (pts) with metastatic castration resistant prostate cancer (mcprc): Results for 2ndline therapy. George DJ et al., J Clin Oncol 36, 2018 (suppl; abstr LBA5009) Khalaf D et al., J Clin Oncol 36, 2018 (suppl; abstr 5015)

30 Phase II Study design Khalaf D et al., J Clin Oncol 36, 2018 (suppl; abstr 5015)

31 Best PSA decline at 12 weeks for 2 nd line therapy Khalaf D et al., J Clin Oncol 36, 2018 (suppl; abstr 5015)

32 Outcomes on 2 nd line therapy Psa response rate and time to progression were better for second-line enzalutamide compared to abiraterone plus prednisone Khalaf D et al., J Clin Oncol 36, 2018 (suppl; abstr 5015)

33 Treatment Outcomes from start of 1 st line therapy Khalaf D et al., J Clin Oncol 36, 2018 (suppl; abstr 5015)

34 Proportion of ctdna at baseline and outcome Presence of ctdna is associated with worse outcomes on Abi+P and Enza Khalaf D et al., J Clin Oncol 36, 2018 (suppl; abstr 5015)

35 Genomic alterations on baseline ctdna predict outcome Worse outcomes BRCA2/ATM truncating mutation TP53 defects AR amplification (new AR mutations were detected at crossover or progression) Better outcomes SPOP mutations Khalaf D et al., J Clin Oncol 36, 2018 (suppl; abstr 5015)

36 Abi+P vs. Enza cross-over trial: What did we learn? The optimal sequencing of Abi+P and Enza remains unknown No difference in OS Larger studies with longer follow up are needed ctdna as a liquid biopsy approach Risk stratification/prognostication Treatment selection Monitoring treatment response

37 Kidney Cancer

38 Novel Combinations for Advanced Renal Cell Carcinoma Doublet Nivolumab-Ipilimumab will be SOC in intermediate/poor risk mrcc

39 Phase 3 Nivolumab + Ipilimumab Escudier B et al. ESMO 2017; Abstract LBA5

40 CheckMate 214 Results Escudier B et al. ESMO 2017; Abstract LBA5

41 CheckMate 214 Results Escudier B et al. ESMO 2017; Abstract LBA5

42 Novel Combinations for Advanced Renal Cell Carcinoma Doublet Nivolumab-Ipilimumab will be SOC in intermediate/poor risk mrcc Furthermore, IO-VEGF combination trials may add in the first line treatment approach in all risk group or biomarker based population However, either upfront or secondary acquired resistance raise the question of alternative or rescue treatment Therefore, there is a need for new strategy development New targets identification Which backbone in case of combination: PD-1? VEGF?

BMS-986016 Tyrosin kinase inhibitors PD-1

43 PD-1 blockade.in combination with? Anti PD-L1 MEDI4736 DC vaccines Anti LAG3 BMS Tyrosin kinase inhibitors PD-1 blockade Anti-CTLA-4 Ipilimumab IDO1 inhibitors 41BB agonist monoclonal antibody NK cell therapy Modified by Santoni M, AIOM 2014

44 New Combinations trials in mrcc Abstract #4509: Pegilodecakin with nivolumab (nivo) or pembrolizumab (pembro) in patients (pts) with metastatic renal cell carcinoma (RCC). Abstract #4510: A phase 1/2 study evaluating the efficacy and safety of the oral CXCR4 inhibitor X4P-001 in combination with axitinib in patients with advanced renal cell carcinoma. Tannir NM et al., J Clin Oncol 36, 2018 (suppl; abstr 4509) Vaishampayan UN et al., J Clin Oncol 36, 2018 (suppl; abstr 4510)

45 New Combinations trials in mrcc Abstract #4509: Pegilodecakin with nivolumab (nivo) or pembrolizumab (pembro) in patients (pts) with metastatic renal cell carcinoma (RCC). Abstract #4510: A phase 1/2 study evaluating the efficacy and safety of the oral CXCR4 inhibitor X4P-001 in combination with axitinib in patients with advanced renal cell carcinoma. Tannir NM et al., J Clin Oncol 36, 2018 (suppl; abstr 4509) Vaishampayan UN et al., J Clin Oncol 36, 2018 (suppl; abstr 4510)

Pegilodecakin (AM0010) Mechanism of Action Pegilodecakin (AM0010) ia a pegylated recombinant human IL-10 Interleukin-10 (IL-10) stimulates the expansion and cytotoxicity of tumorinfiltrating CD8+ T

46 Pegilodecakin (AM0010) Mechanism of Action Pegilodecakin (AM0010) ia a pegylated recombinant human IL-10 Interleukin-10 (IL-10) stimulates the expansion and cytotoxicity of tumorinfiltrating CD8+ T cells and inhibits inflammatory CD4+ T cells Rationale for Pegilodecakin + anti-pd-1 Anti-PD-1 increases TCR signal Pegilodecakin prevents exhaustion and apoptosis Pegilodecakin induces CD8+ T cell activation Tannir NM et al., J Clin Oncol 36, 2018 (suppl; abstr 4509)

47 Pegilodecakin + anti-pd-1 in RCC Patients population Anti-PD-1 naive Tannir NM et al., J Clin Oncol 36, 2018 (suppl; abstr 4509)

48 Pegilodecakin + anti-pd-1 in RCC Safety The selected MTD/ph2 for AM0010 is 10 µg/kg in combination with anti-pd-1 Tannir NM et al., J Clin Oncol 36, 2018 (suppl; abstr 4509)

49 Pegilodecakin + anti-pd-1 in RCC Activity Modified by Laurence Albiges, ASCO 2018 Tannir NM et al., J Clin Oncol 36, 2018 (suppl; abstr 4509)

50 Pegilodecakin Biomarker analysis Modified by Laurence Albiges, ASCO 2018 Pegilodecakin + Anti-PD-1 induces clonal T cell expansion in the blood of RCC patients Tannir NM et al., J Clin Oncol 36, 2018 (suppl; abstr 4509)

51 Pegilodecakin + anti-pd-1 in RCC Open questions Shall we move this combination further? YES Where to fit in the treatment landscape? Are the data strong enough in first line? Probably not against nivo-ipi or VEGF TKI-IO combination How would Pg IL-10- PD-1i combination work in immune checkpoint inhibitor combination pretreated patients?

52 New Combinations trials in mrcc Abstract #4509: Pegilodecakin with nivolumab (nivo) or pembrolizumab (pembro) in patients (pts) with metastatic renal cell carcinoma (RCC). Abstract #4510: A phase 1/2 study evaluating the efficacy and safety of the oral CXCR4 inhibitor X4P-001 in combination with axitinib in patients with advanced renal cell carcinoma. Tannir NM et al., J Clin Oncol 36, 2018 (suppl; abstr 4509) Vaishampayan UN et al., J Clin Oncol 36, 2018 (suppl; abstr 4510)

Renal Cell Carcinoma and CXCR4 The CXCR4 chemokine receptor is expressed in many tumors, including clear cell RCC, where it promotes angiogenesis and enhances tumor infiltration by myeloidderived

53 Renal Cell Carcinoma and CXCR4 The CXCR4 chemokine receptor is expressed in many tumors, including clear cell RCC, where it promotes angiogenesis and enhances tumor infiltration by myeloidderived suppressor cells (MDSCs) and T regulatory cells (Tregs) Elevated expression of CXCR4 by RCC tumors is correlated with poor prognosis X4P-001 is an orally available, selective, CXCR4 antagonist that allosterically inhibits receptor binding by CXCL12 Burger e Kipps, Blood 2006; 107,1761

X4P-001 + Axitinib Phase 1-2, multi-center, open label study of X4P-001 in combination with axitinib in patients with clear cell RCC who have received at least 1 prior systemic therapy Safety

54 X4P Axitinib Phase 1-2, multi-center, open label study of X4P-001 in combination with axitinib in patients with clear cell RCC who have received at least 1 prior systemic therapy Safety analysis included 65 patients from phase 1-2 that were treated with 400 mg X4P-001 (200 mg BID or 400 mg QD) + 3 mg BID axitinib Treatment response were assessed using RECIST v1.1 every 8 weeks by blinded, indipendent central review Vaishampayan UN et al., J Clin Oncol 36, 2018 (suppl; abstr 4510)

55 X4P Axitinib Patient population Vaishampayan UN et al., J Clin Oncol 36, 2018 (suppl; abstr 4510)

X4P-001 + Axitinib Safety 8 patients discontinued treatment due treatment-related Aes Hypertension Creatinine increase

56 X4P Axitinib Safety 8 patients discontinued treatment due treatment-related Aes Hypertension Creatinine increase Diarrhea Fatigue Hyperkalemia Retinal vein occlusion Sepsis Vaishampayan UN et al., J Clin Oncol 36, 2018 (suppl; abstr 4510)

X4P-001 + Axitinib Preliminary activity Vaishampayan

57 X4P Axitinib Preliminary activity Vaishampayan UN et al., J Clin Oncol 36, 2018 (suppl; abstr 4510)

58 X4P Axitinib Open questions Shall we move this combination further? NO based on current data Was VEGFR TKI the right backbone for the agent? Could PD-1i+CXCR4i be more relevant? NCT (nivolumab+x4p- 001)

Francesco Massari Oncologia Medica Azienda Ospedaliero Universitaria di Bologna Policlinico S. Orsola-Malpighi

Focus sulla malattia metastatica ormonosensibile (mhspc) ADT e Chemioterapia: quando e a chi? Francesco Massari Oncologia Medica Azienda Ospedaliero Universitaria di Bologna Policlinico S. Orsola-Malpighi