Tumori Genito-Urinari. Fabio Calabrò Oncologia Medica Azienda Ospedaliera San Camillo Forlanini

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1 Tumori Genito-Urinari Fabio Calabrò Oncologia Medica Azienda Ospedaliera San Camillo Forlanini

2 Prostate cancer treatment paradigm is evolving PROSTATE CANCER TREATMENT PARADIGMIS EVOLVING Non metatasticcrpc Clinically localized Rising PSA? Metastatic CRPC Local treatment with curative intent +/- adjuvant RT or RT+ADT? ADT + ADT + Metatasticnon castrate Docetaxel* Abiraterone* Abiraterone Enzalutamide Docetaxel (if no prior use) Cabazitaxel Radium-223 Sipuleucel-T** *Not licenced **USA only Supportive care (eg denosumab/bisphosphonates)

3 Advanced prostate cancer consensus conference 2017 Gillesen S, Eur Urol 2017

4 Prostate cancer treatment paradigm is evolving Year Trial/Treatment/Setting mos 1990 Prednisone M1 mcrpc TAX 327 Docetaxel prednisone M1 CRPC TROPIC/Cabazitaxel M1 CRPC COU-AA-301 Abiraterone post docetaxel M1 CRPC COU-AA-302 Abiraterone pre docetaxel M1 CRPC PREVAIL Enzalutamide pre docetaxel M1 CRPC CHARTEED (ADT + docetaxel M1 HSPC STAMPEDE ADT + Docetaxel M1 HSPC LATITUDE STAMPEDE ADT + Abiraterone M1 HSPC nr

5 Prostate cancer treatment paradigm is evolving

6 Why Did Patients Live So Long? Subsequent Therapy 1 ABI + P (n=546 ) P (n=542) Subsequent Therapy 2 ENZA (n = 872) Placebo (n = 845) N (%) with selected subsequent therapy Subsequent therapies 365 (67%) 435 (80%) Abiraterone 69 (13%) 238 (44%) Cabazitaxel 100 (18%) 105 (19%) Docetaxel 311 (57%) 331 (61%) Enzalutamide 87 (16%) 54 (10%) Ketoconazole 42 (8%) 68 (13%) Radium (4%) 7 (1%) Sipuleucel-T 45 (8%) 32 (6%) N (%) with 1 subsequent life-extending therapy Subsequent therapies 457 (52.4%) 685 (81.1%) Docetaxel 358 (41.1%) 504 (59.6%) Abiraterone acetate 256 (29.4%) 417 (49.3%) Cabazitaxel 79 (9.1%) 149 (17.6%) Enzalutamide* 21 (2.4%) 249 (29.5%) Sipuleucel-T 17 (1.9%) 11 (1.3%) Radium (1.8%) 22 (2.6%) Ryan C, Lancet Oncol. 2015; Beer TM, N Engl J Med. 2014

7 Taxanes stabilize microtubules leading to cell-cycle arrest in metaphase-anaphase Normal cell cycle a. Prometaphase b. Metaphase c. Anaphase d. Telophase Taxanes Taxanes stabilize microtubules, inhibit disassembly and inhibit both ligand-dependent and ligand independent AR transcriptional activity Jordan & Wilson. Nature Reviews Cancer 2004

8 AR blockade induce proliferation of AR independent clones R-BLOCKADE INDUCE PROLIFERATION OF AR- DEPENDENT CLONES Isaacs J et al, The prostate 1984; 5: 1-17 Isaac J, The prostate 1984

9 Intratumor heterogeneity

10 Intratumor heterogeneity Broutos PC, Nat Genetics 2015

11 SWOG Trial 9346 A PSA of 4 ng/ml or less after 7 months of AD is a strong predictor of survival Hussain M, J Clin Oncol 2006, NEJM 2013

12 Prognostic tools Halabi S, J Clin Oncol 2014

13 Prognostic tools Halabi S, J Clin Oncol 2014

14 Many Nomograms are available

15 Is an old story Dawson NA, J Clin Oncol 1998

16 Cross-resistance between AR-targeted agents Only retrospective evidence Author Year published N pts Duration of 2 nd treatment PSA 50% Median PFS ENZ ABI Loriot et al mo 8% 2.7 mo Noonan et al wks 3% 3.6 mo ABI ENZ Schrader et al mo 29% - Badrising et al mo 21% - Bianchini et al mo 23% - Schmid et al mo 10% - Brasso et al mo 18% -

17 Integrative landscape analysis of somatic and germline aberrations in mcrpc 90% of mcrpc harbor clinically actionable molecular alterations 20% of mcrpc harbor DNA repair pathway aberrations 8% harbor germline mutations Robinson D, Cell. 2015

18 Distribution of Presumed Pathogenic Germline Mutations Pritchard CC et al. N Engl J Med 2016;375: Shown are mutations involving 16 DNA-repair genes Pritchard, N Engl J Med 2016

19 Defects in DNA repair genes associated with PARP inhibitor sensitivity 49 heavily pretreated mcrpc men PARP inhibitor (olaparib 400 mg BID) Genomic signature of PARP inhibitor sensitivity in 16/49 (33%) pts BRCA2, ATM, BRCA1, PALB2, CHEK2, FANCA, HDAC2 Response to PARP in 14/16 Mateo J et al. New Engl J Med. 2015

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21 The begin at the beginning Yang JC, NEJM 2003

22 An Era of discovery in RCC

23 Figure 1 Selected immune therapies under investigation for renal cell carcinoma (RCC). Checkpoint inhibitors under investigation include the cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) inhibitors ipilimumab and tremelimumab, the programmed cell death protein 1 (PD-1) inhibitors nivolumab (which is FDA approved), pembrolizumab and pidilizumab, and the programmed cell death 1 ligand 1 (PD-L1) inhibitors atezolizumab, BMS , durvalumab, and avelumab. Vaccine strategies investigated in RCC include the single peptide vaccines TroVax and Immunotherapeutic strategies in mrcc S Novel immunotherapies being studied for renal cell carcinoma Checkpoint inhibitors Vaccines Adoptive T-cell therapy T-cell agonists CTLA-4 inhibitors Ipilimumab Tremelimumab PD-1 inhibitors Nivolumab (FDA approved) Pembrolizumab Pidilizumab PD-L1 inhibitors Atezolizumab BMS Durvalumab Avelumab Single peptide TroVax TG4010 Dendritic cell AGS-003 Multipeptide IMA901 CAR T cells CIK cells Cytokines IL-2 IFN-g IL-21 Agonist antibodies CD137 OX40 CD27 GITR

24 Combinatorial explosion Ledford H, Nature 2016

25 First Line Phase III Trials CheckMate214 - NCT : Combination PD-1 + CTLA-4 inhibition Eligibility: Locally advanced or mrcc Previously untreated with any systemic therapy Karnofsky PS 70 RANDOMIZATION Phase III N=1070 Nivolumab + Ipilimumab 3mg/kg IV + 1mg/kg IV every 3 weeks X4 then Nivolumab 3mg/kg IV q2w Sunitinib 50 mg PO daily, 4 weeks on/2 weeks off Co-Primary endpoint: PFS, OS IMmotion NCT : Combination PD-L1 + VEGF inhibition Eligibility: Locally advanced or mrcc with clear-cell and/or sarcomatoid component Previously untreated with any systemic therapy Karnofsky PS 70 RANDOMIZATION Phase III N=900 Atezolizumab + Bevacizumab 1200 mg IV + 15 mg/kg IV q3w Sunitinib 50 mg PO daily, 4 weeks on/2 weeks off Co-Primary endpoint: PFS, OS Javelin Renal NCT : Combination PD-L1 + VEGFR TKI Eligibility: Locally advanced or mrcc with clear cell component Previously untreated with any systemic therapy Karnofsky PS 70 Primary endpoint: PFS RANDOMIZATION Phase III N=583 Avelumab + Axitinib 10mg/kg IV q2w + 5mg PO BID Sunitinib 50 mg PO daily, 4 weeks on/2 weeks off

26 First Line Phase III Trials KEYNOTE NCT : Pembrolizumab + Axitinib Eligibility: Advanced/mRCC with clear cell component Previously untreated with any systemic therapy Karnofsky PS 70 Co-Primary endpoint: PFS, OS RANDOMIZATION Phase III N=840 Pembrolizumab + Axitinib 200 mg IV every 3 weeks + 5 mg PO BID Sunitinib 50 mg PO daily, 4 weeks on/2 weeks off NCT : Lenvatinib + Everolimus or Pembrolizumab Eligibility: Advanced/mRCC with clear cell component Previously untreated with any systemic therapy Karnofsky PS 70 Sunitinib Primary endpoint: PFS 50 mg PO daily, 4 weeks on/2 weeks off ADAPT - NCT : Autologous Dendritic Cell Vaccine Eligibility: Advanced/mRCC, predominantly clear cell histology Previously untreated with any systemic therapy RANDOMIZATION Phase III N=450 Karnofsky PS 70 Sunitinib Primary endpoint: OS RANDOMIZATION Phase III N=735 Lenvatinib + Everolimus 18 mg PO daily + 5 mg PO daily Lenvatinib + Pembrolizumab 20 mg PO daily mg IV q3w AGS intradermal injections in first year followed by quarterly boosters

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28 Nuzzo R. Nature 2014

29 Management of metastatic UC until 2016 Management of metastatic UC until 2016 First-line metastatic urothelial cancer Cisplatin-eligible patients Cisplatin-ineligible patients Dose-dense MVAC Cisplatingemcitabine Carboplatingemcitabine Single-agent Or BSC Platinum-resistant metastatic urothelial cancer No standard chemotherapy: Vinflunine and taxanes are options

30 How do these data translate in clinical practice? FDA approval EMA approval 1st line Atezolizumab Pembrolizumab Atezolizumab pembrolizumab 2nd line Atezolizumab Pembrolizumab (benefit on OS) Nivolumab Avelumab Durvalumab Nivolumab Atezolizumab pembrolizumab

31 Open questions and problems with immunotherapy FDA approvals Lack of predictive biomarkers Treatment beyond progression Hyperprogressive disease Treatment option for patients who progress on CPI Trial design and interpretation

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33 ORR by PD-L1 status Drug Phase setting n PD-L1 definition ORR in favorable ORR in negative CR % Atezolizumab 1 Post DDP 67 IC 2/3 43% 11% 7/0 Atezolizumab 2 Post DDP 315 IC 2/3 28% 11% 11/2 Atezolizumab 2 DDP unfit 119 IC2/3 28% 21% 3/5 Atezolizumab 3 Post DDP 912 IC 2/3 23% NR 8/0 Nivolumab 1/2 Post DDP 78 PD-L1>1% 24% 26% 1/4 Nivolumab 2 Post DDP 270 PD-L1>1% or 5% Durvalumab 1 Post DDP 61 PD-L1 TC or IC >25% 23% 16% 4/0 46% 0 NR Avelumab 1b Post DDP 44 PD-L1>5% 25% 13% NR Pembrolizumab 1b Post DDP 33 PD-L1>1% in TC 14% 27% NR Pembrolizumab 2 DDP unfit 100 CPS>10% 51% 23% 13/5 Pembrolizumab 3 Post DDP 542 CPS> 10% 20% NR 8/NR

34 Outcome by subtypes Drug Phase Setting n Better results in Atezolizumab 1 Post DDP 67 ECOG PS=-1, smokers, no visceral mets Atezolizumab 2 Post DDP 315 ECOG PS 0, LN only, high mutational load, Luminal II TCGA Atezolizumab 2 DDP unfit 119 Upper tract, LN only, perioperative CT, TCGA luminal Atezolizumab 3 Post DDP 912 Current smoker, urethra primary, LN only Nivolumab 1/2 Post DDP 78 No visceral mets, LN only, Hb > 10 Nivolumab 2 Post DDP 270 Basal I and luminal II, 25 genes IGN gamma signature Avelumab 1b Post DDP 44 No viscetal mets, HB > 10, > 3 lines of CT Pembrolizumab 2 DDP unfit 100 Liver mets, upper tract, visceral disease, T cell inflamed GEP signature Pembrolizumab 3 Post DDP 542 Current smokers, PS=2, LN only, preoperatiove CT

35 Association among TCGA subtype, mutation load and clinical activity C: Mutation load as a fuction of response D: Mutation load versus response disaggregated by subtype or PD-L1 IC score E: Kaplan-Meier estimate of overall survival according to estimated mutation load (per megabase), binned into quartile (log-rank p=0.0041for a difference in overall survival between quartiles 1-3 and quartile 4 Balar AV et al., Lancet. 2017

36 Predictors of response to Atezolizumab Predictors of Response to Atezolizumab PD-L1 IC TCGA Subtype P = P = P = P = Mutation Load P < PD-L1 IHC, TCGA subtype and mutation load were significant independent predictors of response PD-L1 IC + subtype combination significantly improved on PD-L1 IC alone or subtype alone PD-L1 IC + TCGA Subtype P = PD-L1 IC + TCGA Subtype + Mutation Load P = biomarker combination significantly improved on PD-L1 IC + subtype combination These data highlight the importance of the interaction between the tumor and its microenvironment in understanding response to atezolizumab Based on data cutoff: March 14, Rosenberg J, et al. IMvigor210: biomarkers of atezolizumab in muc. ASCO 2016 Rosenberg J. ASCO 2016

37 Outcome of Patients Treated Beyond Progression (n=134) Subsequent reductions in target lesion SLD were seen in patients treated with atezolizumab beyond progression, highlighting the potential the potential for non -classical responses In patients treated beyond PD 19% (26/134) had SLD reductions 30% in target lesions 28% (38/134) had disease stabilization (> -30% to +20% SLD change) mos was 11.4 mo in all patients treated beyond progression 12-mo OS was 50% in all patients treated beyond progression Patients without post-pd baseline tumor assessments (n = 29) are not included in plot. Data cutoff: March 14, The safety of atezolizumab was consistent with that in the ITT population Dreicer R, J Clin Oncol 2016

38 Hyperprogressive disease 10% Not associated with higher tumor burden Associated with increased age Worse outcome Slower growing tumors less likely to respond Champiat S, Clin Cancer Res 2016

39 Immunotherapy combinations in urothelial cancer Study Arms Line of therapy IMvigor 130 Atezolizumab vs atezolizumab + platinum based CT vs platinum based CT n Phase 1st KEYNOTE 361 Pembrolizumab +/- platinum based combination CT vs CT 1st BISCAY Durvalumab +/- targeted agent matched to tu or profile FGFR, PARP, PI3K inhibitor 1, 2, b/2 NCI Nivolumab + Cabozantinib +/- ipilimumab 2nd 66 1/2 BMS CA Anti-LAG3 +/- nivolumab 2nd 30 1 Celldex CDX CORVUS CPI PsiOxus Therapeutics Varlilumab + atezolizumab 2nd 55 1 CPI-444 +/- atezolizumab 2nd Enadenotucirec (oncolytic virus) + nivolumab 2nd 30 1 Yale Ramuvirumab + pembrolizumab 2nd Plexxicon CSF1R, KIT or FLT3 inhibitor + pembrolizumab 2nd 400 1/2 USC Pembrolizumab + sephb4-hsa 2nd 60 2

40 Multiple factors influence tolerance and immunity Chen DS and Mellman I, Nature 2017

41 Factors influencing the cancer-immune set point Chen DS and Mellman I, Nature 2017

42 A stochastic process

43 Cancer evolution Mutation, selection and drift Lipinski KA, Trends in Cancer 2016

44 Conclusions None of the trials address the question of combinations vs sequences Patient selection remains undefined Is combination therapy suitable for every patient? Will we cure patients? What will be our strategy after combination? The pace of immunotherapy studies has outstripped our understanding of the underlying basic science The inundation of clinical trial will (hopefully) help in defining the optimal sequence, combination and duration of therapy The stochastic nature of cancer must be taken into account