Immunoterapia nella malata avanzata. Daniele Raggi Fondazione IRCCS Isttuto Nazionale dei Tumori, Milano

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1 Immunoterapia nella malata avanzata Daniele Raggi Fondazione IRCCS Isttuto Nazionale dei Tumori, Milano

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3 Five checkpoint inhibitors now approved for UC! BCG Atezolizumab (US/EU) (2L) Atezolizumab (US/EU) (1L) cisplatn-ineligible Avelumab (US) (2L) 26-year gap MAY 2016 FEB 2017 APR 2017 MAY 1, 2017 MAY 9, 2017 MAY 18, 2017 Vinfunine (EU only) Nivolumab (US/EU) (2L) Durvalumab (US) (2L) Pembrolizumab (US/EU) (1L cisplatn-ineligible) (2L) L, frswclinve;.l, secovnvwclinve; BCG, Bacillus Calm/etteeGuérinv waccinve; UC, urovwhelial carcinvovm/a.

4 Rationale for immuine checkpoint inhibitors in UC

5 Invwrawesical BCG is whe frsw im/m/unvovwherapy fdovr NMIBC BCG was the first immunotherapy to receive approval from the FDA for cancer treatment and remains the gold standard for NMIBC 1,2 BCG is anv attenvuawew fdovrm/ ovfd Mycobacterium bovis, whe bacwerium/ whaw causes bovwinve wuberculovsis 1 The MOA ovfd BCG is nvovw yew covm/plewely unvwerswovovw, wespiwe iws lovnvg hiswovry ovfd use inv blawwer canvcer 1,3 Attachm/envw wov urovwhelial cells Invwernvalisatovnv by blawwer canvcer cells Anvtgenv presenvwatovnv anvw cywovkinve release by blawwer canvcer cells Im/m/unve cell recruiwm/envw Cywovkinve provwuctovnv Im/m/unvecm/ewiawew cywovwovxiciwy 1. Ghasem/zaweh A, ew al. Clin Cancer Res.112;..:693e.11;.. Necchi A, ew al. Curr Opin Urol.116;.6 [Epub aheaw ovfd prinvw]; 3. Rewelm/anvcSiwi G, ew al. Nat Rev Urol.1146;11:103e12.. BCG, Bacillus Calm/etteeGuérinv waccinve; FDA, Fovovw anvw Drug Awm/inviswratovnv; MOA, m/echanvism/ ovfd actovnv; NMIBC, nvovnvcm/usclecinvwasiwe blawwer canvcer.

6 PDcL1 expressiovnv is assovciawew wiwh grawe anvw swage inv UC PD-L1 positvity increases with advancing local tumour stage in UC 111 PD-L1 positvity is signifcantly associated with high tumour grade in UC 111 PDcL1 povsitwiwy, % (90% CI) pta pt1 pt. pt3//46 Cis PDcL1 povsitwiwy, % (90% CI) Lovw grawe OR=..46 (90% CI 1..1e46.6.) p=1.119 High grawe CI, covnvfwenvce invwerwal; OR, ovwws ratov; PDcL1, provgram/m/ew weawhcliganvw 1; UC, urovwhelial carcinvovm/a.

7 Blawwer canvcer is covnvsiwerew wov be a highly im/m/unvovgenvic wum/ovur 1 1. Zehir A, ew al. Nat Med.116;.3:613e613 6

8 1L metastatic setng

9 Phase II IMvigor210 & KN052 Study Design and Objectves Invovperable lovcally awwanvcew ovr m/ewaswatc UC Prewovm/invanvwly UC hiswovlovgy Tum/ovr tssue ewaluable fdovr PDcL1 westnvg a Key covhovrw 1 invclusiovnv criweria: Nov priovr wreawm/envw fdovr m/uc (> 1. m/ovnvwhs sinvce periovperatwe chem/ovwherapy) ECOG PS 1c. Cisplatnv inveligibiliwy basew ovnv 1 ovfd whe fdovllovwinvg: 1 GFR < 21 anvw > 31 m/l//m/inv (CovckcrovfcGaulw), Grawe. hearinvg lovss (.0 wb aw. covnvtguovus fdrequenvcies) ovr peripheral nveurovpawhy, ECOG PS. Envwpovinvws: Cohort 1 (N = 119): 1L cisplatnv inveligible Cohort 2: Platnvum/cwreawew m/uc Awezovlizum/ab 1.11 m/g IV q3w unvtl RECIST w1.1 provgressiovnv Awezovlizum/ab 1.11 m/g IV q3w unvtl lovss ovfd clinvical benvefw Prim/ary: covnvfrm/ew ORR per RECIST w1.1 (cenvwral IRF) Key secovnvwary: DOR, OS, safdewy Balar AV ew al, Lanvcew..116 Janv 6;3.9(111246):26c62 Balar AV, ew al. Lanvcew Onvcovl.116; //S14661c.1460(16)3121.c.

10 Recruitng Clinical Trials: First-Line Metastatc Bladder Cancer Swuwy Agenvw Phase anvw Type Prim/ary Envwpovinvw MK34660c321// KEYNOTEc321 1 Pem/brovlizum/ab ± chem/ovwherapy a ws chem/ovwherapy 3 Ranvwovm/isew, covnvwrovllew PFS, OS IMwigovr131. Awezovlizum/ab ± chem/ovwherapy a ws chem/ovwherapy 3 Ranvwovm/isew, covnvwrovllew PFS, OS, % wiwh AEs DANUBE 3 Durwalum/ab ± wrem/elim/um/ab ws SOC chem/ovwherapy 3 Ranvwovm/isew, ovpenv label PFS, OS CheckMawe Galsky MD et al. TPS 539 Niwovlum/ab+Ipilim/um/ab ws chem/ovwherapy 3 Ranvwovm/isew, ovpenv label PFS, OS

11 2L metastatic setng

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13 Outcomes of IMvigor211 - Efcacy US FDA and EMA approval for platnum-treated, advanced UC Povwles T. ew al, Lanvcew.116 & GUcASCO.11.

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15 Summary 2L Updated results confrm that clinical beneft with ICI use is maintained at long term Clinvical provgnvovstc fdacwovr m/ovwels weriwew fdrovm/ nvovnvccovm/paratwe wrials wiw suppovrw whe benvefw fdrovm/ ICI wherapy covm/parew wov swanvwarw chem/ovwherapy Resulws fdrovm/ wranvslatovnval swuwies will likely provwiwe whe basis fdovr unvwerswanvwinvg patenvw ovuwcovm/e inv whis setnvg

16 How Emerging Clinical Data Will Impact the European/US Treatment Algorithm for Metastatc Urothelial Cancer FIRST LINE 1,2 Eligible for cisplatin? Yes PS 0-1 GFR 60 ml/min Standard chemotherapy: GC, MVAC, HD-MVAC, PCG PS 2 or GFR <60 ml/min Combination chemotherapy: Carboplatin-based Immune checkpoint inhibitor 3 No PS 2 and GFR <60 ml/min NO combination chemotherapy: Monotherapy, BSC Immune checkpoint inhibitor 3 Consider clinical trial of new or more tolerable therapy 3 SECOND LINE 1,2 PS 0-1 Consider immune checkpoint inhibitor therapy 3 PS 2 Standard second-line chemotherapy BSC Consider clinical trial BSC: besw suppovrtwe care; GFR: glovm/erular flwratovnv rawe; (HDc)MVAC: (highcwovse) m/ewhovwrexawe, winvblastnve, wovxovrubicinv, cisplatnv; PCG: pacliwaxel, cisplatnv, gem/ciwabinve. 1. Wiwjes JA ew al. Eur Urol..116;61:462.c Wiwjes JA ew al. cmusclecinvwasiwecanvwcmewaswatccblawwerccanvcercguiwelinvesc.112.pwfd. Publishew.112. Accessew March 3, Natovnval Covm/prehenvsiwe Canvcer Newwovrk (NCCN). Blawwer Canvcer (Versiovnv ). Accessew February 9,.116.

17 @DanvieleRaggi.3 16