NOVÉ MOŽNOSTI LÉČBY NÁDORŮ MOČOVÉHO MĚCHÝŘE A JEJICH ZAŘAZENÍ DO ALGORITMU LÉČBY. Jindřich Fínek LF UK a FN Plzeň

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1 NOVÉ MOŽNOSTI LÉČBY NÁDORŮ MOČOVÉHO MĚCHÝŘE A JEJICH ZAŘAZENÍ DO ALGORITMU LÉČBY Jindřich Fínek LF UK a FN Plzeň 1

2 KARCINOM MOČOVÉHO MĚCHÝŘE INCIDENCE A MORTALITA 2

3 KARCINOM MOČOVÉHO MĚCHÝŘE ZASTOUPENÍ DLE STÁDIÍ 3

4 MODRÁ KNIHA PREDIKTIVNÍ ODHADY CELKOVÉ INCIDENCE A PREVALENCE 217 4

5 MODRÁ KNIHA - ODHADY POČTU PACIENTŮ NOVĚ LÉČENÝCH PROTINÁDOROVOU TERAPIÍ 217 5

6 METASTAZUJÍCÍ KARCINOM MOČOVÉHO MĚCHÝŘE (MUBC) LÉČEBNÉ MOŽNOSTI A PROGNÓZA 1st-Line Metastatic 1-1 2nd-Line Metastatic Cisplatin-based (~5% of patients) 1-8 Carboplatin-based (~5% of patients) 2,6,9,1 Vinflunine Taxane-based CT M-VAC Cisplatin: ORR: ~36 72% mos: ~13 16 mo Cisplatin: ORR: ~28 56% mos: ~8 15 mo ORR: ~9 3% mos: ~5 11 mo 5-ti leté přežití pacientů s mubc: ~15% 16

7 Somatic Mutation Frequency (/Mb) KARCINOM MOČOVÉHO MĚCHÝŘE PROČ IMUNOTERAPIE? Mutation Frequencies Observed in Cancers 1 N= AD, adenocarcinoma; AML, acute myeloid leukemia; CLL, chronic lymphocytic leukemia; DLBCL, diffuse large B-cell lymphoma; PD-1, programmed death-1; RCC, renal cell carcinoma; SQ, squamous. 1. Lawrence MS et al. Nature. 213;499(7457):

8 KEY APPROVALS FOR I-O TREATMENT IN GU TUMORS Checkpoint inhibitors, discovered in the 199s, have had a major impact on the treatment of GU cancer types, particularly over the past few years APPROVALS BY CANCER TYPE RCC Bladder Cancer MSI-H/dMMR Tumors* Nivolumab 2 Nivolumab 9 Pembrolizumab 1, Atezolizumab Nivolumab 1 Atezolizumab 3 Pembrolizumab 8 Durvalumab 5, Avelumab 6, Pembrolizumab 7 Nivolumab 4 *Indicated for all solid tumor types which are unresectable or metastatic, MSI-H or dmmr that have progressed following prior treatment and who have no satisfactory alternative treatment options. dmmr, mismatch repair deficient; GU, genitourinary; I-O, immuno-oncology; MSI-H, microsatellite instability high; RCC, renal cell carcinoma. Bristol-Myers Squibb receives FDA approval for Opdivo (nivolumab), the only treatment to deliver significant overall survival in advanced renal cell carcinoma vs. a standard of care, in patients who have received prior anti-angiogenic therapy [press release]. November 23, 215. Accessed October 3, European commission approves Bristol-Myers Squibb s Opdivo (nivolumab) for previously treated advanced renal cell carcinoma [press release]. April 6, 216. Accessed October 3, Roche. FDA grants Roche s cancer immunotherapy Tecentriq (atezolizumab) accelerated approval for people with a specific type of advanced bladder cancer [press release]. May 19, 216. Accessed September 12, Bristol-Myers Squibb. Bristol-Myers Squibb receives FDA approval for Opdivo (nivolumab) in previously treated locally advanced or metastatic urothelial carcinoma, a type of bladder cancer [press release]. February 2, 217. Accessed September 12, AstraZeneca UK Limited. AstraZeneca s Imfinzi (durvalumab) receives US FDA accelerated approval for previously treated patients with advanced bladder cancer [press release]. May 1, 217. Accessed September 12, Pfizer. FDA grants BAVENCIO (avelumab) approval for a common type of advanced bladder cancer [press release]. May 9, 217. Accessed September 12, Merck and Co., Inc. FDA Approves Merck s KEYTRUDA (pembrolizumab) for certain patients with locally advanced or metastatic urothelial carcinoma, a type of bladder cancer [press release]. May 18, 217. Accessed September 12, FDA Approves Merck s KEYTRUDA (pembrolizumab) for adult and pediatric patients with unresectable or metastatic, microsatellite instability-high (MSI-H) or mismatch repair deficient cancer [press release]. May 23, 217. Accessed October 1, Bristol-Myers Squibb. European Commission approves Bristol-Myers Squibb s Opdivo (nivolumab) for previously treated locally advanced unresectable or metastatic urothelial carcinoma in adults after failure of prior platinum-containing therapy [press release]. June 2, 217. Accessed September 12, Merck and Co., Inc. European Commision approves Merck s KEYTRUDA (pembrolizumab) for the treatment of certain patients with locally advanced or metastatic urothelial carcinoma, a type of bladder cancer [press release]. September 5, 217. Accessed September 12, Roche. Roche receives EU approval for TECENTRIQ (atezolizumab) in a specific type of metastatic lung and two types of metastatic bladder cancer [press release]. September 22, Accessed September 25, 217.

9 CHECKMATE 275: KLINICKÁ STUDIE FÁZE 2 N=27 Metastazující nebo lokálně pokročilý uroteliální karcinom Progrese onemocnění na předchozím režimu na základě platiny Vzorky vhodné pro hodnocení PD-L1* Nivolumab 3 mg/kg IV q2w (N=27) Léčba do progrese nebo neakceptovatelné toxicity Primární cíl: ORR (BIRC) u všech pacientů a pacientů s PD-L1 expresí 1% a 5% Sekundární cíle: PFS, OS, bezpečnost, QoL, biomarkery Léčba po progresi povolena pouze za dodržení podmínek definovaných protokolem studie * Patients were required to have an evaluable tumor tissue sample for PD-L1 expression testing at screening, but were not excluded based on PD-L1 status. RECIST v1.1. BIRC, blinded independent review committee; CNS, central nervous system; CTLA-4, cytotoxic T-lymphocyte antigen-4; ECOG PS, Eastern Cooperative Oncology Group performance status; IV, intravenous; ORR, objective response rate; OS, overall survival; PD-L1, programmed death ligand 1; PFS, progression-free survival; q2w, every 2 weeks; QoL, quality of life; tx, treatment. Galsky M et al. Oral presentation at ESMO 216. LBA31_PR.

10 CHECKMATE 275 LÉČEBNÁ ODPOVĚĎ (ORR) DLE HLADINY EXPRESE PD-L1 Outcome, % All PD-L1 <1% N=265 n=143 PD-L1 1% n=122 PD-L1 5% n=81 Confirmed ORR by BIRC* % CI Best overall response Complete response 2.3 < Partial response Stable disease Progressive disease Unable to determine Data reported as of October 216. Median follow-up was 7 months (minimum of 6 months). * By RECIST v of 27 patients were evaluated for efficacy, as 5 patients had insufficient fo BIRC, blinded independent review committee; CI, confidence interval; ORR, objective response rate PD-L1, programmed death ligand 1. Galsky M et al. Oral presentation at ESMO 216. LBA31_PR.

11 Pravděpodobnost PFS CheckMate mpfs Medián PFS, měsíce (95% CI)* Všichni pacienti 2, ( ) PD-L1 <1% 1,87 ( ) PD-L1 1% 3,55 ( ) No. at Risk Měsíce PD-L1 1% PD-L1 <1% All treated patients PD-L1 <1% PD-L1 1% All treated patients Data reported as of October 216. * Similar results were seen using the 5% PD-L1 tumor expression cutoff. CI, confidence interval; PD-L1, programmed death ligand 1; PFS, progression-free survival. Galsky M et al. Oral presentation at ESMO 216. LBA31_PR.

12 Pravděpodobnost OS CheckMate mos Medián OS, měsíce (95% CI)* 1. Všichni pacienti 8,74 (6,5 NR) PD-L1 <1% 5,95 (4,3 8,8) PD-L1 1% 11,3 (8,74 NR) PD-L1 <1% PD-L1 1% All treated patients. No. at Risk All treated patients PD-L1 <1% PD-L1 1% Měsíce Data reported as of October 216. * Similar results were seen using the 5% PD-L1 tumor expression cutoff. CI, confidence interval; NR, not reached; OS, overall survival; PD-L1, programmed death ligand 1. Galsky M et al. Oral presentation at ESMO 216. LBA31_PR.

13 Mean Change From Baseline (95% CI) CheckMate 275 Kvalita života (QoL) EORTC QLQ-C3, a validated QoL instrument commonly used in oncology studies, assesses QoL using 5 function scales, 8 symptom scales, a global QoL scale, and a finance scale 1 A clinically meaningful change in QoL score may be regarded as 1 points EORTC QLQ-C3 Global Health Status Score 2 * Better Worse -25 Week 9 n=138 Week 17 n=95 Week 25 n=73 Week 33 n=52 Week 41 n=23 Quality of life was maintained throughout 41 weeks of nivolumab treatment 2 Adapted from Galsky et al, 216, ESMO. Similar results were observed for general health status using the EQ5D assessment tool 2 Data reported as of October 216. * Completion rates for all treated patients met or exceeded 75% at all QoL assessments through the first 49 weeks of on-treatment visits. CI, confidence interval; EORTC QLQ-C3, European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire for Cancer Patients Version 3.; EQ5D, EuroQoL Five Dimensions Questionnaire; QoL, quality of life. 1. Khan I et al. Health Qual Life Outcomes. 215;13: Galsky M et al. Oral presentation at ESMO 216. LBA31_PR.

14 Overall survival (probability) Chemotherapy VINFLUNINE + BSC VERSUS BSC: RANDOMIZED PHASE 3 STUDY OF PATIENTS WITH muc WHO PROGRESSED AFTER 1L 2L+ muc 1. OS in the Eligible Population* VFL + BSC BSC Time (months) Adapted from Bellmunt et al, 29. Efficacy in the ITT Population Vinflunine + BSC (n=253) BSC (n=117) ORR, % 8.6 (95% CI) ( ) CR, % mdor, mos mpfs, mos mos, mos (95% CI)* 6.9 (5.7 8.) 4.3 ( ) HR:.78; 95% CI,.61.99; P=.43 Most Common Treatment-Related Adverse Events and Hematologic Abnormalities Adverse event, % Vinflunine + BSC (n=248) All- Grade Grade 3-4 BSC (n=117) All- Grade Grade 3-4 Anemia Neutropenia <1 Thrombocytopenia <1 Fatigue/asthenia Constipation <1 Nausea <1 Stomatitis/ mucositis Alopecia 29 2 Vomiting Infusion/injection site 27 <1 * The eligible population excludes 13 patients who presented at least one major protocol violation at baseline. 2L, second line; BSC, best supportive care; CR, complete response; DOR, duration of response; HR, hazard ratio; m, median; mos, months; muc, metastatic urothelial carcinoma; ORR, objective response; OS, overall survival; PFS, progression-free survival; VFL, vinflunine. Bellmunt J et al. J Clin Oncol. 29;27(27):

15 I-O monotherapy 2L 3L muc KEYNOTE-45: PEMBROLIZUMAB VS CT IN RECURRENT OR PROGRESSIVE muc Randomized, phase 3 trial of pembrolizumab versus chemotherapy in patients with previously treated recurrent or progressive metastatic urothelial carcinoma 1,2 N=542 Urothelial carcinoma of the renal pelvis, ureter, bladder, or urethra Disease progression after 1 2 lines of platinum-based therapy or recurrence within 12 months of perioperative platinum-based therapy ECOG PS 2 Transitional cell predominant Provision of tumor sample for biomarker assessment R Pembrolizumab 2 mg (IV) q3w for 2 years PTX, DTX, or VFL (175, 75, or 32 mg/m 2, respectively, IV) q3w Primary Outcome Measures: OS and PFS (in total and PD-L1 CPS 1% population) Secondary Outcome Measures: ORR and DOR (in total and PD-L1 CPS 1% population) and safety in total population 2L, second line; 3L, third line; CPS, combined positive score; CT, chemotherapy; DOR, duration of response; DTX, docetaxel; ECOG PS, Eastern Cooperative Oncology Group performance status; I-O, immuno-oncology; IV, intravenous; muc, metastatic urothelial carcinoma; ORR, objective response rate; OS, overall survival; PD-L1, programmed death ligand 1; PFS, progression-free survival; PTX, paclitaxel; q3w, every 3 weeks; R, randomized; VFL, vinflunine. 1. Bellmunt J et al. N Engl J Med. 217;376: Clinicaltrials.gov. NCT Accessed October 3,

16 I-O monotherapy Overall Survival, (%) Overall Survival, (%) 2L 3L muc KEYNOTE-45: OVERALL SURVIVAL AND ORR* Outcomes in All Pts Pembro Chemo mos, mos (95% CI)* 1.3 ( ) 7.4 ( ) ORR, % (95% CI)* 21.1 ( ) 11.4 ( ) CR, % PR, % mdor, mos (range) NR ( ) 4.3 ( ) Outcomes in CPS 1% Pembro Chemo mos, mos (95% CI)* 8. ( ) 5.2 (4. 7.4) ORR, % (95% CI)* 21.6 ( ) 6.7 ( ) CR, % PR, % mdor, mos (range) Pembro Chemo 1 Overall Survival: Total 1 1 Overall Survival: CPS 1% Pembro 8 Pembro 7 Chemo 7 Chemo HR (95% CI):.73 (.59.91), P=.2 HR (95% CI):.57 (.37.88), P= Time (months) No. at Risk Adapted from Bellmunt et al, 217. No. at Risk Pembro 74 Chemo 9 Time (months) Adapted from Bellmunt et al, 216. *Confirmed ORR and OS were assessed per RECIST v1.1 by blinded, independent central review. Data cutoff date: September 7, 216. CPS is the percentage of PD-L1 positive tumor cells and tumor-infiltrating immune cells relative to the total number of tumor cells. 2L, second line; 3L, third line; chemo, chemotherapy; CI, confidence interval; CPS, combined positive score; CR, complete response; HR, hazard ratio; I-O, immunooncology; mdor, median duration of response; mos, median overall survival; mos, months; muc, metastatic urothelial carcinoma; NR, not reached; ORR, objective response rate; OS, overall survival; pembro, pembrolizumab; PR, partial response; Pts, patients; RECIST, Response Evaluation Criteria In Solid tumors. 1. Bellmunt J et al. N Engl J Med. 217;376: Bellmunt J et al. Oral presentation at SITC

17 I-O monotherapy Global Health Status/QoL Score Without Deterioration, % 2L 3L muc KEYNOTE-45: QUALITY OF LIFE EORTC QLQ-C3 Global Health Status/QoL Score by Visit* Kaplan-Meier Estimates of Time to Deterioration in the EORTC QLQ-C3 Global Health Status/QoL Score Pembrolizumab Events (n) Median (mos) Pembrolizumab HR (95% CI).7 (.55.9) P=.2 Chemotherapy Chemotherapy Time (weeks) Time (months) No. completed EORTC QLQ-C3 Pembro Chemo Adapted from Vaughn et al, 217. Global health status/qol score was better with pembrolizumab starting at Week 3 and maintained through Week 27 Pembro Chemo No. at risk Adapted from Vaughn et al, 217. Time to deterioration in the global health status/qol score was prolonged with pembrolizumab vs chemo * Data are shown as mean ± standard error. The range of possible scores for the global health status/qol score is to 1. 2L, second line; 3L, third line; chemo, chemotherapy; CI, confidence interval; EORTC QLQ-C3, European Organization for Research and Treatment of Cancer core 3 Quality of Life Questionnaire version 3; HR, hazard ratio; mos, months; muc, metastatic urothelial carcinoma; pembro, pembrolizumab; QoL, quality of life. Vaughn DJ et al. Poster presentation at ASCO GU

18 I-O monotherapy 2L+ muc IMvigor 21: ATEZOLIZUMAB IN LOCALLY ADVANCED OR muc Multicenter, single-arm, phase 2 trial of atezolizumab in patients with locally advanced or metastatic urothelial carcinoma N=31 Locally advanced or metastatic urothelial carcinoma (including renal pelvis, ureters, urinary bladder, or urethra) Disease progression during or following at least 1 Pt-containing regimen (cohort 2) ECOG PS 1 Atezolizumab 12 mg IV q3w Primary Outcome Measure: ORR (CR or PR)* Secondary Outcome Measures: DOR,* PD,* PFS, * OS, PK, ATA *As assessed by the Independent Review Facility (IRF) and investigator using RECIST v1.1. Using modified RECIST. 2L, second line; ATA, anti-therapeutic antibodies; CR, complete response; DOR, duration of response; ECOG PS, Eastern Cooperative Oncology Group performance status; I-O, immuno-oncology; IV, intravenous; muc, metastatic urothelial carcinoma; ORR, objective response rate; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PK, pharmacokinetics; PR, partial response; Pt, platinum; q3w, every 3 weeks; RECIST, Response Evaluation Criteria In Solid tumors. Clinicaltrials.gov. NCT Accessed October 3,

19 I-O monotherapy Overall Survival (%) Overall Survival (%) 2L+ muc IMvigor 21: COHORT 2 OVERALL SURVIVAL & ORR Outcomes in All Patients 1 * Atezolizumab mos, months (95% CI) 7.9 ( ) ORR, % (95% CI) 16 (12 2) CR, % 6 mdor, months (range) NR Outcomes by PD-L1 1 * mos, months (95% CI) PD-L1 5%* 11.9 (9. NE) PD-L1 <5%* PD-L1 1%* 6.7 (5.4 8.) NA PD-L1 <1%* ORR, % (95% CI) 28 (19 38) NA 19 (14 25) 9 (4 16) CR, % 14 NA 8 2 NA No. at Risk All patients: Overall Survival in All Patients 1 * Atezolizumab All treated Time (months) Adapted from Loriot et al, 216. PD-L1 5% PD-L1 1% but <5% PD-L1 <1% Longer OS observed in patients with higher PD-L1 IC status 32 of 49 responding patients had ongoing responses at data cutoff* Overall Survival by PD-L1 Expression PD-L1 5% Censored No. at risk Time (months) Atezolizumab PD-L1 1% but <5% PD-L1 <1% Adapted from Rosenberg et al, 216. *Data cutoff: March 14, 216. PD-L1 expression on IC: IC2/3 ( 5%), IC/IC1 (< 5%), ICO1/2/3 ( 1%), ICO (<1%). Data cutoff: September 14, 215. CI, confidence interval; CR, complete response; IC, tumor-infiltrating immune cells; mdor, median duration of response; mos, median OS; NA, not available; NE, not estimable; NR, not reached; OS, overall survival; ORR, objective response rate; PD-L1, programmed death ligand 1; PR, partial response. 1. Loriot Y et al. Poster presentation at ESMO 216. Abstract 783P. 2. Rosenberg et al. Lancet. 216;387:

20 Post-Progression Overall Survival, % I-O monotherapy IMvigor 21: COHORT 2 TREATMENT BEYOND PROGRESSION 2L+ muc 1 Post-PD OS by Post-PD Treatment Status 8 6 Atezolizumab Other systemic therapy No systemic therapy Censored No. of Patients at Risk Time (months) Atezolizumab Other systemic therapy No systemic therapy Adapted from Necchi et al, % (45 of 137) of all patients TBP experienced a reduction in the sum of target lesion tumor diameters from their measurements at time of PD 5 patients experienced objective responses following their continued use of atezolizumab TRAEs were evaluated in 137 patients who were TBP with atezolizumab; any Grade TRAEs were reported in 53% of patients, and Grade 3 4 TRAEs in 9% of patients *RECIST v1.1 (IRF- assessed) and imrecist (investigator-assessed). TRAEs reported during post-progression. 2L, second line; CR, complete response; IRF, independent review facility; IV, intravenously; muc, metastatic urothelial cancer; ORR, objective response rate; OS, overall survival; PD, progressive disease; PD-L1, programmed death ligand 1; PR, partial response; q3w, every 3 weeks; RECIST, Response Evaluation Criteria In Solid tumors; TBP, treated beyond progression; TRAE, treatment-related adverse events. Necchi A et al. Poster presentation at ESMO PD. 2

21 I-O monotherapy 2L 3L muc IMvigor 211: PHASE 3 TRIAL OF ATEZOLIZUMAB VERSUS CHEMOTHERAPY IN PLATINUM-TREATED ADVANCED UROTHELIAL CARCINOMA 1,2 N=931 Key Inclusion Criteria muc with progression during or following platinum-based chemotherapy ( 2 prior lines of therapy) Measurable disease (RECIST v1.1) ECOG PS or 1 Sample for PD-L1 testing TCC histology primary component R Atezolizumab* 12 mg q3w 1:1 Chemotherapy* (investigator s choice) Vinflunine q3w Docetaxel q3w Paclitaxel q3w Until loss of clinical benefit Until disease progression Stratification Factors: Number of risk factors ( vs 1/2/3) Liver metastases (yes vs no) PD-L1 status (<5% vs 5%) Chemotherapy (vinflunine vs taxanes) Primary Outcome Measure: OS Secondary Outcome Measures: ORR, PFS, DOR, safety, ATAs, pharmacokinetics, QoL PD-L1 <5% is defined as IC/1 and PD-L1 5% is defined as IC2/3. *No crossover permitted. Defined by time from prior chemotherapy <3 mo, ECOG performance status > and hemoglobin <1 g/dl. Confirmed response was not required for secondary efficacy endpoints. This analysis reports exploratory confirmed responses. 2L, second line; 3L, third line; ATA, antitherapeutic antibodies; DOR, duration of response; ECOG, Eastern Oncology Cooperative Group; IC, immune cell; I-O, immunooncology; muc, metastatic urothelial carcinoma; ORR, objective response rate; OS, overall survival; PD-L1, programmed death ligand 1; PFS, progression-free survival; PS, performance status; q3w, every 3 weeks; R, randomized; QoL, quality of life; RECIST, Response Criteria In Solid Tumors; TCC, transitional cell carcinoma. 1. Powles T et al. Oral presentation at EAS-AACR-SIC Clinicaltrials.gov NCT Accessed October 17,

22 Powles I-O monotherapy T, et al. EAS 217, IMvigor211. Overall Survival, (%) Overall Survival, (%) 2L 3L muc IMvigor 211: OVERALL SURVIVAL AND ORR* Outcomes in ITT Atezo Chemo mos, mos (95% CI) 8.6 ( ) 8. ( ) ORR, % (95% CI) 13 (11 17) 13 (11 17) CR, % 3 3 mdor, mos (range) 21.7 ( ) 7.4 ( ) PD-L1 5% Population Atezo Chemo mos, mos (95% CI) 11.1 ( ) 1.6 ( ) ORR, % (95% CI) 23 (16 32) 22 (15 3) CR, % 7 7 mdor, mos (range) Overall Survival: ITT Population 1 Overall Survival: PD-L1 5% Population 8 Atezolizumab Chemo 8 Atezolizumab Chemo No. at Risk Atezolizumab Chemo HR =.85 (95% CI:.73.99); P = Time (months) Adapted from Powles et al, No. at Risk Atezolizumab Chemo HR =.87 (95% CI: ), P = Time (months) Adapted from Powles et al, Data cutoff date: March 13, 217. Median follow-up duration in ITT population: 17.3 months (range: 24.5) * Confirmed ORR was assessed by RECIST v1.1 as an exploratory endpoint. IC2/3 is defined as PD-L1 5% on tumor-infiltrating immune cells. IC3 defined as PD-L1 1% on ICs; IC2 defined as PD-L1 5% and < 1% on ICs. 2L, second line; 3L, third line; Atezo, atezolizumab; CI, confidence interval; Chemo, chemotherapy; CR, complete response; DCR, disease control rate; HR, hazard ratio. IC, immune cell; ITT, intent-to-treat; mdor, median duration of response, mos, median overall survival; muc, metastatic urothelial carcinoma; ORR, objective response rate;pd-l1, programmed death ligand-1; RECIST, Response Evaluation Criteria in Solid Tumors. 22 Powles T, et al. EAS 217, IMvigor211.

23 I-O monotherapy SUMMARY OF SELECT RECENT INVESTIGATIONAL AND REGISTRATIONAL TRIALS IN PRETREATED muc* (1 OF 2) 2L+ muc Study design Median follow-up (range) ORR, % (95% CI) CR PR Study Durvalumab Phase 1/2 N=191 Durvalumab 1 mg/kg IV q2w for 1 year Phase 1/2, single-arm muc cohort 1 EP: Safety (AEs/SAEs), ORR by BICR 5.78 months (.4 to 25.9) 17.8 ( ) 3.7% 14.1% Javelin Solid Tumor 2 Avelumab Phase 1 N=242 Avelumab 1 mg/kg IV q2w Phase 1, single-arm muc cohorts 1 EP: ORR by IERC, ORR by BICR 19.6 months (12. to 3.4 ) 16.1 ( ) 5.% 11.2% mos (95% CI) 18.2 months (8.1 NE) 7.7 months ( ) mpfs (95% CI) 1.5 months ( ) 1.5 months ( ) Evaluation of PD-L1 ORR by PD-L1 % of PD-L1 expressing TCs or ICs PD-L1 25%: 27.6% PD-L1 <25%: 5.1% % of PD-L1 expressing TCs PD-L1 5%: 23.8% PD-L1 <5%: 11.5% Durvalumab and avelumab are currently not approved in Europe for the treatment of urothelial carcinoma (status as of 1 October 217). *No head-to-head studies have been conducted and direct comparisons cannot be made between these studies. As-treated population included 9 1L patients in Study 118. OS data were considered immature at data cutoff. 1, primary; AE, adverse event; BICR, blinded independent review committee; CI, confidence interval; CR, complete response; EP, endpoint; IC, immune cell; IERC, independent endpoint review committee; IV, intravenously; I-O, immuno-oncology; NA, not available; NE, not evaluable; mos, median overall survival; mpfs, median progression-free survival; muc, metastatic urothelial carcinoma; q2w, every 2 weeks; ORR, objective response rate; PD-L1, programmed death ligand 1; PR, partial response; SAE, serious adverse event; TC, tumor cell. 1. Hahn NM et al. Poster presentation at ASCO Apolo AB et al. Poster presentation at.esmo p. 23

24 Overall survival (probability) Overall survival (probability) Chemotherapy 1L muc MVAC VS GEM-CIS IN 1L CISPLATIN-ELIGIBLE AND GEM-CARBO VS M-CAVI IN 1L CISPLATIN-INELIGIBLE muc PATIENTS Gem-cis MVAC mos (months) HR=1.9 (log rank p=.66) M-CAVI (n=119) Gem-carbo (n=119) mos (months) HR=.94 (log rank p=.64) Time (months) Adapted from von der Maase et al, 25. Time (years) Adapted from De Santis et al, 212. ORR (%) Median PFS (months) Median OS (months) Top 3 Grade 3/4 AEs (%) Phase 3 study of classic MVAC vs Gem-cis (n=45) 1,2 Classic MVAC: 46 Gem-cis: 49 Classic MVAC: 8.3 Gem-cis: 7.7 Classic MVAC: 15.2 Gem-cis: 14. Classic MVAC: Neutropenia (82.3), Alopecia (55.2), Mucositis (21.9) Gem-cis: Neutropenia (71.1), Thrombocytopenia (57.), Anemia (27.) Phase 2/3 study of Gem-carbo vs M-CAVI in cisplatin-unfit patients (n=238) 3 Gem-carbo: 41 M-CAVI: 3 Gem-carbo: 5.8 M-CAVI: 4.2 Gem-carbo: 9.3 M-CAVI: 8.1 Gem-carbo* : Neutropenia (52.5), Thrombocytopenia (48.3), Leucopenia (44.9) M-CAVI* : Neutropenia (63.5), Leucopenia (46.6), Thrombocytopenia (19.4) *Common Toxicity Criteria v2.. Adverse events reported in 118 patients for each arm. Gem-carbo, Gencitabine + Carboplatin; Gem-cis, Gemcitabine + Cisplatin; M-CAVI, Methotrexate + carboplatin + vinblastine; MVAC, Methotrexate + vinblastine + adriamycin + cisplatin. 1. von der Maase H et al. J Clin Oncol. 2;18: von der Maase H, et al. J Clin Oncol. 25;23: De Santis M et al. J Clin Oncol. 212;3:

25 I-O monotherapy IMvigor 21: PHASE 2 TRIAL OF ATEZOLIZUMAB IN LOCALLY ADVANCED OR METASTATIC UROTHELIAL CARCINOMA (COHORT 1: 1L CPT-INELIGIBLE) 1L muc Outcome Confirmed ORR, % (n) (95% CI) Atezolizumab N= (27) (16 31) IC 21 (8) IC1 21 (1) IC2/3 28 (9) IC1/2/3 24 (19) Complete response, % (n) 9 (11) IC 8 (3) IC1 8 (4) IC2/3 13 (4) IC1/2/3 1 (8) mdor all patients, months (95% CI) mos all patients, months (95% CI) Efficacy Summary NE (14.1 NE) 15.9 (1.4 NE) 5 most frequent any-grade TRAEs (%) 5 most frequent Grade 3 4 TRAEs (%) Treatment-Related AEs Atezolizumab N=119 Overall (66) Fatigue (3) Diarrhea (12) Pruritus (11) Decreased appetite (9) Hypothyroidism (7) Overall (16) Fatigue (3) ALT increased (3) AST increased (3) Diarrhea (2) Blood bilirubin increased (2) Hypophosphatemia (2) Renal failure (2) 1 death was attributed to a TRAE (sepsis) 1L, first line; AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CI, confidence interval; CPT, cisplatin; IC, immune cell; I-O, immunooncology; mdor, median duration of response; mos, median overall survival; muc, metastatic urothelial carcinoma; NE, not estimable; ORR, objective response rate; TRAE, treatment-related adverse event. Balar AV et al. Lancet. 217;389:

26 I-O monotherapy 1L muc KEYNOTE-52: A PHASE 2 TRIAL OF PEMBROLIZUMAB IN 1L CISPLATIN-INELIGIBLE ADVANCED OR muc Outcome Confirmed ORR,* % (n) 95% CI All N=37 24 (89) 2 29 CPS 1% n=8 39 (31) 28 5 CPS 1 to <1% n=139 2 (28) CPS <1% n=46 11 (5) 4 24 Best overall response, % (n) Complete response 5 (17) 1 (8) 1 (1) () Partial response 19 (72) 29 (23) 19 (27) 11 (5) Stable disease 23 (84) 3 (24) 26 (36) 17 (8) Progressive disease 42 (156) 25 (2) 42 (59) 57 (26) Non-evaluable 3 (1) () 3 (4) 4 (2) No assessment 8 (31) 6 (5) 9 (12) 11 (5) Median time to 2 response, months % CI Median duration of response, months 95% CI Efficacy Summary NR 9 NR most frequent any-grade TRAEs (%) 4 most frequent Grade 3 5 TRAEs (%) Treatment-related AEs Pembrolizumab N=37 Any (62) Fatigue (17) Pruritus (15) Rash (1) Decreased appetite (1) Diarrhea (8) Any (16) Fatigue (2) Colitis (<2) Asthenia (<2) Decreased appetite (<2) 1 patient s death was attributed to a TRAE (myositis) Data cutoff date: September 1, 216. Median follow-up was 5 months (IQR: ). CPS is the number of PD-L1 positive cells (tumor cells, macrophages, lymphocytes) over total tumor cells, expressed as a percentage. *By central review per RECIST v1.1. Patient had post-baseline imaging, but images were not of sufficient quality to determine response. Patient had no post-baseline imaging. 1L, first line; AE, adverse event; CI, confidence interval; CPS, combined positive score; I-O, immuno-oncology; muc, metastatic urothelial carcinoma; NR, not reached; ORR, objective response rate; PD-L1, programmed death ligand 1; RECIST, Response Evaluation Criteria In Solid tumors; TRAE, treatment-related AE. Balar AV et al. Lancet Oncol. 217;pii: S (17)

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