Sergio Vázquez Estévez Sº Oncoloxía Médica Hospital Universitario Lucus Augusti. Lugo

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1 PAPEL ACTUAL Y DE FUTURO DE LA INMUNOTERAPIA EN EL ABORDAJE TERAPÉUTICO DEL CÁNCER DE VEJIGA Y OTRAS VÍAS DE PROGRESO. CÓMO SELECCIONAR PACIENTES PARA INMUNOTERAPIA O PARA QUIMIOTERAPIA. Sergio Vázquez Estévez Sº Oncoloxía Médica Hospital Universitario Lucus Augusti. Lugo

2 A MODO DE INTRODUCCIÓN

3 El cáncer de vejiga es un tumor agresivo que responde a la quimioterapia, aunque con pocas RC. Impacto en población anciana, y en pacientes con bajo PS y aclaramiento de creatinina. Es uno de los tumores sólidos con más alta tasa de mutaciones somáticas. El tratamiento más efectivo para tumores CIS/T1 alto grado es la BCG. 3

4 IO PRIMERA LÍNEA PACIENTES UNFIT PARA CDDP 4

5 ATEZOLIZUMAB

7 Baseline Characteristics Representative of the cisplatin-ineligible population Presented By Arjun Balar at 2016 ASCO Annual Meeting

8 Baseline Characteristics Representative of the cisplatin-ineligible population Presented By Arjun Balar at 2016 ASCO Annual Meeting

9 Baseline Characteristics Representative of the cisplatin-ineligible population Presented By Arjun Balar at 2016 ASCO Annual Meeting

10 Baseline Characteristics Representative of the cisplatin-ineligible population Presented By Arjun Balar at 2016 ASCO Annual Meeting

11 Baseline Characteristics Representative of the cisplatin-ineligible population Presented By Arjun Balar at 2016 ASCO Annual Meeting

13 Efficacy Response by Baseline Characteristic Presented By Arjun Balar at 2016 ASCO Annual Meeting

15 PEMBROLIZUMAB

22 IO SEGUNDA LÍNEA

23 ATEZOLIZUMAB

25 IMvigor210 Cohort 2: Baseline Characteristics Representative of the Greater muc Population Presented By Robert Dreicer at 2016 ASCO Annual Meeting

26 26 Efficacy Responses to Atezolizumab by PD-L1 IC Subgroup IC1/2/ IC2/3 3 n = 100 n = 207 ORR: confirmed IRF RECIST 28% v1.1 (95% CI) CR rate: confirmed IRF RECIST v1.1 (95% CI) 19% Alla N= % IC1 IC0 n = 107 n = % (19, 38) (14, 25) (12, 20) (6, 19) 9% (4, 16) 15% 9% 7% 4% 2% (9, 24) (6, 14) (4, 10) (1, 9) (0, 7) Responses were seen in all IC subgroups, but ORR was enriched with higher PD-L1 status Complete responses accounted for nearly half of the observed responses CRs were observed in all PD-L1 subgroups, with the highest rate in IC2/3 patients ORRs per immune-modified RECIST were concordant Dreicer R, et al. IMvigor210: atezolizumab in platinum-treated muc. ASCO 2016

28 Efficacy Overall Survival by Subgroups Presented By Robert Dreicer at 2016 ASCO Annual Meeting

30 DURVALUMAB

Study 1108 Bladder Cohort: Updated Efficacy and Tolerability of Durvalumab in Locally Advanced or Metastatic Urothelial Carcinoma Study 1108 is an ongoing Phase I/II study that has shown a tolerable

31 Study 1108 Bladder Cohort: Updated Efficacy and Tolerability of Durvalumab in Locally Advanced or Metastatic Urothelial Carcinoma Study 1108 is an ongoing Phase I/II study that has shown a tolerable safety profile with durvalumab as well as early and durable antitumour activity in several tumour types patients with UC were enrolled; 103 patients were eligible for efficacy analysis6 Tumour assessments were conducted at Weeks 6, 12, 16 then every 8 weeks during the treatment period After one year of treatment, patients entered follow-up Upon evidence of progressive disease, patients were offered retreatment with durvalumab DCR = disease control rate; DoR = duration of response; ORR =objective response rate; OS = overall survival; PD-L1 = programmed cell death ligand-1; PFS = progression-free survival; RECIST =Response Evaluation Criteria in Solid Tumors; UC = urothelial cancer. ATLAS ID: ESMPDUR Segal NH et al. Poster presented at: ESMO; September 26-30, 2014; Madrid, Spain; 2. Lutzky J et al. Presented at: ASCO; May 30-June 3, 2014; Chicago, IL; 3. Rizvi N et al. J Clin Oncol 2015;33(Suppl). Abstract 8032; 4. Segal NH et al. J Clin Oncol 2015;33(Suppl), Abstract 3011; 5. Massard C, et al. Presented at: ASCO; June 4-7, 2016; Chicago, IL Presentation Powles T et al. Presented at: ASCO-GU; February 16-18, Orlando, FL.

32 CARACTERÍSTICAS BASALES DE LOS PACIENTES Powles T et al. Presented at: ASCO-GU; February 16-18, Orlando, FL.

PD-L1 high defined as >25% of tumour/immune cell staining; PD-L1 low/negative defined as <25% of tumour/immune cell staining. C.

33 Confirmed ORR and DCR by PD-L1 Expression A. Includes 3 patients with unknown PD-L1 status due to biopsy samples with insufficient tumour who are not included in the PD-L1 high or low groups. B. PD-L1 high defined as >25% of tumour/immune cell staining; PD-L1 low/negative defined as <25% of tumour/immune cell staining. C. Objective response rate (ORR) defined as confirmed complete (CR) or partial response (PR) per RECIST v1.1 in responseevaluable patients.2 D. Disease Control Rate (DCR) defined as confirmed CR or PR or stable disease (SD) for 6 weeks. 1. Adapted from Powles T et al. Presented at: ASCO-GU; February Data cut off July 24, , Orlando, FL. 2. Massard C et al. J Clin Oncol. 2016;34:

34 Kaplan-Meier Survival Estimates in Primary Efficacy Population of UC Cohort Data cut-off July 24, 2016; NE = not evaluable; No. = number; OS = overall survival; PFS = progression free survival. 1. Powles T et al. Presented at: ASCO-GU; February 1618, Orlando, FL.

35 AVELUMAB

36 Figure 1. JAVELIN Solid Tumor pooled muc analysis study design Apolo AB et al. ASCO

not assessable information: 24 patients had no post-baseline tumor assessment (21 died within 8 weeks, and 3 withdrew from the trial); 1 patient had postbaseline

37 Table 2. Clinical activity in patients with 6 months of follow-up * Persistence of 1 nontarget lesion(s) and/or maintenance of tumor markers above normal levels Missing and/or not assessable information: 24 patients had no post-baseline tumor assessment (21 died within 8 weeks, and 3 withdrew from the trial); 1 patient had postbaseline assessments with an overall response of not evaluable; 3 patients started new anticancer therapy prior to the first post-baseline assessment; and 1 patient had stable disease of insufficient duration Proportion of patients with a best overall response of complete response, partial response, or stable disease Apolo AB et al. ASCO

38 Figure 5: ORR by subgroup in patients with 6 months of followup (1 of 2) Apolo AB et al. ASCO

39 Figure 5: ORR by subgroup in patients with 6 months of followup (2 of 2) Apolo AB et al. ASCO

40 Figure 4: PFS and OS in all post-platinum patients (2 of 2) Apolo AB et al. ASCO

41 PEMBROLIZUMAB

50 NIVOLUMAB

51 CheckMate 275: Study design Open-label, single-arm, phase II study Patients Blinded independent review committee (BIRC) assessment of response using RECIST v1.1 Treatment Metastatic or locally advanced muc Disease progression on a prior platinumbased therapy Nivolumab 3 mg/kg IV Q2W Evaluable PD-L1 tumor tissue samplea N=270 apatients Treat until progressionb or unacceptable toxicity 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 bpatients could have been treated beyond progression under protocol-defined circumstances Sharma P et al. Lancet Oncol 2017

52 Checkmate 275: Patient Demographics and Baseline Characteristics Characteristic and Demographics Median age, years (range) Nivolumab (N=270) 66 (38 90) Male, % 78.1 Race, % White Asian Black Other/not reported < No. of prior regimens in metastatic setting, % ECOG PS, % 0 1* Baseline metastases,% Visceral (overall) Liver Lymph node only PD-L1 expression, % 1% 5% One patient had ECOG performance status of Galsky M et al. Oral presentation at ESMO LBA31_PR.

53 Antitumor activity to nivolumab Median follow-up was 7 months (minimum of 6 months) All N=265b PD-L1 <1% n=143 PD-L1 1% n=122 PD-L1 5% n= Complete response 2.3 < Partial response Stable disease Progressive disease Unable to determine Outcome, % Confirmed ORR by BIRCa 95% CI Best overall response aby RECIST v1.1 of 270 patients were evaluated for efficacy, as 5 patients had insufficient follow-up b265 Confirmed ORR in patients with PD-L1 <5% was 15.8% (95% CI, ) Sharma P et al. Lancet Oncol 2017

54 Overall survival Median OS, Months (95% CI)a 1.0 Overall Survival (Probability) All treated 8.74 (6.05 NR) PD-L1 <1% 5.95 ( ) PD-L1 1% (8.74 NR) PD-L1 1% 0.4 All treated patients PD-L1 <1% No. at Risk All treated patients 265 PD-L1 <1% 143 PD-L1 1% 122 asimilar Months results were seen using the 5% PD-L1 tumor expression cutoff; NR, not reached 3 0 Sharma P et al. Lancet Oncol 2017

57 Bellmunt NEJM, 2016 III Pembrolizumab Post platinum 542 1% tumor o stroma 10% 28.5% 21.6% 21.1% Balar ASCO-GU, 2017 II Pembrolizumab First line cis ineligible 370 1% tumor o stroma 10%, 22% 39% 24% Presented by Elizabeth Plimack at 2016 ASCO Annual Meeting

58 CARACTERÍSTICAS MOLECULARES

60 PD-L1

PD-L1 as a biomarker: lights and shadows PD-L1 expression is generally associated with higher response rate, although responses can still occur in PD-L1 negative tumors1-25 Pitfalls of using PD-L1

61 PD-L1 as a biomarker: lights and shadows PD-L1 expression is generally associated with higher response rate, although responses can still occur in PD-L1 negative tumors1-25 Pitfalls of using PD-L1 IHC as a biomarker test26 Small biopsy specimens Changes over time and anatomical part Effect of previous treatments Epitopes instability Different antibodie, different affinities Multiple cells expressing PD-L1, different algorithms 1. Weber, et al. Lancet 2015; 2. Robert, et al. N Engl J Med 2015; 3. Wolchok, et al. ASCO 2016; 4. Sharma, et al. ASCO 2016; 5. Borghaei, et al. N Engl J Med 2015; 6. Brahmer, et al. N Engl J Med 2015; 7. Motzer, et al. J Clin Oncol 2015; 8. Janjigan, et al. ASCO 2016; 9. Kefford, et al. ASCO 2014; 10. Plimack, et al. ASCO 2015; 11. Hui, et al. ASCO Hodi, et al. SMR 2014; 13. Dreicer, et al. ASCO 2016; 14. Balar, et al. ASCO 2016; 15. Smith, et al. ASCO 2016; 16. McDermott, et al. J Clin Oncol 2015; 17. Massard, et al. ASCO 2016; 18. Antonia, et al. ASCO 2016; 19. Segal, et al. ASCO 2015; 20. Kaufman, et al. ASCO 2016; 21. Apolo, et al. ASCO 2016; 22. Verschraegen, et al. ASCO 2016; 23. Dirix, et al. SABCS 2015; 24. Chung, et al. ASCO 2016; 25. Disis, et al. ASCO 2016; 26. Topalian. Nat Rev Cancer 2016; 26. Topalian S. Nature Reviews Cancer 2016

62 Potential biomarkers under investigation Immunologically unresponsive tumour Mutation burden Activation signature Treg/CD3 ratio Immunologically responsive tumour Low High CD3 cells Antibody response CD3 count Poor Low High Clonality Low High Effector cells Teff/Treg ratio Suppressor cells PD-L1 on tumour/til T Low Robust T T T T T T T T T T T T T High T Blood Lymph Live Dying Naïve Memory ImmatureMature Vessel Node tumour tumour T-cell T-cell DC DC In-depth understanding of the immune biology of tumors will help guide the development of personalised cancer immunotherapies Yuan, et al. J Immunother Cancer 2016; Rizvi, et al. Science 2015; Fehrenbacher, et al. Lancet 2016

63 CARGA MUTACIONAL

64 Presented by Min Yuen Teo at ASCO 17

65 Presented by Min Yuen Teo at ASCO 17

66 MUTACIONES SOMÁTICAS EN LOS GENES REPARADORES DEL DNA

67 Presented by Min Yuen Teo at ASCO 17

68 Presented by Min Yuen Teo at ASCO 17

69 SUBTIPO TCGA

70 TCGA 2017 Lerner SP et al. J Clin Oncol 35, 2017 (suppl; abstr 4500)

71 TCGA 2017 Lerner SP et al. J Clin Oncol 35, 2017 (suppl; abstr 4500)

72 TCGA 2017 Lerner SP et al. J Clin Oncol 35, 2017 (suppl; abstr 4500)

73 TCGA 2017 Lerner SP et al. J Clin Oncol 35, 2017 (suppl; abstr 4500)

74 TCGA 2017 Lerner SP et al. J Clin Oncol 35, 2017 (suppl; abstr 4500)

75 Lerner SP et al. J Clin Oncol 35, 2017 (suppl; abstr 4500)

76 CONCLUSIONES 76

77 La elevada carga mutacional del cáncer de vejiga y el tipo de población que lo padece ha abierto una ventana de oportunidades para la IO En 1ª línea unfit : SM de Atezolizumab >datos históricos de GEM + CBCDA. No datos maduros para Pembrolizumab Si no hay contraindicación a IO, Pembrolizumab es ya un SOC en 2ª línea Datos no extrapolables, por ahora, a 1ª línea fit, donde CDDP produce respuestas duraderas Hay un 40% de progresiones: perfil molecular de paciente idóneo para IO, a confirmar en estudios prospectivos. No perfil clínico, al menos en 1ª línea unfit y 2ª línea Papel para la QT en 3ª línea?

78 Author: Robert Dreicer MD

79 GRACIAS 79

Updates in Immunotherapy for Urothelial Carcinoma

Updates in Immunotherapy for Urothelial Carcinoma Andrew J Armstrong MD ScM FACP DUA 2018 Copyright 2006 SciMed. Talk Outline Immunotherapy progress in 2017: 5 new approved PD-1/PD-L1 inhibitory agents