José Luis Pérez Gracia Departamento de Oncología Clínica Universidad de Navarra Madrid, 20 de noviembre de 2014

Transcripción

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2 Inmunoterapia en cáncer renal y futuro de las combinaciones con TKI José Luis Pérez Gracia Departamento de Oncología Clínica Universidad de Navarra Madrid, 20 de noviembre de 2014

3 Steps leading to an anti tumour immune response 4 Trafficking of T cells to tumours (CTLs) 3 Priming and activation (APCs and T cells) 5 Infiltration of T cells into tumours (CTLs, endothelial cells) Blood vessel Lymph node 2 Cancer antigen presentation (dendritic cells/apcs) Tumour 6 Recognition of cancer cells by T cells (CTLs, cancer cells) 1 Release of cancer cell antigens (cancer cell death) 7 Killing of cancer cells (immune and cancer cells) Chen and Mellman. Immunity 2013

4 Melero, Clin Cancer Res 2013

5 Melero, Clin Cancer Res 2013

6 Sznol, Clin Cancer Res 2013

7 PD-L1=B7-H1 Sznol, Clin Cancer Res 2013

8 Perez Gracia, Curr Opinion Immunol 2014

9 Inmunoterapia en cáncer renal y futuro de las combinaciones con TKI Búsqueda bibliográfica Diseño clínico Evaluación de respuesta Estudios en muestras biológicas

10 Búsqueda bibliográfica PubMed / otros Congresos: ASCO, otros Bases de ensayos clínicos:

11 Motzer, Asco 2014

12 Slide 13 Presented By Robert Motzer at 2014 ASCO Annual Meeting Motzer, Asco 2014

13 Duration of response Presented By Robert Motzer at 2014 ASCO Annual Meeting Motzer, Asco 2014

14 Progression-free survival Presented By Robert Motzer at 2014 ASCO Annual Meeting Motzer, Asco 2014

15 Overall survival Presented By Robert Motzer at 2014 ASCO Annual Meeting Motzer, Asco 2014

16 Slide 19 Presented By Robert Motzer at 2014 ASCO Annual Meeting Motzer, Asco 2014

17 Treatment-related adverse events <br />( 10% of patients in any arm) Presented By Robert Motzer at 2014 ASCO Annual Meeting Motzer, Asco 2014

18 Treatment-related select adverse events Presented By Robert Motzer at 2014 ASCO Annual Meeting Motzer, Asco 2014

19 Búsqueda bibliográfica PubMed / otros Congresos: ASCO, otros Bases de ensayos clínicos:

20 Combinations with targeted agents: IPILIMUMAB Ipilimumab +vemurafenib I Advanced BRAF V600 mutation positive melanoma 18 Terminated, has results NCT Ipilimumab + vemurafenib I II Advanced BRAF V600 mutation positive melanoma 95 Terminated NCT Vemurafenib followed by Ipilimumab II Advanced BRAF V600 mutation positive melanoma 42 Ongoing, not recruiting patients NCT Ipilimumab + dabrafenib I II Advanced BRAF V600 mutation positive melanoma 12 Not yet accruing NCT Ipilimumab + dabrafenib +/ trametinib (2 cohorts) I Advanced BRAF V600 mutation positive melanoma 72 Ongoing NCT Ipilimumab + dabrafenib and/ or trametinib I Advanced BRAF V600 mutation positive melanoma 40 Suspended NCT Ipilimumab + imatinib I Advanced tumors for escalation cohort. Advanced c kit positive tumors for dose expansion levels 96 Ongoing NCT Ipilimumab + dasatinib I Advanced sarcoma for escalation cohort. Advanced GIST for expansion cohort 39 Ongoing NCT Ipilimumab +erlotinib or crizotinib I Stage IV NSCLC with EGFR mutations or ALK translocations 46 Ongoing NCT TREMELIMUMAB Tremelimumab + gefitinib I Advanced EGFR mutation positive NSCLC 24 Ongoing NCT NIVOLUMAB Nivolumab + sunitinib or pazopanib or ipilimumab I Advanced untreated renal cell carcinoma 175 Ongoing, not recruiting patients NCT Nivolumab + dasatinib I Relapsed Chronic Myeloid Leukemia 69 Ongoing NCT Nivolumab + ipilimumab followed by dabrafenib/ trametinib or opposite III Advanced BRAF V600 mutation positive melanoma 300 Not yet accruing NCT sequence PEMBROLIZUMAB Pembrolizumab + dabrafenib and or Advanced BRAF V600 mutation positive melanoma or advanced I II trametinib melanoma 204 Ongoing NCT Pembrolizumab + axitinib Advanced renal cell carcinoma 60 Ongoing NCT PIDILIZUMAB Pidilizumab +rituximab II Relapsed follicular lymphoma 30 Ongoing, not recruiting patients NCT Pidilizumab + lenalidomide II Relapsed or refractory multiple myeloma 53 Ongoing NCT MPDL3280A MPDL3280A + vemurafenib I Advanced BRAF V600 mutation positive melanoma 44 Ongoing NCT MPDL3280A + cobimetinib I Advanced solid tumors for escalation cohort. Advanced melanoma, NSCLC or KRAS mutant colorectal cancer for 90 Ongoing NCT expansion cohorts MPDL3280A +/ bevacizumab vs sunitinib II Advanced untreated renal cell carcinoma 150 Ongoing NCT MPDL3280A + erlotinib I Advanced EGFR mutation positive NSCLC 32 Ongoing NCT MEDI4736 MEDI4736 +/ trametinib +/ dabrafenib I II Advanced BRAF V600 mutation positive melanoma 69 Ongoing NCT MEDI gefitinib I Advanced NSCLC 47 Ongoing NCT Gefitinib or AZD9291 or selumetinib + docetaxel or tremelimumab followed by sequential MEDI4736 II Locally advanced or metastatic NSCLC 40 Ongoing NCT

21 Combinations with targeted agents: NIVOLUMAB Nivolumab + sunitinib or pazopanib or ipilimumab I Advanced untreated renal cell carcinoma 175 Ongoing, not recruiting patients NCT PEMBROLIZUMAB Pembrolizumab + axitinib Advanced renal cell carcinoma 60 Ongoing NCT MPDL3280A MPDL3280A +/ bevacizumab vs sunitinib II Advanced untreated renal cell carcinoma 150 Ongoing NCT

22 Nivolumab (anti-pd-1; BMS ; ONO-4538) in combination with sunitinib or pazopanib in patients (pts) with metastatic renal cell carcinoma (mrcc) Presented By Asim Amin at 2014 ASCO Annual Meeting

23 Inmunoterapia en cáncer renal y futuro de las combinaciones con TKI Búsqueda bibliográfica Diseño clínico Evaluación de respuesta Estudios en muestras biológicas

24 Diseño clínico Objetivo? Qué fármacos? TKI? Anti PD 1 o antipd L1? Cual?

25 Chow, ASCO Companies Developing PD-1 checkpoint inhibitors!

26 Latchman, Nature Immunol 2001

27 Targeting PD L1 Anti-PDL1 Targeting of PD-L1 can block co-inhibitory signalling between the tumour cell and both PD-1 and B7.1, preventing down-regulation of T-cell activity 1,2,3 Anti-PD1 Targeting of PD-1 blocks co-inhibitory signalling between the tumour cell and PD-1, sparing the interaction between the tumour cell and B7.1 1,2,3 Tumour cell PD-L1 X Preserves PD-L2/PD-1 interaction, minimising effects on immune homeostasis. This interaction may contribute to the prevention of autoimmune responses, particularly in the lung 1 PD-1 B7.1 B7.1 PD-L1 X T cell PD-1 PD-L2 Macrophage Tumour cell PD-L1 Blocks PD-L2/PD-1 interactions involved in immune homeostasis, potentially increasing autoimmunity 1,4 X PD-1 B7.1 B7.1 PD-L1 T cell X PD-1 PD-L2 Macrophage 1. Chen, et al. 2012; 2. Paterson, et al Yang, et al. 2011; 4. Brahmer, et al. 2012

28 Diseño clínico Objetivo? Qué fármacos? TKI Anti PD 1 o anti PDL1? Diseño? Población?

29 Diseño clínico Pauta TKI? Pauta PD 1/PD L1? Dosis fija de TKI y escalar anti PD 1/PDL1? Dosis fija de anti PD 1/PDL1 y escalar TKI? Escalar ambos? Número de pacientes?

30 Inmunoterapia en cáncer renal y futuro de las combinaciones con TKI Búsqueda bibliográfica Diseño clínico Evaluación de respuesta Estudios en muestras biológicas

31 Evaluación de respuesta TAC? PET? Otros estudios? Cada cuanto tiempo?

32 Immune response Wolchok, Clin Cancer Res 2009

33 80 yr old NSCLC patient treated with anti PD 1 In the first disease evaluation, subcarinal lymph nodes and some pulmonary nodules increased in size. Oct 7th 2013 Jan 7th 2014

34 80 yr old NSCLC patient treated with anti PD 1 In the first disease evaluation, subcarinal lymph nodes and some pulmonary nodules increased in size. Oct 7th 2013 Jan 7th 2014

35 80 yr old NSCLC patient treated with anti PD-1 He also presented a major partial response of a pancreatic lesión. Oct 7th 2013 Jan 7th 2014

36 Estudio Fase I CP-675,206

37 Phase I study presented at ASCO

38 Nivolumab (anti-pd-1; BMS ; ONO-4538) in combination with sunitinib or pazopanib in patients (pts) with metastatic renal cell carcinoma (mrcc) Presented By Asim Amin at 2014 ASCO Annual Meeting

39 Primary objective: safety and MTD CA (NCT ): <br />phase I study design (TKI cohorts) Presented By Asim Amin at 2014 ASCO Annual Meeting

40 Key inclusion and exclusion criteria Presented By Asim Amin at 2014 ASCO Annual Meeting

41 Dose escalation Presented By Asim Amin at 2014 ASCO Annual Meeting

42 Grade 3-4 treatment-related AEs in 10% of patients Presented By Asim Amin at 2014 ASCO Annual Meeting

43 Treatment-related select AE categories Presented By Asim Amin at 2014 ASCO Annual Meeting

44 Treatment-related AEs leading to discontinuation of TKI or both study drugs ( 5% of patients) Presented By Asim Amin at 2014 ASCO Annual Meeting

45 Antitumor activity (per RECIST 1.1) Presented By Asim Amin at 2014 ASCO Annual Meeting

46 Maximum tumor burden reduction in baseline target lesions by nivolumab dose Presented By Asim Amin at 2014 ASCO Annual Meeting

47 Time to response and duration <br />of response Presented By Asim Amin at 2014 ASCO Annual Meeting

48 Progression-free survival Presented By Asim Amin at 2014 ASCO Annual Meeting

49 ORR by baseline PD-L1 expression Presented By Asim Amin at 2014 ASCO Annual Meeting

50 Conclusions Presented By Asim Amin at 2014 ASCO Annual Meeting

51 Inmunoterapia en cáncer renal y futuro de las combinaciones con TKI Búsqueda bibliográfica Diseño clínico Evaluación de respuesta Estudios en muestras biológicas

52 OCUPACIÓN DEL RECEPTOR Brahmer, JCO 2010

53 DNA: SNP, mutaciones tumor Expresión génica RNA mirna Proteínas Tumor Solubles Fenotipo Células circulantes + EPIGENÉTICA Subpoblaciones linfocitarias

54 Muestras biológicas Qué tipo de muestras? Sangre periférica: suero, plasma, Tumor: congelado, parafina?, Células: CTC PBMC, Cuándo se obtienen? Basal Secuenciales: eventos clínicos relevantes Respuesta Progresión: primaria o tras respuesta inicial Toxicidad relevante

55 Immunomodulatory activity of nivolumab in <br />previously treated and untreated metastatic renal cell carcinoma (mrcc): <br />biomarker-based results from a <br />randomized clinical trial Presented By Toni Choueiri at 2014 ASCO Annual Meeting

56 Study design Presented By Toni Choueiri at 2014 ASCO Annual Meeting

57 Clinical activity Presented By Toni Choueiri at 2014 ASCO Annual Meeting

58 Nivolumab mechanism of action: seeking pharmacodynamic and correlative evidence Presented By Toni Choueiri at 2014 ASCO Annual Meeting

59 Tumor biopsy chemokines: IFN and CXCL9 and CXCL10 gene expression Presented By Toni Choueiri at 2014 ASCO Annual Meeting

60 Serum chemokines: <br />CXCL9 and CXCL10 Presented By Toni Choueiri at 2014 ASCO Annual Meeting

61 <br />CD3D and CD8A: <br />tumor biopsy gene expression Presented By Toni Choueiri at 2014 ASCO Annual Meeting

62 CD3/CD8 multiplexed IHC and tumor T-cell infiltrates Presented By Toni Choueiri at 2014 ASCO Annual Meeting

63 Tumor T-cell infiltrates at baseline correlate with tumor burden decrease Presented By Toni Choueiri at 2014 ASCO Annual Meeting

64 Baseline and on-treatment tumor T-cell infiltrates (CD3 and CD8): association with response Presented By Toni Choueiri at 2014 ASCO Annual Meeting

65 Response according to PD-L1 status by IHC Presented By Toni Choueiri at 2014 ASCO Annual Meeting

66 Conclusions Presented By Toni Choueiri at 2014 ASCO Annual Meeting

67 Muchas gracias por vuestra atención José Luis Pérez Gracia Departmento de Oncología Clínica Universidad de Navarra Madrid, 20 de noviembre de 2014