Expresión de PD-L1 como Factor Predictivo de Respuesta: Resultados Clínicos con Inmunoterapia Dolores Isla Servicio de Oncología Médica HCU Lozano

Transcripción

1 Expresión de PD-L1 como Factor Predictivo de Respuesta: Resultados Clínicos con Inmunoterapia Dolores Isla Servicio de Oncología Médica HCU Lozano Blesa de Zaragoza

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4 Immune Checkpoint Inhibitors

5 Biomarkers and Immunotherapy Immunotherapy Targeted Therapy Efficacy of Immunotherapy defined by long lasting tumor stabilization Purpose of Biomarker development in Immunotherapy: A Biomarker to identify patients with high benefit A Biomarker to exclude patients without benefit Currently both strategies are under exploration

6 Introduction New era of Precision Medicine, searching a predictive biomarker to select real p. who would benefit from checkpoint blockades is crucial: to prevent them from autoimmune adverse effects high cost

7 Predictive Role of PD-L1 expression PD-L1 is up-regulated in selected solid tumors and it can be detected by IHC on TCs and ICs The association of PD-L1 expression and the efficacy of PD-1/PD-L1 checkpoint blockades are investigated in a lot of studies

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9 Association of PD-L1 expression with immune response of anti PD-1/PD-L1 Ab

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11 Lancet 2015 HR=0.71, p= (2 mg/kg) HR=0.61, p= (10 mg/kg) PD-L1 as a Predictive Marker

12 CASO CLÍNICO Varón, 61 años HTA, Dislipemia desde 2012 Exfumador desde hace 2 años, IPA=15 Abril/2013: nódulos subcutáneos a nivel lumbar y torácico dcho de 2 m. de evolución EXPLORACIÓN FÍSICA: Múltiples letálides y nódulos en región torácica dcha, axilar dcha, subpectoral dcho, pared abdominal, lumbar ANALÍTICA: LDH 753 U/L MARCADORES TUMORALES: Enolasa 24 ng/ml TAC cérvico-torácico-abdomino-pélvico: Nódulo LSI 2,5 cms Lesión subpectoral dcha 5 cms Adenopatía axilar dcha 2,5 cms Lesión subescapular dcha 5 cms Nódulo suprarrenal dcho 1,2 cms Nódulo suprarrenal izdo 3,8 cms Lesión hepática 3 cms Lesión m. recto anterior 2,5 cms Lesión lumbar 3 cms TAC cerebral: Normal GAMMAGRAFÍA ÓSEA: metástasis óseas en D8 y tibia dcha

13 PRUEBAS COMPLEMENTARIAS PET-TC: Nódulo LSI SUVmax 5,6 Nódulo suprarrenal dcho SUVmax 8,1 Nódulo suprarrenal izdo SUVmax 6 Lesión hepática SUVmax 6,8 Metástasis en D8 SUVmax 7 Adenopatías supraclaviculares, axilar dcha, abdominales, iliacas, inguinales con SUVmax hasta 13,2 Masas a nivel muscular subescapular dcha, recto anterior dcho, paravertebrales, glúteos Masas subcutáneas pared torácica, pared abdominal, lumbar, EEII SUVmax hasta 11,6

14 PET-TC Mayo/2013

15 PRUEBAS COMPLEMENTARIAS PAAF nódulo subcutáneo subescapular dcho: carcinoma poco diferenciado BIOPSIA masa m. recto anterior: Carcinoma Indiferenciado de alto grado de posible origen pulmonar (No Microcítico, posible Adenocarcinoma): IHQ: Ki 67 90% CK7 + TTF1 P63 Enolasa, Sinaptofisina, Cromogranina Resto (melanoma, linfoma, ): Mutación EGFR: Translocación ALK: Fractura patológica tibia dcha: Junio 2013

16 1ª LÍNEA DE TRATAMIENTO CARBOPLATINO AUC:6 iv día 1 PACLITAXEL 200 mg/m 2 iv día 1 BEVACIZUMAB 15 mg/kg iv día 1 (1 ciclo) Cada 21 días x 6 ciclos PEMETREXED 500 mg/m 2 iv día 1 x 1 ciclo + Ac. Zoledrónico 4 mg iv/21 días Mayo/2013 a Noviembre/2013 RESPUESTA PARCIAL

17 2ª LÍNEA DE TRATAMIENTO GEMCITABINA 1500 mg/m 2 iv día 1 Cada 15 días x 10 ciclos + Ac. Zoledrónico 4 mg iv/28 días Diciembre/2013 a Abril/2014 ENFERMEDAD ESTABLE

18 TAC Mayo/2014 TAC cérvico-torácico-abdomino-pélvico: Nódulo LSI 1,6 x 2 cms Adenopatía supraclavicular dcha 4,5 x 4,5 cms Adenopatía axilar dcha 6 x 6 cms Lesión subescapular dcha 9 x 5 cms Nódulo suprarrenal dcho 1,2 x 0,8 cms Nódulo suprarrenal izdo 3,2 x 1,5 cms Lesión m. recto anterior 2 x 2 cms Lesión m. oblícuo externo 1,5 x 1 cms Lesión m. glúteo mayor izdo 3,5 x 3 cms Nódulo pancreático 1 x 1 cm

19 TAC Mayo/2014

20 TAC Mayo/2014

21 3ª LÍNEA DE TRATAMIENTO KEYNOTE 010 Randomized Study of Pembrolizumab vs. Docetaxel in Patients with Previously Treated PD L1 Positive* NSCLC Patients: (n = 920) Metastatic NSCLC Previously treated (progression after 2 cycles of platinum doublet OR prior EGFR TKI in mutant) Measurable disease ECOG PS 0 1 Newly obtained formalin fixed specimens strongly encouraged PD L1 Positive (defined as staining in 1% of tumor cells) No CNS metastases hgu R A N D O M I Z A T I O N 1:1:1 N=920 R 1:1:1 Pembrolizumab 2 mg/kg Q3W Pembrolizumab 10 mg/kg Q3W Docetaxel 75 mg/m2 Q3W Primary Endpoints: OS, PFS, Safety (adverse events and drug discontinuation) Secondary Endpoints: ORR and response duration (RECIST 1.1) a Positive defined as 1% tumor PD-L1 expression determined using a prototype IHC assay (22C3 antibody). 52 Mayo/2014 a HOY

22 TAC Julio/2014

23 TAC Julio/2014

24 TAC Enero/2015

25 TAC Marzo/2016

26 EVOLUCIÓN CICLOS: 33 (max. 35 sin PR y suspender tto hasta PR por IrRC) CLÍNICA: desaparición completa de letálides/nódulos. Asintomático TOXICIDAD: Ninguna RESPUESTA (irrc): RP: Basal: mm 2 C4: mm 2 : RP ( 50% disminución tumor respecto de superficie basal) C7: 360 mm 2 C10: 450 mm 2 C13: 311 mm 2 C23: 229 mm2,... SLP: 23 meses (3,9 m en Estudio KEYNOTE 010) SG: 35 meses (10,4 m en Estudio KEYNOTE 010)

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28 SE DEBE CONSIDERAR LA EXPRESIÓN DE PD-L1 SÓLO EN ADENOCARCINOMA DE PULMÓN? 1. SI 2. NO 3. SÓLO CON PEMBROLIZUMAB 4. SÓLO CON NIVOLUMAB

29 Lancet 2015 HR=0.71, p= (2 mg/kg) HR=0.61, p= (10 mg/kg)

30 NSCLC

31 N= 3790 p.? YES 1. Benefit from PD-1 inhibitors versus docetaxel in second line treatment of NSCLC is limited to the PD-L1 > 1% subpopulation. 2. Potential benefit from PD-1/PD-L1 targeted agents does exist with higher intensity associated with higher ORR. NO JAMA Oncology 2016

32 N=1979 p. 24-weeks PFS Aguiar P, 2016

33 N=914 p.

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36 Association of PD-L1 expression with immune response of anti PD-1/PD-L1 Ab Wide variability of PD-L1 expression is observed in different tumor types The overexpression of PD-L1 is significantly associated with better response to PD-1/PD-L1 blockade in: Melanoma NSCLC: Pembrolizumab, Nivolumab (non-squamous), Atezolizumab Bladder cancer Ovarian cancer Others

37 Association of PD-L1 expression with immune response of anti PD-1/PD-L1 Ab Some studies have shown the efficacy of PD- 1/PD-L1 antibodies independent of PD-L1 expression: Advanced RCC and Nivolumab Squamous NSCLC and Nivolumab

38 N= 1475 p. 20 trials (not very updated) ORR= 34,1% vs 19,9%, p< PLoS One 2015

39 Carbognin L, PLoS One 2015

40 N=5959 p. (MM, NSCLC, RCC)

41 Sunshine J, Curr Opin Pharmacol 2015

42 Lancet 2015

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44 We observed cogain or coamplification of CD274 and PDCD1LG2 in 32 of 48 cervical SCCs (67%) and 10 of 23 vulvar SCCs (43%). Median PD-L1 protein expression was highest among tumors with CD274 and PDCD1LG2 coamplification and lowest among tumors with disomy. J Thorac Oncol 2015

45 Prognostic Role of PD-L1 expression on Lung Cancer Cells

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47 PD-L1 expression on TCs and ICs Multiple studies with PD-L1 expression on TCs and ICs as a predictor of response to PD-1/PD-L1 checkpoint blockades

48 PD-L1 expression on TCs and ICs Not all tumors show simultaneous PD-L1 positive both on TCs and ICs Which is more important in predicting the response? TCs was correlated significantly with ORR and clinical benefit to anti-pd-1 therapy ICs with ORR that does not reach the statistical significance in multiple solid cancers, but not always (genitourinary cancer)

49 Herbst R, Nature 2014

50 Dynamic PD-L1 expression Expression of PD-L1 can be induced by activated tumor antigenspecific T cells: dynamic process during the recognition of effective T-cell antigen (Taube et al, Sci Transl Med 2012) Microsatellite instability high (MSI-H) colorectal cancer can attract TILs and upregulate PD-L1 expression in tumor (Gatalica et al, Cancer Epidemiol Biomarkers Prev 2014) Potential inducibility of PD-L1 expression by First-line CT Increased PD-L1 expression in the serial tumor biopsy during the Atezolizumab therapy exhibited accompanied with ORR TKI-targeted therapy: compared in pre- and post-tki biopsies in EGFR-mutant and ALKpositive metastatic NSCLC expression levels of PD-L1 in biopsies changed due to TKI therapy (22% and 25%) (Gainor et al, J Clin Oncol 2015) Evaluation at a single time point may not reflect an evolving immune response or predict response to PD-1/PD-L1 inh.

51 PD-L1 expression is Dynamic and may change after exposure to Treatment Baseline On-treatment CD8 T-cells PD-L1 CD8 T-cells PD-L1 MPDL3280A (PD-L1 inhibitor) T-cells and tumor cells expressing PD- L1 PD-L1 = programmed cell death-ligand 1. Powderly J, et al. Oral presentation at ASCO 2013 (abstr. 3001).

52 Prior TKI Therapy in NSCLC EGFR Mutant Patients Associates with Lack of Response to Anti-PD-1 Treatment Study objective To determine the relationship between prior TKI therapy and response to anti-pd-1 therapy in patients with NSCLC EGFR mutations (EGFRm) Study design In vitro Western blot analysis of PD-L1 expression in NSCLC cell lines in response to erlotinib and afatinib Clinical Retrospective analysis of patients from KEYNOTE-001 clinical trial in which patients received pembrolizumab 2 mg/kg q3w or 10 mg/kg q2 3w IMMUNOTHERAPY and Key results In vitro PD-L1 levels decrease in response to EGFR TKI in cell lines sensitive to TKI Clinical EGFR mut + p.: Among 29 EGFRm patients in KEYNOTE-001, 2 of 3 EGFR-naïve patients achieved a PR vs. 1 of 26 with a history of prior EGFR Wait TKI (p<0.001) and See situation 18 of these patients had a 9-week follow-up scan Both of the EGFR TKI-naïve patients achieved a PR compared with only 1 of 16 with a history of prior EGFR TKI (p<0.001) In EGFR wild-type patients, prior TKI did not affect RR (p<0.601) A lower proportion (perhaps of EGFRm patients continued for on trial to PD-L1 the 9-week scan (62% +) [18/29]), compared with EGFR wild-type patients (87% [60/69]) Conclusions There was a strong correlation between response and lack of prior EGFR TKI treatment, especially in those with a sensitising mutation PD-L1 levels decreased in response to an EGFR in cell lines sensitive to TKI PD-1/PD-L1 inhibition prior to an EGFR TKI may be more efficacious than a strategy in which the PD-1/PD-L1 inhibition follows, or is given concurrently with an EGFR TKI Garon et al. J Thorac Oncol 2015

53 SE DEBE REBIOPSIAR PARA CONOCER LA EXPRESIÓN DE PD-L1? 1. SI 2. NO 3. SÓLO CON PEMBROLIZUMAB 4. SÓLO CON NIVOLUMAB

54 Rebiopsy?? Lancet S PFS NOT NOT

55 Heterogeneity of PD-L1 expression intra-patient Frequently discordant between primary tumor and metastasis (melanoma, RCC, NSCLC) Different expression levels in different lesions intra-patient (melanoma)

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57 CORE 4 CORE 3 CORE 2 AQUA scores CORE 1 Intra-tumour and intra-patient heterogeneity PD-L1 expression can vary between different sites within the primary tumour There is only a weak correlation between PD-L1 expression in the primary tumour and the metastases Cytokeratin DAPI PD-L1 P = Cytokeratin DAPI PD-L Cytokeratin DAPI PD-L Cytokeratin DAPI PD-L1 Metastatic Primary PD-L1 expression (red) in 4 sites within the same primary RCC tumour PD-L1 expression in metastatic and primary specimens from patients with mrcc Jilaveanu LB, et al. J Cancer. 2014;5(3):

58 Reliability of detection methods PD-L1 expression in human cancers is usually investigated using the anti-pd-l1 antibody by IHC staining in formalin-fixed paraffin-embedded tissue samples Different anti-pd-l1 mabs and staining techniques (manual vs automated techniques) may result in different positive rates for TCs or ICs Limitations for IHC assay, but it is cheap and easy to conduct FISH??

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60 DAKO

61 What is the reasonable Cut-off value? Cut-off values of 1%, 5%, 10%, 25% or 50% are frequently used to define the positive rate of PD-L1 staining Different cut-off values may lead to the difference in predicting function No clear definition for PD-L1 positive rate limits the validation of PD-L1 as a predictor to PD-1/PD-L1 checkpoint blockades It may not be reasonable to make consistent cut-off value for all tumors However, it is difficult to decide the cut-off value according to different cancers because there are: so many kinds of cancers various biological properties in the same cancer, especially for NSCLC

62 Target prevalence in Solid Tumors Solid Tumors??? PD-L

63 Efforts to identify determinants of Response with Immunotherapy PD-L1 Expression (TCs or ICs) CD8+ Tumor Infiltrating Lymphocytes (TILs) BCL-2-interacting mediator of cell death-bim (melanoma) Interferon-γ (melanoma, Durvalumab) PD-L2 expression (Pembrolizumab) Mutation / Neoantigen Burden / Mismatch-repair status / Microsatellite Instability / JAK2-3 genes Immune gene messenger RNA expression signatures Smoking Status

64 Immunotherapy and EGFR or RAS mut + Checkmate 057 Study Borghaei N, NEJM 2015

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66 Immunotherapy and EGFR mut + KEYNOTE-010 Study Herbst R, Lancet 2015

67 Median 6,4 m. Mutation burden correlates with immune response and is higher with mismatch-repair deficiency Median NR Le DT, NEJM 2015

68 Are we ready to Select Patients?

69 Translational view of the complex patient-tumor immune interactions

70 PD-L1 as a Good Predictive Marker? PD-L1 expression is enriching for p. who respond to single agent PD-1 inh., but there are high levels of false negative (response with negative test) Assay dependent: Propietary antibody used Laboratory performing the assay Scoring methodology Tumor dependent: Sampling: Surgical vs biopsy Archival vs fresh Heterogeneity Tumor biology

71 PD-L1 expression by IHC Positive Predictive Value Negative Predictive Value

72 Challenges with PD-L1 Assessment TCs and/or ICs PD-L1 expression may change over time Fresh tumor or archival samples: rebiopsy? Tumor heterogeneity Reliability of detection methods Different IHC mab for PD-L1 positivity: multiple clones What cut-off (1 vs 5 vs 10 vs 50%)? Care when using in combination with other therapies, which may impact the predictive value of PD-L1 Randomized trials with PD-L1 stratification awaited

73 Clinical Trial Design in Checkpoint Blockades Identification of Predictive Biomarkers: Precision Medicine Pembrolizumab and NSCLC: Other possible biomarkers much be explored in clinical trials

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76 One standardized assay

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78 Conclusions IHC-based PD-L1 expression on TCs and/or ICs is an important but not a definitive predictive biomarker for the response to PD-1/PD-L1 blockade: In some cancers, the response to PD-1/PD-L1 blockades is independent of PD-L1 expression PD-L1 + p. show higher response and some PD-L1 - p. also reveal the response to PD-1/ PD-L1 inhs. Variability in methods and antibodies may lead to different results Clear definition for PD-L1 positivity is still not achieved Standardization of staining and scoring methods before PD-L1 widely used to predict response Expression is dynamic and heterogeneous due to changes of microenvironment or therapy Evaluation of PD-L1 at a single time point or single tumor may not predict the response to PD-1/PD-L1 inhs. PD-L1 does not seem a true patient selection biomarker up to now PD-L1 does not seem a solitary biomarker Blueprint Project

79 Our testing strategy could be improved, perhaps by additional markers or incorporation of some assessment of the immune cellular environment in the tumors, but a much greater quantity of validated data is required before our testing strategies can change Kerr KK, Arch Pathol Lab Med 2016

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