Mesa VI: Cáncer de Pulmón. Aspectos de futuro: Bartomeu Massutí

Transcripción

1 Mesa VI: Cáncer de Pulmón Aspectos de futuro: Bartomeu Massutí

2 Contenido Evolución epidemiológica Estadios iniciales Enfermedad localmente avanzada Enfermedad avanzada y metastática Criterios evaluación resultados y costes

3 Contenido Evolución epidemiológica Estadios iniciales Enfermedad localmente avanzada Enfermedad avanzada y metastática Criterios evaluación resultados y costes

4

5 JAMA Oncol. doi: /jamaoncol Published online December 3, 2016.

6 Don t forget antiangiogenic therapy

7 Alternativas tratamiento cáncer de pulmón avanzado Tratamientos inmunoestim.: Cels. no neop. Tratamientos dirigidos: Genoma QT citotóxica: Ciclo celular OS 1ª linea 16-22m OS 2ª línea: 9-12 m HR Largos superv? Criterios selección? OS 24 m HR Poblaciones seleccionadas / BM OS 12 m HR Fases III

8 Central role of chemotherapy in lung cancer

9 Contenido Evolución epidemiológica Estadios iniciales Enfermedad localmente avanzada Enfermedad avanzada y metastática Criterios evaluación resultados y costes

10 Competing risks for death in localized lung cancer (St I-II) Annals of Oncology 26: , 2015 doi: /annonc/mdv061 DOI: /JCO

11 Adjuvant chemotherapy for resected early-stage non-small cell lung cancer (Review) Copyright 2015 The Cochrane Collaboration. Published by John W iley & Sons, Ltd. Figure 4. Sim ple (non-st ratified Kaplan-Meier cur ves for trials of Surger y (S) and c cell lung cancer (Review) versus surger y alone and for trials of surger y and chem otherapy and radiotherapy (RT S +/- CT; S+RT +/- CT radiotherapy. Adjuvant chemotherapy for resected early-stage non-small Burdett S, Pignon JP, Tierney J, Tribodet H, Stewart L, Le Pechoux C, Aupérin A, Le Chevalier T, StephensRJ, Arriagada R, HigginsJPT, Johnson DH, Van Meerbeeck J, Parmar MKB, Souhami RL, Bergman B, Douillard JY, Dunant A, Endo C, Girling D, Kato H, Keller SM, Kimura H, Knuuttila A, Kodama K, Komaki R, KrisMG, Lad T, Mineo T, Piantadosi S, Rosell R, Scagliotti G, Seymour LK, Shepherd FA, Sylvester R, Tada H, Tanaka F, Torri V, Waller D, Liang Y, for the Non-Small Cell Lung Cancer Collaborative Group Thisisareprint of acochranereview, preparedandmaintainedbythecochranecollaboration andpublishedinthecochranelibrary 2015, Issue3

12 S vs S + QT Drugs Number trials Patients exp. Patients control HR Platinum+Vinca Alc/Etopóside ( ) Platinum+Vinorelbine ( ) Platinum+Taxane ( ) Platinum+Other ( ) Platinum+Vinc Alc+Tegafur ( ) Tegafur+Other ,79 ( ) Tegafur ( ) Sur + RT vs Sur + RT + QT Drugs Number trials Patients experimental Patients control HR Platinum+Vinc Alc/Etopóside HR: 0.88 ( ) ( ) Platinum+Vinorelbine ( ) Platinum+Other ( ) Antimetabolite ( )

13 Chemotherapy and Stage/ LACE Stage % Population Hazard Ratio 95% c.i. Global 100% Stage IA 8% Stage IB 30% Stage II 35% Stage III 27%

14 Postop Erlotinib: RADIANT Trial

15 RADIANT: Outcomes

16 Adding Bevacizumab to postoperative chemotherapy: E1505 Trial Study objective To evaluate the addition of bevacizumab to adjuvant chemotherapy in early stage resected NSCLC Key patient inclusion criteria Resected Stage IB ( 4 cm) IIIA 6 12 weeks post-op No prior chemotherapy ECOG PS 0 1 (n=1,501) *Chemotherapy regimens q3w Cisplatin 75 mg/m 2 D1 combined with any of the following: vinorelbine 30 mg/m 2 D1, 8 docetaxel 75 mg/m 2 D1 gemcitabine 1200 mg/m 2 D1, 8 pemetrexed 500 mg/m 2 D1 R 1:1 Stratification Arm A: Chemotherapy* x 4 cycles (n=749) Cisplatin doublet, stage, histology, gender Arm B: Chemotherapy* x 4 cycles + bevacizumab 15 mg/kg q3w x 1 yr (n=752) Primary endpoint: OS Secondary endpoints: DFS, safety

17 Overall survival probability Disease-free survival probability E 1505 Results OS OS HR (B:A) %CI 0.81, 1.21 p= DFS DFS HR (B:A) %CI 0.84, 1.14 p= Chemo (208 events/749 cases) Chemo + bevacizumab (204 events/752 cases) Months from registration Chemo (338 events/749 cases) Chemo + bevacizumab (334 events/752 cases) Months from registration Wakelee et al. J Thorac Oncol 2015; 10 (suppl 2): PLEN04.03

18 ADJUVANT study design (NCT ) Presented By Yi-Long Wu at 2017 ASCO Annual Meeting

19 Primary endpoint: DFS (ITT population) Presented By Yi-Long Wu at 2017 ASCO Annual Meeting

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21 Completely resected St IB (>4 cm), II, III NSCLC The promise of immunotherapy: the current race ongoing trials R E G II S T E R LINC: Study design Central Lab Assessment PD-L1 CT 4 cycles R A N D O M 2 : 1 EXP: ARM A Durvalumab For 1 year CONT: ARM B Placebo IV For 1 year Planned sample size of 1100 After 600 patients have been accrued, only patients with PD-L1 positive (defined as > 25%; strata A plus B) tumours will be enrolled.

22 26

23 Accrual by Country / Group Total registrations = 583 Total randomizations = 415 Current as of 30 May 2017

24 Contenido Evolución epidemiológica Estadios iniciales Enfermedad localmente avanzada Enfermedad avanzada y metastática Criterios evaluación resultados y costes

25 Dosis RT / Anti-EGFR en enfermedad localmente avanzada: RTOG 0617 Lancet Oncol 2015; 16:

26 Study Design Presented By Harry Groen at 2017 ASCO Annual Meeting

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28 Promise of inmunotherapy in locally advanced disease?

29 Contenido Evolución epidemiológica Estadios iniciales Enfermedad localmente avanzada Enfermedad avanzada y metastática Criterios evaluación resultados y costes

30 Repurposing other drugs in maintenance strategy

31 Antiangiogenic therapy beyond first line?

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33 Elderly patients and cytotoxic chemotherapy: single agent /combination CT?

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36 El valor absoluto y relativo de la inmunoterapia: supervivencia? JAMA Oncol. doi: /jamaoncol Published online June 15, 2017.

37 JAMA Oncol. doi: /jamaoncol Published online June 15, 2017.

38 JAMA Oncol. doi: /jamaoncol Published online June 15, 2017.

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40 Cancer immunogram Blank Science 2016 Can the immune system see this tumor as foreign? Is the immune status of the patient likely to be sufficient? Is there evidence for infiltration of effector T cells into the tumor site? Are there checkpoints, soluble mediators, or metabolic factors that may hamper the activity of these cells? Would the tumor cells be sensitive to an unleashed T cell response?

41 Not all Ags are created equal McGranahan et al., Science /science.aaf490 (2016).

42 Sharma Science 2015

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44 Cell 168, February 9, 2017

45 Chemo Other Immune Checkpoint blockade Immune Checkpoint blockade TKI Vaccines Radiation Therapy

46 Combining IT plus RT: the Abscopal effect Systemic effects of RT are mediated by CD8+ T-cell activation Hypofractionated RT can induce the expression of checkpoints as PD-L1, PD-L2 and CTLA4 (master regulators of T-cell activation and associated with dysfunctional CD8+ T-cells) Removing this obstacles preventing antitumor immunity can enhances the abscopal effect of RT Priming and effector phase of antitumor immune response RT has the potential to induce by enhancing the number and function of DCs and by promoting extravasation of effector T cells at the tumor site

47 Carbo-Pem +/- Pembrolizumab Ph II KEYNOTE Published online October 9, (16) ORR: 56.7 vs 30.2%; p= ASCO 2017

48 PFS (%) KEYNOTE-021 Cohort G: PFS by Independent Central Review Pts at Risk, n Mos Mo 63.2% 48.1% Mo 56.4% 33.9% Pembrolizumab + CP 13 8 Papadimitrakopoulou V, et al. ASCO Abstract Reproduced with permission. 6 3 Median, Mos (95% CI) NR (8.5-NR) CP alone 8.9 ( ) HR (95% CI) 0.50 ( ) P Value.0038

49 OS (%) KEYNOTE-021 Cohort G: OS Pts at Risk, n Mos Mo 84.6% 82.3% Mo 76.0% 69.3% Pembrolizumab + CP CP alone Median, Mos (95% CI) NR (NR-NR) NR (15.8-NR) Papadimitrakopoulou V, et al. ASCO Abstract Reproduced with permission HR (95% CI) 0.69 ( ) P Value.13

50 KEYNOTE-021 Cohort G: Safety Treatment-Related AEs, n (%) Pembrolizumab + CP (n = 59) CP (n = 62) Any grade 55 (93.2) 57 (91.9) Grade (39.0) 18 (29.0) Leading to discontinuation 8 (13.6) 8 (12.9) Leading to death 1 (1.7) 2 (3.2) Papadimitrakopoulou V, et al. ASCO Abstract 9094.

51 Nivolumab + Ipilimumab 1st line: CheckMate Vol 18 January 2017

52 Vol 18 January 2017

53 Vol 18 January 2017

54 Global, Open-label, Phase 1b Study<br />(NCT ) Presented By Enriqueta Felip at 2017 ASCO Annual Meeting

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56 Epacadostat (Inh IDO) + Pembrolizumab Ph I-II Key patient inclusion criteria Stage IIIB/IV or recurrent NSCLC Measurable disease (RECIST) Prior platinum-based CT No prior treatment with checkpoint inhibitors (n=58) Phase 1: Dose Escalation Epacadostat 25, 50, 100, 300 mg bid PO + pembrolizumab 2 mg/kg or 200 mg IV q3w Phase 2: Cohort Expansion Epacadostat 100 mg bid + pembrolizumab 200 mg IV q3w Primary endpoint (40 evaluable p) ORR: 35% (14/40) Secondary endpoints DCR (63%), DoR, safety Gangadhar T et al. J Clin Oncol 2017;35(suppl):Abstr 9014

57 Epacadostat (Inh IDO) + Pembrolizumab Ph I-II

58 Contenido Evolución epidemiológica Estadios iniciales Enfermedad localmente avanzada Enfermedad avanzada y metastática Criterios evaluación resultados y costes

59 Costes JAMA Oncol. 2016;2(1):19-21 Annals of Oncology 28: , 2017 doi: /annonc/mdw548

60 Costes, distribución y márgen beneficio: USA Nat Rev Clin Oncol 2017, Advance online

61 ESMO MCBS Annals of Oncology 26: , 2015 doi: /annonc/mdv249 Eligible studies can have either a randomised or comparative cohort design or a meta-analysis which report statistically significant benefit from any one, or more of the evaluated outcomes.. Studies with pre-planned subgroup analyses with a maximum of three subgroups can be scored.. findings from un-planned (post hoc) subgroup analysis cannot be graded

62 n engl j med 363;8 nejm.org august 19, 2010 PROs, Supportive care measures and survival

63 En la adversidad conviene muchas veces tomar un camino atrevido. Ningún descubrimiento se haría ya si no contásemos con lo que sabemos. L.A. Seneca Seguir pensando sin mover las ideas se parece a seguir volando sin mover las alas J. Wagensberg