Tratamiento de la enfermedad avanzada en cáncer de pulmón

Transcription

1 Tratamiento de la enfermedad avanzada en cáncer de pulmón S. Ponce Aix! S. Oncología Médica Hospital Universitario 12 de Octubre Madrid

2 Survival by stage NSCLC Stage Distribution NSCLC Stage 5-year Survival Current AJCC Guidelines 5-year Survival IASLC Proposal I 13%-24% IA 50% 50% IB 40% 43% II 5%-10% IIA 24% 36% IIB 25% 25% III 31%-44% IIIA 18% 19% IIIB 8% 7% IV 32%-39% IV 2% 2% 1.Bülzebruck et al. Cancer 1992;70: Goldstraw et al. J Thorac Oncol 2007;2: Edge et al. AJCC Cancer Staging Manual 7th ed. Springer 2009.

3 Tratamiento Primera Línea basado en quimioterapia:

4 Which is the most effective regimen? Study Drugs # Pts %, St. IV %, ORR MST %, 1-YS Kelly,2001 SWOG 9503 Vnr/Cis Tax225/Cb Schiller,2002 ECOG 1594 Tax135/Cis Gem/Cis Txt/Cis Tax225/Cb Scagliotti,2002 ILCP Vnr/Cis Gem/Cis Tax225/Cb Belani,2002 TAX 326 Vnr/Cis Txt/Cis TxT/Cb

5 ECOG 1594 OS by treat group Schiller NEJM 2002

6

7 Chemotherapy is the first treatment step! Platinum based chemo results in prolongation of survival, symptom control, and superior QoL compare to BSC alone! Platinum is the backbone of chemo, no differences between the others drugs

8

9 E4599 OS and PFS E4599: Overall survival OS: 12.3 m vs m, HR = 0.79 ( ), p=0.003 PFS: 6.2 m vs. 4.5 m, HR = 0.66 ( ), p<0.001 CP Avastin + CP Time (months) Adenocarcinoma Hystology CP + Bv CP Hazard ratio Overall Survival 14.2 months 10.3 months 0.69 ( ) Progression-free survival 6.6 months 5.0 months 0.65 ( ) Sandler NEJM 2006; Sandler JTO 2008

10

11 AVAIL OS and PFS (end point) PFS: Primary endpoint Probabilidad de SLP 1,0 0,8 0,6 0,4 0,2 HR (95% CI) Placebo + CG Avastin 15mg/kg + CG 0,85 (0,73 1,00) Avastin 7,5mg/kg + CG 0,75 (0,64 0,87) p-value 0,0456 0,0003 Median PFS (months) 6,2 6,6 6, Tiempo (meses) Placebo + CG Bev 15 + CG Bev CG Median Survival (months) Reck JCO 2009

12 Scagliotti JCO 2008

13 Scagliotti JCO 2008

14 Rational for Maintenance Therapy Aim: * To keep disease (and symptoms) under control Rational: * More is better * Early switch to a non cross resistant treatment (Goldie & Colman) * Sequential therapy (Norton & Simon) * We do maintenance treatment in other oncological and rational diseases!

15

16 Población Mantenimiento Sandler, et al. WCLC 2011

17 MetaAnalisis Soria ESMO 2010

18 Ciuleanu. The Lancet 2010 JMEN Study Design Stage IIIB/IV NSCLC ECOG PS prior cycles of GEM, DOC, or PAC+CIS or CARB, with CR, PR, or SD! Randomization factors: Sex Performance status Disease stage Best tumor response* Non-platinum drug* Brain metastases 2:1 Randomization Pemetrexed IV 500 mg/m 2 (d1, q21d)+ BSC (N=441) Primary Endpoint=PFS Placebo IV (d1, q21d)+bsc (N=222)

19 Ciuleanu. The Lancet 2010 JMEN Switch Maintenance: PFS HR=0.50 (95% CI: ) p< Progression-free Probability PEM 4.3 months PLA 2.6 months Time (months)

20 Ciuleanu. The Lancet 2010 JMEN Switch Maintenance: OS HR=0.79 (95% CI: ) p=0.012 Survival Probability PLA 10.6 months PEM 13.4 months Time (months)

21 Paz Arez et al; The Lancet 2012 JCO 2013 PARAMOUNT: Study Design Study Treatment Period Induction Therapy (4 cycles) 21 to 42 Days Maintenance Therapy (Until PD) Progression Patients enrolled if: Nonsquamous NSCLC No prior systemic treatment for lung cancer ECOG PS 0/1 500 mg/m 2 Pemetrexed + 75 mg/m 2 Cisplatin, d1, q21d CR, PR, SD 2:1 Randomization Stratified for: PS (0 vs 1) Disease stage (IIIB vs IV) prior to induction Response to induction (CR/PR vs SD) 500 mg/m 2 Pemetrexed + BSC, d1, q21d Placebo + BSC, d1, q21d PD! Primary objective: progression-free survival (PFS)! Secondary Objectives: OS, RR, QOL, Resource utilization & adverse events

22 PARAMOUNT: Investigator Assessed PFS (from Maintenance) Pem + BSC Placebo + BSC Pemetrexed: median =4.1 mos ( ) Placebo: median =2.8 mos ( ) Log-rank P= Unadjusted HR: 0.62 ( ) Patients at Risk Pem + BSC N= Placebo + BSC N=

23 PARAMOUNT: Investigator Assessed PFS (from Induction) Pem + BSC Placebo + BSC Pem: median = 6.90 ( ) Placebo: median = 5.59 ( ) Log Rank p< Unadjusted HR : 0.59 ( ) Patients at Risk Pem + BSC N= Placebo + BSC N=

24 PARAMOUNT: Final OS from Randomization

25 PARAMOUNT: Final OS from Induction

26 AVAPERL Barlesi EMCC 2011

27 AVAPERL: PFS desde Randomización Barlesi EMCC 2011

28 AVAPERL: PFS desde Inducción Barlesi EMCC 2011

29 Continuation maintenance with Bev + Pem in an unselected population of nsnsclc pts who had achieved disease control after induction was associated with an increase by almost 4 months in OS benefit over standard Bev alone Barlesi ASCO 2013

30 Tto de Mantenimiento sólo importa si se administra...

31 Tratamiento Primera Línea guiado por alteraciones moleculares

32 Cambio Status Ca. Pulmón Histología Alt. Genéticas

33 EGFR Paez et al. Science Lynch et al. NEJM Pao et al. PNAS

34

35

36 IPASS Mok NEJM 2009

37 Rosell ASCO 2011

38 Rosell ASCO 2011

39 EGFR Trials Trial Compound RR (%) Median PFS (mo) Median OS (mo) IPASS (mut+) (Mok TS et al, 2009) First-SIGNAL (mut+) (Han JY et al, 2012) WJTOG (Mitsudomi T et al, 2010) NEJ002 (Inoue A et al, 2009) OPTIMAL (Zhou C et al, 2011) EURTAC (Rosell R et al, 2012) Afatinib (LUX-Lung 3) (Keating GM, 2014) Afatinib (LUX-Lung 6) (Keating GM, 2014) TKI Chemo TKI Chemo TKI Chemo Gefitinib Gefitinib Gefitinib NR Gefitinib Erlotinib Erlotinib Afatinib Afatinib

40 Lux Lung 3 / 6

41

42 EGFR Progression Jäne Nature 2012

43

44 IMPRESS

45 AURA

46 AURA

47

48 ALK Fusion gene

49 Methods to detect ALK postive tumors

50 Profile 1001:Phase I in previously treated NSCLC

51 Profile 1001: Best Response in Target Lesions 100 N=133* evaluable patients Decrease or increase from baseline (%) Disease progression SD PR CR Tan W, et al. J Clin Oncol 2010;28:15S:

52 Profile 1007

53 Profile 1007: PFS Crizotinib vs Pemetrexed vs Docetaxel 100 Crizotinib (n=172 Pemetrexed (n=99 Docetaxel (n=72 Probability of survival without progression (%) Median, mo HR 0.59 (0.43 to 0.80) 0.30 (0.21 to 0.43) P <0.001 <0.001 No. at risk Crizotinib Pemetrexed Docetaxel Time (months) Shaw AT, et al. N Engl J Med 2013;368:

54 Profile 1014: First Line

55 Profile 1014: First Line ORR

56 Profile 1014: First Line PFS

57 BEYOND CRIZOTINIB

58 Ph I: Ceritinib in ALK Rearranged NSCLC Primary objective: determination of MTD Secondary objectives: characterize safety, PK and antitumor activity Dose escalation guided by a two-parameter BLRM employing escalation with overdose control principle Patients received treatment until disease progression, unacceptable toxicity, or withdrawal of consent Shaw AT, et al. N Engl J Med 2014;370:

59 Ceritinib in ALK Rearranged NSCLC: Best % Change Tumor Response Shaw AT, et al. N Engl J Med 2014;370:

60 Timelines

61 Efficacy and safety of crizotinib in patients with advanced ROS1-rearranged non-small cell lung cancer (NSCLC) ROS1 receptor tyrosine kinase rearrangements define a subset of NSCLC sensitive to the small-molecule tyrosine kinase inhibitor crizotinib, approved multinationally for the treatment of advanced ALK-positive NSCLC. Updated efficacy and safety data are presented for crizotinib in patients with advanced ROS1-rearranged NSCLC As observed in ALK- positive NSCLC, crizotinib had dramatic antitumor activity with a high ORR (56%) in patients with ROS1- positive NSCLC and a generally tolerable and manageable AE profile. These findings indicate that crizotinib is an effective therapy for advanced ROS1 -positive NSCLC

62 Interim results of phase II study BRF of dabrafenib in BRAF V600E mutation positive non-small cell lung cancer (NSCLC) patients Activating BRAF V600E mutations in NSCLC are present in < 2% of tumors, primarily adenocarcinoma. The BRAF inhibitor dabrafenib has demonstrated clinical activity in BRAF V600 mutation positive melanoma. Here we report interim efficacy and safety data obtained in 17 BRAF V600E mutant NSCLC patients enrolled in dabrafenib phase II study BRF113928

63 Dabrafenib shows early antitumor activity in BRAF V600E mutation positive pretreated NSCLC pts, with an ORR of 54% and with the longest duration of response of 49 weeks thus far. Dabrafenib is generally well tolerated, and the study has met the minimum response rate (>/=3 of first 20 pts) to continue into the second stage. This study represents the first clinical evidence of BRAF as a therapeutic target in NSCLC

64 Killing of cancer cells: immune and cancer cells Cancer cells have mutations that make them recognizable by immune system However, cancer cells can evade the immune surveillance by expressing proteins such as PD-L1 Inhibiting the PD-L1/PD-1 interaction can restores anti T cell activity, potentially leading to long lasting responses Chen DS Immunity 2013

65 Clinical development of PD-1Immune Checkpoint Target Antibody Molecule Company PD-1 Nivolumab Fully human IgG4 BMS Pidilizumab Humanized IgG1 CureTech Development Stage Ph III Multiple Tumors Ph II Multiple Tumors MK-3475 Humanized IgG4 Merck Ph I-III PD-L1 BMS Fully human IgG4 BMS Ph I Medl-4736 Engineered human IgG1 Medimmune Ph I MPDL-3280A Engineered human IgG1 Genentech Ph I-III

66 Ph 1 Nivolumab: Efficacy in NSCLC RR % Median Duration Resp (wk) SD rate at 24 wks Median PFS (mo) Median OS (mo) Overal N= % % Squamous N= % Not Reported 14.8 % Not Reported 9.2 NonSquamous N= % Not Reported 6.8 % Not Reported year survival 42% 2 year survival 14% Brahmer ASCO 2013

67 Ph 1 MK-3475: preliminary activity Subgroup irrc, Investigator Review N ORR, n (%) Median PFS wks RECIST 1.1, Independet Review N ORR, n (%) Median PFS wks Median OS, wks ALL 38 9 (24%) (21%) Non Squamous 31 7 (23%) (16%) Squamous 6 2 (33%) (33%) 15.2 Not Reach Patients with measurable disease on baseline imaging and evaluable tumor specimen for PD-L1 Score > cut point Score < cut point 9 6 (67%) (57%) (4%) (9%) - - Garon WCLC 2013

68 Phase I MPDL3280A: efficacy in NSCLC Overall population N= 175 NSCLC N= 53 Non Squamous n= 42 Squamos n= 11 Response Rate RECIST 1.1 Stable D. of 24 wks or longer 24 wk PFS Rate 21% 19% 42% 23% 17% 45% 21% 17% 44% 27% 18% 46% Herbst ASCO 2013, Soria ECCO 2013

69 Phase I MPDL3280A: Response by PD-L1 expression Tumor Type Estimated PD-L1 prevalence Squamous 50% Non Squamous 45% Spiegel ASCO 2013 Population (n= 53) ORR (n/n) PD rate (n/n) IHC 3 83% (5/6) 17% (1/6) IHC 2 and 3 46% (6/13) 23% (3/13) IHC 1/2/3 31% (8/26) 38% (10/26) All patients 23% (12/53) 40% (21/53) Soria ECC 2013

70 Estratificación por EGFR, ALK e Histología! EGFR Mut +! ALK trasloc +! EGFR wt / ALK wt! No Escamoso! EGFR wt / ALK wt! Escamoso! EGFR TKI! ALK TKI! Doblete de platino + bevacizumab! o! Platino + Pemetrexed! Doblete de platino