Aportación/integración de las novedades en angiogénesis en la era de la individualización del tratamiento en cáncer de pulmón no microcítico

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1 Aportación/integración de las novedades en angiogénesis en la era de la individualización del tratamiento en cáncer de pulmón no microcítico Antonio Calles Oncología Médica HGUGM

2 Objetivos Actualizar la evidencia disponible de la eficacia de terapias antiangiogénicas en 2ª línea de CPNCP Resaltar el papel fundamental e integrador del oncólogo en la toma de decisiones terapéuticas en 2ª línea de CPNCP

3 Survival probability TAX 317B 1 JMEI 2 BR-21 3 Docetaxel 7.5 months Pemetrexed 8.3 months Erlotinib 6.7 BSC 4.6 months Docetaxel 7.9 months Placebo Tratamiento estándar en 2L para CPNM avanzado hasta 2014 P: 0.01 HR: 0.99 (0.82, 1.20) HR: 0.70 (0.58, 0.85) Survival (months) Survival (months) Survival (months) Note: Data are provided as a summary of different trials findings. Data pertaining to different trials cannot be compared due to inherent differences in trial design and methodology. 1. Shepherd FA, et al. J Clin Oncol. 2000;18: ; 2. Hanna N, et al. J Clin Oncol. 2004;22: ; 3. Shepherd FA, et al. N Engl J Med 2005;353:

4 Overall survival (months) Estancamiento terapéutico de la SG en 2ª línea de CPNM durante 10 años 14 Therapeutic plateau months

5 Opciones de tratamiento en Adenocarcinoma de pulmón tras fallo a la 1ª L * ** *** (*) No reembolso en España (**) Aprobado en todos los pacientes independientemente de la expresión de PD-L1 (***) Aprobado en pacientes con expresión PD-L1 > 1%

6 Individualización del tratamiento COMBINACIÓN ANTIANGIOGÉNICOS INMUNOTERAPIA

7 La angiogénesis es uno de las señas de identidad del cáncer Hanahan D, Weinberg RA. Cell 2011;144(5):

8 Ligandos y receptores de la familia VEGF Aprile G, et al. Drugs 2015

9 Fármacos anti-vegf activos frente a Cáncer de Pulmón No Microcítico

10 Nintedanib: inhibidor triple angioquinasa Nintedanib inhibits all types of three key RTKs involved in angiogenesis* VEGFRs, PDGFRs and FGFRs VEGFR=vascular endothelial growth factor receptor; PDGFR=platelet-derived growth factor receptor; FGFR=fibroblast growth factor receptor *Hilberg F, et al. Cancer Res 2008;68:

11 Reck et al. Lancet Oncol. 2014;15:

12 Significant Improvement in Median Overall Survival in Patients With Adenocarcinoma Key Secondary Endpoint, Pre-specified Hierarchical Analysis

13 Probability of survival (%) CheckMate 057: Updated 2-year survival rates show similar results as LUME-Lung 1 Lume Lung 1 Median 12.6 vs 10.3 mo Patients (number) Time (months) 1 H. Borghaei: Nivolumab vs docetaxel in patients with advanced NSCLC: CheckMate -017/ year update and exploratory cytokine profile analyses Abstract #9025, Poster Board #348, ASCO 2016

14 LUME LUNG 1: Significant Improvement in Disease Control Rate by Independent Central Review *Significant improvement in disease control rate with nintedanib + docetaxel (Odds ratio 1.93; P< for adenocarcinoma and Odds ratio 1.68, P< for all patients) CR = complete response; HR = hazard ratio; OR = odds ratio; OS = overall survival; PR = partial response; SD = stable disease; PD = progressive disease. Reck M, et al. Lancet Oncol. 2014;15:

15 LUME LUNG 1: Best Change from Baseline in Tumour Size based on Central Independent Review Adenocarcinoma Supplementary Appendix LUME Lung 1, page 24

16 Waterfall Plots CheckMate 057: ORR More and deeper responses with Nivolumab BUT Also more and stronger progressions Supplementary Appendix CM057, NEJM

17 HR (95% CI) Lessons from the LUME Trials Inverse Relationship Between HR for OS and Time Since Start of First-Line Therapy Final OS Analysis in Patients with Adenocarcinoma Time since start of first-line therapy (months) The shorter the time from start of first-line therapy to randomization, the better the treatment effect from nintedanib CI = confidence interval; HR = hazard ratio; OS = overall survival. Kaiser R, et al. Eur J Cancer 2013;49(Suppl. 2):Abstract 3479 and poster P388.

18 LUME-Lung 1: OS in Patients with Adenocarcinoma who Progressed in <9 Months After Start of First-Line Therapy Key Secondary Endpoint, Pre-specified Hierarchical Analysis

19 Overall Survival in Patients with Adenocarcinoma and No Response to First-Line Chemotherapy 1,2 (Exploratory Analysis) Adenocarcinoma and PD as Best Response to First-Line Chemotherapy 1. Reck M, et al. Lancet Oncol. 2014;15(2): Mellemgaard A, et al, European Cancer Congress 2013; oral presentation.

20 Sum of longest diameter of target lesions (mm) LUME-Lung 1: Tumour growth over time All adenocarcinoma patients Placebo plus docetaxel Nintedanib plus docetaxel Patients who progressed <9 months after start of first-line therapy Placebo plus docetaxel Nintedanib plus docetaxel PD as best response to first-line therapy Placebo plus docetaxel Nintedanib plus docetaxel OS HR 0.83 OS HR 0.75 OS HR 0.62 Treatment difference at 6 months: 9.7 mm 88.3 mm Treatment difference at 6 months : 16.8 mm Treatment difference at 6 months: 19.7 mm Time since randomization in LUME-Lung 1 (months) The more aggressive the course of disease, the greater the OS-advantage for Nintedanib + Docetaxel Tumor burden was measured as sum of longest diameter of target lesions Reck et al. Oral presentation at WCLC 2015.

21 Earlier Progress Earlier Progress Patients with aggressive course of disease Results from LUME Lung 1 and Checkmate 057 LUME-Lung 1: OS benefit for patients with adenocarcinoma 1 LUME-Lung 1 (Nintedanib + Docetaxel vs. Docetaxel + Placebo) n % of patients Hazard Ratio 1st line refractory % 0,62 (0,41 0,94) Time since start of 1 st line until PD <9 months % 0,75 (0,60 0,92) 9 months % 0,89 (0,66 1,19) Nintedanib + Docetaxel: Increasing benefit with earlier progression Favors Nintedanib + Docetaxel HR Favors Docetaxel CheckMate 57: OS benefit for patients with non.squamous NSCLC 2 CheckMate 057 (Nivolumab vs. Docetaxel) n % of patients Hazard Ratio Time since completion of prior therapy < 3 months % 0,85 (0,67 1,08) 3-6 months % 0,69 (0,44 1,08) > 6 months % 0,46 (0,27 0,79) Nivolumab: Increasing benefit with later progression Favors Nivolumab HR Favors Docetaxel 1. Reck M et al. Lancet Oncol. 2014;15(2): Borghaei H et al. N Engl J Med. 2015;373(17):

22 Early vs Late Progressors: Mechanistic Hypothesis Rapidly progressing adenocarcinomas depend more strongly on vascularization for oxygen and nutrient supply than slowly growing tumors High intrinsic rate of tumor cell proliferation (oncogenome-dependent) Rapid disease progression High-level production of angiogenic growth factors by tumor cells High-level angiogenesis NINTEDANIB

23 Adverse Events Leading to Discontinuation and Dose Reduction (Adenocarcinoma Population) Nintedanib + docetaxel (n=320) n; % Placebo + docetaxel (n=333) n; % All grades Grade 3 All grades Grade 3 Any AE leading to permanent discontinuation of last study medication Any AE leading to dose reduction of nintedanib/ placebo Any AE leading to dose reduction of docetaxel 67; 20.9% 57; 17.8% 59; 17.7% 43; 12.9% 69; 21.6% 22; 6.6% 41; 12.8% (17%, 1 dose reduction) (4,6%, 2 dose reduction) (6.6%, 1 dose reduction) 19; 5.7% 53; 16.6% 41; 12.8% 41; 12.3% 32; 9.6% The median number of docetaxel courses: 5 (1-45) in the nintedanib arm vs. 4 (1-42) placebo. The mean dose intensity of docetaxel was >98% in both arms. 90 pts (28%) of pts continued with Nintedanib as monotherapy. Reck et al. Lancet Oncol. 2014;15: Suppl.

24 Adverse Events Occurring in 5% of the Patients With Adenocarcinoma Nintedanib + docetaxel (n=320) n (%) Placebo + docetaxel (n=333) n (%) All grades Grade 3 All grades Grade 3 Any AE 308 (96.3) 243 (75.9) 314 (94.3) 228 (68.5) Diarrhoea 139 (43.4) 20 (6.3) 82 (24.6) 12 (3.6) Neutrophil count decreased 131 (40.9) 116 (36.3) 135 (40.5) 116 (34.8) ALT increased 121 (37.8) 37 (11.6) 31 (9.3) 3 (0.9) Fatigue 99 (30.9) 15 (4.7) 98 (29.4) 14 (4.2) AST increased 97 (30.3) 13 (4.1) 24 (7.2) 2 (0.6) Nausea 91 (28.4) 3 (0.9) 59 (17.7) 2 (0.6) White blood cell count decreased 89 (27.8) 63 (19.7) 94 (28.2) 61 (18.3) Decreased appetite 75 (23.4) 4 (1.3) 52 (15.6) 5 (1.5) Vomiting 62 (19.4) 4 (1.3) 41 (12.3) 2 (0.6) Alopecia 56 (17.5) 1 (0.3) 68 (20.4) 0 (0) Dyspnoea 54 (16.9) 15 (4.7) 52 (15.6) 20 (6.0) Neutropenia 44 (13.8) 38 (11.9) 51 (15.3) 45 (13.5) Cough 42 (13.1) 3 (0.9) 63 (18.9) 2 (0.6) Only 1.2% of the patients in the nintedanib arm discontinued treatment due to diarrhoea Pyrexia 39 (12.2) 2 (0.6) 47 (14.1) 1 (0.3) -1.7% Stomatitis of the patients treated with nintedanib 36 (11.3) discontinued 4 (1.3) due to liver-related 26 (7.8) investigations 1 (0.3) Haemoglobin decreased 35 (10.9) 3 (0.9) 46 (13.8) 7 (2.1) Constipation 22 (6.9) 0 (0) 39 (11.7) 1 (0.3) Adverse events were classified according to Common Terminology Criteria for Adverse Events Reck version et al. 3.0 Lancet Oncol. 2014;15: Suppl.

25 Patients (%) Low Frequency of VEGF/VEGFR Inhibitor-associated Adverse Events in Adenocarcinoma Population All grades (%) Grade 3 (%) Nintedanib + docetaxel Placebo + docetaxel Nintedanib + docetaxel Placebo + docetaxel ATE = arterial thromboembolism; GI = gastrointestinal; VEGF = vascular endothelial growth factor; VEGFR = vascular endothelial growth factor receptor; VTE = venous thromboembolism Reck M, et al. J Clin Oncol 32:5s, 2014 (suppl; abstr 8100 and poster); Boehringer Ingelheim data on file.

26 Summary of LUME-Lung 1 Results LUME-Lung 1 met its primary endpoint and demonstrated: Significant prolongation of PFS regardless of histology Median PFS 3.4 vs 2.7, HR=0.79 (95% CI: ), p= Significant improvement in OS in patients with adenocarcinoma Median OS 12.6 vs 10.3 months, HR=0.83 (95% CI: ), p= Time since start of 1 st line therapy <9 months (HR 0.75, p=0.0073, median OS 7.9 to 10.9 mo) Manageable safety profile Commonly reported AEs included gastrointestinal events and reversible liver enzyme elevations No compromise to patients self-reported QoL HR = hazard ratio; OS = overall survival; PFS = progression-free survival; AE = adverse event; QoL = quality of life. Reck M, et al. Lancet Oncol. 2014;15:143-55; Novello S, et al. J Thorac Oncol 2013;8(Suppl 2):S1207 (abstract and poster).

27 Ramucirumab (IMC-1121B)

28 REVEL study - phase 3 study in NSCLC (2nd-line: docetaxel plus Ramucirumab/placebo) S C R E E N Inclusion Criteria Stage IV NSCLC progressing on or after 1 platinum-based regimen Prior Bev allowed Squamous or nonsquamous histologies ECOG PS 0/1 Stratification Geography (East Asia or other) ECOG PS Gender Prior maintenance therapy (Y or N) R A N D O M I Z E 1:1 N=1253 Ramucirumab 10 mg/kg + adocetaxel 75 mg/m2 N=628 Placebo + adocetaxel 75 mg/m2 N=625 Every 3 weeks adocetaxel 60 mg/m2 in Korea and Taiwan Treatment until disease progression or unacceptable toxicity Study design Primary endpoint Secondary endpoints Phase 3, randomized, multisite study of ramucirumab or placebo plus docetaxel following progression on or after a platinum-based regimen Overall survival Progression-free survival, overall response rate, safety, patient-reported outcomes Garon E, et al. Lancet 2015

29 REVEL: Overall Survival ITT Population Median (95% CI) Censoring Rate RAM+DOC 10.5 ( ) 31.8% PL+DOC 9.1 ( ) 27.0% RAM+DOC vs. PL+DOC Stratified HR (95% CI)=0.86 ( ) p=.023 Number at Risk RAM+DOC PL+DOC Garon E, et al. Lancet 2015

30 REVEL: Forest Plot of OS by Subgroups Unstratified Analysis Garon E, et al. Lancet 2015

31 REVEL: Progression-free Survival ITT Population Median (95% CI) Censoring Rate RAM+DOC 4.5 ( ) 11.1% PL+DOC 3.0 ( ) 6.7% RAM+DOC vs. PL+DOC Stratified HR (95% CI)=0.76 ( ) p<.0001 Number at Risk RAM+DOC PL+DOC Garon E, et al. Lancet 2015

32 REVEL: Tumor Response by RECIST v1.1 ITT Population, Investigator Assessment Response RAM+DOC (N=628) PL+DOC (N=625) p-value n (%) n (%) Complete response 3 (0.5) 2 (0.3) Partial response 141 (22.5) 83 (13.3) Stable disease 258 (41.1) 244 (39.0) Progressive disease 128 (20.4) 206 (33.0) Unknown 98 (15.6) 90 (14.4) Objective response rate (95% CI) Disease control rate (95% CI) 144 (22.9) 85 (13.6) ( ) ( ) 402 (64.0) 329 (52.6) ( ) ( ) <.001 <.001 Garon E, et al. Lancet 2015

33 REVEL: Adverse Events of Special Interest Adverse Event, % RAM+DOC (N=627) PL+DOC (N=618) Any Grade Grade 3 Any Grade Grade 3 Bleeding or hemorrhage Epistaxis 19 <1 6 <1 GI hemorrhage <1 Pulmonary hemorrhage Hemoptysis Hypertension Infusion-related reaction Proteinuria 3 <1 1 - Venous thromboembolic Renal failure 2 <1 2 <1 Arterial thromboembolic Congestive heart failure <1 GI perforation 1 1 <1 <1 Garon E, et al. Lancet 2015

34 REVEL Refractory Patients OS Refractory Patients PFS Refractory Patients Response a RAM+DOC (N = 178) PBO+DOC (N = 182) Objective response rate (CR+PR), % (95% CI) 23 (17, 29) 13 (8, 18) P-value Disease control rate (CR+PR+SD), % (95% CI) 52 (45, 60) 42 (35, 50) P-value Reck M, et al. ASCO 2016

35 REVEL Subgroup Analysis of Patients Refractory to 1L Chemotherapy: Exploratory Sensitivity Analysis (ITT Patients) ITT Population RAM+DOC (N = 33) Duration of First-Line Therapy 4 weeks 8 weeks 12 weeks PBO+DOC (N = 24) RAM+DOC (N = 112) PBO+DOC (N = 88) RAM+DOC (N = 244) PBO+DOC (N = 204) Median OS, months (95% CI) 8.8 (4.5, 15.3) 3.2 (2.4, 4.7) 8.6 (6.5, 10.4) 6.9 (5.0, 9.3) 9.2 (8.3, 10.3) 7.2 (5.9, 9.3) Unstratified HR (95% CI) 0.40 (0.22, 0.73) 0.83 (0.61, 1.15) 0.85 (0.68, 1.05) Unstratified log-rank P-value Median PFS, months (95% CI) 2.9 (2.2, 5.3) 1.4 (1.1, 1.5) 3.3 (2.8, 4.2) 2.5 (1.5, 2.9) 4.1 (3.2, 4.4) 2.8 (1.8, 3.2) Unstratified HR (95% CI) 0.44 (0.25, 0.78) 0.85 (0.64, 1.14) 0.75 (0.61, 0.91) Unstratified log-rank P-value ORR (CR+PR), % (95% CI) 24 (11, 42) 0 (0, 14) 23 (16, 32) 11 (6, 20) 26 (21, 32) 12 (8, 17) P-value < DCR (CR+PR+SD), % (95% CI) 52 (34, 69) 21 (7, 42) 52 (42, 61) 46 (35, 56) 58 (52, 65) 47 (40, 54) P-value In the control arm, median OS among refractory patients was 6.3 months versus 10.3 months for patients not meeting this criterion, demonstrating the poor prognosis of refractory patients. Although these patients did not respond to first-line therapy, refractory patients treated with second-line ramucirumab plus docetaxel had increased median OS (RAM: 8.3 months vs PBO: 6.3 months; HR=0.86; 95% CI: 0.68, 1.08), increased median PFS (RAM: 4.0 months vs PBO: 2.5 months; HR=0.71; 95% CI: 0.57, 0.88), and increased ORR in the REVEL study. Reck M, et al. ASCO 2016

36 Conclusions Ramucirumab is a fully human monoclonal IgG1 that binds to the extracellular domain of VEGF receptor 2 with high affinity. Addition of ramucirumab to standard second-line docetaxel achieved a consistent and significant improvement of response rate, progression-free survival and overall survival, irrespective of histology. The safety profile of ramucirumab added to docetaxel was as expected for an antiangiogenic agent targeting the VEGF pathway.

37 BEVACIZUMAB Taimeh Z, et al. Nature Reviews Cardiology 2013; 10:

38 Weekly Paclitaxel plus Bevacizumab versus Docetaxel as Second or Third-Line Treatment in Advanced Non-Squamous Non-Small Cell Lung Cancer (NSCLC): Results from the Phase III Study IFCT-1103 ULTIMATE

39 Supervivencia libre de progresión wpb Mediana SLP: 5.4 meses, 95%CI:[ ] DOC Mediana SLP: 3.9 meses, 95%CI:[ ] HR: 0.62 [ ] p: Cortot A, et al. ASCO 2016

40 SLP: Análisis Subgrupos

41 ULTIMATE: TASA RESPUESTA Tasa de Respuestas a las 8 semanas DOCETAXEL n: 55 TAXOL-BEVA n: 111 Valor p ORR, % [95% CI] 5.5 [0.0%-11.5%] 22.5 [14.8%-30.3%] Respuesta completa, % 0 0 Respuesta parcial, % Enfermedad Estable, % DCR, % PGR, % No evaluable, %

42 ULTIMATE: SG wpb Mediana SG: 9.9 meses, 95%CI:[ ] DOC Mediana SG: 11.4 meses, 95%CI:[ ] HR: 1.18 [ ] p: 0.40

43 ULTIMATE: Tratamiento/Tolerancia

44 ULTIMATE: Tratamiento/Tolerancia Aumento de la Neuropatía* en el brazo wpb (8.3% G3-4) Toxicidad típica BEVA*: sangrado, TEE, HTA, Proteinuria (G %, 4.6%, 7.3%, 0% respectivamente)

45 ULTIMATE: QOL EVA2 vs Basal EVA3 vs Basal Mejoría Estabilidad Deterioro 10 ptos basal 10 ptos basal Cuestionario LCSS (Calidad de vida global) No diferencias basales entre el brazo de DOC y wpb en los 9 items

46 Conclusiones Bevacizumab y paclitaxel semanal: Es superior frente a Docetaxel en ORR y SLP, reducción 38% riesgo de PGR Menos toxicidad hematológica y = QOL. Similar actividad en pts pre-tratados DOCE. Cross-over demuestra eficacia wpb en 2,3,4L. Análisis exploratorio del impacto del cross-over en la SG: los pacientes tratados con wpb podrían tener una SG superior comparada con los no expuestos al tratamiento.

47 Slide 25 Presented By Jean-Charles Soria at 2016 ASCO Annual Meeting

48 Comparación Anti-angiogénicos Overall survival (months) Therapeutic plateau months 1. Garon EB, et al. Lancet. 2014;384: Reck M, et al. Lancet Oncol. 2014;15: Cotot AB, et al. ASCO Abstract 9005.

49 Conclusiones Asociar antiangiogénicos a taxanos en 2L en adenocarcinoma de pulmón tras progresión a platino mejora el pronóstico de pacientes candidatos Nintedanib, Ramucirumab y Bevacizumab (Nivel evidencia IA) Análisis exploratorios sugieren que es especialmente útil en pacientes con enfermedad rápidamente progresiva (cut-off 9 meses?) Perfil de tolerancia es bueno (efectos secundarios de clase bien reconocidos) Importancia de la selección clínica para determinar la terapia a utilizar en 2L y definir la secuencia terapéutica para optimizar el tratamiento en CPNCP Comorbilidades, CI IO, CI antiangiogénicos, expresión PD-L1, tiempo a la progresión de una primera línea, otros (?) Escenarios cambiantes: 2L en pacientes sin expresión de PD-L1 tras 1L (o PD-L1 desconocido), sobre todo si asocia factores clínicos de mal pronóstico 3L en pacientes que recibieron una 2L de inmunoterapia Pacientes PD-L1+ a progresión inmunoterapia 1ªL (precisa progresión a platino)

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