Tratamiento del Cáncer de Pulmón. Donde estamos ahora?

Tratamiento del Cáncer de Pulmón Donde estamos ahora?

Evolución del tratamiento del CPNM avanzado Evolución del tratamiento en el CPNM -Umbral terapéutico Supervivencia Global Platinum doublet with Pemetrexed Maintenance JMEN 15,5 m Ŧ SATURN 12 m Ŧ PARAMOUNT 16,9 m* EGFR+ First line TKI 23 m EML-ALK translocation Crizotinib 20,7 m (p not significant, preliminary data) or BSC 2-4 m Platinum doublet 6-8 m Platinum doublet with 3 rd generation drug 8-10 m Platinum triplet with 3 rd generation drug and Bevacizumab 12-13 m < 1970s 1980s 1990 2005 1990-2005 2005-2009 2010-2010- 2013 Ŧ From randomization *From induction

Cáncer de Pulmón dónde estamos ahora?

ALIMTA, Histology and Survival Overall survival was statistically superior for cisplatin/pemetrexed versus cisplatin/gemcitabine in patients with adenocarcinoma (n = 847; 12.6 v 10.9 months, respectively) In patients with squamous cell histology, there was a significant improvement in survival with cisplatin/gemcitabine versus cisplatin/pemetrexed (n = 473; 10.8 v 9.4 months, respectively). CP, cisplatin/pemetrexed; CG, cisplatin/gemcitabine; HR, hazard ratio Scagliotti, JCO 26:3543, 2008

Major Themes in Therapy of Advanced NSCLC 2013: Interrelationships Among Histology, Maintenance Therapy, and Predictive Biomarkers Histology Maintenance Predictive Biomarkers Factors are interlinking and not independent

Overview of Predictive Analyses used in NSCLC First-line/Maintenance therapy Avastin (bevacizumab) and ALIMTA (pemetrexed) Adenocarcinoma vs Squamous Cell Carcinoma (IHC) Chemotherapy Platinum-based drugs ERCC1 (IHC or gene expression) Gemcitabine RRM1 (IHC or gene expression) ALIMTA TS (IHC or gene expression) Biologic Small molecule, EGFR-directed TKI: Tarceva and Iressa EGFR mutation (gene sequencing or allele-specific) KRAS (Molecular) ALK-directed crizotinib ALK-EML4 translocation ALK rearrangement

Adenocarcinoma: Incidencia de mutaciones drivers Mutation found in 54% (280/516) of tumours completely tested (CI 50-59%) Kris et al. J Clin Oncol 29: 2011 (suppl; abstr 7506)

Epidermoid NSCLC

Li T et al. JCO 2013;31:1039-1049 Evolution of non small-cell lung cancer (NSCLC) subtyping from histologic to molecular based.

Potential Druggable Molecular Targets? AKT1 NRAS MEK1 MET AMP HER2 PIK3CA 2% BRAF 2% Double Mutants 3% Lung Cancer Molecular Consortium Lung Adenocarcinomas No Mutation Detected EML4-ALK 7% EGFR 17% KRAS 22% Mutations found in 54% (280/516) Emerging Druggable Targets in NSCLC-Squamous Subtype Gene Event Type Frequency, % FGFR1 Amplification 20-25 FGFR2 Mutation 5 PIK3CA Mutation 9 PTEN Mutation deletion 18 CCND1 Amplification 8 CDKN2A Deletion/mutation 45 PDGFRA Amplification mutation 9 EGFR Amplification 10 MCL1 Amplification 10 BRAF Mutation 3 DDR2 Mutation 4 ERBB2 Amplification 2 Kris MG, et al. ASCO 2011. CRA7506. Johnson BE, et al. IASLC WCLC 2011. Abstract O16.01 Hammerman P, et al. IASLC WCLC 2011. Abstract PRS.1

Cuántos Genes Mut-Driver existen? Vogelstein B et al. Science 2013 Aunque se han estudiado 20000 genes que codifican proteínas de 3284 tumores con un total de 294881 mutaciones solo 125 genes son mut driver, de estos 71 son supresores de tumores y 54 oncogenes

Cuántos Genes están sutilmente mutados en un Cáncer Humano típico? Vogelstein B et al. Science 2013

Major Themes in Therapy of Advanced NSCLC 2012: Interrelationships Among Histology, Maintenance Therapy, and Predictive Biomarkers Histology Maintenance Therapy Predictive Biomarkers Looking Forward to 2015: Moving From Empiric to Individualized From One Size Fits All to Tailored and Individualized Therapy

2. BIOPSIA PACIENTE 1 Localización de las biopsias y regiones extraídas a partir de la nefrectomía y metastasectomía. G indica el grado de tumor. Análisis de 9 regiones diferentes de un tumor de riñón, incluidas tres metástasis Secuenciación de todo el ADN de cada zona, además de comprobar alteraciones en el número y forma de los cromosomas.

Secuencia terapéutica

NCCN Guidelines Update for NSCLC Non-Small Cell Lung Cancer NCCN Guidelines recommend that molecular diagnostic studies be included in the pathologic evaluation of NSCLC. Histologic type should be established before EGRF testing EGFR mutation testing should be performed on adenocarcinoma, large cell carcinoma, and NSCLC not otherwise specified Testing is not recommended for squamous cell carcinoma, which has a mutation rate of ~3.6% KRAS mutations are associated with intrinsic TKI resistance, and KRAS testing should be used for the selection of patients as candidates for TKI therapy EGFR mutations are generally exclusive of ALK rearrangements; ALK testing should not be considered for those who test positive for a mutation NCCN Non-Small Cell Lung Cancer Clinical Practice Guidelines in Oncology (Version 2.2012)

Tsao Algorithm: Histology and Molecular Profiling NSCLC PATIENT Non-SCC SCC Neuroendocrine Adenocarcinoma Avoid pemetrexed or bevacizumab Platinum-etoposide; Switch Maintenance: pemetrexed, erlotinib EGFR mutation EML 4 ALK, ROS1 EGFR wild-type Consider 2 nd line EGFR TKI or maintenance erlotinib (BR.21, SATURN) EGFR TKI 1 st or 2 nd line Maintenance (IPASS, BR.21, SATURN) crizotinib Platinum-doublet-bevacizumab Platinum-pemetrexed Non-platinum or platinum based doublet Switch Maintenance: pemetrexed, erlotinib (E4599, AVAiL, Pointbreak, SATURN, JMEN)

Potential Future of NSCLC - Molecular Profiling Adenocarcinoma EGFR mutation BRAF mutation PI3K mutant Met + KRAS mutant EGFR TKI EML 4 ALK or ROS1 mutant BRAF inhibitor PI3K inhibitor Resistance rebiopsy T790M irreversible EGFR TKI MET upregulation Met inhibitor crizotinib Resistance rebiopsy Novel agent Resistance rebiopsy Novel agent Met inhibition MEK inhibitor combination Resistance rebiopsy Hsp90 inhibitor novel agent targeting ALK resistance mutation Resistance rebiopsy Novel agent Resistance rebiopsy Novel Agent Platinum-doublet-bevacizumab Platinum-pemetrexed + bevacizumab Non-platinum or platinum based doublet Switch Maintenance: pemetrexed, erlotinib (E4599, AVAiL, Pointbreak, SATURN, JMEN)

Nuevos fármacos en Cáncer de Pulmón Individualización terapéutica Conocimiento de mecanismos de resistencia Tratamientos a la medida Biomarcadores de cada paciente Nuevos agentes dirigidos Cambios de estrategia. Mantenimiento?

Mantenimiento Tenemos que revisar el concepto?

Only ~50% of patients in clinical trials go on to receive second-line therapy Maintenance therapy could delay disease progression and provide active treatment for more patients Socinski et al. 2002 1 Belani et al. 2003 2 Brodowicz et al. 2006 3 von Plessen et al. 2006 4 Barata et al. 2007 5 Park et al. 2007 6 Ciuleanu et al. 2009 7 Pirker et al. 2008 8 Scagliotti et al. 2008 9 Fidias et al. 2009 10 0 25 50 75 100 Patients receiving 2nd-line therapy (%) 1. JCO 2002; 2. JCO 2003; 3. Lung Cancer 2006; 4. Br J Cancer 2006; 5. WCLC 2007; 6. JCO 2007; 7. Lancet 2009; 8. ASCO 2008; 9. JCO 2008; 10. JCO 2009

Objetivos de la terapia de mantenimiento: Prolongar el control de la enfermedad Objectivos 1 Mantener la tolerabilidad Mejorar la Supervivencia Global La Tolerabilidad es importante en el ámbito de mantenimiento, en el que el tratamiento se continúa hasta progresión de la enfermedad. 1,2 1. Paz-Ares et al. Lancet Oncol 2012;13:247.

Switch maintenance Concept Immediate introduction of a new agent after induction chemotherapy can overcome an emerging resistance 9 Potential advantages All patients receive one additional treatment 3 Bypass potential resistance to the cytotoxic agent used in the induction treatment Downsides Loss of a 2 nd -line option at the onset of disease progression Uncertainty about the efficacy and tolerability of the maintenance agent

Evolución del paradigma en el tratamiento de CPNM 1 Paradigma Anterior Doblete basado en platino Intervalo libre de tratamiento Progresión Monoterapia de segunda linea Periodo libre de progresión Sólo BSC Tratamiento hasta la progresión Nuevo Paradigma Doblete o triplete basado en platino Tratamiento de mantenimiento (monoterapia o combinación) Más tiempo hasta la progresión Progresión Siguientes líneas de tratamiento CPNM: cáncer de pulmón no microcítico; BSC: mejores cuidados de soporte (Best supportive care). 1. Hensing et al. Lung Cancer 2005;47(2):253.

Options for maintenance chemotherapy Continuing CT for more cycles than standard Predefined number of extra cycles / Until progression Induction chemotherapy Continuing only the non-platinum component Switching to a different cytotoxic CT agent

Options for maintenance targeted therapy Continuing the same targeted therapy that was concurrently administered with induction CT (x 4-6 cycles) Induction CT +/- targeted therapy Adding a 2 nd targeted therapy after completion of induction treatment Switching to a new targeted therapy after induction CT

Maintenance Therapy Terminology: A Rose by Any Other Name? Platinum-based doublet chemotherapy: 4 cycles of induction eg, cisplatin + agent A Same agent A until PD or toxicity Continuation maintenance Different agent C until PD or toxicity Switch maintenance

General design scheme of clinical trials evaluating maintenance therapy in advanced NSCLC Prolongation of treatment Duration Duration of disease of disease control: control: PFS benefit PFS benefit Tumour status assessments Overall survival benefit Maintenance Prog 2 nd -line 1 st -line platinumbased doublet x 4 cycles Objective response or stabilisation 1:1 or 2:1 Placebo or observation Prog 2 nd -line Progression-free survival Overall survival

2º PART Maintenance chemotherapy: Points to Ponder Definition of maintenance varies Benefit for pemetrexed confined to non-squamous histology Many patients never received second-line therapy! Survival in control arms may have diminished due to lack of life-prolonging second line therapy The interpretation of the results is hampered by the heterogeneity of studies and the different maintenance approaches used (continuation vs. switch) Heterogeneity in design and results.

Summary of Switch Maintenance Trials Fidias [1] Ciuleanu [2] Cappuzzo [3] Miller [4] Perol [5] Zhang [6] Agent/Control Arm N PFS Salvage Treatment, % Docetaxel Delayed docetaxel Pemetrexed Placebo Erlotinib Placebo Erlotinib + bevacizumab Placebo + bevacizumab Erlotinib Observation Gefitinib Placebo 309 5.7 mos HR: 0.63 2.7 mos P =.001 663 4.0 mos HR: 0.50 2.6 mos P <.0001 889 12.3 wks HR: 0.71 11.1 wks P <.0001 768 4.8 mos HR: 0.72 3.8 mos P =.001 310 2.9 mos HR: 0.82 1.9 mos P =.002 296 4.8 mos HR: 0.42 2.6 mos P <.0001 OS 63 12.3 HR: 0.80 9.7 P =.085 67 13.4 HR: 0.79 10.6 P =.012 72 12.0 HR: 0.81 11.0 P =.0088 55.5 15.9 HR: 0.90 13.9 P =.2686 81.9 NA HR:.91 NA 58.8 18.7 HR:.84 16.9 P =.2608 1. Fidias P, et al. J Clin Oncol. 2010;28:5116-5123. 2. Ciuleanu T, et al. Lancet. 2009;374:1432-1440. 3. Cappuzzo F, et al. Lancet Oncol. 2010;11:521-529. 4. Miller VA, et al. ASCO 2009. Abstract LBA8002. 5. Perol M, et al. ASCO 2010. Abstract 7507. 6. Zhang L, et al. ASCO 2011. Abstract LBA7511. J Thorac Oncol. 2012;7: 1331 1336

Continuation Maintenance Trials Study Yr Induction Therapy Maintenance Therapy Median PFS, Mos Brodowicz [1] 2006 Gemcitabine 1250 mg/m 2 on Days 1, 8 + cisplatin 80 mg/m 2 on Day 1 x 4 Belani [2] 2010 Gemcitabine 1000 mg/m 2 on Days 1, 8 + carboplatin AUC 5 on Day 1 x 4 Perol [3] 2010 Gemcitabine 1250 mg/m 2 on Days 1, 8 + cisplatin 80 mg/m 2 on Day 1 x 4 Gemcitabine 1250 mg/m 2 on Days 1,8 BSC Gemcitabine 1000 mg/m 2 on Days 1,8 BSC Gemcitabine 1000 mg/m 2 on Days 1,8 BSC 6.6 5.0 (P <.001) 7.4 7.7 (P =.575) 3.8 1.9 (P <.0001) Median OS, Mos 13.0 11.0 8.0 9.3 (P =.838) NR NR Main Grade 3/4 Toxicities Maintenance Gem: ANC 14.9%, Plts 1.7%; blood transfusion: 20% gemcitabine vs 6.3% BSC ANC: 15% chemo, 2% BSC; Plts: 9% chemo, 4% BSC; fatigue: 5% chemo, 2% BSC At least 1 grade 3/4 AE: chemotherapy 27.9%, observation 2.6% Paz Ares [4] 2011 Pemetrexed 500 mg/m 2 on Day 1 + cisplatin 75 mg/m 2 on Days 1 x 4 Pemetrexed 500 mg/m 2 on Day 1 BSC 4.1 2.8 (P =.00006) 13.8 NR 11.1 NR Fatigue: 4.2% pem, 0.6% BSC; Anemia: 4.5%, 0.6% BSC; ANC: 3.6% pem, 0 BSC 1. Brodowicz T, et al. Lung Cancer. 2006;52:155-163. 2. Belani CP, et al. ASCO 2010. Abstract 7506. 3. Perol M, et al. ASCO 2010. Abstract 7507. 4. Paz-Ares LG, et al. ASCO 2011. Abstract CRA7510. J Thorac Oncol. 2012;7: 1331 1336

Maintenance and Benefit

Issues to Consider Regarding Maintenance Therapy The big question about maintenance therapy is WHO to treat and WHEN to treat If 6 cycles of platinum chemotherapy are given, are the maintenance data still relevant? If a patient achieves no response (SD) and remains symptomatic, is subsequent therapy maintenance or early second-line therapy? If a patient achieves response and becomes asymptomatic, is maintenance therapy always better than watch and wait? What about the underlying molecular profile of the patient? In the emerging era of personalized therapy, these decisions should be made on an individual basis: One size does not fit all

Problems of Maintenance therapy Why can continuation of a single agent until progresion provide survival benefit in spite of the completely negative results of continuous administration of a platinum doublet? Why did control patients not recieved second-line therapy? Cost, Toxicity and inconvenience are problems Many patients desire a drug holiday No clear benefit on OS by pure maintenance therapy PFS is apropiate for the evaluation of the effect of maintenance therapy?

Are four cycles of chemotherapy Truly adequated? SLP Yu Yang Soon et al. J Clin Oncol 27:3277-3283. SG

Did the control group perform adequately? J Thorac Oncol. 2012;7: 1331 1336

Benefits of Maintenance and Response Status J Thorac Oncol. 2012;7: 1331 1336

Who actually benefits? Stable disease is sometimes early progresion J Thorac Oncol. 2012;7: 1331 1336

Questions to be answered Some of them used PFS, while others used OS as primary end- point. 1. The use of PFS has the advantages of eradicating the confounding impact of post-study treatment, while usually requires smaller sample size compared with OS analysis 2. PFS is more subject to inter-observer bias, subject to testing intervals and small absolute improvements in PFS may not translate into OS improvement. 3. OS is a more definitive endpoint, but requires larger patient cohorts to demonstrate differences and there can be considerable variability in the rate and type of poststudy therapies that could have an impact on the final results. 4. All studies using PFS demonstrated a statistically significant difference in favor of maintenance treatment, while studies with OS as an end-point were negative

Questions to be answered 2 Second question is which strategy is more effective; the continuation or the switch maintenance. Metanalysis by Behera et al: switch maintenance therapy was associated with significant OS and PFS (OS: HR 0.86, 95% CI 0.80 0.93, p-value = 0.00046; PFS: HR 0.71, 95% CI 0.66 0.77, p- value <0.0001). Despite a modest improvement in PFS (HR: 0.92, 95% CI 0.87 0.98, p-value = 0.007), continuation maintenance therapy was not associated with OS benefit (HR: 0.92, 95% CI 0.77 1.08, p-value = 0.33). The two trials that demonstrated PFS and OS benefit were both switch maintenance trials Third question is the selection of patients who should be treated with maintenance treatment. The major disadvantage of maintenance treatment is that it commits patient to treatment and does not allow treatment breaks in a disease in which the primary goal of treatment is palliation. Although maintenance treatment in all studies was overall well tolerated, it should be noted that the incidence of grade III/IV toxicities were higher in the maintenance arm.

Cost-Effectiveness and QoL of Maintenance Therapy for Advanced NSCLC

Coste-efectivo Perspectiva desde el Sistema Sanitario Español Monthly-perpatient cost 1 ICER vs BSC 1 SWITCH ERLOTINIB (SATURN) 2048 27.584 /LYG PEMETREXED (JMEN) 3164 27.372 /LYG CONTINUATION PEMETREXED (PARAMOUNT) No studies Perspectiva desde Sistema Sanitario NICE 2 ICER vs BSC MEETS END-of- LIFE CRITERIA RECOMMENDED SWITCH ERLOTINIB 44.812 /QALY squa. SD 68.120 /QALY non-squa. SD YES NO PEMETREXED 47.000 /QALY YES YES CONTINUATION PEMETREXED TA in process In process In process TA: Technology Appraisal 1. Nuitjen et al, Lung cancer 2012, 465-471. 2. www.nice.org.uk

SATURN Estudio SATURN Supervivencia según respuesta a la 1ª Línea Evolución de la Calidad de vida (QoL) 1 Time to deterioration in HRQoL in the SD population (FACT-L) Impacto de Erlotinib como tratamiento secuencial de mantenimiento en la QoL 1. Juhasz et al, Eur J Cancer 2013 49, 6 1205.

PARAMOUNT Datos de QoL EQ-5D index scores: Items mantenidos a través de todo el treatmento 1 0.8 Improvement Mean score 0.7 Pemetrexed Placebo 0.6 1 2 3 4 1 2 3 4 5 6 Induction cycles Maintenance cycles * p 0.05, within-group change from baseline. p 0.05, comparing the difference in mean changes from baseline between treatment arms. 1. Adapted from Gridelli C et al J Thorac Oncol. 2012;7(11):1713-1721.

Maintenance Pemetrexed

Personalized maintenance therapy

Optimal design of a switch maintenance trial J Thorac Oncol. 2012;7: 1331 1336

Predictores de beneficio para el tratamiento de mantenimiento Opciones de tratamiento a la progresión Preferencia de los pacientes Respuesta a la primera línea de inducción Histology Molecular Chacteristics Performance status Objetivos del tratamiento Gerber et al, J Clin Oncol 2013, 31, 8, 1009

SLCG 2013 We are working on..

New international BREC (BRCA1 Expression Customization) CONTROL Docetaxel/Cis Advanced NSCLC 1:1 T1 RAP80 (T1-T3 BRCA1) Gem/Cis EXPERIMENTAL T2-T3 RAP80 (T1-T2 BRCA1) Docetaxel/Cis T2-T3 RAP80 (T3 BRCA1) Docetaxel

ETOP 2-11 BELIEF An open-label phase II trial of erlotinib and bevacizumab in patients with advanced non-small cell lung cancer and activating EGFR mutations BELIEF Bevacizumab and ErLotinib In EGFR mut+ NSCLC A clinical trial of ETOP coordinated by the SLCG In cooperation with Hoffmann-La Roche Chair: R Rosell Co-Chair: R Stahel Co-Chair Translational Research: M. A Molina 53 ETOP 2-11 BELIEF Center Training 2013

54 ETOP 2-11 BELIEF Center Training 2013 EURTAC cutoff January 2013

G1: Erlotinib and T790M present (n=34) G2: Erlotinib and T790M absent (n=16) G3: Chemotherapy and T790M present (n=28) G4:Chemotherapy and T790M absent (n=17) G2 G4 5 1 6 0 9 7 15 8 G3 G1 Patients at risk 55 ETOP 2-11 BELIEF Center Training 2013 EURTAC cutoff January 2013

BELIEF Trial design 56 ETOP 2-11 BELIEF Center Training 2013

Objectives Long-term outcome of patients with advanced non-squamous NSCLC harbouring EGFR mutations with or without T790M mutation at diagnosis and treated with the combination of erlotinib and bevacizumab. Efficacy and tolerability of the combination Correlation of BIM mrna and mrna expression of camp-related genes and T790M with progression-free survival EGFR mutations including T790M mutation in serum longitudinally Molecular biomarkers related to EGFR TKI and bevacizumab 57 ETOP 2-11 BELIEF Center Training 2013