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NSCLC Adiuvante

NSCLC Adiuvante. Dott. Domenico Galetta. Adjuvant Therapy Timeline. Kelly K USA EO3.4. BLT HR = 1.02 N=381. RADIANT. JBR.10 HR = .69 N=482. ANITA HR = .76 N=840. IALT HR = .86 N=467. MAGRIT. ~6. 20 13. 2006. 20 03. 2004. 2005. 20 08. 2014. E1505 Closed to Accrual.

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NSCLC Adiuvante

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  1. NSCLC Adiuvante Dott. Domenico Galetta

  2. Adjuvant Therapy Timeline Kelly K USA EO3.4 BLT HR = 1.02 N=381 RADIANT JBR.10 HR = .69 N=482 ANITA HR = .76 N=840 IALT HR = .86 N=467 MAGRIT ~6 20 13 2006 20 03 2004 2005 20 08 2014 E1505 Closed to Accrual CALGB 9633 HR = .83 N=344 ALPI HR = .96 N=1207 ALPI–MVP vs OBS Stage I-IIIA Scagliotti GV et al. J Natl Cancer Inst 2003; 95: 1453-61 BLT-CPPP-based vs OBS Stage I-III Waller D et al. Eur J CardiothorcicSurg 2004;26:173-182 IALT–CDDP-based vs OBS Stage I-IIIAArriagada R et al. N Engl J Med 2004; 350: 350-61 JBR.10–CDDP-VNRvs OBS Stage IB-II Winton T et al. N Engl J Med 2005; 352:2589-97 ANITA–CDDP-VNRvs OBS Stage IB-IIIADouillandJY et al. Lancet Oncol 2006; 7: 719-27 CALGB 9633–PAC-CARBOvs OBS Stage IB Strauss GM et al. J ClinOncol 2008; 26: 5043-51

  3. Adjuvant Therapy Timeline adapted BLT HR = 1.02 N=381 RADIANT JBR.10 HR = .69 N=482 ANITA HR = .76 N=840 IALT HR = .86 N=467 MAGRIT ~6 2003 2004 2005 2006 2008 2013 2014 ITACA E1505 Closed to Accrual CALGB 9633 HR = .83 N=344 ALPI HR = .96 N=1207 CALGB 30506 ALCHEMIST ? CTONG1104 ALPI–MVP vs OBS Stage I-IIIA Scagliotti GV et al. J Natl Cancer Inst 2003; 95: 1453-61 BLT-CPPP-based vs OBS Stage I-III Waller D et al. Eur J CardiothorcicSurg 2004;26:173-182 IALT–CDDP-based vs OBS Stage I-IIIAArriagada R et al. N Engl J Med 2004; 350: 350-61 JBR.10–CDDP-VNRvs OBS Stage IB-II Winton T et al. N Engl J Med 2005; 352:2589-97 ANITA–CDDP-VNRvs OBS Stage IB-IIIADouillandJY et al. Lancet Oncol 2006; 7: 719-27 CALGB 9633–PAC-CARBOvs OBS Stage IB Strauss GM et al. J ClinOncol 2008; 26: 5043-51 Afatinib Adjuv EURECA

  4. Adjuvant CT ± post-op RT, in operable NSCLC: two meta-analyses of individual patient data 34 trials, 8447 patients HR 0.86 (95 CI : 0.81-0.92) P<0.0001 4% benefit 13 trials, 2660 patients HR 0.88 (95 CI : 0.81-0.97) P<0.009 4% benefit NSCLC Meta-analyses Collaborative Group Lancet 2010; 375:1267

  5. LACE Analysis by Stage Adjuvant chemo has greatest benefit for stage II and III and is detrimental for stage IA patients Pignon JP, et al. J Clin Oncol 2008; 26:3552-9

  6. Stage IB T Size Analysis CALGB Stage IB and Tumor Diameter > 4 cm JBR .10 7th edition of TNM staging Tumors > 5 -7 cm are Stage IIA Tumors > 7 cm are Stage IIB Strauss GM,et al. J Clin Oncol 2008; 31: 5043-51 Butts CA, et al. J Clin Oncol 2010; 28: 29-34

  7. What Have We Learned? Kelly K USA EO3.4 • CDDP based adjuvant chemotherapy improves the cure rate for patients with Stage II-IIIA NSCLC with a PS of 0-1. • No role for adjuvant chemotherapy in patients with a tumor size < 3 cm (Stage IA in both 6th and 7th Staging classification). • Controversial role for adjuvant chemotherapy in patients with a tumor size of > 4 cm with subset analyses suggesting a benefit. • Non-cancer mortality may be increased in patients receiving chemotherapy.

  8. Early Stage NSCLCNo Biomarker, Unselected Population Scagliotti GVItaly MS 13.3 PredictiveFactors Patients with residual micrometastases resistant to adjuvant therapy Pro b ability Patients cured with local regional therapy patients with residual micrometastases sensitive to adjuvant therapy PrognosticFactors Survival Time

  9. Do «goodprognosis»lungcancerexist? Mark G Kris, USA, PC02.4 Rami-Porta J Thor Oncology 2007

  10. Prognosticfactors in lungcancer Kris M USA PC 02.4 There are no “good prognosis lung cancers” 23% of patients with tumor less than 2 cm (stage pT1aN0M0) are dead at 5 years. All patients with breast cancer with this degree of risk are reccomended additional therapy with primary treatment • Phase II “proof of concept” studieslessapplicabletoadjuvantsetting. • In adjuvantstudiesoverallresponse rate is NOT anendpoint. • Survivalismuchlonger and potentiallyimpactedbyadditionallines of therapy at relapse. • Quality of life issues and adverseevents. • Early stage NSCLC are lessfrequentlyreportedthan in othertypes of tumors (e.g. breast). Scagliotti GVItaly MS 13.3

  11. Strategies to selectDrugs for use with surgery in Early Stage LungCancer • Gene expression profiles (microarrays) • Repair/Metabolism genotype • Immunotherapy • Molecular driven mutation • New targets • Assess radiographic response in induction “window of opportunity”

  12. Strategies to selectDrugs for use with surgery in Early Stage LungCancer • Gene expressionprofiles (microarrays) • Repair/Metabolismgenotype • Immunotherapy • Moleculardrivenmutation • New targets • Assessradiographicresponse in induction “window of opportunity”

  13. Use of microarrays in NSCLC Scagliotti GVItaly MS 13.3 • Need for complicated methods. • Large number of genes used in gene profilings. • In most of the studies need of fresh tissue. • Lack of both reproducibility and independent validation of the results. • Genes varied considerably and only few genes have been consistently included. • Gene expression profiles can vary according to the microarray platform and the analytic strategy used.

  14. CALGB 30506 Schema (Stage IA/IB) Resection T (1.75 to 4.0) N0 Patients + Array N=1296 LM Score <0.55; 850 LM Score > 0.55; 446 Randomize Randomize Adjuvant Chemotherapy N=425 Observation N=425 Adjuvant Chemotherapy N=223 Observation N=223 LM Scores Blinded to Investigators

  15. Gene ExpressionSurvivalPrediction in Lung Adenocarcinoma : ValidationStudy All stages All stages with covariates Stage I only with covariates Stage I only • Training-testing multi-institution validation study (UM,HLM,CAN/DF,MSK), 442 adenocarcinoma • Eight Classifiers Shedden K. et al. Nature Med. 2008; 14::822

  16. Strategies to selectDrugs for use with surgery in Early Stage LungCancer • Gene expressionprofiles (microarrays) • Repair/Metabolismgenotype • Immunotherapy • Moleculardrivenmutation • New targets • Assessradiographicresponse in induction “window of opportunity”

  17. Early Stage NSCLC Prognostic Biomarkers Scagliotti GVItaly MS 13.3 1. Fouret P, et al. ASCO 2009. Abstract CRA7502. 2. Olaussen KA, et al. N Engl J Med. 2006;355:983-991. 3. Filipits M, et al. Clin Cancer Res. 2007;13:3892-3898. 4. Tsao MS, et al. J Clin Oncol. 2007;25: 5240-5247. 5. Seve P, et al. Clin Cancer Res. 2007;13:994-999, Annals Onc 2012. 6. Cappuzzo F, et al. J Clin Oncol. 2009;27:1667-1674. 7. Rosell R, et al. PLoS One. 2007;2:e1129.

  18. TASTE -Adjuvant Trial IFCT0704: Non Squamous Stage II and IIIA ARM A (Control) CDDP pemetrexed EGFRmutated Erlotinib ARM B (Experimental) customized ERCC1+ Observation EGFR wt CDDP-Pemetrexed ERCC1-

  19. TASTE: biomarker distribution Biomarker distribution Expected Observed • Study was stopped at 150 patients due to ERCC1 IHC which behavior during TASTE trial was significantly different from the one observed in IALT-bio analysis1 • Phase III did not proceed due to the unexpected lack of reliability of ERCC1 IHC 2 • ERCC1 IHC is unable to distinguish the different isoforms. Only isoform 2 is active in DNA repair. (Friboulet NEJM 2013) EGFRmutated 10% 9% ARM B (Experimental) customized 44% 25% ERCC1+ EGFR WT or UND ERCC1- or UND 56% 75% 2Soria JC ASCO 2013 Abst# 7507) 1Olaussen K et al. NEJM 2006

  20. Massuti B Spain MOo8.01 First analysis of toxicity and treament compliance in customized postoperative chemotherapy based on BRCA1 levels after NSCLC resection: SCAT (Spanish Customized Adjuvant Therapy) trial. Spanish Lung Cancer Group/GECP Bartomeu Massuti1, Manuel Cobo2, Manuel Rodriguez-Paniagua1, Isabel Ballesteros3, Teresa Moran4, Ricardo Arrabal2, Jose Luis Gonzalez Larriba5, Isidoro Barneto6, Yat Wah Pun3, Javier de. Castro Carpeño7, Lara Iglesias8, Carlos Baamonde6, Miguel Angel Muñoz9, Guillermo Lopez-Vivanco10, JJ Rivas de Andres11, Dolores Isla12, Rafael Lopez13, Ramon De Las Peñas14, Delvis Rodriguez15, Pedro Lopez De Castro16, Angel Artal17, Emilio Esteban Gonzalez18, Florentino Hernando Trancho19, Mariano Provencio20, J Valdivia21, Prudencio Diaz Agero7, Jose Luis Martin De Nicolas8, Eva Pereira22, Jose Miguel Sanchez23, Rafael Rosell16; 1Alicante University Hospital, Alicante/SPAIN, 2Hospital Carlos Haya, Malaga/SPAIN, 3Hospital La Princesa, Madrid/SPAIN, 4Catalan Institute of Oncology, Badalona/SPAIN, 5Hospital Clínico San Carlos, Madrid/SPAIN, 6Hospital Reina Sofia, Cordoba/SPAIN, 7Hospital Universitario La Paz, Madrid/SPAIN, 8Hospital 12 de Octubre, Madrid/SPAIN, 9Instituto Valenciano Oncología, Valencia/SPAIN, 10Hospital de Cruces de Barakaldo, Vizcaya/SPAIN, 11Hospital Miguel Servet, Zaragoza/SPAIN, 12Hospital Lozano Blesa, Zaragoza/SPAIN, 13Hospital Clinico Universitario de Santiago de Compostela, Santiago De Compostela/SPAIN, 14Hospital Provincial de Castellón, Castellón/SPAIN, 15Hospital Universitario Insular de Gran Canaria, Las Palmas De Gran Canaria/SPAIN, 16Hospital Germans Trias i Pujol, Badalona/SPAIN, 17Hospital Universitario Miguel Servet, Zaragoza/SPAIN, 18Hospital Universitario Central de Asturias, Oviedo/SPAIN, 19Hospital Clinico San Carlos, Madrid/SPAIN, 20Hospital Puerta de Hierro, Madrid/SPAIN, 21Hospital Virgen de las Nieves, Granada/SPAIN, 22Grupo Español de Cancer de Pulmon (GECP), Barcelona/SPAIN, 23MD Anderson Cancer Center, Madrid/SPAIN

  21. Resected NSCLC pN1 / pN2 Customized BRCA1 Adjuvant Treatment in Stage II-II NSCLC (SCAT) Massuti B Spain MOo8.01 Docetaxel/Cis CONTROL 1 : 3 Gem/Cis Q 1 BRCA1 Q 2 & 3 BRCA1 EXPERIMENTAL Docetaxel/Cis Statification factors: - Stage: N1 vs. N2 - Age <65 vs > 65 y - Histology: Non-SCC vs. SCC - Type of resection: Lobectomy vs Pneumonectomy Docetaxel Q 4 BRCA1 Planned number of patients: 432 (ammended) CT should start until 8 weeks after surgery PORT in N2 patients Eudract: 2007-000067-15NCTgov: 00478699

  22. SCAT: BRCA1 expression Massuti B Spain MOo8.01 • Median mRNA BRCA1 levels: 15.78 (0.73-132) • Quartiles distribution: • Q1: 212 (42.4%) • Q2-3: 150 (30%) • Q4: 138 (27.6%) • Mean BRCA1: • Adenocarcinoma: 6.95 vs Squamous 20.29 (p<0.001) • EGFR mut: 5.6% (incomplete data)

  23. SCAT trial Le Chevalier T, France MO08.06

  24. ITACA Adjuvant Trial Pharmacogenomics: Yes or No? Standard Chemotherapy N= 700 R HIGH ERCC1 & HIGH TS Radically Resected II-IIIA No prior Chemotherapy or Radiation Therapy prior surgery Docetaxel Standard Chemotherapy ERCC1 and TS Assessment by RT-PCR R HIGH ERCC1 & LOW TS Pemetrexed Standard Chemotherapy Stratification Factors Pathological stage (II vs. III) Smoking status (current vs. former vs. never smoker) R LOW ERCC1 & HIGH TS Cisplatin/Gemcitabine Standard Chemotherapy R LOW ERCC1 & LOW TS Cispplatin/Pemetrexed

  25. Strategies to selectDrugs for use with surgery in Early Stage LungCancer • Gene expressionprofiles (microarrays) • Repair/Metabolismgenotype • Immunotherapy • Moleculardrivenmutation • New targets • Assessradiographicresponse in induction “window of opportunity”

  26. MAGE-A3 as Adjuvant Non-Small Cell LunGCanceRImmunoTherapy Phase III Study in NSCLC: MAGRIT Resected MAGE-A3 (+) NSCLC N= 2300 Pathological stage IB, II, IIIA No chemo Chemo Up to 4 cycles of platinum-based chemo Randomization Randomization MAGE-A3 ASCI Placebo Powered for efficacy MAGE-A3 ASCI Placebo Powered for efficacy - 27 - 2014 ASCO results awaited 2011 accrual completed

  27. Strategies to selectDrugs for use with surgery in Early Stage LungCancer • Gene expressionprofiles (microarrays) • Repair/Metabolismgenotype • Immunotherapy • Moleculardrivenmutation • New targets • Assessradiographicresponse in induction “window of opportunity”

  28. Adjuvant Gefitinib: JBR.19 Unselected for EGFR mut+ Gefitinib 250 mg po q day x 2 years N = 503 All patients • Path stage IB - III NSCLC • Complete surgical resection • PS 0-2 • Adjuvant chemo and /or XRT • allowed EGFR Mutated R Placebo PO q day x 2 years Goss GD, et al. J Clin Oncol 2013; 31: 3320-26

  29. Adjuvant Therapy: Erlotinib Unselected for EGFR mut+ RADIANT N = 945 Erlotinib Stage IB-IIIA CTX4/ No CT Surgery R* Placebo * Selection FISH + and/or IHC+ Primary endpoint: Disease Free Survival

  30. EGFR mutation in early stage LungCancer: Rationale Mark G Kris, USA, PC02.4 • All stages need more cure • Eradicating metastases the goal • EGFR as target • Results in patients with early stages • Trials in progress • Seizing the opportunities

  31. AdjuvantImatinib in GIST1 year vs 3 Years Joensuu H et al JAMA. 2012;307(12):1265-1272. doi:10.1001/jama.2012.347

  32. SELECT Trial EGFR mutation positive Surgically resected Stage I-IIIA NSCLC < 6-9 months following adjuvant chemo ± XRT Initial 36, expanded to 100 A multicenter phase II trial of adjuvant erlotinib in 100 EGFR-mutant lung cancer ERLOTINIB 150 mg/daily, 2 years total Scan every 6 months for 3 years, annually yr 4-5 Primary End point : Disease Free Survival Neil JW et al. J. Clin. Oncol. 2012;30 (abstr.7010)

  33. SELECT: Adjuvant Erlotinib Patients surgically reected stage I-IIIA harboring activating EGFR mutations Neil JW et al. J. Clin. Oncol. 2012;30 (abstr.7010)

  34. Furtherhurdlestobeconsideredwithmolecularalterations….. • Is the alteration equally present in early disease? • Is the molecular alteration stable overtime? • Is the targeted treatment equally effective as adjuvant (maintenance) treatment or should be reserved at relapse? • Are long term toxicities tolerable?

  35. Mark G Kris, USA, PC02.4 TTP and OS from start of TKI retreatment, in patients who develop a recurrence of EGFR-mutant lung cancer after stopping adjuvant TKI. A portion of patients gain durable disease control on TKI despite prior adjuvant exposure. Oxnard G R et al. Clin Cancer Res 2011;17:6322-6328

  36. EURECAErlotinib UsedasAdjuvant Therapy in Resected EGFR mutantLungCarcinoma Mark G Kris, USA, PC02.4 • Resected stage I-III EGFR-mutation positive lungcancer with activating EGFR mutation(exon 19 deletion, L858R, L861Q, G719X) • Perioperativecitotoxycchemotherapy and radiation therapy asindicated • Stratified by staging and perioperativechemotherapy • N=286 Adjuvant erlotinib up to 24 months with CT chest every 6 months than yearly N=190 • CT scan at 30 months • Follow patients for recurrence or death • Patients with recurrence will be biopsed to confirm recurrence and test for molecular determination of acquired resistance • Record of subsequent chemotherapies CT chest every 6 months than yearly N=96 Lung Cancer Mutation Consortium PI Cristopher Azzoli

  37. AdjuvantAfatinib: 3 months vs 2 years Mark G Kris, USA, PC02.4 Baseline CT need R A N D O M I Z E Afatinib oraldaily x 3 months Resected stage I-III EGFR+ lungcancer s/p completion of standard adjuvantchemotherapy +/- RT CT Chest every 6 months x 3 years and then annualy RFSat 5 years Afatinib oraldaily x 2 years 92 patientswill be stratified for pathological stage (I,II,III) powered to detect a recurrence free survivalimprovement of 20% Adjuvant Afatinib PI Lecia Sequist

  38. ALCHEMIST (Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing Trial) Alliance PI: Govindan R. • CLIA-approved LAB • EGFR mutation test • ALK rearrangement • SOP-driven FF/FFPE • After resection, buffy coat Pre-op Cohort E4512: Crizotinib Consent & Register: A151216 Screening & Follow-up Protocol ECOG 4512 PI: Ramalingam S. Post-op Cohort • Assess FFPE • buffy coat • TCGA • Genomic sequencing • Transciptome • Methylation Other Adjuvant Studies

  39. ALCHEMIST (Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing Trial) N = 410 A151216 Registry Study Screening and Follow up protocol N= 6000 -8000 Erlotinib A081105 R* Placebo Actionable target and trial identified E4512 N= 360 Primary Endpoint: OS

  40. Kelly K USA EO3.4 Adjuvant Therapy: Molecular Selection

  41. Strategies to selectDrugs for use with surgery in Early Stage LungCancer • Gene expressionprofiles (microarrays) • Repair/Metabolismgenotype • Immunotherapy • Moleculardrivenmutation • New targets • Assessradiographicresponse in induction “window of opportunity”

  42. WCLC 2013: what’s new Besse B, France MO08.02

  43. IFCT-0703: phase II studyresults Besse B, France MO08.02

  44. Adjuvant Therapy Timeline adapted BLT HR = 1.02 N=381 RADIANT JBR.10 HR = .69 N=482 ANITA HR = .76 N=840 IALT HR = .86 N=467 MAGRIT ~6 2003 2004 2005 2006 2008 2013 2014 ITACA E1505 Closed to Accrual CALGB 9633 HR = .83 N=344 ALPI HR = .96 N=1207 CALGB 30506 ALCHEMIST ? CTONG1104 ALPI–MVP vs OBS Stage I-IIIA Scagliotti GV et al. J Natl Cancer Inst 2003; 95: 1453-61 BLT-CPPP-based vs OBS Stage I-III Waller D et al. Eur J CardiothorcicSurg 2004;26:173-182 IALT–CDDP-based vs OBS Stage I-IIIAArriagada R et al. N Engl J Med 2004; 350: 350-61 JBR.10–CDDP-VNRvs OBS Stage IB-II Winton T et al. N Engl J Med 2005; 352:2589-97 ANITA–CDDP-VNRvs OBS Stage IB-IIIADouillandJY et al. Lancet Oncol 2006; 7: 719-27 CALGB 9633–PAC-CARBOvs OBS Stage IB Strauss GM et al. J ClinOncol 2008; 26: 5043-51 Afatinib Adjuv Knowledge Gaps EURECA

  45. <65 >70 No treatment interaction Elderly patients should receive adjuvant chemotherapy Fruh M, et al. J Clin Oncol 2008; 26:3573-81

  46. Adjuvant Chemotherapy – Optimal Regimen Phase II Cis/Pemetrexed vs. Cis/Vinorelbine (TREAT) p =.001; p<.0001 Kueter M et al. Ann Oncol 24: 986-992;2012

  47. Adjuvant Chemotherapy – Optimal Regimen Most extensively studied regimen is Vinorelbine and Cisplatin LACE meta-analysis showed a benefit of VNR/CDDP over “other” CDDP regimens Cisplatin – based Chemotherapy E1505 R A N D O M I Z E pStage IB-IIIA IB > 4 cm Cisplatin – based Chemotherapy Bevacizumab: 15 mg/kg Primary endpoint: Overall Survival Wakelee ASCO 2012, Abstr 7013

  48. Lymphovascular Invasion in Stage I Variables HR 95% CI P-value Variables HR 95% CI P-value N = 433 patients (1995-2010; 7th edition TNM staging) Yanagawa N et al European J Cardio-Thoracic Surgery 44:e200-e206, 2013

  49. Induction (Neoadjuvant) vs AdjuvantFactorsFavoringInductionChemotherapy • Attacks micrometastasesatearliest time • Betterdrug delivery and tolerability • Ability to assesssensitivity of agents used in induction and planned for adjuvant • Platform for new agent testing • Surgicalfindings an outcome surrogate • Time to identifyunsuspectedmetastases and comorbiditiesbeforelocal therapy • Randomized trials equivalent or better • Providequickanswers

  50. Chaft JE, USA O02.05 Major pathologic response (≤10% viable tumor) following neoadjuvant chemotherapy as a surrogate for overall survival in patients with pathologically documented stage IIIA (N2) lung adenocarcinomas Jamie E. Chaft1, Matthew D. Hellmann1, William D. Travis2, Valerie Rusch3, Mark G. Kris1 Memorial Sloan-Kettering Departments of 1Medicine, 2Pathology, 3Surgery

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