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The presenter and authors declare no relevant disclosures for this trial

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.

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The presenter and authors declare no relevant disclosures for this trial

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  1. Firstanalysis of toxicity and treamentcompliance in customizedpostoperativechemotherapybasedon BRCA1 levelsafter NSCLC resection: SCAT (SpanishCustomizedAdjuvantTherapy) trial. SpanishLungCancerGroup/GECP Bartomeu Massuti1, Manuel Cobo2, Manuel Rodriguez-Paniagua1, Isabel Ballesteros3, Teresa Moran4, Ricardo Arrabal2, Jose Luis Gonzalez Larriba5, Isidoro Barneto6, YatWah 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 Instituteof 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 GermansTrias 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

  2. Thepresenter and authors declare no relevantdisclosuresforthis trial

  3. Rationale • Postop platinum-based CT improves outcomes in completely resected NSCLC with nodal involvement, (St II-IIIA). • Standard adjuvant chemotherapy is still insufficient to provide optimal survival • Overall NNT around 15 if N+ • Better risk selection or customized selected therapy needs to be explored • Customization is feasible in adjuvant setting (tissue availability) • Analysisof expression in genes involved in DNA repaircouldhelpustoindividualizetheoptimalchemotherapycombination • BRCA1 plays an important role in DNA repair pathways and functions as a differential regulator of response to cisplatin and antimicrotubule agents • BRCA1 expression level could acts as a differential modulator of CT. In advanced disease p with low BRCA1 benefit from Cisplatin-doublets meanwhile p with high levels BRCA1 attained longer survival when were treated with taxanes (Rosell et al 2008). • Complianceis a keyissue in adjuvantsetting.

  4. high risk cisplatin-sensitive tumors cisplatin-based chemotherapy High levels cisplatin-resistant tumors taxane-based chemotherapy low risk Customizing chemotherapy BRCA1 as a prognostic and predictive marker Low levels BRCA1 Hypothesis: significant proportion of high-risk patients are cisplatin-resistant Modified from Fig S5 (Rosell et al. PLoS ONE. Nov 2007)

  5. SCAT: Endpoints • Primary end-point: • Overall survival • Secondary end-points: • Disease free survival • Toxicity profiles: NCI-CTCAE v 3.0 • Recurrence pattern

  6. Customized BRCA1 Adjuvant Treatment in Stage II-II NSCLC (SCAT) Resected NSCLC pN1 / pN2 Docetaxel/Cis CONTROL 1 : 3 Gem/Cis Q 1 BRCA1 Q 2 & 3 BRCA1 EXPERIMENTAL Docetaxel/Cis Statificationfactors: - 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

  7. Patient´sflow-chart 1st inclusion: June/07 LastinclusionMay/13 Median f-u: 21.3 m (2-65 months)

  8. Treatmentflow chart

  9. Patientscharacteristics (n = 500)

  10. SCAT: BRCA1 expression • Median mRNA BRCA1 levels: 15.78 (0.73-132) • Quartilesdistribution: • 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)

  11. SCAT: Compliance and toxicityanalysis • Sample: 297 patients evaluable forcompliance of plannedadjuvanttreatment • Grade 3-4 toxicities: • Neutropenicfever: • Cis-Doc 10% vs Doc 4.4% vs Cis-Gem 0% (p=0.056) • Nausea/vómits: • Cis-Gem 11.1% vs Cis-Doc 10.4% vs Doc 0% (p=0.0198) • Hypersensitivity: • Doc 5.97% (NS)

  12. Dosecompliance • Dose-reductions: (p=0.0044) • Control arm 34.24% vs Experimental 18.30% • Full 4 cyclesdelivery: (p=0.052) • Cis-Doc control: 80.83% • Cis-Docexper: 79.2% • Cis-Gemexper: 91.2% • Docexper: 88.1% • CT Complianceaccordingextent of surgery: • Lobectomy 86.4% vs Pneumonectomy 85.5% (NS) • CT complianceaccordingage: • < 70 y 91.1% vs > 70 y 66.6% (p<0.01) • PORT compliance (pN2): 55.31% planned cases

  13. Conclusions • Planned trial recruitmentachievedwith median f-u 21.3 m • Pharmacogenomic customization is feasible in adjuvant setting due to tissue availability and timelines after surgery. • Majorityof resected NSCLC showedlowlevelsexpressionBRCA1 • Adenocarcinoma lowerlevelsthanSquamous • Safety profilesdifferencesobservedbetweentreatmentschedules: neutropenicfever (CD), nausea/vomits (CG) • Customizedtreatmentachieveshighercompliance and requireslessdose-reductions. • TrendtopoorcompliancewithCis-Doc • No relationbetweenextensión of surgery and adjuvantTxcompliance • Compliance CT significantlylowerforage > 70 y • LowcomplianceforPORT • Efficacyresultsawaited

  14. Acknowledgements • Toallpatients and relatives • To JJ Sánchez and M. Sánchez-Ronco forstatisticalanalysis • To SLCG Management Office (Eva Pereira, María Fernández) • To central labteamlocated in ICO Badalona (M. Taron) • Toallparticipating centers of theSpanishLungCancerGroup (47 centers) • Toallinvestigators,co-investigators, research nurses and data managers and local clinicalresearchteams • To Sanofi-Aventis foreconomicsupport

  15. Backupslides

  16. Complianceadjuvanttherapy in NSCLC

  17. Pilot SCAT: Time toRelapse Median Time toRelapse: 22.99 months (13.46-32.52) D D/Cis G/Cis 83 patients: 49 relapsed (59%) Median follow-up forthewholegroup: 43.88 months(1.6-71.4) Median follow-up forpatientsalive: 63 months(21.9-72)

  18. Pilot SCAT: OverallSurvival Median overallsurvival: 63.62 months (54.22-73.02) D D/Cis Patientsalive: 41/83 (49%) G/Cis

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