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Comparison of chemoradiotherapy (CRT) and chemotherapy (CT) in patients with a locally advanced pancreatic cancer (LAPC) controlled after 4 months of gemcitabine with or without erlotinib : Final results of the international phase III LAP 07 study

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  1. Comparison of chemoradiotherapy (CRT) and chemotherapy (CT) in patients with a locally advanced pancreatic cancer (LAPC) controlled after 4 months of gemcitabine with or without erlotinib : • Final results of the international phase III LAP 07 study • Pascal Hammel*, Florence Huguet, Jean-Luc van Laethem, David Goldstein, Bengt Glimelius, Pascal Artru, Ivan Borbath, Olivier Bouché, Jenny Shannon, Thierry André, Laurent Mineur, Benoist Chibaudel, Franck Bonnetain, and Christophe Louvet • *Hopital Beaujon (APHP), Clichy & Faculty Denis Diderot, Paris VII, France • France, Belgium, Australia, Sweden

  2. Background • Locally advanced pancreatic cancer (LAPC) is a non-metastatic, but non-resectable cancer due to involvement of a major arterial axis (superior mesenteric artery, celiac trunk) • Overall median survival (9-12 months) higher than in metastatic form • Treatment of LAPC is a matter of debate, particularly the role of chemoradiotherapy (CRT)

  3. Frontline CRT versus chemotherapy in LAPC Gem ChemoRT Loehrer P et al, J Clin Oncol 2011 Chauffert B et al, Ann Oncol 2008

  4. Induction CT followed by CRT in LAPC CRT after 2.5-3 months of chemotherapy  Huguet F et al, J Clin Oncol 2007 Krishnan S et al, Cancer 2007 Induction chemotherapy : promising option

  5. Objectives of the study • Primary objective: to assess whether administering CRT increases overall survival in patients whose tumor is controlled after 4 months induction chemotherapy • Secondary objectives: • - Role of erlotinib • - Impact of radiation therapy quality assessment (RTQA) • - Tolerance • - Predictive molecular markers, CTC (1) (1) Clément-Bidard F et al, Ann Oncol 2013

  6. Design of LAP07 study Cape RT Random 1 Random 2 EVALUATION : non progressive EVALUATION : non progressive EVALUATION EVALUATION EVALUATION Until Progression Cape RT 1 month = Gemcitabine 1000 mg/m2/wk x 3 Erlotinib with gem : 100 mg/d 150 mg/d as single agent (maintenance) Secondary surgery allowed at any time Cape Capecitabine 1600 mg/m2/d plus radiation therapy 54 Gy (5 x 1.8 Gy/d) RT

  7. Statistics • Primary objective : • 722 patients (392 events, deaths) required to demonstrate a median OS increase from 9 to 12 months in the CRT arm (HR 0.75, 2-sides a = 5%, b = 20%, taking into account 30% of progression before Random 2 and 5% of patients lost to follow-up) • Intermediate analysis planned 21 months after the first patient randomized (projected accrual 420 patients and/or 196 events) using spending function and O’Brien Flemming boundaries (to reject H0 or H1) • Kaplan-Meier, log rank and univariate Cox tests used

  8. Main eligibility criteria . Histologically proven adenocarcinoma . De novo LAPC (stage III, according to UICC 2002) . Measurable or evaluable disease . No prior abdominal radiotherapy or chemotherapy . Performance status WHO 0-2 . Adequate biological tests (blood, liver and renal)

  9. Interim analyses - IDMC 1st advice January 2012: 1st planned interim analysis (22 months, 442 patients included, 125 events) Number of included patients could be sufficient to conclude (superiority or futility), but data not mature enough Inclusion of additional patients will not be informative for the study and would increase the time of enrollment and delay the final results Need to continue to perform Random 2 for the included patients

  10. IDMC - 2nd advice • March 2013: • 269 patients reached Random 2 • 221 deaths, median follow-up 36 months • This second analysis showed that it could be the final one for the primary objective of the study

  11. Flow Chart Assessed for eligibility (n= 449) Excluded (n= 7) 1st Randomization Intent-to-treat principle (n= 442) Excluded (n= 173, 39%) Progressive disease 114 Toxicity 16 Delay 14 Patients' decision 11 Investigators’ decision 11 Intercurrent disease 4 Surgery 3 Gemcitabine (n= 223) Gemcitabine + erlotinib (n= 219) 2nd Randomization Intent-to-treat principle (n= 269, 61%) Chemotherapy (n= 136) Chemoradiotherapy (n= 133)

  12. Patients characteristics, Random 1

  13. Overall survival by Random 2 status

  14. Random 2, interim analyses Futility (no chance to demonstrate a significant difference between the two arms)

  15. PFS by Random 2 status

  16. Tolerance, Random 2 Toxic death 0 1 (not related to RT)

  17. Radiation Therapy Quality Assessment • RT guidelines defined from international consensus1 • Before including, each participating centre had to validate a Dummy Run to ensure that the guidelines have been understood and accepted • Using the prospectively defined guidelines, each patient treatment graded as per protocol (PP), minor deviation (MID), or major deviation (MAD) Among the 133 patients treated in the CRT arm : - PP = 37 (31.6%) - MID = 59 (50.4%) - MAD = 21 (18%) - non evaluable / non treated= 4/12 1 Huguet F et al. Int J Radiat Oncol Biol Phys 2012

  18. Radiation Therapy Quality Assessment • Deviations of planned schedule: did not have significantly influenced unfavorably the outcome of patients • Data of Quality Control and radiation therapy will be presented at the ASTRO meeting 2013

  19. Overall Survival by Random 1 status

  20. PFS by Random 1 status

  21. Tolerance (Random 1)

  22. Overall survival combining Random 1 & Random 2 status Interaction test P = 0.871, ns

  23. Conclusions (1) • Lack of superiority of CRT vs continuing chemotherapy in LAPC patients with tumor controlled after 4 months of chemotherapy • Good tolerance in the CRT arm with this schema • Erlotinib: not beneficialin LAPC, increased the toxicity • Encouraging OS: 15.2 to 16.4 months in patients achieving Random 2

  24. Conclusions (2) • In LAPC, standard of care should remain chemotherapy, CRT being an option after tumor control by chemotherapy • Further analyses of LAP 07 results are ongoing, with the aim to identify a subgroup of patients who could benefit from CRT • Other schemas of radiotherapy and/or chemotherapy (i.e., FOLFIRINOX, nab-paclitaxel) should be tested in LAPC

  25. Acknowledgements . Patients and their families . All professionals of medical teams . All data managers and CRAs . GERCOR staff : D. Notelet, A. Hadengue, N. Le Scodan and R. Moukoko . Roche

  26. Thanks to all investigators FRANCE S. N’GUYEN R. FAROUX L. WANDER JM. GORNET P. ARTRU F. MORNEX P.ROUGIER C.PLATINI D.LUET J. TAIEB P. MARTIN L.MINEUR A.GONCALVES O.BOULAT N.GOUJON N. BONICHON-LAMICCHANE F. HOHNADEL F. FEIN O. BOUCHE P.TEXEREAU Y. RINALDI F. DESSEIGNE P.MICHEL T. ANDRE BELGIUM J.L VAN LAETHEM M. POLUS J. JANSSENS P. WERGAUWE A. BORBATH J. DECAESTECKER B. NEUVILLE S. LAURENT G.DEMOLIN E. VAN CUTSEM M. DE MAN T. DELAUNOIT M. PEETERS E. MONSAERT SWEDEN B. GLIMELIUS G. NAUCLER P. LIND A.JOHNSSON M. ALBERTSSON AUSTRALIA D. GODSTEIN N. TEBUTT R. LYNCH J SHANNON M. BURGE R. YOUNG A. KNEEBONE S. NG G. HRUBY A. HAYDON L. LIPTON NEW ZEALAND M. PEARSE D. HARRIS M.FONCK S. OBLED C.LOCHER P.MAINGON M.YCHOU F. AUDEMAR M. RAMDANI J.L JOUVE L.GILBEAU J.F CODOUL J.L LEGOUX A.L VILLING A. PELAQIUER D.PEZET N. ALBIN T. LECOMTE L. BAUMGAERTNER C. LECAILLE L.BOUHIER M. GASMI A.THIROT-BIDAULT B.ROULLET G. BORDES J.F SEITZ

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