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2007 A.S.C.O. Annual Meeting Chicago (USA), June 1-5

2007 A.S.C.O. Annual Meeting Chicago (USA), June 1-5. Updated results, multivariate and subgroups analysis confirm improved activity and efficacy for FOLFOXIRI vs FOLFIRI in the G.O.N.O. randomized phase III study in metastatic colorectal cancer.

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2007 A.S.C.O. Annual Meeting Chicago (USA), June 1-5

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  1. 2007 A.S.C.O. Annual Meeting Chicago (USA), June 1-5 Updated results, multivariate and subgroups analysis confirm improved activity and efficacy for FOLFOXIRI vs FOLFIRI in the G.O.N.O. randomized phase III study in metastatic colorectal cancer. A. Falcone1,3, M. Andreuccetti1, I. Brunetti2, S. Ricci2, C. Barbara1, W. Evangelista4, V. Passeri5, S. Chiara6, G. Allegrini1, G. Masi1 1 U.O. Oncologia Medica, Azienda USL-6, Livorno; 2 U.O. Oncologia Medica, Ospedale S. Chiara, Pisa; 3 Università degli Studi di Pisa, 4 Centro Oncologico ed Ematologico Subalpino, Ospedale S. Giovanni Battista Le Molinette, Torino, 5 Dipartimento di Medicina Sperimentale e Patologia, Oncologia Medica, Università la Sapienza, Roma, 6 Istituto Nazionale per la Ricerca sul Cancro, Genova ITALY

  2. ABSTRACT Background: As previously reported (ASCO 2006) the G.O.N.O. conduced a phase III study comparing FOLFIRI to FOLFOXIRI in 244 patients (pts) with not resectable MCRC. At a median follow-up of 18.4 months (mos) we reported significant improvements in response-rate (RR), R0 resection of metastases (mts), PFS and OS for FOLFOXIRI. Methods: Results have been updated (median follow-up of 36.2 mos) and 14 variables were tested as possible prognostic factors for response, R0 resection, PFS and OS. Results: At this updated analysis 225 (111 vs 114) pts have progressed and 180 (84 vs 96) have died. Results confirm the significant improvements for FOLFOXIRI in terms of confirmed RR (60% vs 34% p<0.001), R0 resection of residual mts (15% vs 6% p=0.033 and 36% vs 12% p=0.017 for pts with liver only mts), PFS (median 9.8 vs 6.9 mos p<0.001) and OS (median 23.6 vs 16.7 mos p=0.042) at the cost of a modest and acceptable increase in toxicity. In the logistic regression multivariate analysis treatment with FOLFOXIRI was the only independent predictive factor for response (HR:2.9, p<0.001) and for achieving an R0 surgical resection of mts (HR:3.1, p=0.018). The Cox’s multivariate analysis demonstrates that independent prognostic factors for improved time to progression were treatment with FOLFOXIRI (HR:0.64, p<0.001), and ECOG PS = 0 (HR:0.73, p=0.02) and for time to death were treatment with FOLFOXIRI (HR:0.74, p=0.04) and liver involvement < 25% (HR:0.57, p=0.006). The benefits of FOLFOXIRI was consistent across all subgroups, including those with unfavorable prognosis such as pts with time from diagnosis to randomization < 3 mos, multiple site of disease or liver involvement > 25%. Conclusions: FOLFOXIRI confirms to be the first combination demonstrated to be superior to an infusional 5FU containing doublet as FOLFIRI in terms of RR, R0 resections, PFS and OS. FOLFOXIRI represents a new treatment option in MCRC and its use and study is of particular interest in a neoadjuvant strategy, in pts with few chances to achieve a three-drug exposure in a sequential strategy and in combination with targeted agents. Partially supported by Fondazione ARCO.

  3. RATIONALE FOLFOXIRI RATIONALE • Preclinical synergism between CPT-11, LOHP and 5FU and different dose-limiting toxicities (Fischel, BJC 2001) • FOLFOXIRI can expose 100% of pts to all the 3 active agents (CPT-11, LOHP and 5-FU) while in a sequential strategy 25-50% of pts does not receive II line CT and therefore is not exposed to all the 3 agents (Grothey, JCO 2004) • FOLFOXIRI, if more active, may improve post-CT resection-rate of mts (Folprecht, Ann Oncol 2005) STUDY RATIONALE • FOLFIRI was a reference standard combination in MCRC (Douillard, Lancet 2000) • FOLFOXIRI was a feasible regimen with manageable toxicities and promising activity in phase I-II studies (Falcone JCO 2002; Masi Ann Onc 2004)

  4. STUDY DESIGN FOLFIRI* CPT-11 180 mg/m2 1-h d.1 L-LV 100 mg/m22-h d.1,2 5FU 400 mg/m2 bolus d.1,2 5FU 600 mg/m2 22-h d.1,2 q. 2 wks x 12 cycles R A N D O M • Stratification • Center • PS 0/1-2 • Adjuvant CT * Douillard Lancet 2000 FOLFOXIRI** CPT-11 165 mg/m2 1-h d.1 LOHP 85 mg/m2 2-h d.1 L-LV 200 mg/m2 2-h d.1 5FU 3200 mg/m2 48-h CI d.1 q. 2 wks x 12 cycles ** Masi Ann Oncol 2004 • In pts progressed after FOLFIRI a second-line CT with an LOHP containing regimen (FOLFOX) was recommended

  5. FOLFOXIRI SCHEDULE Day 1 Day 2 Day 3 CPT-11 165 mg/m2 Oxaliplatin 85 mg/m2 L-LV 200 mg/m2 5FU flat continuous infusion 3200mg/m2 1 hour 2 hours 48 hours Repeated every 14 days

  6. MAIN PATIENTS SELECTION CRITERIA • Metastatic and unresectable colorectal cancer • Measurable disease • Age 18-75 yrs • ECOG PS 0-2 (ECOG PS=0 for pts 71-75 yrs) • Adjuvant CT ended > 6 mos • Adequate renal, hepatic and bone-marrow functions • No previous CPT-11 or LOHP • No previous CT for metastatic disease

  7. PATIENTS CHARACTERISTICS *Accrual from November 2001 to April 2005

  8. NON-HEMATOLOGICAL TOXICITY (NCI) GRADE 3-4 PER PATIENT (N=122) (N=122) p < 0.0001 ** ** Grade 2-3

  9. HEMATOLOGICAL TOXICITY (NCI) GRADE 3-4 PER PATIENT (N=122) (N=122) p =0.0006

  10. RESPONSES (ITT analysis) INVESTIGATORS’ ASSESSMENT *p = 0.0002

  11. RESPONSES (ITT analysis) EXTERNALLY REVIEWED *p < 0.0001

  12. Logistic regression multivariate analysis of predictive factors for Response Variables tested: Treatment, sex, age, PS, primary, N. organs involv., sites of mts,% liver involv., time from diagnosis to mets, previous adjuvant CT, LDH, CEA, WBC, HB

  13. POST-CT SURGICAL RESECTIONS (all patients) * p=0.033

  14. POST-CT SURGICAL RESECTIONS (patients with liver mts only) * p=0.017

  15. Logistic regression multivariate analysis of predictive factors for secondary R0-Surgery Variables tested: Treatment, Sex, age, PS, primary, N. organs involv., Sites of mts,% liver involv., Time from diagnosis to mets, previous adjuvant CT, LDH, CEA, WBC, HB

  16. PROGRESSION FREE SURVIVAL

  17. Cox’s multivariate analysis of prognostic factors for Progression Free Survival Variables tested: Treatment, sex, age, PS, primary, N. organs involv., sites of mts,% liver involv., time from diagnosis to mets, previous adjuvant CT, LDH, CEA, WBC, HB

  18. Hazard ratios for risk of progression in subgroups (1) FOLFIRI FOLFOXIRI

  19. Hazard ratios for risk of progression in subgroups (2) FOLFIRI FOLFOXIRI

  20. SECOND-LINE CHEMOTHERAPY

  21. OVERALL SURVIVAL 19% 13% Median follow up: 36.2 months

  22. Cox’s multivariate analysis of prognostic factors for Survival Variables tested: Treatment, Sex, age, PS, primary, N. organs involv., Sites of mts,% liver involv., Time from diagnosis to mets, previous adjuvant CT, LDH, CEA, WBC, HB

  23. Hazard ratios for risk of OS in subgroups (1) FOLFIRI FOLFOXIRI

  24. Hazard ratios for risk of OS in subgroups (2) FOLFIRI FOLFOXIRI

  25. Survival of pts radically resected after FOLFOXIRI in phasae II and III GONO’s trials Median Survival: 39.0+ months 5-years Survival: 40% N. of pts: 37 N. of events: 18 Median Follow up: 55 months Falcone at al. J Clin Oncol 2002; Masi et al. Ann Oncol 2004; Falcone et al. J Clin Oncol 2007

  26. Survival improves with availability of three active drugs * “GONO” FOLFOXIRI P=0.0001 Grothey A, Sargent D. J Clin Oncol. 2005;23:9441-9442.

  27. CORRELATION BETWEEN TUMOR RESPONSE AND RESECTION RATES Studies incl. selected pts. (liver metastases only, no extrahepat. disease) r=.96, p=.002 “GONO” FOLFOXIRI * Studies incl. all patients with metastatic CRC (solid line) r=.74, p<.001 Phase III studies in metastatic CRC (dashed line) r=.67, p=.024 “GONO” FOLFOXIRI * G Folprecht, A Grothey, S Alberts, HR Raab, and CH Köhne, Ann Oncol 2005

  28. Doublet + 1 biologic or Triplet in phase III studies

  29. CONCLUSIONS • “GONO” FOLFOXIRI is the first studied combination, in a phase III study, that compared to an infusional doublet as FOLFIRI, although at the cost of a modest increase in toxicity, significantly improves ORR, post-CT resection of mts,PFS and OS • “GONO” FOLFOXIRI represents a new first-line option in metastatic colorectal cancer patients with similar characteristics to those included in this study • The study of FOLFOXIRI should be of particular interest in a neoadjuvant strategy, in pts with few chances to achieve a 3 drugs exposure in a sequential strategy and in combination with targeted agents

  30. Gruppo Oncologico Nord Ovest Thank you to all patients and investigators!

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