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Efficacy and safety of bevacizumab (BEV)-based combination regimens in patients with metastatic colorectal cancer (mCRC): randomized phase II study of.

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Presentation on theme: "Efficacy and safety of bevacizumab (BEV)-based combination regimens in patients with metastatic colorectal cancer (mCRC): randomized phase II study of."— Presentation transcript:

1 Efficacy and safety of bevacizumab (BEV)-based combination regimens in patients with metastatic colorectal cancer (mCRC): randomized phase II study of BEV + FOLFIRI vs. BEV + XELIRI (FNCLCC ACCORD 13/0503 study) Ducreux M, 1 Adenis A, 2 Mendiboure J, 1 François E, 3 Boucher E, 4 Chauffert B, 5 Ychou M, 6 Pierga J, 7 Montoto-Grillot C, 8 Conroy T 9 1 Institut Gustave Roussy, Villejuif; 2 Centre Oscar Lambret, Lille; 3 Centre Antoine Lacassagne, Nice; 4 Centre Eugène Marquis, Rennes; 5 Centre Georges-François Leclerc, Dijon; 6 Centre Val d'Aurelle, Montpellier; 7 Institut Curie, Paris; 8 FNCLCC, Paris; 9 Centre Alexis Vautrin, Nancy, France

2 Background Bevacizumab (Avastin ® ) is a humanized monoclonal antibody that inhibits vascular endothelial growth factor, a key mediator in angiogenesis. 1–3 In randomized clinical trials in patients with metastatic colorectal cancer (mCRC), bevacizumab improved response rates, overall survival (OS) and progression-free survival (PFS) when combined with standard chemotherapies such as infusional 5- fluorouracil/leucovorin (5-FU/LV) plus irinotecan 4 and 5-FU/LV plus oxaliplatin. 5,6  Capecitabine (Xeloda ® ), an oral fluoropyrimidine, in combination with oxaliplatin has shown similar activity compared with infusional 5-FU/LV plus oxaliplatin with or without bevacizumab. 7,8 However, data on the capecitabine plus irinotecan combination (XELIRI) remain unclear as a result of toxicity issues. 9–11

3 Objective The aim of this randomized non-comparative phase II trial was to evaluate the efficacy and safety of bevacizumab in combination with either XELIRI or an infusional 5-FU/LV plus irinotecan (FOLFIRI) regimen as first-line therapy for mCRC.

4 Methods Study design This was a prospective, randomized, non-comparative phase II study. Patients were eligible for inclusion in this study if they had histologically proven measurable mCRC, were aged 18–75 years, and had an ECOG performance status of 0–2. Treatment Patients received either: – XELIRI: irinotecan 200 mg/m 2 on Day 1 and capecitabine 1000 mg/m 2 bid on Days 1–14 plus bevacizumab 7.5 mg/kg on Day 1, every 3 weeks for a maximum of 8 cycles (Figure 1), or – FOLFIRI: irinotecan 180 mg/m 2 on Day 1 plus 5-FU 400 mg/m 2 + leucovorin 400 mg/m 2 on Day 1 followed by 5-FU 2400 mg/m 2 as a 46-h infusion plus bevacizumab 5 mg/kg on Day 1, every 2 weeks for a maximum of 12 cycles (Figure 1).

5 Figure 1. Study design Patients with histologically proven measurable mCRC Age 18–75 years ECOG performance status 0–2 1 8 15 22 29 36 43 Day Capecitabine 1000 mg/m 2 bid Bevacizumab 7.5 mg/kg iv Eligible for study Irinotecan 200 mg/m² iv XELIRI for 8 cycles 5-FU 400 mg/m 2 /LV 400 mg/m 2 + 5-FU 2400 mg/m 2 46-h ci Bevacizumab 5 mg/kg iv Irinotecan 180 mg/m² iv FOLFIRI for 12 cycles

6 In both treatment arms, bevacizumab alone was continued until disease progression. Patients aged ≥65 years received a lower daily dose of capecitabine (800 mg/m 2 bid). Endpoints The primary endpoint was crude PFS at 6 months. Secondary endpoints included objective response rate (evaluated by Response Evaluation Criteria in Solid Tumors), PFS, OS and safety (evaluated by National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0). Statistical analysis Response and survival rates are reported with 95% confidence intervals

7 Results In total, 145 patients were entered in the study between March 2006 and January 2008; 72 patients received bevacizumab + XELIRI and 73 patients received bevacizumab + FOLFIRI. Patients’ baseline characteristics in the two treatment arms are shown in Table 1. A total of 558 and 835 cycles of bevacizumab + chemotherapy were administered in the XELIRI and FOLFIRI arms, respectively, with 78% and 81% of patients receiving at least the initially planned number of cycles (8 cycles for bevacizumab + XELIRI and 12 for bevacizumab + FOLFIRI). A total of 276 and 231 cycles of bevacizumab alone were administered with a median number of cycles of 4 and 3 in the XELIRI and FOLFIRI arms, respectively.

8 Table 1. Patients’ baseline characteristics Bevacizumab + XELIRI (n=72) Bevacizumab + FOLFIRI (n=73) Median age, years (range) Age >65 years, % 61 (38-74) 35 61 (24-75) 36 Male/female, %64/3648/52 ECOG performance status, % 0–1 2 92 8 90 10 Metastatic sites, % 1  2 46 54 44 56 Tumor type, % Colon Rectum 65 35 79 21 Previous adjuvant chemotherapy, % FOLFOX FOLFIRI Other 22 8 0 14 15 4 0 11

9 Efficacy The 6-month objective response rate was 54% in the XELIRI arm and 59% in the FOLFIRI arm (Table 2). The 6-month “crude PFS rates” were 72% and 80% in the XELIRI- and FOLFIRI-treated patients, respectively. The 12-month PFS were 26% (95% CI: 17-37%) and 17% (86% CI: 10-27%) in the XELIRI and FOLFIRI arm, respectively with a median PFS of 9 months in both arms (Figures 2 and 3). The 18-month OS were 75% (95% CI: 64-84%) and 69% (86% CI: 57-79%) in the XELIRI and FOLFIRI arm, respectively, with a median OS of 23 months in both arms and a global median follow-up of 19 months (Figures 2 and 3).

10 Table 2. 6-month response rates Bevacizumab + XELIRI (n=72) Bevacizumab + FOLFIRI (n=73) n%n% Overall response rate (95% CI) Complete response (CR) Partial response (PR) 39 3 36 54(48–60) 4 50 43 2 41 59(53–65) 3 56 Stable disease (SD)13181521 Progression14191014 Early stopping*6857 * Considered as failure for the 6 months crude PFS rates

11 Figure 2. PFS and OS in mCRC patients receiving bevacizumab + XELIRI (n=72)

12 Figure 3. PFS and OS in mCRC patients receiving bevacizumab + FOLFIRI (n=73)

13 Tolerability All 145 patients were evaluable for safety (bevacizumab + XELIRI n=72; bevacizumab + FOLFIRI n=73). Clinical adverse events were generally similar, acceptable, and manageable in both treatment arms. Overall, 61% of patients in the bevacizumab + XELIRI arm experienced at least 1 grade 3/4 adverse event and 60% of patients in the bevacizumab + FOLFIRI arm (Table 3). 21% of bevacizumab + XELIRI- and 16% of bevacizumab + FOLFIRI-treated patients experienced a bevacizumab specific adverse event. 13% of bevacizumab + XELIRI- and 7% of bevacizumab + FOLFIRI-treated patients discontinued treatment due to toxicity.

14 Table 3. Most frequent clinical and hematological grade 3/4 adverse events Adverse event Bevacizumab + XELIRI (n=72), % Bevacizumab + FOLFIRI (n=73), % Grade 3Grade 4Grade 3Grade 4 Any event of grade 3/45384812 Bevacizumab specific adverse events Veinous thrombosis11130 Hypo/Hyper-tension3080 Embolism1111 CVA1001 Proteinuria1010 Digestive haemorrhage1000 Cutaneous bleeding1000 Perforation0010 Cardiac ischemia0000 Arterial thrombosis0000

15 Table 3. Most frequent clinical and hematological grade 3/4 adverse events Adverse event Bevacizumab + XELIRI (n=72), % Bevacizumab + FOLFIRI (n=73), % Grade 3Grade 4Grade 3Grade 4 Neutropenia153234 Asthenia140110 Diarrhea11150 Vomiting7070 Hand-foot syndrome6010 Nausea3050 Anemia3010 Alopecia1000 Stomatitis1010 Fever1000 Thrombocytopenia 1000

16 Conclusions This randomized, non-comparative study has shown that bevacizumab + XELIRI and bevacizumab + FOLFIRI are active and similarly effective treatment options for patients with mCRC. Both treatment regimens had manageable toxicity profiles. The efficacy and safety findings reported here are similar to those reported with the same regimens in a German study of patients with mCRC. 12

17 References 1.Ferrara N. Am J Physiol Cell Physiol 2001;280:C1358–66. 2.Ferrara N, et al. Nat Med 2003;9:669–76. 3.Jain RK. Nat Med 2001;7:987–9. 4.Hurwitz H, et al. N Engl J Med 2004;350:2335–42. 5.Giantonio BJ, et al. J Clin Oncol 2007;25:1539–44. 6.Saltz L, et al. J Clin Oncol 2008;26:2013–19. 7.Cassidy J, et al. J Clin Oncol 2008;26:2006–12. 8.Fuchs CS, et al. J Clin Oncol 2007;25:4779–86. 9.Kohne CH, et al. Ann Oncol 2008;19:920–6. 10.Grothey A, et al. Proc Am Soc Clin Oncol 2003;22:1022 11.Koopman M, et al. Lancet 2007;370:135–42. 12.Reinacher-Schick A, et al. J Clin Oncol 2008;26(May 20 Suppl):Abst#4030. Presented at the ASCO Annual Meeting, May 29 – June 2, 2009, Orlando, USA.

18 Acknowledgements Patients and Families Co-investigators : David MALKA, Valérie BOIGE, Anne-Laure VILLING, Pierre ZIMMERMANN, Rahmane OUABDESSELAM, Institut Gustave Roussy (VILLEJUIF) ; Bruno COUDERT, Centre Georges François Leclerc (DIJON) ; Philippe FOLLANA, Centre Antoine Lacassagne (NICE) ; Frédérique CVITKOVIC, Fawzia MEFTI, Barbara DIEUMEGARDE, Nicole RENODY, Centre René Huguenin (SAINT-CLOUD) ; Sophie DOMINGUEZ, Armelle CATY, Hélène DELMARRE, Fabienne PICHON, Centre Oscar Lambret (LILLE) ; Pierre SENESSE, Emmanuelle SAMALIN, Eric ASSENAT, Centre Val d'Aurelle (MONTPELLIER) ; Lionel UWER, Marie-Christine KAMINSKY, Centre Alexis Vautrin, ‘VANDOEUVRE-LES-NANCY) ; Frédéric VIRET, Marc GIOVANNINI, Patrice VIENS, Carole TARPIN, Delphine TOPART, Anne MADROSZUK, Gwénaëlle GRAVIS, Anthony GONCALVES, François BERTUCCI Institut Paoli Calmettes, (MARSEILLE) ; Jean-Yves PIERGA, Véronique GIRRE, Stéphanie HENRY, Sophie PIPERNO-NEUMANN, Institut Curie, (PARIS) ; Marie-Pierre GALAIS, J. Henri JACOB, Jean- Michel OLLIVIER, Jean-Marc GUILLOIT, Centre François Baclesse (CAEN) ; Sylvain MANFREDI, Jean-Luc RAOUL, Florence TRIVIN, Centre Eugène Marquis (RENNES) ; Charles-Briac LEVACHE, Laurent CANY, Polyclinique de Francheville (PERIGUEUX) ; Pierre GUICHARD, Polyclinique des 4 pavillons (LORMONT) ; Claire GARNIER, Cécile LEYRONNAS, David COEFFIC, Institut Privé de cancérologie (GRENOBLE) ; Sarah TAIEB, Patrice EUVRARD, Eric LEPRINCE Polyclinique des minguettes (VENISSIEUX) – FRANCE. Sponsor : J. Genève, M. Torres-Macque, S. Levêque, F. Nait-Atmane, AC. Le Gall (FNCLCC, BECT, Paris). Data center : JP. Pignon, M. Abbas (IGR, Villejuif) Grants from Roche and Pfizer and Chugai

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