Tobias Arkenau Infusional 5-FU/FA plus Oxaliplatin (FUFOX) vs. Capecitabine plus Oxaliplatin (CAPOX) as first-line treatment for metastatic colorectal cancer: safety and efficacy analysis from a phase III trial of the German AIO

Rationale for CAPOX in 1st-line ACRC Addition of oxaliplatin to i.v. 5-FU/LV (FOLFOX/FUFOX) significantly improves efficacy Capecitabine provides superior response rates and safety vs. bolus 5-FU/LV In phase II trials, XELOX/CAPOX showed clear antitumor efficacy and good tolerability

Prospective, randomized, multicenter phase III study of CAPOX vs. FUFOX Metastatic CRC, no prior chemotherapy for metastatic CRC, adjuvant treatment > 6 months, Measurable disease (RECIST), Age >18 years; ECOG PS 2 Normal renal, hepatic and hematological parameters Stratification: WBC, Alk. Phos., No. of sites, ECOG PS, Center Randomization (n=476) 08/02 – 08/04 69 German centers

Patient disposition 476 pts randomized 242 CAPOX 234 FUFOX Median # cycles 6 (1–21) 3-week cycles Median # cycles 4 (1–13) 5-week cycles

Treatment schedules CAPOX FUFOX Day 1 8 15 22 29 36 43 Capecitabine 1000 mg/m2 bid CAPOX Oxaliplatin 70 mg/m2 5-FU 2000 mg/m2 FA 500 mg/m2 FUFOX Oxaliplatin 50 mg/m2

Endpoints/statistical design Primary endpoint: progression-free survival (PFS) Secondary endpoints: OS, RR, toxicity, TTF, QOL Statistical design: 440 patients needed to exclude inferiority of 41% vs. 50% PFS rate at 9 months calculating a one-sided 95% CI for the HR (power: 80%) The study was monitored by an external review committee

Baseline characteristics

Most common (20%) treatment-related clinical adverse events (all grades) % of patients CAPOX (n=235) FUFOX (n=229) 100 80 60 40 20 Diarrhea Nausea Vomiting HFS Neurosensory

Most common (>5%) treatment-related grade 3/4 clinical adverse events % of patients CAPOX (n=235) FUFOX (n=229) 50 40 30 20 10 * Diarrhea Nausea Vomiting Mucositis HFS Neurosensory grade 2/3 *p<0.01

Most common treatment-related grade 3/4 hematological adverse events % of patients CAPOX (n=235) FUFOX (n=229) 50 40 30 20 10 Anemia Leukopenia Neutropenia Thrombocytopenia

Efficacy analysis: response rates

Progression-free survival Estimated probability Median CAPOX (n=238) 7.0 months FUFOX (n=230) 8.0 months 1.0 0.8 0.6 0.4 0.2 HR = 1.19 (95% CI: 0.97–1.48) p=0.11 (Log-rank) 0 20 40 60 80 100 120 140 Weeks

PFS: multivariate analysis (n=474) Hazard ratio (95% CI) CAPOX 1.16 (0.94–1.44) p=0.17 ECOG 2 1.73 (1.15–2.59) p=0.009 Metastatic sites >1 1.36 (1.10–1.70) p=0.006 Leukocytes >8000/µL 1.33 (1.06–1.66) p=0.012 Alk. Phos. >300 U/I 1.40 (1.02–1.91) p=0.038

HR = 1.05 (95% CI: 0.79–1.41) p=0.72 (Log-rank) Overall survival Estimated probability Median CAPOX (n=238) 16.3 months FUFOX (n=230) 17.2 months 1.0 0.8 0.6 0.4 0.2 HR = 1.05 (95% CI: 0.79–1.41) p=0.72 (Log-rank) 0 20 40 60 80 100 120 140 Weeks

Conclusions Similar safety profile for CAPOX and FUFOX: significantly higher HFS grade 2/3 with CAPOX CAPOX shows no inferiority compared to FUFOX within our statistical assumptions: response rate: 47% vs. 49% median PFS: 7.0 vs. 8.0 months (p=0.11) median OS: 16.3 vs. 17.2 months (p=0.72)

Acknowledgements Thanks to all of the investigators, patients and their families who participated in the study Participating investigators: Aachen (Tummes); Ansbach (Hahn); Aschersleben (Deist); Augsburg (Heinrich); Aurich (Langer); Bad Homburg (Rohwedder); Bad Soden (Seipelt); Berlin (Zuchold, Reichardt, Kretzschmar); Bietigheim-Bissingen (Dietrich); Bochum (Andre, Ansorge, Behringer, Schmiegel); Bonn (Fronshoff, Ko); Bremen (Arkenau, Doering, Porschen); Bremerhaven (Ahlf); Dernbach (Hoffknecht); Dortmund (Hagen); Duisburg (Selbach, Petrasch); Eschweiler (Fuchs); Flensburg (Hartwigsen); Frankfurt (Trojan); Geilenkirchen (Schardt, Zeidler); Goch (Runde); Göttingen (Hilden); Greven (Nischik); Grevenbroich (Prangischvili); Hagen (Lindemann, Zinngrebe); Halle (Arnold, Behrens, Steudel, Schmoll); Hamburg (Lipp); Hannover (Kubicka, Greten); Hildesheim (Freier); Homburg (Lubomierski); Jena (Eigendorff); Karlsruhe (Ebenezer); Koblenz (Hermesdorf); Kronach (Stauch); Leer (Köchling); Leipzig (Abelius); Lemgo (Constantin); Lüneburg (Heinkele); Magdeburg (Kröning); Mainz (Höhler, Möhler); Marburg (Balser); Mönchengladbach (Koch, Graeven); Münster (Bremer, Wehmeyer); Nordhausen (Keppler, Parchim, Hesse); Recklinghausen (Heer); Riedlingen (Pernice); Rinteln (Krause); Rotenburg (Schlichting); Rüsselsheim (Fried-Proell); Saarbrücken (Jacobs, Preiß); Salzburg (Greil, Hausmaninger); Salzwedel (Roth); Siegen (Gaska); Stuttgart (Hiller); Troisdorf (Forstbauer); Ulm (Seufferlein, Hahn, Adler); (Unna, Steinmeister); Vechta (Diers); Velbert (Nusch); Weiden (Weiß); Weißenfels (Bornschein); Werningerode (Wilhelm); Wuppertal (Papavasiliou)