Articles
FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): a randomised, open-label, phase 3 trial Volker Heinemann, Ludwig Fischer von Weikersthal, Thomas Decker, Alexander Kiani, Ursula Vehling-Kaiser, Salah-Eddin Al-Batran, Tobias Heintges, Christian Lerchenmüller, Christoph Kahl, Gernot Seipelt, Frank Kullmann, Martina Stauch, Werner Scheithauer, Jörg Hielscher, Michael Scholz, Sebastian Müller, Hartmut Link, Norbert Niederle, Andreas Rost, Heinz-Gert Höffkes, Markus Moehler, Reinhard U Lindig, Dominik P Modest, Lisa Rossius, Thomas Kirchner, Andreas Jung, Sebastian Stintzing
Summary Background Cetuximab and bevacizumab have both been shown to improve outcomes in patients with metastatic colorectal cancer when added to chemotherapy regimens; however, their comparative effectiveness when partnered with first-line fluorouracil, folinic acid, and irinotecan (FOLFIRI) is unknown. We aimed to compare these agents in patients with KRAS (exon 2) codon 12/13 wild-type metastatic colorectal cancer. Methods In this open-label, randomised, phase 3 trial, we recruited patients aged 18–75 years with stage IV, histologically confirmed colorectal cancer, an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2, an estimated life expectancy of greater than 3 months, and adequate organ function, from centres in Germany and Austria. Patients were centrally randomised by fax (1:1) to FOLFIRI plus cetuximab or FOLFIRI plus bevacizumab (using permuted blocks of randomly varying size), stratified according to ECOG performance status, number of metastatic sites, white blood cell count, and alkaline phosphatase concentration. The primary endpoint was objective response analysed by intention to treat. The study has completed recruitment, but follow-up of participants is ongoing. The trial is registered with ClinicalTrials.gov, number NCT00433927. Findings Between Jan 23, 2007, and Sept 19, 2012, 592 patients with KRAS exon 2 wild-type tumours were randomly assigned and received treatment (297 in the FOLFIRI plus cetuximab group and 295 in the FOLFIRI plus bevacizumab group). 184 (62·0%, 95% CI 56·2–67·5) patients in the cetuximab group achieved an objective response compared with 171 (58·0%, 52·1–63·7) in the bevacizumab group (odds ratio 1·18, 95% CI 0·85–1·64; p=0·18). Median progression-free survival was 10·0 months (95% CI 8·8–10·8) in the cetuximab group and 10·3 months (9·8–11·3) in the bevacizumab group (hazard ratio [HR] 1·06, 95% CI 0·88–1·26; p=0·55); however, median overall survival was 28·7 months (95% CI 24·0–36·6) in the cetuximab group compared with 25·0 months (22·7–27·6) in the bevacizumab group (HR 0·77, 95% CI 0·62–0·96; p=0·017). Safety profiles were consistent with the known sideeffects of the study drugs. The most common grade 3 or worse adverse events in both treatment groups were haematotoxicity (73 [25%] of 297 patients in the cetuximab group vs 62 [21%] of 295 patients in the bevacizumab group), skin reactions (77 [26%] vs six [2%]), and diarrhoea (34 [11%] vs 40 [14%]). Interpretation Although the proportion of patients who achieved an objective response did not significantly differ between the FOLFIRI plus cetuximab and FOLFIRI plus bevacizumab groups, the association with longer overall survival suggests that FOLFIRI plus cetuximab could be the preferred first-line regimen for patients with KRAS exon 2 wild-type metastatic colorectal cancer. Funding Merck KGaA.
Introduction Fluorouracil with folinic acid and irinotecan (FOLFIRI) is a frequently used chemotherapy regimen for the firstline treatment of metastatic colorectal cancer. Results of the phase 3 CRYSTAL trial showed that the addition of the EGFR antibody cetuximab to FOLFIRI in this setting improved clinical outcome in patients whose tumours did not have mutations at KRAS codons 12 and 13.1,2 Addition of the VEGF-A antibody bevacizumab to a firstline regimen including irinotecan, bolus fluorouracil, and folinic acid was also shown in a phase 3 trial to improve outcome in patients with metastatic colorectal
cancer.3 However, a survival benefit associated with the addition of bevacizumab to standard first-line infusional fluorouracil-based regimens has not yet been shown. The FIRE-3 trial of the Arbeitsgemeinschaft Internistische Onkologie (AIO) was designed to explore whether cetuximab or bevacizumab was a more effective partner for FOLFIRI in the fi rst-line treatment of metastatic colorectal cancer. Patients were initially recruited without regard to KRAS tumour mutation status. However, following reports that cetuximab was not active in patients with tumour KRAS exon 2 mutations (codon 12 or 13),4,5 enrolment was restricted
www.thelancet.com/oncology Published online August 1, 2014 http://dx.doi.org/10.1016/S1470-2045(14)70330-4
Lancet Oncol 2014 Published Online August 1, 2014 http://dx.doi.org/10.1016/ S1470-2045(14)70330-4 See Online/Comment http://dx.doi.org/10.1016/ S1470-2045(14)70360-2 Department of Medical Oncology & Comprehensive Cancer Center, University Hospital Grosshadern, Munich, Germany (Prof V Heinemann MD, D P Modest MD, L Rossius MD, S Stintzing MD); Gesundheitszentrum St Marien, Amberg, Germany (L Fischer von Weikersthal MD); Oncological Practice, Ravensburg, Germany (T Decker MD); Department of Medicine IV, Klinikum Bayreuth GmbH, Bayreuth, Germany (Prof A Kiani MD); Oncological Practice, Landshut, Germany (U Vehling-Kaiser MD); Department of Hematology and Oncology, Krankenhaus Nordwest, Frankfurt/Main, Germany (Prof S-E Al-Batran MD); Department of Medicine II, Städtisches Klinikum Neuss, Neuss, Germany (Prof T Heintges MD); Oncological Practice, Münster, Germany (C Lerchenmüller MD); Haematology and Oncology, Städtisches Klinikum Magdeburg, Magdeburg, Germany (C Kahl MD); Oncological Practice, Bad Soden, Germany (G Seipelt MD); Department of Medicine I, Klinikum Weiden, Germany (Prof F Kullmann MD); Oncological Practice, Kronach, Germany (M Stauch MD); Department of Internal Medicine I and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria (Prof W Scheithauer MD);
1
Articles
Department of Surgery, Klinikum Chemnitz gGmbH, Chirurgische Onkologie, Chemnitz, Germany (J Hielscher); Department of Medicine, Klinikum Stuttgart Krankenhaus Bad Cannstatt, Stuttgart, Germany (M Scholz MD); Oncological Practice, Ansbach, Germany (S Müller MD); Department of Medicine I, Westpfalz-Klinikum GmbH, Kaiserslautern, Germany (Prof H Link PhD); Department of Oncology, Haematology and Palliative Care, Klinikum Leverkusen gGmbH, Leverkusen, Germany (Prof N Niederle MD); Medical Clinic V (Haematology and Oncology), Klinikum Darmstadt, Darmstadt, Germany (A Rost MD); Klinikum Fulda, Tumorklinik, Fulda, Germany (Prof H-G Höffkes MD); Medical Department 1, Johannes-Gutenberg Universität Mainz, Mainz, Germany (Prof M Moehler MD); Klinik für Innere Medizin II, Abteilung Hämatologie/ Onkologie, Universitätsklinikum Jena, Jena, Germany (R U Lindig MD); and Institute of Pathology, University of Munich, Munich, Germany (L Rossius, Prof T Kirchner MD, A Jung PhD) Correspondence to: Prof Volker Heinemann, Klinikum Grosshadern, University of Munich, Department of Medical Oncology and Comprehensive Cancer Center, D-81377 Munich, Germany [email protected]
2
by protocol amendment to patients without such mutations. Subsequently, an unplanned subgroup analysis was done to compare treatment efficacy in patients with KRAS exon 2 mutations enrolled before the protocol amendment.6 Particular tumour mutations occurring in exons 3 or 4 of KRAS or exons 2–4 of NRAS have recently also been shown to be negative predictors of outcome in patients receiving first-line therapy with the EGFR antibody panitumumab combined with a regimen of folinic acid, fluorouracil, and oxaliplatin (FOLFOX4).7,8 When patients with such mutations were excluded from the KRAS exon 2 wild-type population, a more pronounced survival benefit associated with the addition of panitumumab to FOLFOX4 was reported than before the exclusion of these patients.7 Our objective in this study was therefore to compare cetuximab or bevacizumab, plus FOLFIRI, in FIRE-3 trial patients without tumour KRAS exon 2 mutations.
Methods Study design and patients In this two-group, open-label, multicentre, randomised, phase 3 trial, we recruited patients from hospitals, outpatient clinics, and private practices in Germany and Austria. Eligible patients were those aged 18–75 years with stage IV, histologically confirmed, adenocarcinoma of the colon or rectum, an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2, an estimated life expectancy of greater than 3 months, and adequate organ function (white blood cell count ≥3·0 × 10⁹ cells per L, with neutrophils ≥1·5 × 10⁹ cells per L, platelets ≥100 × 10⁹ per L and haemoglobin ≥5·6 mmol/L [corresponding to 9 g/dL]; serum bilirubin ≤1·5 × upper limit of normal [ULN]; alanine aminotransferase and aspartate aminotransferase ≤2·5 × ULN or ≤5 × ULN in the presence of liver metastases, and serum creatinine ≤1·5 × ULN), and who had not had surgery within the 4 weeks before the start of study treatment. The presence of at least one measurable reference lesion according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.09 was also required. Due to the emerging evidence on the negative predictive value of KRAS exon 2 mutations10,11 and the subsequent changes to the label of cetuximab, a protocol amendment was submitted on Oct 7, 2008, and inclusion was restricted to only patients with KRAS exon 2 wild-type tumours. Key exclusion criteria included known or suspected brain metastases; previous treatment with an EGFR-targeting agent or bevacizumab; previous chemotherapy for colorectal cancer, excluding adjuvant therapy completed at least 6 months before trial enrolment; or receipt of any experimental drug treatment within 30 days before enrolment. Patients were also excluded if they had clinically relevant coronary heart disease, myocardial infarction within the past 12 months or a risk of uncontrolled arrhythmia; acute or subacute intestinal
obstruction or a history of chronic inflammatory disease or chronic diarrhoea; symptomatic peritoneal carcinomatosis; serious, non-healing wounds, ulcers or bone fractures; uncontrolled hypertension; pronounced proteinuria (nephrotic syndrome); arterial thromboembolisms or severe haemorrhages within 6 months before study enrolment (except a bleeding tumour before tumour resection surgery); haemorrhagic diathesis or thrombotic tendency; a pre-existing dihydropyrimidine dehydrogenase deficiency; a pre-existing glucuronidation defect (Gilbert-Meulengracht syndrome); a history of secondary malignancy within the past 5 years, except for basalioma or carcinoma in situ of the cervix if treated with curative intent; or been receiving therapeutic anticoagulation therapy. The sponsor of the study was the Klinikum Grosshadern, University of Munich. Randomisation, data management, and primary data analyses were done by a contract research organisation (ClinAssess GmbH, Leverkusen, Germany). The trial was done in accordance with the protocol and in compliance with the Declaration of Helsinki. The protocol was approved by the ethics committees of all participating centres. All patients provided written informed consent before trial entry.
Randomisation and masking Patients were randomly assigned in a 1:1 ratio to receive either FOLFIRI plus cetuximab or FOLFIRI plus bevacizumab. Randomisation was done centrally by fax using permuted blocks of randomly varying size, with stratification according to ECOG performance status (0–1 or 2), number of metastatic sites (one or more than one), white blood cell count (
FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): a randomised, open-label, phase 3 trial Volker Heinemann, Ludwig Fischer von Weikersthal, Thomas Decker, Alexander Kiani, Ursula Vehling-Kaiser, Salah-Eddin Al-Batran, Tobias Heintges, Christian Lerchenmüller, Christoph Kahl, Gernot Seipelt, Frank Kullmann, Martina Stauch, Werner Scheithauer, Jörg Hielscher, Michael Scholz, Sebastian Müller, Hartmut Link, Norbert Niederle, Andreas Rost, Heinz-Gert Höffkes, Markus Moehler, Reinhard U Lindig, Dominik P Modest, Lisa Rossius, Thomas Kirchner, Andreas Jung, Sebastian Stintzing
Summary Background Cetuximab and bevacizumab have both been shown to improve outcomes in patients with metastatic colorectal cancer when added to chemotherapy regimens; however, their comparative effectiveness when partnered with first-line fluorouracil, folinic acid, and irinotecan (FOLFIRI) is unknown. We aimed to compare these agents in patients with KRAS (exon 2) codon 12/13 wild-type metastatic colorectal cancer. Methods In this open-label, randomised, phase 3 trial, we recruited patients aged 18–75 years with stage IV, histologically confirmed colorectal cancer, an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2, an estimated life expectancy of greater than 3 months, and adequate organ function, from centres in Germany and Austria. Patients were centrally randomised by fax (1:1) to FOLFIRI plus cetuximab or FOLFIRI plus bevacizumab (using permuted blocks of randomly varying size), stratified according to ECOG performance status, number of metastatic sites, white blood cell count, and alkaline phosphatase concentration. The primary endpoint was objective response analysed by intention to treat. The study has completed recruitment, but follow-up of participants is ongoing. The trial is registered with ClinicalTrials.gov, number NCT00433927. Findings Between Jan 23, 2007, and Sept 19, 2012, 592 patients with KRAS exon 2 wild-type tumours were randomly assigned and received treatment (297 in the FOLFIRI plus cetuximab group and 295 in the FOLFIRI plus bevacizumab group). 184 (62·0%, 95% CI 56·2–67·5) patients in the cetuximab group achieved an objective response compared with 171 (58·0%, 52·1–63·7) in the bevacizumab group (odds ratio 1·18, 95% CI 0·85–1·64; p=0·18). Median progression-free survival was 10·0 months (95% CI 8·8–10·8) in the cetuximab group and 10·3 months (9·8–11·3) in the bevacizumab group (hazard ratio [HR] 1·06, 95% CI 0·88–1·26; p=0·55); however, median overall survival was 28·7 months (95% CI 24·0–36·6) in the cetuximab group compared with 25·0 months (22·7–27·6) in the bevacizumab group (HR 0·77, 95% CI 0·62–0·96; p=0·017). Safety profiles were consistent with the known sideeffects of the study drugs. The most common grade 3 or worse adverse events in both treatment groups were haematotoxicity (73 [25%] of 297 patients in the cetuximab group vs 62 [21%] of 295 patients in the bevacizumab group), skin reactions (77 [26%] vs six [2%]), and diarrhoea (34 [11%] vs 40 [14%]). Interpretation Although the proportion of patients who achieved an objective response did not significantly differ between the FOLFIRI plus cetuximab and FOLFIRI plus bevacizumab groups, the association with longer overall survival suggests that FOLFIRI plus cetuximab could be the preferred first-line regimen for patients with KRAS exon 2 wild-type metastatic colorectal cancer. Funding Merck KGaA.
Introduction Fluorouracil with folinic acid and irinotecan (FOLFIRI) is a frequently used chemotherapy regimen for the firstline treatment of metastatic colorectal cancer. Results of the phase 3 CRYSTAL trial showed that the addition of the EGFR antibody cetuximab to FOLFIRI in this setting improved clinical outcome in patients whose tumours did not have mutations at KRAS codons 12 and 13.1,2 Addition of the VEGF-A antibody bevacizumab to a firstline regimen including irinotecan, bolus fluorouracil, and folinic acid was also shown in a phase 3 trial to improve outcome in patients with metastatic colorectal
cancer.3 However, a survival benefit associated with the addition of bevacizumab to standard first-line infusional fluorouracil-based regimens has not yet been shown. The FIRE-3 trial of the Arbeitsgemeinschaft Internistische Onkologie (AIO) was designed to explore whether cetuximab or bevacizumab was a more effective partner for FOLFIRI in the fi rst-line treatment of metastatic colorectal cancer. Patients were initially recruited without regard to KRAS tumour mutation status. However, following reports that cetuximab was not active in patients with tumour KRAS exon 2 mutations (codon 12 or 13),4,5 enrolment was restricted
www.thelancet.com/oncology Published online August 1, 2014 http://dx.doi.org/10.1016/S1470-2045(14)70330-4
Lancet Oncol 2014 Published Online August 1, 2014 http://dx.doi.org/10.1016/ S1470-2045(14)70330-4 See Online/Comment http://dx.doi.org/10.1016/ S1470-2045(14)70360-2 Department of Medical Oncology & Comprehensive Cancer Center, University Hospital Grosshadern, Munich, Germany (Prof V Heinemann MD, D P Modest MD, L Rossius MD, S Stintzing MD); Gesundheitszentrum St Marien, Amberg, Germany (L Fischer von Weikersthal MD); Oncological Practice, Ravensburg, Germany (T Decker MD); Department of Medicine IV, Klinikum Bayreuth GmbH, Bayreuth, Germany (Prof A Kiani MD); Oncological Practice, Landshut, Germany (U Vehling-Kaiser MD); Department of Hematology and Oncology, Krankenhaus Nordwest, Frankfurt/Main, Germany (Prof S-E Al-Batran MD); Department of Medicine II, Städtisches Klinikum Neuss, Neuss, Germany (Prof T Heintges MD); Oncological Practice, Münster, Germany (C Lerchenmüller MD); Haematology and Oncology, Städtisches Klinikum Magdeburg, Magdeburg, Germany (C Kahl MD); Oncological Practice, Bad Soden, Germany (G Seipelt MD); Department of Medicine I, Klinikum Weiden, Germany (Prof F Kullmann MD); Oncological Practice, Kronach, Germany (M Stauch MD); Department of Internal Medicine I and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria (Prof W Scheithauer MD);
1
Articles
Department of Surgery, Klinikum Chemnitz gGmbH, Chirurgische Onkologie, Chemnitz, Germany (J Hielscher); Department of Medicine, Klinikum Stuttgart Krankenhaus Bad Cannstatt, Stuttgart, Germany (M Scholz MD); Oncological Practice, Ansbach, Germany (S Müller MD); Department of Medicine I, Westpfalz-Klinikum GmbH, Kaiserslautern, Germany (Prof H Link PhD); Department of Oncology, Haematology and Palliative Care, Klinikum Leverkusen gGmbH, Leverkusen, Germany (Prof N Niederle MD); Medical Clinic V (Haematology and Oncology), Klinikum Darmstadt, Darmstadt, Germany (A Rost MD); Klinikum Fulda, Tumorklinik, Fulda, Germany (Prof H-G Höffkes MD); Medical Department 1, Johannes-Gutenberg Universität Mainz, Mainz, Germany (Prof M Moehler MD); Klinik für Innere Medizin II, Abteilung Hämatologie/ Onkologie, Universitätsklinikum Jena, Jena, Germany (R U Lindig MD); and Institute of Pathology, University of Munich, Munich, Germany (L Rossius, Prof T Kirchner MD, A Jung PhD) Correspondence to: Prof Volker Heinemann, Klinikum Grosshadern, University of Munich, Department of Medical Oncology and Comprehensive Cancer Center, D-81377 Munich, Germany [email protected]
2
by protocol amendment to patients without such mutations. Subsequently, an unplanned subgroup analysis was done to compare treatment efficacy in patients with KRAS exon 2 mutations enrolled before the protocol amendment.6 Particular tumour mutations occurring in exons 3 or 4 of KRAS or exons 2–4 of NRAS have recently also been shown to be negative predictors of outcome in patients receiving first-line therapy with the EGFR antibody panitumumab combined with a regimen of folinic acid, fluorouracil, and oxaliplatin (FOLFOX4).7,8 When patients with such mutations were excluded from the KRAS exon 2 wild-type population, a more pronounced survival benefit associated with the addition of panitumumab to FOLFOX4 was reported than before the exclusion of these patients.7 Our objective in this study was therefore to compare cetuximab or bevacizumab, plus FOLFIRI, in FIRE-3 trial patients without tumour KRAS exon 2 mutations.
Methods Study design and patients In this two-group, open-label, multicentre, randomised, phase 3 trial, we recruited patients from hospitals, outpatient clinics, and private practices in Germany and Austria. Eligible patients were those aged 18–75 years with stage IV, histologically confirmed, adenocarcinoma of the colon or rectum, an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2, an estimated life expectancy of greater than 3 months, and adequate organ function (white blood cell count ≥3·0 × 10⁹ cells per L, with neutrophils ≥1·5 × 10⁹ cells per L, platelets ≥100 × 10⁹ per L and haemoglobin ≥5·6 mmol/L [corresponding to 9 g/dL]; serum bilirubin ≤1·5 × upper limit of normal [ULN]; alanine aminotransferase and aspartate aminotransferase ≤2·5 × ULN or ≤5 × ULN in the presence of liver metastases, and serum creatinine ≤1·5 × ULN), and who had not had surgery within the 4 weeks before the start of study treatment. The presence of at least one measurable reference lesion according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.09 was also required. Due to the emerging evidence on the negative predictive value of KRAS exon 2 mutations10,11 and the subsequent changes to the label of cetuximab, a protocol amendment was submitted on Oct 7, 2008, and inclusion was restricted to only patients with KRAS exon 2 wild-type tumours. Key exclusion criteria included known or suspected brain metastases; previous treatment with an EGFR-targeting agent or bevacizumab; previous chemotherapy for colorectal cancer, excluding adjuvant therapy completed at least 6 months before trial enrolment; or receipt of any experimental drug treatment within 30 days before enrolment. Patients were also excluded if they had clinically relevant coronary heart disease, myocardial infarction within the past 12 months or a risk of uncontrolled arrhythmia; acute or subacute intestinal
obstruction or a history of chronic inflammatory disease or chronic diarrhoea; symptomatic peritoneal carcinomatosis; serious, non-healing wounds, ulcers or bone fractures; uncontrolled hypertension; pronounced proteinuria (nephrotic syndrome); arterial thromboembolisms or severe haemorrhages within 6 months before study enrolment (except a bleeding tumour before tumour resection surgery); haemorrhagic diathesis or thrombotic tendency; a pre-existing dihydropyrimidine dehydrogenase deficiency; a pre-existing glucuronidation defect (Gilbert-Meulengracht syndrome); a history of secondary malignancy within the past 5 years, except for basalioma or carcinoma in situ of the cervix if treated with curative intent; or been receiving therapeutic anticoagulation therapy. The sponsor of the study was the Klinikum Grosshadern, University of Munich. Randomisation, data management, and primary data analyses were done by a contract research organisation (ClinAssess GmbH, Leverkusen, Germany). The trial was done in accordance with the protocol and in compliance with the Declaration of Helsinki. The protocol was approved by the ethics committees of all participating centres. All patients provided written informed consent before trial entry.
Randomisation and masking Patients were randomly assigned in a 1:1 ratio to receive either FOLFIRI plus cetuximab or FOLFIRI plus bevacizumab. Randomisation was done centrally by fax using permuted blocks of randomly varying size, with stratification according to ECOG performance status (0–1 or 2), number of metastatic sites (one or more than one), white blood cell count (
