|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
Originally published as JCO Early Release 10.1200/JCO.2008.19.8135 on December 29 2008 © 2009 American Society of Clinical Oncology. A Randomized Phase IIIB Trial of Chemotherapy, Bevacizumab, and Panitumumab Compared With Chemotherapy and Bevacizumab Alone for Metastatic Colorectal CancerFrom the David Geffen School of Medicine at UCLA, University of California at Los Angeles, Los Angeles; Amgen Inc, Thousand Oaks, CA; Kimmel Cancer Center of Thomas Jefferson University, Philadelphia, PA; M. Zangmeister Center, Columbus, OH; NEA Clinic, Jonesboro, AR; Suburban Hematology-Oncology Associates, Lawrenceville, GA; Sarah Cannon Research Institute, Nashville, TN; Georgetown University Hospital, Washington, DC; Rocky Mountain Cancer Centers, Denver, CO; Baylor-Sammons Cancer Center, Dallas, TX, St. Joseph Mercy Hospital, Ann Arbor, MI. Corresponding author: J. Randolph Hecht, MD, David Geffen School of Medicine at UCLA, 2825 Santa Monica Blvd, #221, Santa Monica, CA 90404; e-mail: jrhecht{at}mednet.ucla.edu.
Purpose Panitumumab, a fully human antibody targeting the epidermal growth factor receptor, is active in patients with metastatic colorectal cancer (mCRC). This trial evaluated panitumumab added to bevacizumab and chemotherapy (oxaliplatin- and irinotecan-based) as first-line treatment for mCRC. Patients and Methods Patients were randomly assigned within each chemotherapy cohort to bevacizumab and chemotherapy with or without panitumumab 6 mg/kg every 2 weeks. The primary end point was progression-free survival (PFS) within the oxaliplatin cohort. Tumor assessments were performed every 12 weeks and reviewed centrally. Results A total of 823 and 230 patients were randomly assigned to the oxaliplatin and irinotecan cohorts, respectively. Panitumumab was discontinued after a planned interim analysis of 812 oxaliplatin patients showed worse efficacy in the panitumumab arm. In the final analysis, median PFS was 10.0 and 11.4 months for the panitumumab and control arms, respectively (HR, 1.27; 95% CI, 1.06 to 1.52); median survival was 19.4 months and 24.5 months for the panitumumab and control arms, respectively. Grade 3/4 adverse events in the oxaliplatin cohort (panitumumab v control) included skin toxicity (36% v 1%), diarrhea (24% v 13%), infections (19% v 10%), and pulmonary embolism (6% v 4%). Increased toxicity without evidence of improved efficacy was observed in the panitumumab arm of the irinotecan cohort. KRAS analyses showed adverse outcomes for the panitumumab arm in both wild-type and mutant groups. Conclusion The addition of panitumumab to bevacizumab and oxaliplatin- or irinotecan-based chemotherapy results in increased toxicity and decreased PFS. These combinations are not recommended for the treatment of mCRC in clinical practice.
The treatment of metastatic colorectal cancer (mCRC) has undergone important advances in the past decade, including the introduction of multiagent chemotherapy and biologic agents. Bevacizumab, a humanized antibody against vascular endothelial growth factor-A (VEGF-A) has been shown to improve overall survival when combined with chemotherapy in first- or second-line treatment for mCRC.1–3 Panitumumab and cetuximab, antibodies against epidermal growth factor receptor (EGFR), are active as monotherapy or in combination with chemotherapy for advanced disease.4–13 Recently, it has been shown that the activity of EGFR antibodies is confined to patients whose tumors do not contain activating mutations in the KRAS gene.14,15 Early studies have suggested that blocking both the VEGF and EGFR pathways may increase antitumor activity.16–20 The combination of bevacizumab and the small molecule EGFR inhibitor erlotinib yielded promising activity in non–small-cell lung cancer,19 and the combination of cetuximab and bevacizumab either with or without irinotecan showed promising activity in irinotecan-refractory mCRC.20 To formally explore the effectiveness of this combination, the Panitumumab Advanced Colorectal Cancer Evaluation (PACCE) study, designed as a US community–based, randomized, phase IIIB trial, evaluated the efficacy and safety of bevacizumab and chemotherapy with or without panitumumab in patients with previously untreated mCRC.
Patients Eligible patients had pathologic diagnosis of mCRC with measurable disease per modified Response Evaluation Criteria in Solid Tumors (RECIST).21 Other inclusion criteria included Eastern Cooperative Oncology Group performance status of 0 or 1; adequate hematologic, hepatic, and renal functions; and available paraffin-embedded tumor tissue or unstained slides. Key exclusion criteria were prior chemotherapy or biologic therapy for metastatic disease; adjuvant chemotherapy within 6 months of undergoing random assignment; major surgery within 28 days of random assignment; pre-existing bleeding diathesis or coagulopathy or need for full-dose anticoagulation; and clinically significant cardiovascular disease within 1 year of random assignment. EGFR tumor expression was not required. The study protocol was approved by institutional review boards at each participating center. All patients provided written informed consent before study-related procedures were performed.
Study Design
Panitumumab doses were withheld for grade 3 skin/nail-related toxicities and for nonskin/nail-related toxicities requiring intervention, eventually followed by escalation back to the original dose if tolerated or resolution. For nonskin/nail-related toxicities requiring intervention, chemotherapy was reduced per standard of care before panitumumab dose modifications. For grade 4 toxicities, panitumumab was discontinued.
Study Assessments
Study Objectives and End Points Exploratory analyses by KRAS mutational status were performed in both cohorts. KRAS testing was done using allele-specific PCR (DxS, Manchester, UK) in paraffin-embedded tumor tissue as previously described.14
Statistical Analyses
Patient Disposition and Demographics From March 2005 through October 2006, 1,240 patients were screened and 1,053 patients were enrolled and randomly assigned in 200 US centers: 823 patients to the Ox-CT cohort and 230 patients to the Iri-CT cohort (Fig 1). Approximately 20% of patients in each arm in the Ox-CT cohort were enrolled by sites that enrolled  three patients. The most common reasons for screening failure were inadequate hepatic function (n = 51), inability to comply with study procedures (n = 37), and inadequate hematologic function (n = 16). Three planned safety reviews were conducted by the DMC after approximately 25, 75, and 150 patients were randomly assigned. An additional unplanned analysis of safety and response on approximately 500 patients was conducted at the DMC request, resulting in no study modifications. After the fifth (planned) analysis of safety and response on approximately 800 patients, the DMC recommended changes to the patient informed consent because of imbalances in diarrhea, dehydration, and infections favoring the control arm. An investigator letter informed of these imbalances and highlighted guidelines for toxicity management and dose modifications for severe diarrhea and infections. A planned interim analysis of safety and efficacy was conducted at approximately 50% progression or death events in the Ox-CT cohort using a data cutoff of October 30, 2006. Because of decreased PFS and increased toxicity observed in the panitumumab arm, panitumumab was discontinued in both cohorts on March 22, 2007, by the sponsor. The trial continued without panitumumab treatment, and no further protocol-prespecified, hypothesis-testing analyses were conducted. An updated descriptive analysis of efficacy and safety was conducted on data available as of May 31, 2007. Results from both the primary analysis (October 2006) and the descriptive update (May 2007) are included herein. Baseline demographics and clinical characteristics were well balanced among treatment arms within each chemotherapy cohort (Table 1). Median follow-up time was 7.5 months (range, 0.0 to 19.3 months) for the Ox-CT cohort and 6.2 months (range, 0.2 to 18.6 months) for the Iri-CT cohort at the October 2006 cutoff, and 12.3 months (range, 0.2 to 26.2 months) for the Ox-CT cohort and 9.0 months (range, 0.3 to 24.0 months) for the Iri-CT cohort at the May 2007 cutoff.
As of the May 2007 cutoff, 94% of patients in the Ox-CT cohort and 87% in the Iri-CT cohort had ended study treatment. Most patients in both cohorts discontinued treatment because of nonprogressive events (68% and 65% for Ox-CT and Iri-CT cohorts, respectively); the most frequent reasons were AEs, treatment refusal, and requirement for alternative therapy. More patients in the panitumumab arms ended treatment for progressive events (progression or death) than in the control arms (Appendix Table A1, online only).
Efficacy As of May 2007, there were 467 (57%) PFS events. By central review, PFS continued to favor the control arm (HR, 1.27; 95% CI, 1.06 to 1.52). Median PFS times were 10.0 months (95% CI, 8.9 to 11.0 months) for panitumumab and 11.4 months (95% CI, 10.5 to 11.9 months) for control (Fig 2A). By local review, median PFS times were 9.6 months (95% CI, 8.8 to 10.7 months) and 11.0 months (95% CI, 10.2 to 11.8 months) for panitumumab and control, respectively (HR, 1.27; 95% CI, 1.07 to 1.5; Appendix Fig A1A, online only).
For the Iri-CT cohort, median PFS (secondary end point) by central review in the October 2006 analysis was 10.1 month for panitumumab and 11.9 months for the control (HR, 1.57; 95% CI, 0.71 to 3.46). In the May 2007 analysis, median PFS was 10.1 month for panitumumab and 11.7 months for control by central review (HR, 1.19; 95% CI, 0.79 to 1.79; Fig 2A) and 11.0 months for panitumumab and 10.7 months for control by local review (HR, 0.92; 95% CI, 0.63 to 1.34; Appendix Fig A1B, online only).
Secondary End Points
An unplanned interim analysis of survival was performed in October 2006 after results of the primary end point demonstrated shorter PFS time in the panitumumab arm. In this analysis, median OS time in the Ox-CT cohort was 18.4 months for panitumumab and was not reached for control (HR, 1.56; 95% CI, 1.11 to 2.19). In the updated analysis (Fig 2B), median OS time for the Ox-CT cohort was 19.4 months (95% CI, 18.4 to 20.8 months) for panitumumab and 24.5 months (95% CI, 20.4 to 24.5 months) for control (HR, 1.43; 95% CI, 1.11 to 1.83). In the Iri-CT cohort, median OS time for the panitumumab arm was 20.7 months (95% CI, 17.8 to not estimable months) and 20.5 months (95% CI, 19.8 to not estimable months) for the control arm (HR, 1.42; 95% CI, 0.77 to 2.62; Fig 2B).
KRAS Analyses
Drug Exposure Of all patients receiving panitumumab, more than 97% received panitumumab 6 mg/kg Q2W as their first dose. Approximately 95% of all patients received bevacizumab at approximately 5 mg/kg Q2W as their first dose.
In both the Ox-CT and Iri-CT cohorts, the proportion of patients with chemotherapy and/or antibody dose delays was higher in the panitumumab arms, with a difference in favor of the control arms ranging from 6% to 17% (Appendix Table A3, online only). While small differences in relative dose intensity for each individual agent favored the control arms, the proportion of patients receiving a relative dose intensity of
Safety
Two-hundred fifty (31%) and 43 (19%) patients had died in the Ox-CT and Iri-CT cohorts, respectively. For both cohorts combined, deaths within 60 days of the first dose occurred in 15 (2.9%) and eight (1.6%) patients in the panitumumab and control arms, respectively. For both cohorts combined, deaths within 30 days after the last dose occurred in 41 (8%) and 17 (3%) patients in panitumumab and control arms, respectively. There were seven (1%) deaths attributed by the investigator to be panitumumab-related: five in the Ox-CT cohort (pulmonary embolism, cardiac arrest, cancer progression, arrhythmia, and intestinal perforation) and two in the Iri-CT cohort (intestinal perforation and sepsis).
In the PACCE trial, the combination of panitumumab with bevacizumab and chemotherapy resulted in a decrease in PFS and in excess serious toxicity, particularly diarrhea, infections, and pulmonary embolism in patients with mCRC. Results were largely consistent between the oxaliplatin and irinotecan cohorts. While the exact explanation for these results is unknown, several hypotheses can be postulated. Although pharmacokinetic interactions between antibodies or between antibodies and chemotherapy are uncommon, we cannot exclude this possibility, as drug concentration levels were not collected in this study. Toxicity was exacerbated by dual-pathway inhibition in combination with chemotherapy. Bevacizumab with an anti-EGFR antibody and chemotherapy could have enhanced diarrhea and skin toxicity by inhibiting tissue repair, and more complete inhibition of the VEGF axis could have increased the incidence of pulmonary embolism. Toxicity likely contributed to the increases in dose delays and reductions, decreases in dose intensity, and increases in mortality in the panitumumab arm. Lower dose intensity could explain the similar response rates observed with worse results of time-dependent end points. In contrast with the safety profile observed in this study, panitumumab given with fluorouracil, leucovorin, and oxaliplatin (FOLFOX) or with fluorouracil, leucovorin, and irinotecan (FOLFIRI) in the absence of bevacizumab appears to be well tolerated.22,23 Potentially, a pharmacodynamic interaction induced by EGFR inhibition could have led to a blunting of the therapeutic effects of bevacizumab and/or chemotherapy. Possible mechanisms include EGFR-mediated alterations of downstream targets required for the activity of bevacizumab and/or chemotherapy or the induction of EGFR-mediated cell-cycle arrest leading to resistance to cytotoxics. Since both classes of agents improve outcome when combined with chemotherapy in mCRC, cell-cycle mediated effects appear less likely, although definitive data on the role of EGFR-inhibiting antibodies in combination with oxaliplatin-based chemotherapy in mCRC is still awaited. There are methodological and design factors in PACCE that could have affected outcomes. First, the chemotherapy treatments were not uniform, possibly confounding outcomes and complicating the ability to provide standardized dose modification instructions with consequent excess toxicity. Nevertheless, the arms were well-balanced with respect to regimens and doses. Second, the open-label nature of the study may have resulted in toxicity-reporting bias. Lastly, a high degree of PFS censoring due to treatment discontinuation before disease progression could have masked treatment effects emerging later in the course of therapy. Despite the above observations, recently reported data strongly suggest that the results of PACCE are generalizable to the triple combination of anti-EGFR agents, bevacizumab, and chemotherapy in mCRC. A recent report from a phase III study investigating capecitabine, oxaliplatin, and bevacizumab with or without cetuximab in first-line mCRC (CAIRO2)24 also showed inferior PFS in the investigational arm with excess toxicity, particularly skin toxicity and diarrhea, without significant differences in RR or OS. A phase II study examining FOLFOX plus bevacizumab and erlotinib in mCRC likewise demonstrated poor tolerability.25 The positive predictive value of KRAS mutations as an exclusion marker for EGFR antibody treatment has been demonstrated.8,9,14,15,26–28 However, in the PACCE study, a trend towards worse survival was observed with panitumumab in the WT KRAS group of the oxaliplatin cohort. Differential exposure to EGFR antibodies in later lines of therapy could also have affected survival in the WT KRAS group. Similarly, in the CAIRO2 study, the triple combination of cetuximab, bevacizumab, and capecitabine plus oxaliplatin did not provide additional benefit in the WT KRAS group.24 This observation raises the possibility of a negative interaction between anti-EGFR antibodies and bevacizumab when combined with chemotherapy, even in a setting where anti-EGFR antibodies can effectively inhibit EGFR signaling. Understanding this potential interaction would help identify patient populations, therapeutic combinations, and, potentially, sequencing schedules that are more likely to result in clinical benefit. The ongoing CALGB 80405 phase III trial investigating bevacizumab, cetuximab, and chemotherapy for first-line mCRC,29,30 which was recently amended to include only patients with WT KRAS tumors (Alan Venook, personal communication), may provide further insights. In conclusion, our results do not support the use of panitumumab in combination with bevacizumab and oxaliplatin- or irinotecan-based chemotherapy for the treatment of mCRC. Administration of chemotherapy and dual EGFR/VEGF inhibition should be conducted only in a research setting, using selected populations and/or novel administration schedules or combinations. Molecular markers in this setting should expand beyond the KRAS biomarker.
Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: Robert Deeter, Amgen Inc (C); Seta Shahin, Amgen Inc (C); Rafael G. Amado, Amgen Inc (C) Consultant or Advisory Role: Edith Mitchell, Amgen Inc (C); David Spigel, Amgen Inc (U), Pfizer (C); John Marshall, Amgen Inc (C) Stock Ownership: Robert Deeter, Amgen Inc; Seta Shahin, Amgen Inc; Rafael G. Amado, Amgen Inc, Genentech Honoraria: Edith Mitchell, Amgen Inc; David Spigel, Genentech; Bristol-Myers Squibb Co, Sanofi-aventis, Allen Cohn, Amgen Inc, Bristol-Myers Squibb Co, Genentech; David McCollum, Roche, Sanofi-aventis; John Marshall, Amgen Inc Research Funding: John Marshall, Amgen Inc; David McCollum, ImClone Systems Inc Expert Testimony: None Other Remuneration: None
Conception and design: J. Randolph Hecht, Robert Deeter Administrative support: Robert Deeter, Rafael G. Amado Provision of study materials or patients: J. Randolph Hecht, Edith Mitchell, Carroll Scroggin, Christopher Hagenstad, David Spigel, John Marshall, Allen Cohn, David McCollum, Philip Stella Collection and assembly of data: J. Randolph Hecht, Edith Mitchell, Tarek Chidiac, Carroll Scroggin, Christopher Hagenstad, David McCollum, Robert Deeter, Rafael G. Amado Data analysis and interpretation: J. Randolph Hecht, Edith Mitchell, Christopher Hagenstad, John Marshall, Allen Cohn, Robert Deeter, Seta Shahin, Rafael G. Amado Manuscript writing: J. Randolph Hecht, John Marshall, Seta Shahin, Rafael G. Amado Final approval of manuscript: J. Randolph Hecht, Edith Mitchell, Tarek Chidiac, Carroll Scroggin, Christopher Hagenstad, David Spigel, John Marshall, Allen Cohn, David McCollum, Philip Stella, Robert Deeter, Seta Shahin, Rafael G. Amado
The Appendix is included in the full-text version of this article, available online at www.jco.org. It is not included in the PDF version (via Adobe® Reader®).
We thank the patients and their families and friends. We also thank the study site personnel and the following individuals from Amgen Inc: Thomas Griffin, MD, and Mona Shing, MD, for study management and critical data review; David Reese, MD, for critical review and editing of the manuscript; Mick O'Quigley, MS, and Yvonne Denkins, PhD, for study management; Sam Suzuki, MS, for KRAS biomarker analyses; Feng Xu, MS, for additional biostatistical analyses; and Mee Rhan Kim, PhD, for assistance with the writing and preparation of the manuscript.
Supported by Amgen Inc. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article. Clinical Trials repository link available on www.jco.org.
1. Hurwitz H, Fehrenbacher L, Novotny W, et al: Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350:2335–2342, 2004. 2. Kabbinavar FF, Schulz J, McCleod M, et al: Addition of bevacizumab to bolus fluorouracil and leucovorin in first-line metastatic colorectal cancer: Results of a randomized phase II trial. J Clin Oncol 23:3697–3705, 2005. 3. Giantonio BJ, Catalano PJ, Meropol NJ, et al: Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: Results from the Eastern Cooperative Oncology Group Study E3200. J Clin Oncol 25:1539–1544, 2007. 4. Van Cutsem E, Peeters M, Siena S, et al: Open-label, randomized, phase 3 clinical trial of panitumumab plus best supportive care versus best supportive care in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol 25:1658–1664, 2007. 5. Van Cutsem E, Siena S, Humblet Y, et al: An open-label, single-arm study assessing safety and efficacy of panitumumab in patients with metastatic colorectal cancer refractory to standard chemotherapy. Ann Oncol 18:92–98, 2007. 6. Hecht JR, Patnaik A, Berlin J, et al: Panitumumab monotherapy in patients with previously treated metastatic colorectal cancer. Cancer 110:980–988, 2007.[CrossRef][Medline] 7. Berlin J, Posey J, Tchekmedyian S, et al: Panitumumab with irinotecan/leucovorin/5-fluorouracil for first-line treatment of metastatic colorectal cancer. Clin Colorectal Cancer 6:427–432, 2007.[Medline] 8. Cohn AL, Smith DA, Neubauer MA, et al: Panitumumab (pmab) regimen evaluation in colorectal cancer to estimate primary response to treatment (PRECEPT): Effect of KRAS mutation status on second-line treatment (tx) with pmab and FOLFIRI. J Clin Oncol 26:209s; 2008 (suppl) abstr 4127. 9. Mitchell EP, Lacouture M, Shearer H, et al. Updated results of STEPP, a phase 2, open-label study of skin toxicity evaluation in metastatic colorectal cancer (mCRC) patients receiving panitumumab + FOLFIRI or irinotecan-only chemotherapy as second-line treatment 10th Annual World Congress of Gastrointestinal Cancers, Barcelona, Spain, June 25-28, 2008, (abstr 527). 10. Jonker DJ, O'Callaghan CJ, Karapetis CS, et al: Cetuximab for the treatment of colorectal cancer. N Engl J Med 357:2040–2048, 2007. 11. Cunningham D, Humblet Y, Siena S, et al: Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 351:337–345, 2004. 12. Sobrero AF, Maurel J, Fehrenbacher L, et al: EPIC: Phase III trial of cetuximab plus irinotecan after fluoropyrimidine and oxaliplatin failure in patients with metastatic colorectal cancer. J Clin Oncol 26:2311–2319, 2008. 13. Van Cutsem E, Nowacki M, Lang I, et al: Randomized phase III study of irinotecan and 5-FU/FA with or without cetuximab in the first-line treatment of patients with metastatic colorectal cancer (mCRC): The CRYSTAL trial. J Clin Oncol 25:18s; 2007 (suppl) abstr 4000. 14. Amado RG, Wolf M, Peeters M, et al: Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol 26:1626–1634, 2008. 15. Van Cutsem E, Lang I, D'haens G, et al: KRAS status and efficacy in the first-line treatment of patients with metastatic colorectal cancer (mCRC) treated with FOLFIRI with or without cetuximab: The CRYSTAL experience. J Clin Oncol 26:5s; 2008 (suppl) abstr 2.[CrossRef] 16. Ciardiello F, Bianco R, Damiano V, et al: Antiangiogenic and antitumor activity of anti-epidermal growth factor receptor C225 monoclonal antibody in combination with vascular endothelial growth factor antisense oligonucleotide in human GEO colon cancer cells. Clin Cancer Res 6:3739–3747, 2000. 17. Shaheen RM, Ahmad SA, Liu W, et al: Inhibited growth of colon cancer carcinomatosis by antibodies to vascular endothelial and epidermal growth factor receptors. Br J Cancer 85:584–589, 2001.[CrossRef][Medline] 18. Jung YD, Mansfield PF, Akagi M, et al: Effects of combination anti-vascular endothelial growth factor receptor and anti-epidermal growth factor receptor therapies on the growth of gastric cancer in a nude mouse model. Eur J Cancer 38:1133–1140, 2002.[CrossRef][Medline] 19. Herbst RS, Johnson DH, Mininberg E, et al: Phase I/II trial evaluating the anti-vascular endothelial growth factor monoclonal antibody bevacizumab in combination with the HER-1/epidermal growth factor receptor tyrosine kinase inhibitor erlotinib for patients with recurrent non-small-cell lung cancer. J Clin Oncol 23:2544–2555, 2005. 20. Saltz LB, Lenz HJ, Kindler HL, et al: Randomized phase II trial of cetuximab, bevacizumab, and irinotecan compared with cetuximab and bevacizumab alone in irinotecan-refractory colorectal cancer: The BOND-2 study. J Clin Oncol 25:4557–4561, 2007. 20a. Douillard JY, Cunningham D, Roth AD, et al: Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: A multicentre randomised trial. Lancet 355:1041–1047, 2000.[CrossRef][Medline] 21. Therasse P, Arbuck SG, Eisenhauer EA, et al: New guidelines to evaluate the response to treatment in solid tumors: European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92:205–216, 2000. 22. Peeters M, Wilson G, Ducreux M, et al: Phase III study (20050181) of panitumumab (pmab) with FOLFIRI versus FOLFIRI alone as second-line treatment (tx) in patients (pts) with metastatic colorectal cancer (mCRC): Pooled safety results. J Clin Oncol 26:194s; 2008 (suppl) abstr 4064. 23. Siena S, Tabernero J, Burkes RL, et al: Phase III study (PRIME/20050203) of panitumumab (pmab) with FOLFOX compared with FOLFOX alone in patients (pts) with previously untreated metastatic colorectal cancer (mCRC): Pooled safety data. J Clin Oncol 26:186s; 2008 (suppl) abstr 4034. 24. Punt CJ, Tol J, Rodenburg CJ, et al: Randomized phase III study of capecitabine, oxaliplatin, and bevacizumab with or without cetuximab in advanced colorectal cancer (ACC), the CAIRO2 study of the Dutch Colorectal Cancer Group (DCCG). J Clin Oncol 26:180s; 2008 (suppl) abstr LBA4011. 25. Meyerhardt JA, Stuart K, Fuchs CS, et al: Phase II study of FOLFOX, bevacizumab and erlotinib as first-line therapy for patients with metastatic colorectal cancer. Ann Oncol 18:1185–1189, 2007. 26. Bokemeyer C, Bondarenko I, Hartmann JT, et al: KRAS status and efficacy of first-line treatment of patients with metastatic colorectal cancer (mCRC) with FOLFOX with or without cetuximab: The OPUS experience. J Clin Oncol 26:178s; 2008 (suppl) abstr 4000. 27. Karapetis CS, Khambata-Ford S, Jonker DJ, et al: K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med 359:1757–1765, 2008. 28. Tejpar S, Peeters M, Humblet Y, et al: Relationship of efficacy with KRAS status (wild type versus mutant) in patients with irinotecan-refractory metastatic colorectal cancer (mCRC), treated with irinotecan (q2w) and escalating doses of cetuximab (q1w): The EVEREST experience (preliminary data). J Clin Oncol 26:178s; 2008 (suppl) abstr 4001. 29. Cetuximab and/or bevacizumab combined with combination chemotherapy in treating patients with metastatic colorectal cancer. http://www.clinicaltrials.gov/ct2/show/NCT00265850?term=80405&rank=1. 30. Phase III randomized study of cetuximab and/or bevacizumab in combination with either oxaliplatin, fluorouracil, and leucovorin calcium (FOLFOX) or irinotecan hydrochloride, fluorouracil, and leucovorin calcium (FOLFIRI) in patients with previously untreated metastatic adenocarcinoma of the colon or rectum. http://www.cancer.gov/search/ViewClinicalTrials.aspx?cdrid=455161&version=HealthProfessional&protocolsearchid=5389732. Submitted August 31, 2008; accepted November 20, 2008.
Related Article
Related Editorial
This article has been cited by other articles:
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2009 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
TOP
ABSTRACT
INTRODUCTION
2 test based on a Cox model adjusted for randomization factors was used to test a difference in PFS. To control the overall type I error, the Lan-DeMets alpha-spending function with O'Brien-Fleming boundaries was used: 0.00305 at the interim analysis and 0.04900 at the final analysis. Kaplan-Meier methodology estimated time to event end points, including 95% CI for event-free rates and rate differences. PFS was calculated from the day of randomization until radiologic progression or death. Patients alive without progression or having nonradiologic progression (ie, clinical progression) were censored. Central review censoring was based on the last available scan read centrally; local review censoring was based on the last day of patient contact or visit without known disease progression. OS was calculated from the day of randomization until death, censoring patients at the last day known to be alive. To obtain descriptive safety information following review of the interim results of the PFS end point, an unplanned interim analysis of OS in the Ox-CT cohort was conducted. Descriptive statistics were provided for patient demographics, baseline characteristics, and incidence of AEs. Efficacy analyses included any patient who was randomly assigned (intent-to-treat). Safety analyses included patients who received at least one dose of study treatment. 
85% of bevacizumab and each chemotherapy agent in both chemotherapy cohorts was lower in the panitumumab arms (33% for panitumumab v 42% for control for Ox-CT; 34% for panitumumab v 44% for control for Iri-CT). 
