|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
Journal of Clinical Oncology, Vol 25, No 36 (December 20), 2007: pp. 5777-5784 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.13.0856 Randomized Phase II Study of Gemcitabine Plus Cisplatin or Carboplatin, With or Without Cetuximab, As First-Line Therapy for Patients With Advanced or Metastatic Non–Small-Cell Lung Cancer
From the Cross Cancer Institute, Edmonton, Alberta; Windsor Regional Cancer Center, Windsor; Juravinski Cancer Centre at Hamilton Health Sciences, Hamilton, Canada University Health Network, Princess Margaret Hospital, Toronto, Ontario; Sir Mortimer B. Davis Jewish General Hospital, Montreal, Quèbec, Canada; Sharp Health Care, San Diego, CA; Dallas Oncology Consultants, Dallas, TX; The Florida Wellcare Alliance, Inverness, FL; Charleston Hematology/Oncology, Charleston, SC; Annapolis Oncology Center, Annapolis, MD; Oncology Partners Network, Cincinnati, OH; Earle A. Chiles Research Institute, Portland, OR; Hanover Medical Specialists, Wilmington, NC; North Shore Cancer Research Association, Skokie, IL; Bristol-Myers Squibb Company, Braine l'Allued, Belgium; and Bristol-Myers Squibb Company, Wallingford, CT Address reprint requests to Charles A. Butts, MD, Cross Cancer Institute, 11560 University Ave, Edmonton, Alberta, Canada; e-mail: charlesb{at}cancerboard.ab.ca
Purpose To evaluate the efficacy of cetuximab added to first-line gemcitabine/platinum in chemotherapy-naïve patients with advanced non–small-cell lung cancer (NSCLC). Patients and Methods In this noncomparative, randomized trial, chemotherapy-naïve patients with recurrent/metastatic NSCLC (stage IV or stage IIIB with malignant pleural effusion) were eligible. Patients received cisplatin (75 mg/m2 IV, every 3 weeks) or carboplatin (area under the concentration-versus-time curve of 5 intravenously [IV], every 3 weeks), and gemcitabine (1,250 or 1,000 mg/m2 IV, days 1 and 8) plus cetuximab (400 mg/m2 IV day 1, followed by 250 mg/m2 weekly), in arm A, or chemotherapy alone, in arm B. Response rate was the primary end point; safety, progression-free survival, and overall survival were secondary end points. Results Sixty-five patients were randomly assigned to arm A and 66 to arm B. Partial responses were observed in 18 patients (27.7%; 95% CI, 17.3 to 40.2) in arm A and 12 (18.2%; 95% CI, 9.8 to 29.6) in arm B. Median progression-free survival was 5.09 months for arm A (95% CI, 4.17 to 5.98) and 4.21 months (95% CI, 3.81 to 5.49) in arm B. Median overall survival was 11.99 months (95% CI, 8.80 to 15.18) and 9.26 months (95% CI, 7.43 to 11.79) in arms A and B, respectively. Overall toxicity was acceptable and consistent with the profiles of the individual agents. Conclusion First-line treatment with cetuximab plus gemcitabine/platinum is well tolerated and can be administered safely in patients with advanced NSCLC. Differences in response rate, progression-free survival, and overall survival suggest that the addition of cetuximab to platinum/gemcitabine may improve clinical outcomes. Larger studies are in progress to address this hypothesis.
Lung cancer is the leading cause of cancer death among men and women in North America,1,2 and non–small-cell lung cancer (NSCLC, including the histologic subtypes of squamous cell, large cell, and adenocarcinoma), accounts for 80% to 85% of cases.3 First-line treatment of advanced NSCLC primarily consists of platinum-based doublets that include paclitaxel, docetaxel, vinorelbine, camptothecin analogs, or gemcitabine. The similar efficacy across these doublets implies that cytotoxic treatment has reached a therapeutic plateau in this disease.3,4 The epidermal growth factor receptor (EGFR) is a potential target in the treatment of advanced/metastatic NSCLC. Overexpression of EGFR is common in NSCLC (40% to 80% of tumors),5 and abnormal EGFR signaling may drive several oncogenic processes. Studies in tumor models suggest that inhibition of EGFR may enhance cytotoxic treatment.6 Although the tyrosine kinase inhibitor (TKI) erlotinib is active as a single agent in patients refractory to chemotherapy,7 studies investigating the addition of EGFR TKIs to standard platinum-based chemotherapy have produced disappointing results. Both gefitinib and erlotinib failed to improve overall survival when added to platinum-based chemotherapy for the first-line treatment of unselected patients with advanced NSCLC.8-11 Subsequent research, however, has revealed that the activity of EGFR TKIs seems to be restricted to a subset of tumors with specific molecular characteristics, thus illustrating the need for appropriate patient selection tools before these therapies can be incorporated effectively into clinical practice.12-16 The immunoglobulin (Ig) G1 monoclonal antibody (MoAb) cetuximab is a unique EGFR inhibitor. Cetuximab binds to the extracellular domain of the EGFR, blocking ligand-receptor interaction and promoting receptor internalization.17 Additionally, cetuximab may disrupt ligand-independent EGFR activity, such as DNA repair stimulated by EGFR internalization.18 EGFR blockade by cetuximab inhibits cell proliferation as well as angiogenic and metastatic processes, promotes apoptosis, and ablates cellular responses to cytotoxic damage.17-21 As an IgG1 antibody, cetuximab also invokes antitumor antibody-dependent cell-mediated cytotoxicity (ADCC).20,22,23 Cetuximab has improved the therapeutic index when combined with other treatment modalities, and has been approved in North America and Europe for the treatment of metastatic colorectal cancer and head and neck cancer in combination with chemotherapy and radiation, respectively.24-27 In advanced NSCLC, phase I and II trials have shown that the addition of cetuximab as a single agent added to platinum-based chemotherapy is both tolerable and feasible.28-32 Results from randomized phase II studies suggest that adding cetuximab to first-line chemotherapy may improve efficacy in an unselected population with advanced NSCLC.28,31 This multicenter, noncomparative, open-label, randomized phase II study was designed to evaluate the efficacy of cetuximab with gemcitabine/platinum chemotherapy, or gemcitabine/platinum alone, as first-line therapy for advanced or metastatic NSCLC. The primary end point was response rate per treatment arm; safety, progression-free survival, and overall survival were secondary end points.
Eligibility Criteria Chemotherapy-naïve patients at least 18 years of age and with an Eastern Cooperative Oncology Group (ECOG) performance status less than 2, with histologically or cytologically documented advanced NSCLC (stage IIIB with pleural effusion or stage IV) of all histologic subtypes were eligible. Patients with brain metastases, including those treated with anticonvulsants, were eligible, but patients requiring glucocorticoids or with symptomatic or uncontrolled brain metastases were excluded. This study was performed after approval by a local human investigations committee and in accord with an assurance filed with and approved by the Department of Health and Human Services where appropriate. Informed consent was obtained from each participant.
Treatment
Dose reductions for toxicity were permanent except those required for day 8 gemcitabine because of neutropenia or thrombocytopenia in either arm. Cetuximab dose was modified after infusion reactions, per the manufacturer's package insert.33 If one or more study drugs were discontinued, further treatment with the remaining drugs was allowed in the absence of progression.
Patient Assessments Physical examinations and assessments of toxicity, weight, and ECOG performance status were performed before each cycle and at the end of therapy. Blood counts were performed weekly until the end of therapy (every 3 weeks in arm A if therapy was discontinued without PD). WHO response criteria were used on the basis of investigator measurements of index and nonindex lesions. Toxicity and adverse events were graded according to version 3.0 of the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE).
Statistical Design The primary objective was to estimate the objective response rate in each treatment arm. With a total of 60 patients per arm, the exact two-sided 95% CIs would extend to a maximum width of 27%.34 Secondary end points included progression-free survival, overall survival, safety, disease control rate, duration of response, and time to response. The sponsor conducted centralized reviews to confirm investigator measurements and to determine best response. These reviews were blinded, as the sponsor reviewer did not receive information as to which treatment the patients were receiving. Objective response rate was defined as the proportion of patients who achieved a complete response (CR) or partial response (PR) as determined and confirmed by the sponsor. Progression-free survival was defined as the time (months) from random assignment until PD or death. Analyses of safety and dosing data were restricted to treated patients. Efficacy analyses were performed on an intent-to-treat basis. Continuous variables were summarized using descriptive statistics, and categoric variables were summarized by frequencies and percents. Objective response rates and disease control rates were estimated, for each treatment arm, along with their exact two-sided 95% CIs, calculated using the Clopper and Pearson method.35 Difference in response rates, along with an asymptotic two-sided 95% CI, was estimated. For time-to-event variables, the Kaplan-Meier method was used to estimate the median, and its two-sided 95% CI was calculated using the Brookmeyer and Crowley method.38 Kaplan-Meier estimates were used to calculate overall survival rates and 95% CI (using Greenwood's formula for variance) at 6 and 12 months. Time to response was summarized using median, minimum, and maximum.
Patient Demographics Patients (N = 131) from 32 US and nine Canadian sites were randomly assigned to receive cetuximab in combination with platinum/gemcitabine (arm A, n = 65) or platinum/gemcitabine alone (arm B, n = 66; Table 1). At the time, it was decided to amend the protocol to reduce the study sample size, 30 patients had been enrolled, and 99 patients had been randomly assigned by the time the amendment was implemented.
The median age was 66 years (range, 35 to 84 years). The majority of patients (84%) were diagnosed with stage IV disease, in most cases with more than one disease site (77%). The majority of patients received carboplatin: 57 in arm A and 54 in arm B. One hundred thirty patients were assessable for safety and dosing analyses, whereas 131 patients were assessable for demographics and efficacy analysis.
Treatment Exposure
In arm A, approximately 70% of patients (both platinum agents) received at least 90% of the planned dose of cetuximab, with a median number of cetuximab infusions of 12.5 (range, 1 to 66 infusions). The cetuximab infusion was interrupted in 17 patients, eight for infusion reactions. Three patients experienced a grade 3/4 infusion reaction (one patient, grade 2). Cetuximab treatment was discontinued in all four patients. On completion of platinum/gemcitabine, 22 patients in arm A continued to receive cetuximab (median, 11.5 infusions; range, 2 to 48 infusions).
Efficacy
Median progression-free survival time was 5.09 months for patients receiving cetuximab (95% CI, 4.17 to 5.98) and 4.21 months for those receiving platinum/gemcitabine alone (95% CI, 3.81 to 5.49; Fig 2A). Median survival time was 11.99 months in the cetuximab arm (95% CI, 8.80 to 15.18) and 9.26 months in the platinum/gemcitabine arm (95% CI, 7.43 to 11.79). Survival rate at 12 months was 49.9% for those receiving cetuximab (95% CI, 37.4 to 62.4) and 37.5% for patients receiving chemotherapy alone (95% CI, 25.5 to 49.4; Fig 2B). Subsequent post-trial therapy was balanced between the two arms; the use of anti-EGFR agents was higher among patients randomly assigned to receive chemotherapy alone on study (arm A, 21.5%; arm B, 37.9%), but this is unlikely to have affected the overall survival trends observed.
Adverse Events One hundred thirty patients were assessable for toxicity (Table 4). The profile of cetuximab/platinum/gemcitabine was acceptable and consistent with the known safety profiles of the individual drugs. Skin toxicity, hypomagnesemia, diarrhea, and fatigue were more frequent in patients on the cetuximab arm. The addition of cetuximab to platinum/gemcitabine did not increase cardiotoxicity. However, serious adverse events related to treatment were more frequent in patients receiving cetuximab than patients treated with platinum/gemcitabine alone (arm A, n = 18; arm B, n = 8).
The overall incidence of hematologic toxicities was comparable across treatment arms, except for the higher frequency of severe thrombocytopenia in the cetuximab arm (57.8% v 44.6%). Treatment-related grade 3/4 neutropenic fever occurred in 4.7% of patients in arm A versus 1.5% in arm B. Treatment-related acneiform rash occurred in 47 (73.4%) of 64 patients in the cetuximab arm, with nine patients (14.1%) experiencing severe events. Mild to moderate (grade 1/2) hypomagnesemia was more frequent in the cetuximab arm than in the platinum/gemcitabine arm (58% and 30%, respectively). However, severe hypomagnesemia rates were similar in both treatment arms (3% and 2%, respectively). Severe infusion reactions related to treatment occurred in three patients (4.7%) receiving cetuximab, whereas none was observed in patients receiving chemotherapy alone. Discontinuation caused by drug toxicity occurred in 12 (18.5%) and seven (10.6%) patients in arms A and B, respectively. In arm A, eight (12.5%) patients discontinued cetuximab due to skin toxicity and four (6.3%) because of cetuximab-related infusion reactions. There were eight deaths in each study arm during treatment or within 30 days after the final dose, none of them considered related to treatment. Fourteen deaths (seven per arm) were attributed to disease progression, and two to unknown causes.
This trial confirms the feasibility of adding cetuximab to gemcitabine/platinum chemotherapy as first-line treatment of advanced/metastatic NSCLC. More importantly, the study suggests that improvements in efficacy may be associated with this combination. Although this was a noncomparative phase II trial, the addition of cetuximab resulted in a non–statistically significant increase in response rate, as well as progression-free and overall survival times. These emerging data are promising and consistent with earlier studies.28,31 The addition of cetuximab to vinorelbine/cisplatin has also shown greater activity than has chemotherapy alone in chemotherapy-naïve advanced NSCLC patients.28 These encouraging findings, however, must be confirmed prospectively in phase III trials. The safety profile of cetuximab/gemcitabine/platinum in this study, similar to that of Herbst et al,31 was acceptable. Serious adverse events and certain toxicities such as rash, hypomagnesemia, infusion reactions, diarrhea, and fatigue were more frequent in patients receiving cetuximab. However, these toxicities are expected, manageable, and consistent with earlier trials.28,29,31 Although the rates of discontinuation of chemotherapy were higher in patients receiving cetuximab, this did not appear to have a negative impact on efficacy. Combining cetuximab with platinum-based chemotherapy is likely a better strategy than continuously dosing EGFR TKIs plus chemotherapy. Four large phase III studies have demonstrated that EGFR-targeted small-molecule TKIs do not improve response or survival in unselected patients with advanced NSCLC when dosed continuously with concurrent platinum-based chemotherapy,8-11 possibly because of the role that certain molecular characteristics in the tumor, including EGFR mutation status, EGFR gene copy number, and even EGFR protein expression level, play in TKI activity.12-15,36 In contrast, results from this and other studies strongly suggest that cetuximab is effective in combination with platinum-based chemotherapy in unselected patients.32,37,38 Enrollment onto this study did not require immunohistochemical evidence of EGFR expression, a requisite whose lack of predictive value has been repeatedly demonstrated in colorectal cancer (CRC).39,40 There are also consistent indications that the activity of cetuximab is neither dependent on the presence of EGFR mutations nor related to a particular molecular or demographic profile.37,38 Whether patient selection markers or profiles for cetuximab can be identified will likely be determined by ongoing pharmacogenomic research. Profiles and biomarkers predictive of response to cetuximab have been preliminarily defined in metastatic CRC,41 and additional studies are underway in NSCLC, including the analysis of tumor samples collected in the course of this and other trials. Results from those studies will be reported separately. Cetuximab also seems distinct from the other anti-EGFR MoAb currently available, the IgG2 panitumumab. In a randomized phase II study, the addition of panitumumab to carboplatin/paclitaxel did not improve time to progression, response rates, or survival in untreated patients with advanced NSCLC.42 Further preclinical and correlative clinical studies would be required to establish whether this clinical discrepancy is a result of the mechanistic differences between agents. These encouraging results for cetuximab follow the success of the Eastern Cooperative Oncology Group (ECOG 4599) trial of the anti–vascular endothelial growth factor (anti-VEGF) MoAb bevacizumab43 and lend preliminary support to the addition of certain biologics to cytotoxic regimens to improve efficacy in advanced NSCLC. Bevacizumab significantly improved survival when added to carboplatin/paclitaxel in this phase III study (median survival, 12.3 v 10.3 months; P < .003); safety concerns, however, limited eligibility to patients with nonsquamous tumors, no brain metastases, and without a history of prior hemoptysis or thrombotic disorders.43 In contrast, cetuximab studies, including this one, have not been restrictive in their eligibility criteria. This cetuximab study did not exclude any tumor histology, and patients with documented (but asymptomatic) brain metastases were eligible. These results indicate the potential benefit of cetuximab may be widely applicable to a patient population closely resembling clinical reality in advanced NSCLC. Some caveats must be considered in the interpretation of this study. The major limitation of the study was its noncomparative design, not statistically powered to demonstrate significant differences between treatment arms. In addition, the small number of patients receiving cisplatin (n = 19) does not allow for an effective interpretation of the potential effect of cetuximab on this particular combination. This imbalance in the use of platinum agents, however, may be a reflection of true practice patterns for advanced NSCLC in North America, where carboplatin-based doublets are a more frequent choice for first-line therapy in advanced disease because the intent of treatment is palliative. Two larger, statistically powered trials, which have already completed their accrual, are underway to clarify the role of cetuximab in advanced NSCLC (BMS 099 and EMR 62202-046 FLEX). In addition, continued refinement in the design of combination regimens, and ongoing studies with the goal of identifying biomarkers and profiles predictive of response may also optimize patient outcomes for cetuximab in advanced NSCLC. In conclusion, although the results must be interpreted with caution given the noncomparative nature of the study, this trial is consistent with prior reports suggesting that the addition of cetuximab to platinum-based chemotherapy has an acceptable tolerability profile and may provide a clinical advantage in terms of response, progression-free survival, and overall survival in patients with advanced NSCLC.
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: Virginie Pautret, Bristol-Myers Squibb (C); Martin R. Weber, Bristol-Myers Squibb (C) Consultant or Advisory Role: Charles A. Butts, Merck KGaA/EMD (C); Frances A. Shepherd, Bristol-Myers Squibb (C) Stock Ownership: Edward L. Middleman, ImClone; Martin R. Weber, Bristol-Myers Squibb Honoraria: Charles A. Butts, Merck KGaA/EMD, Lilly Oncology; Peter M. Ellis, Eli Lilly Canada; Frances A. Shepherd, Bristol-Myers Squibb Research Funding: Helen J. Ross, Bristol-Myers Squibb Expert Testimony: None Other Remuneration: Charles A. Butts, Bristol-Myers Squibb
Conception and design: Virginie Pautret Provision of study materials or patients: Charles A. Butts, David Bodkin, Edward L. Middleman, Craig W. Englund, David Ellison, Yasmin Alam, Harvey Kreisman, Peter Graze, James Maher, Helen J. Ross, Peter M. Ellis, William McNulty, Edward Kaplan, Frances A. Shepherd Collection and assembly of data: Charles A. Butts, David Bodkin, Harvey Kreisman, Helen J. Ross, Peter M. Ellis, Virginie Pautret, Martin R. Weber, Frances A. Shepherd Data analysis and interpretation: Virginie Pautret, Martin R. Weber Manuscript writing: Charles A. Butts, Helen J. Ross, Martin R. Weber, Frances A. Shepherd Final approval of manuscript: Charles A. Butts, David Bodkin, Edward L. Middleman, Craig W. Englund, David Ellison, Yasmin Alam, Harvey Kreisman, Peter Graze, James Maher, Helen J. Ross, Peter M. Ellis, William McNulty, Edward Kaplan, Martin R. Weber, Frances A. Shepherd
Supported by Bristol-Myers Squibb and ImClone Systems Incorporated. Presented at the 43rd Annual Meeting of the American Society of Clinical Oncology, June 1-5, 2007, Chicago, IL. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. American Cancer Society: Cancer Facts and Figures 2006. Atlanta, GA, American Cancer Society, 2006 2. Canadian Cancer Society/National Cancer Institute of Canada: Canadian Cancer Statistics 2006. Toronto, Canada, 2006 3. Ettinger DS, Akerley W, Bepler G, et al: NCCN clinical practice guidelines in oncology: Non-small cell lung cancer V1.2007. http://www.nccn.org/professionals/physician_gls/PDF/nscl.pdf 4. Pfister DG, Johnson DH, Azzoli CG, et al: American Society of Clinical Oncology treatment of unresectable non–small-cell lung cancer guideline: Update 2003. J Clin Oncol 22:330-353, 2004 5. Herbst RS, Shin DM: Monoclonal antibodies target epidermal growth factor receptive-positive tumors. Cancer 94:1593-1611, 2002[CrossRef][Medline] 6. Yarden Y, Sliwkowski MX: Untangling the ErbB signaling network. Nat Rev 2:127-137, 2001[CrossRef] 7. Shepherd FA, Pereira JR, Ciuleanu T, et al: Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 353:123-132, 2005 8. Giaccone G, Herbst RS, Manegold C, et al: Gefitinib in combination with gemcitabine and cisplatin in advanced non-small-cell lung cancer: A phase III trial—INTACT 1. J Clin Oncol 22:777-784, 2004 9. Herbst RS, Prager D, Fehrenbacher L, et al: TRIBUTE: A phase III trial of erlotinib hydrochloride (OSI-774) combined with carboplatin and paclitaxel chemotherapy in advanced non-small-cell lung cancer. J Clin Oncol 23:5892-5899, 2005 10. Gatzemeier U, Pluzanska A, Szczesna A, et al: Phase III study of erlotinib in combination with cisplatin and gemcitabine in advanced non-small cell lung cancer: The Tarceva Lung Cancer Investigation trial. J Clin Oncol 25:1545-1552, 2007 11. Herbst RS, Giaccone G, Schiller JH, et al: Gefitinib in combination with paclitaxel and carboplatin in advanced non-small-cell lung cancer: A phase III trial—INTACT 2. J Clin Oncol 22:785-794, 2004 12. Lynch JL, Bell DW, Sordella R, et al: Activity mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 350:2129-2139, 2004 13. Paez JG, Jänne PA, Lee JC, et al: EGFR mutations in lung cancer: Correlation with clinical response to gefitinib therapy. Science 304:1497-1500, 2004 14. Pao W, Miller V, Zakowski M, et al: EGF receptor gene mutations are common in lung cancer from "never smokers" and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci U S A 101:13306-13311, 2004 15. Tsao MS, Sakurada A, Cutz JC, et al: Erlotinib in lung cancer: Molecular and clinical predictors of outcome. N Engl J Med 353:133-144, 2005 16. Eberhard DA, Johnson BE, Amler LC, et al: Mutations in the epidermal growth factor receptor in KRAS are predictive and prognostic indicators in patients with non-small-cell lung cancer treated with chemotherapy alone and in combination with erlotinib. J Clin Oncol 23:5900-5909, 2005 17. Mendelsohn J, Baselga J: Status of epidermal growth factor receptor antagonists in the biology and treatment of cancer. J Clin Oncol 21:2787-2799, 2003 18. Dittmann K, Mayer C, Fehrenbacher B, et al: Radiation-induced epidermal growth factor receptor nuclear import is linked to activation of DNA-dependent protein kinase. J Biol Chem 280:31182-31189, 2005 19. Huang S-M, Harari PM: Modulation of radiation response after epidermal growth factor receptor blockade in squamous cell carcinomas: Inhibition of damage repair, cell cycle kinetics, and tumor angiogenesis. Clin Cancer Res 6:2166-2174, 2000 20. Fan Z, Masui H, Altas I, et al: Blockade of epidermal growth factor receptor function by bivalent and monovalent fragments of 225 anti-epidermal growth factor receptor monoclonal antibodies. Cancer Res 53:4322-4328, 1993 21. Balin-Gauthier D, Delord JP, Rochaix P, et al: In vivo and in vitro antitumor activity of oxaliplatin in combination with cetuximab in human colorectal tumor cell lines expressing different level of EGFR. Cancer Chemother Pharmacol 57:709-718, 2006[CrossRef][Medline] 22. Kawaguchi Y, Kono K, Mimura K, et al: Cetuximab induces antibody-dependent cellular cytotoxicity against EGFR-expressing esophageal squamous cell carcinoma. Int J Cancer 120:781-787, 2007[CrossRef][Medline] 23. Kurai J, Chikumi H, Hashimoto K, et al: Antibody-dependent cellular cytotoxicity mediated by cetuximab against lung cancer cell lines. Clin Cancer Res 13:1552-1561, 2007 24. 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 25. Sobrero AF, Fehrenbacher L, Rivera F, et al: Randomized phase III trial of cetuximab plus irinotecan versus irinotecan alone for metastatic colorectal cancer in 1298 patients who have failed prior oxaliplatin-based therapy: The EPIC trial. Presented at the Annual Meeting of the American Association for Cancer Research, April 14-18, 2007, Los Angeles, CA 26. Bonner JA: Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med 354:567-578, 2006 27. Venook A, Niedzwiecki D, Hollis D, et al: Phase III study of irinotecan/5FU/LV (FOLFIRI) or oxaliplatin/5FU/LV (FOLFOX) ± cetuximab for patients (pts) with untreated metastatic adenocarcinoma of the colon or rectum (MCRC): CALGB 80203 preliminary results. J Clin Oncol 24, 2006 (suppl; abstr 3509) 28. Rosell R, Daniel C, Ramlau, R, et al: Randomized phase II study of cetuximab (ERBITUX) in combination with cisplatin/vinorelbine vs. cisplatin/vinorelbine alone in the first-line treatment of patients with EGFR-expressing, advanced NSCLC (study EMR 62202-011 ‘LUCAS’). J Clin Oncol 22:618s, 2004 (suppl; abstr 7012) 29. Robert F, Blumenschein G, Herbst RS, et al: Phase I/IIa study of cetuximab with gemcitabine plus carboplatin in patients with chemotherapy-naive advanced non-small-cell lung cancer. J Clin Oncol 23:9089-9096, 2005 30. Thienelt CD, Bunn PA, Hanna N, et al: Multicenter phase I/II study of cetuximab with paclitaxel and carboplatin in untreated patients with stage IV non-small-cell lung cancer. J Clin Oncol 23:8786-8793, 2005 31. Herbst RS, Chansky K, Kelly K, et al: A phase II randomized selection trial evaluating concurrent chemotherapy plus cetuximab or chemotherapy followed by cetuximab in patients with advanced non-small cell lung cancer (NSCLC): Final report of SWOG 0342. J Clin Oncol 25, 2007 (suppl; abstr 7545) 32. Hanna N, Lilenbaum R, Ansari R, et al: Phase II trial of cetuximab in patients with previously treated non–small-cell lung cancer. J Clin Oncol 24:5253-5258, 2006 33. ERBITUX (Cetuximab) Package Insert. New York, NY, ImClone Systems Incorporated; and Princeton, NJ, Bristol-Myers Squibb Company, 2006 34. Clopper CJ, Pearson ES: The use of confidence or fiducial limits illustrated in the case of the binomial. Biometrika 26:404-413, 1934 35. Brookmeyer R, Crowley J: A confidence interval for the median survival time. Biometrics 38:29-41, 1982[CrossRef] 36. Hirsch FR, Varella-Garcia M, Bunn PA Jr, et al: Molecular predictors of outcome with gefitinib in a phase III placebo-controlled study in advanced non-small-cell lung cancer. J Clin Oncol 24:5034-5042, 2006 37. Tsuchihashi Z, Khambata-Ford S, Hanna N, et al: Responsiveness to cetuximab without mutation in EGFR. N Engl J Med 353:208-209, 2005 38. Steiner P, Joynes C, Bassi R, et al: Tumor growth inhibition with cetuximab and chemotherapy in non-small cell lung cancer xenografts expressing wild-type and mutated epidermal growth factor receptor. Clin Cancer Res 13:1540-1551, 2007 39. Saltz LB, Meropol NJ, Loehrer PJ, et al: Phase II trial of cetuximab in patients with refractory colorectal cancer that expresses the epidermal growth factor receptor. J Clin Oncol 22:1201-1208, 2004 40. Lenz HJ, Van Cutsem E, Khambata-Ford S, et al: Multicenter phase II and translational study of cetuximab in metastatic colorectal carcinoma refractory to irinotecan, oxaliplatin, and fluoropyrimidines. J Clin Oncol 24:4914-4921, 2006 41. Khambata-Ford S, Perkins N-A, Huang X, et al: Preclinical discovery and clinical validation of predictive markers of response to cetuximab (Erbitux) in metastatic colorectal cancer. Proc Am Assoc Cancer Res 47, 2006 (abstr 4032) 42. Crawford J, Swanson P, Prager D, et al: Panitumumab, a fully human antibody, combined with paclitaxel and carboplatin versus paclitaxel and carboplatin alone for first line advanced non-small cell lung cancer (NSCLC): A primary analysis. Eur J Cancer 3:324, 2005 (suppl; abstr 1123) 43. Sandler AB, Gray R, Perry MC, et al: Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 355:2542-2550, 2006 Submitted June 19, 2007; accepted September 19, 2007.
This article has been cited by other articles:
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
TOP
ABSTRACT
INTRODUCTION
) Patents discontinuing chemotherapy without evidence of disease progression continued to receive weekly cetuximab and were monitored every 6 weeks until disease progression or cetuximab intolerance was documented. (
) Patients discontinuing chemotherapy without evidence of disease progression were monitored every 6 weeks until disease progression was observed. Cross-over between treatment arms was not allowed. d, day; q3w, every 3 weeks; AUC, area under the concentration-versus-time curve; ECOG PS, Eastern Cooperative Oncology Group performance status.
