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The Oncologist, Vol. 12, No. 3, 325-330, March 2007; doi:10.1634/theoncologist.12-3-325
© 2007 AlphaMed Press

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Lung Cancer

Second-Generation Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Non-Small Cell Lung Cancer

Lecia V. Sequist

Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA

Key Words. Epidermal growth factor receptor • Non-small cell lung cancer • Tyrosine kinase

Correspondence: Correspondence: Lecia V. Sequist, M.D., M.P.H., Massachusetts General Hospital Cancer Center, 32 Fruit Street, Yawkey Suite 7B, Boston, Massachusetts 02114, USA. Telephone: 617-726-7812; Fax: 617-726-0453; e-mail: lvsequist{at}partners.org

Received November 6, 2006; accepted for publication January 2, 2007.


   LEARNING OBJECTIVES
Top
 Learning Objectives
Abstract
 Introduction
 EKB-569
 HKI-272
 CI-1033
 ZD6474
 Conclusion
 Disclosure of Potential...
 References
 
After completing this course, the reader will be able to:

  1. Describe the magnitude of benefit achieved through the use of first-generation EGFR TKIs in NSCLC.
  2. Discuss the clinical obstacles of primary and secondary resistance to first-generation EGFR TKI agents.
  3. Describe at least two strategies employed in improving the design of second-generation EGFR TKI agents over their predecessors.

Access and take the CME test online and receive 1 AMA PRA Category 1 CreditTM at CME.TheOncologist.com


   ABSTRACT
Top
 Learning Objectives
 Abstract
Introduction
 EKB-569
 HKI-272
 CI-1033
 ZD6474
 Conclusion
 Disclosure of Potential...
 References
 
Inhibiting epidermal growth factor receptor (EGFR) signaling has proven to be an effective strategy for treating non-small cell lung cancer (NSCLC) patients and the first generation of agents developed for this purpose, gefitinib and erlotinib, stimulated a unique escalation in both biologic and clinical research within the field. Second-generation EGFR-targeted agents that aim to further improve patient outcomes are now in preclinical and clinical trials. This review discusses four promising agents that are currently being studied in NSCLC: EKB-569, HKI-272, CI-1033, and ZD6474.

Disclosure of potential conflicts of interest is found at the end of this article.


   INTRODUCTION
Top
 Learning Objectives
 Abstract
 Introduction
EKB-569
 HKI-272
 CI-1033
 ZD6474
 Conclusion
 Disclosure of Potential...
 References
 
The epidermal growth factor receptor (EGFR) signaling pathway is an important mediator of cancer cell oncogenesis, proliferation, maintenance, and survival. For this reason, it has long been an attractive candidate as an anticancer drug target [1]. In the past several years, two compounds that target EGFR signaling have made a significant impact on the understanding of the biology of non-small cell lung cancer (NSCLC) and the treatment options for patients suffering from this disease. Both gefitinib (Iressa®; AstraZeneca Pharmaceuticals, Wilmington, DE) and erlotinib (Tarceva®; Genentech, Inc., South San Francisco, CA), the first-generation EGFR tyrosine kinase inhibitors (TKIs), have single-agent activity against advanced NSCLC, and erlotinib improves survival when given as salvage treatment after chemotherapy [2–5]. The subset of patients that benefit from EGFR-targeted TKIs has been partially defined, by clinical characteristics such as nonsmoking history and well-differentiated adenocarcinoma histology, and by molecular characteristics such as somatic activating EGFR mutations and increased EGFR gene copy number [6–11]. However, there is still much work to be done to further understand the role of EGFR in the molecular biology of NSCLC and the clinical implications of blocking this signaling pathway as a therapeutic strategy.

One thing that is clear from studies performed thus far is that the degree of clinical benefit derived from first-generation EGFR TKIs is modest. The response rate to these agents in the general NSCLC population is low, approximately 10% in North America and 20% in Asia, implying that the majority of patients have primary resistance to treatment [2, 3]. A large body of current research is focusing on how to better identify patients with a high chance of benefiting from first-generation EGFR TKIs, via clinical or molecular profiling. Yet even patients who are exquisitely sensitive to gefitinib and erlotinib by virtue of somatic EGFR mutations ultimately develop resistance, sometimes as a result of a secondary acquired EGFR mutation known as the T790M mutation [12, 13]. In most cases, the specific mechanism(s) of primary or acquired resistance to first-generation EGFR TKIs has not been fully elucidated; however, the general principles of signaling via parallel redundant pathways, constitutive activation of downstream mediators, altered receptor trafficking, efflux of the drug from the cell, and mutation of the drug target itself have been implicated as contributors [12–16]. The combined obstacles of primary and acquired resistance result in a modest survival advantage of 2 months when giving erlotinib as a second-line treatment to an unselected NSCLC population [5].

The second generation of EGFR TKI compounds is now emerging from the developmental pipeline and being introduced into clinical trials. This review describes four of these novel agents that are promising as NSCLC treatments, and focuses on the properties and characteristics by which these drugs attempt to improve upon their predecessors. The two most commonly employed strategies are introducing covalent (irreversible) binding of the drug to the drug target and broadening the affected receptor tyrosine kinase targets of the drug within the cell. The first-generation drugs gefitinib and erlotinib join to their target, the catalytic site in the EGFR TK domain, through classic competitive binding with ATP [17, 18]. In contrast, many of the second-generation compounds form covalent, and therefore permanent, bonds with their target, which should theoretically increase their effectiveness by prolonging the inhibition of EGFR signaling to the entire lifespan of the drug-bound receptor molecule. In cell culture systems, such irreversibly binding TKIs can effectively kill cells that have acquired resistance to first-generation TKIs [15].

The other common theme to the design of the second-generation EGFR TKIs is kinase multitargeting. Gefitinib and erlotinib are both fairly selective for the EGFR TK domain [19, 20]. However, the signaling network that emerges from the ErbB family of transmembrane TK receptors (of which EGFR is a member) is large, interconnected, and redundant, with many possible routes between the ligand at the cell surface and the message destination within the nucleus [21]. It is this diversity in possible signal transduction routes that allows a cell to have flexibility and, in the case of cancer cells treated with targeted anticancer agents, allows for the emergence of resistant cell clones that bypass the inhibited receptor [16]. Blocking multiple signaling pathways with either a combination of agents or a single multitargeted drug has been synergistic in preclinical models [22–25]. Second-generation EGFR TKIs have been developed that, in addition to blocking EGFR signaling, target additional members of the ErbB family such as HER-2 or other downstream or parallel pathways such as the vascular endothelial growth factor receptor (VEGFR) pathway. We now turn our attention to a discussion of selected second-generation EGFR TKI compounds; see Table 1 for a summary.


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  		Table 1. Summary of first- and selected second-generation Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitors

 

   EKB-569
Top
 Learning Objectives
 Abstract
 Introduction
 EKB-569
HKI-272
 CI-1033
 ZD6474
 Conclusion
 Disclosure of Potential...
 References
 
EKB-569 is a second-generation irreversibly binding inhibitor of EGFR TK activity [26]. Animal studies confirmed that even though the drug itself is rapidly cleared from the plasma, inhibition of EGFR signaling is prolonged, as expected with a covalently bound inhibitor [27]. A phase I dose-escalation study examining two different dose schedules was recently reported [28]. Thirty patients were treated daily for 14 days of a 28-day cycle and 29 patients received continuous daily dosing. The dose-limiting toxicity was grade 3 diarrhea and the maximum-tolerated dose on both schedules was 75 mg/day. Other adverse events included rash, nausea, vomiting, and asthenia. No responses were seen in this phase I study, although 24 patients had stable disease for at least 8 weeks, including one NSCLC patient with stable disease for 33 weeks. Another phase I dose-ranging study with EKB-569 in Japanese patients with advanced solid tumors was also recently completed. The full results of the study have not been published, but a case report described two patients with NSCLC, both harboring EGFR mutations and resistant to gefitinib, with clinical responses to treatment [29]. A phase II study of EKB-569 in NSCLC has been completed and results are pending.


   HKI-272
Top
 Learning Objectives
 Abstract
 Introduction
 EKB-569
 HKI-272
CI-1033
 ZD6474
 Conclusion
 Disclosure of Potential...
 References
 
HKI-272 is a second-generation TKI that uses both the strategies of covalent binding and multitargeting; it is an irreversible inhibitor of the EGFR and HER-2 receptors [30]. Animal xenograft models demonstrated activity against both EGFR-dependent and HER-2–dependent cancers, though potency was superior against HER-2–dependent cancers [30]. In a phase I dose-escalation trial including 73 patients whose tumors expressed either the EGFR or HER-2 receptor, HKI-272 was shown to be well tolerated, with primary toxicities of diarrhea, nausea, asthenia, and anorexia [31]. The dose-limiting toxicity was grade 3 diarrhea at 400 mg/day, establishing the maximum-tolerated dose as 320 mg/day. Several patients with breast cancer or NSCLC derived clinical benefit (response or stable disease) from treatment with HKI-272 in this phase I trial. Development of this compound as a breast cancer treatment was under way when preclinical research suggested that HKI-272 might be particularly effective against NSCLC that had previously been treated with first-generation EGFR TKIs and had acquired resistance, either through the T790M mutation or other mechanisms [15]. More recently, NSCLC cells that harbor rare mutations in HER-2 and are resistant to erlotinib were found to be sensitive to killing by HKI-272 [32]. Hence, development of this drug as a treatment for NSCLC is moving forward, and an international phase II trial is ongoing, including patients previously treated with gefitinib or erlotinib as well as those that are TKI naïve.


   CI-1033
Top
 Learning Objectives
 Abstract
 Introduction
 EKB-569
 HKI-272
 CI-1033
ZD6474
 Conclusion
 Disclosure of Potential...
 References
 
CI-1033 is an irreversible pan-ErbB inhibitor, meaning it inhibits EGFR and HER-2, as well as ErbB-4 [33]. The final ErbB family member, ErbB-3, has no intrinsic kinase activity and signals only when dimerized with another ErbB receptor; therefore, blocking TK activity of EGFR, HER-2, and ErbB-4 precludes ErbB-3 signaling [34]. CI-1033 was designed with the hope that a pan-ErbB inhibitor would be more effective than blocking EGFR alone, because activation of EGFR signaling requires dimerization with other members of the family, and because crosstalk between pathways and parallel activation of downstream effectors are important parts of the amplification of the EGFR signal.

Several phase I studies have been performed, examining various oral dosing schedules [34–38]. These studies have shown that the maximum-tolerated dose of CI-1033 is generally lower when the consecutive number of days of treatment administration is increased; for example, 500 mg/day on a once-weekly schedule, 250 mg/day on a 7-day on/7-day off schedule, and 150 mg/day on continuous daily dosing. Diarrhea and rash have been the most common grade 3 and dose-limiting toxicities observed, and thrombocytopenia has also been reported. Patients with various solid tumors have had stable disease on treatment and one patient with squamous cell cancer of the skin had a complete response to treatment that lasted over 20 months [33]. A phase II trial of CI-1033 in NSCLC patients has completed enrollment, though results have not yet been reported.

In addition, preclinical data suggest that CI-1033 may be synergistic with chemotherapy, and a phase I study of CI-1033 with docetaxel has demonstrated the safety of this approach [39–41]. A phase II trial of CI-1033 in combination with carboplatin and paclitaxel chemotherapy has also been completed. Finally, the strategy of administering CI-1033 i.v. has been evaluated in a phase I trial, because the bioavailability by this route is three times that of oral administration [42]. It was hoped that i.v. CI-1033 might decrease gastrointestinal side effects from treatment; however, stomatitis, nausea, vomiting, and diarrhea were still the primary toxicities observed, and the inconvenience of the three-times-a-week infusion will likely limit the further study of this approach.


   ZD6474
Top
 Learning Objectives
 Abstract
 Introduction
 EKB-569
 HKI-272
 CI-1033
 ZD6474
Conclusion
 Disclosure of Potential...
 References
 
ZD6474 is a dual-kinase inhibitor that primarily inhibits VEGFR-2, but also has moderate anti-EGFR activity [43]. VEGFR-2, also known as KDR, plays an important role in tumor angiogenesis, and its overexpression is associated with a poor prognosis in NSCLC and other cancers [44, 45]. Targeting the VEGF pathway with the monoclonal antibody bevacizumab in conjunction with chemotherapy can improve survival in NSCLC patients over chemotherapy alone [46], and there is early clinical evidence that blocking both EGFR and VEGFR together (without chemotherapy) can be active, as a phase I/II study of erlotinib plus bevacizumab demonstrated a response rate of 20% [47]. Preclinical experiments demonstrated that the dual-kinase inhibitor ZD6474 has antitumor activity, even in systems that modeled resistance to first-generation EGFR TKIs [48, 49]. In a phase I clinical study, ZD6474 was given as a daily oral treatment to 77 patients; the most common adverse events observed were diarrhea, rash, hypertension, and asymptomatic QT-prolongation, and the maximally tolerated dose was defined as 300 mg/day [50].

ZD6474 was evaluated in parallel with gefitinib in a population of 168 previously treated NSCLC patients in a randomized phase II study with the option to crossover to the other drug at the time of progression [51]. The response rate was 8% in the ZD6474 arm and 1% in the gefitinib arm, with a longer progression-free survival time for the ZD6474 arm compared with the gefitinib arm (11 weeks versus 8.1 weeks, respectively; p = .03). No survival difference was noted, perhaps because of the crossover design. A similar trial comparing ZD6474 with erlotinib is ongoing.

Given the successful outcome of combining the anti-VEGF agent bevacizumab with chemotherapy in NSCLC patients [52], a second randomized phase II trial was performed using ZD6474 or placebo in combination with docetaxel chemotherapy in 127 previously treated NSCLC patients [53]. The progression-free survival time was longer with ZD6474 than with placebo (18.7 weeks versus 12.0 weeks, respectively; p = .07, which was interpreted as significant because they had a priori established a p-value of <.2 as significant enough to warrant further study). A phase II trial of ZD6474 in combination with carboplatin and paclitaxel for first-line treatment of NSCLC and a randomized phase III trial of docetaxel with ZD6474 or placebo for previously treated NSCLC patients are currently enrolling patients.


   CONCLUSION
Top
 Learning Objectives
 Abstract
 Introduction
 EKB-569
 HKI-272
 CI-1033
 ZD6474
 Conclusion
Disclosure of Potential...
 References
 
Phase I and phase II clinical trial results of the novel second-generation EGFR TKI agents EKB-569, HKI-272, CI-1033, and ZD6474 are intriguing. Further studies are being conducted to establish the utility of these agents in treating NSCLC patients and their role within the existing armamentarium of drugs for this disease. In addition, advances in our understanding of the molecular biology of NSCLC and the effects of blocking various aspects of the oncogenic signaling network within the tumor will help guide the rational development of a third generation of targeted anticancer agents.


   DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST
Top
 Learning Objectives
 Abstract
 Introduction
 EKB-569
 HKI-272
 CI-1033
 ZD6474
 Conclusion
 Disclosure of Potential...
References
 
The authors indicate no potential conflicts of interest.


   REFERENCES
Top
 Learning Objectives
 Abstract
 Introduction
 EKB-569
 HKI-272
 CI-1033
 ZD6474
 Conclusion
 Disclosure of Potential...
 References
 

  1. Mendelsohn J. Targeting the epidermal growth factor receptor for cancer therapy. J Clin Oncol 2002;20(18 suppl):1S–13S.[Medline]
  2. Fukuoka M, Yano S, Giaccone G et al. Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer (The IDEAL 1 Trial) [corrected]. J Clin Oncol 2003;21:2237–2246.[Abstract/Free Full Text]
  3. Kris MG, Natale RB, Herbst RS et al. Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer: A randomized trial. JAMA 2003;290:2149–2158.[Abstract/Free Full Text]
  4. Perez-Soler R, Chachoua A, Hammond LA et al. Determinants of tumor response and survival with erlotinib in patients with non–small-cell lung cancer. J Clin Oncol 2004;22:3238–3247.[Abstract/Free Full Text]
  5. Shepherd FA, Rodrigues Pereira J, Ciuleanu T et al. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 2005;353:123–132.[Abstract/Free Full Text]
  6. Miller VA, Kris MG, Shah N et al. Bronchioloalveolar pathologic subtype and smoking history predict sensitivity to gefitinib in advanced non-small-cell lung cancer. J Clin Oncol 2004;22:1103–1109.[Abstract/Free Full Text]
  7. Lynch TJ, Bell DW, Sordella R et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 2004;350:2129–2139.[Abstract/Free Full Text]
  8. Paez JG, Janne PA, Lee JC et al. EGFR mutations in lung cancer: Correlation with clinical response to gefitinib therapy. Science 2004;304:1497–1500.[Abstract/Free Full Text]
  9. Pao W, Miller V, Zakowski M et al. EGF receptor gene mutations are common in lung cancers from "never smokers" and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci U S A 2004;101:13306–13311.[Abstract/Free Full Text]
  10. Cappuzzo F, Hirsch FR, Rossi E et al. Epidermal growth factor receptor gene and protein and gefitinib sensitivity in non-small-cell lung cancer. J Natl Cancer Inst 2005;97:643–655.[Abstract/Free Full Text]
  11. Sequist LV, Bell DW, Lynch TJ et al. Molecular predictors of response to EGFR antagonists in non-small cell lung cancer. J Clin Oncol 2007;25:587–595.[Abstract/Free Full Text]
  12. Kobayashi S, Boggon TJ, Dayaram T et al. EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N Engl J Med 2005;352:786–792.[Abstract/Free Full Text]
  13. Pao W, Miller VA, Politi KA et al. Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med 2005;2:e73.[CrossRef][Medline]
  14. Camp ER, Summy J, Bauer TW et al. Molecular mechanisms of resistance to therapies targeting the epidermal growth factor receptor. Clin Cancer Res 2005;11:397–405.[Abstract/Free Full Text]
  15. Kwak EL, Sordella R, Bell DW et al. Irreversible inhibitors of the EGF receptor may circumvent acquired resistance to gefitinib. Proc Natl Acad Sci U S A 2005;102:7665–7670.[Abstract/Free Full Text]
  16. Rubin BP, Duensing A. Mechanisms of resistance to small molecule kinase inhibition in the treatment of solid tumors. Lab Invest 2006;86:961–986.
  17. Wakeling AE, Guy SP, Woodburn JR et al. ZD1839 (Iressa): An orally active inhibitor of epidermal growth factor signaling with potential for cancer therapy. Cancer Res 2002;62:5749–5754.[Abstract/Free Full Text]
  18. Stamos J, Sliwkowski MX, Eigenbrot C. Structure of the epidermal growth factor receptor kinase domain alone and in complex with a 4-anilinoquinazoline inhibitor. J Biol Chem 2002;277:46265–46272.[Abstract/Free Full Text]
  19. Ranson M, Hammond LA, Ferry D et al. ZD1839, a selective oral epidermal growth factor receptor-tyrosine kinase inhibitor, is well tolerated and active in patients with solid, malignant tumors: Results of a phase I trial. J Clin Oncol 2002;20:2240–2250.[Abstract/Free Full Text]
  20. Hidalgo M, Siu LL, Nemunaitis J et al. Phase I and pharmacologic study of OSI-774, an epidermal growth factor receptor tyrosine kinase inhibitor, in patients with advanced solid malignancies. J Clin Oncol 2001;19:3267–3279.[Abstract/Free Full Text]
  21. Yarden Y, Sliwkowski MX. Untangling the ErbB signalling network. Nat Rev Mol Cell Biol 2001;2:127–137.[CrossRef][Medline]
  22. 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 2001;85:584–589.[CrossRef][Medline]
  23. Yokoi K, Thaker PH, Yazici S et al. Dual inhibition of epidermal growth factor receptor and vascular endothelial growth factor receptor phosphorylation by AEE788 reduces growth and metastasis of human colon carcinoma in an orthotopic nude mouse model. Cancer Res 2005;65:3716–3725.[Abstract/Free Full Text]
  24. Zhou Y, Li S, Hu YP et al. Blockade of EGFR and ErbB2 by the novel dual EGFR and ErbB2 tyrosine kinase inhibitor GW572016 sensitizes human colon carcinoma GEO cells to apoptosis. Cancer Res 2006;66:404–411.[Abstract/Free Full Text]
  25. Zhou Y, Brattain MG. Synergy of epidermal growth factor receptor kinase inhibitor AG1478 and ErbB2 kinase inhibitor AG879 in human colon carcinoma cells is associated with induction of apoptosis. Cancer Res 2005;65:5848–5856.[Abstract/Free Full Text]
  26. Wissner A, Overbeek E, Reich MF et al. Synthesis and structure-activity relationships of 6,7-disubstituted 4-anilinoquinoline-3-carbonitriles. The design of an orally active, irreversible inhibitor of the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) and the human epidermal growth factor receptor-2 (HER-2). J Med Chem 2003;46:49–63.[CrossRef][Medline]
  27. Torrance CJ, Jackson PE, Montgomery E et al. Combinatorial chemoprevention of intestinal neoplasia. Nat Med 2000;6:1024–1028.[CrossRef][Medline]
  28. Erlichman C, Hidalgo M, Boni JP et al. Phase I study of EKB-569, an irreversible inhibitor of the epidermal growth factor receptor, in patients with advanced solid tumors. J Clin Oncol 2006;24:2252–2260.[Abstract/Free Full Text]
  29. Yoshimura N, Kudoh S, Kimura T et al. EKB-569, a new irreversible epidermal growth factor receptor tyrosine kinase inhibitor, with clinical activity in patients with non-small cell lung cancer with acquired resistance to gefitinib. Lung Cancer 2006;51:363–368.[CrossRef][Medline]
  30. Rabindran SK, Discafani CM, Rosfjord EC et al. Antitumor activity of HKI-272, an orally active, irreversible inhibitor of the HER-2 tyrosine kinase. Cancer Res 2004;64:3958–3965.[Abstract/Free Full Text]
  31. Wong KK, Fracasso PM, Bukowski RM et al. HKI-272, an irreversible pan ErbB receptor tyrosine kinase inhibitor: Preliminary phase 1 results in patients with solid tumors. J Clin Oncol 2006;24(18 suppl):3018.
  32. Shimamura T, Ji H, Minami Y et al. Non-small-cell lung cancer and Ba/F3 transformed cells harboring the ERBB2 G776insV_G/C mutation are sensitive to the dual-specific epidermal growth factor receptor and ERBB2 inhibitor HKI-272. Cancer Res 2006;66:6487–6491.[Abstract/Free Full Text]
  33. Allen LF, Eiseman IA, Fry DW et al. CI-1033, an irreversible pan-ErbB receptor inhibitor and its potential application for the treatment of breast cancer. Semin Oncol 2003;30(suppl 16):65–78.[CrossRef][Medline]
  34. Calvo E, Tolcher AW, Hammond LA et al. Administration of CI-1033, an irreversible pan-ErbB tyrosine kinase inhibitor, is feasible on a 7-day on, 7-day off schedule: A phase I pharmacokinetic and food effect study. Clin Cancer Res 2004;10:7112–7120.[Abstract/Free Full Text]
  35. Nemunaitis J, Eiseman I, Cunningham C et al. Phase 1 clinical and pharmacokinetics evaluation of oral CI-1033 in patients with refractory cancer. Clin Cancer Res 2005;11:3846–3853.[Abstract/Free Full Text]
  36. Rinehart JJ, Wilding G, Willson JK et al. A phase I clinical and pharmacokinetic (PK)/food effect study of oral CI-1033, a pan-Erb B tyrosine kinase inhibitor, in patients with advanced solid tumors. Presented at the 2003 American Society of Clinical Oncology Annual Meeting; May 31–June 3, 2003; Chicago, IL.
  37. Garrison MA, Tolcher A, McCreery H et al. A phase I and pharmacokinetic study of CI-1033, a pan-ErbB tyrosine kinase inhibitor, given orally on days 1, 8, and 15 every 28 days to patients with solid tumors. Presented at the 2001 American Society of Clinical Oncology Annual Meeting; May 12–15, 2001; San Francisco, CA.
  38. Rinehart JJ, Wilding G, Willson JK et al. A phase I clinical and pharmacokinetic study of oral CI-1033, a pan-ErbB tyrosine kinase inhibitor, in patients with advanced solid tumors. Presented at the 2002 American Society of Clinical Oncology Annual Meeting; May 18–21, 2002; Orlando, FL.
  39. Gieseg MA, de Bock C, Ferguson LR et al. Evidence for epidermal growth factor receptor-enhanced chemosensitivity in combinations of cisplatin and the new irreversible tyrosine kinase inhibitor CI-1033. Anticancer Drugs 2001;12:683–690.[CrossRef][Medline]
  40. Erlichman C, Boerner SA, Hallgren CG et al. The HER tyrosine kinase inhibitor CI1033 enhances cytotoxicity of 7-ethyl-10-hydroxycamptothecin and topotecan by inhibiting breast cancer resistance protein-mediated drug efflux. Cancer Res 2001;61:739–748.[Abstract/Free Full Text]
  41. Garland LL, Hidalgo M, Mendelson DS et al. A phase I clinical and pharmacokinetic study of oral CI-1033 in combination with docetaxel in patients with advanced solid tumors. Clin Cancer Res 2006;12:4274–4282.[Abstract/Free Full Text]
  42. Simon GR, Garrett CR, Olson SC et al. Increased bioavailability of intravenous versus oral CI-1033, a pan ErbB tyrosine kinase inhibitor: Results of a phase I pharmacokinetic study. Clin Cancer Res 2006;12:4645–4651.[Abstract/Free Full Text]
  43. Wedge SR, Ogilvie DJ, Dukes M et al. ZD6474 inhibits vascular endothelial growth factor signaling, angiogenesis, and tumor growth following oral administration. Cancer Res 2002;62:4645–4655.[Abstract/Free Full Text]
  44. Lamoreaux WJ, Fitzgerald ME, Reiner A et al. Vascular endothelial growth factor increases release of gelatinase A and decreases release of tissue inhibitor of metalloproteinases by microvascular endothelial cells in vitro. Microvasc Res 1998;55:29–42.[CrossRef][Medline]
  45. Yuan A, Yu CJ, Kuo SH et al. Vascular endothelial growth factor 189 mRNA isoform expression specifically correlates with tumor angiogenesis, patient survival, and postoperative relapse in non-small-cell lung cancer. J Clin Oncol 2001;19:432–441.[Abstract/Free Full Text]
  46. Sandler A, Gray R, Perry MC et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 2006;355:2542–2550.[Abstract/Free Full Text]
  47. 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 2005;23:2544–2555.[Abstract/Free Full Text]
  48. Ciardiello F, Caputo R, Damiano V et al. Antitumor effects of ZD6474, a small molecule vascular endothelial growth factor receptor tyrosine kinase inhibitor, with additional activity against epidermal growth factor receptor tyrosine kinase. Clin Cancer Res 2003;9:1546–1556.[Abstract/Free Full Text]
  49. Ciardiello F, Bianco R, Caputo R et al. Antitumor activity of ZD6474, a vascular endothelial growth factor receptor tyrosine kinase inhibitor, in human cancer cells with acquired resistance to antiepidermal growth factor receptor therapy. Clin Cancer Res 2004;10:784–793.[Abstract/Free Full Text]
  50. Holden SN, Eckhardt SG, Basser R et al. Clinical evaluation of ZD6474, an orally active inhibitor of VEGF and EGF receptor signaling, in patients with solid, malignant tumors. Ann Oncol 2005;16:1391–1397.[Abstract/Free Full Text]
  51. Natale RB, Bodkin D, Govindan R et al. ZD6474 versus gefitinib in patients with advanced NSCLC: Final results from a two-part, double-blind, randomized phase II trial. Presented at the 2006 American Society of Clinical Oncology Annual Meeting; June 2–6, 2006; Atlanta, GA.
  52. Sandler A, Gray R, Brahmer J et al. Randomized phase II/III trial of paclitaxel (P) plus carboplatin (C) with or without bevacizumab (NSC #704865) in patients with advanced non-squamous non-small cell lung cancer (NSCLC): An Eastern Cooperative Oncology Group (ECOG) Trial - E4599. Presented at the 2005 American Society of Clinical Oncology Annual Meeting; May 13–17, 2005; Orlando, FL.
  53. Heymach JV, Johnson BE, Prager D et al. A phase II trial of ZD6474 plus docetaxel in patients with previously treated NSCLC: Follow-up results. Presented at the 2006 American Society of Clinical Oncology Annual Meeting; June 2–6, 2006; Atlanta, GA.



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THE ONCOLOGIST STEM CELLS CME ALPHAMED PRESS JOURNALS
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