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The Oncologist, Vol. 7, Suppl 4, 16-24, August 15, 2002
© 2002 AlphaMed Press

ZD1839 (IressaTM): For More Than Just Non-Small Cell Lung Cancer

Malcolm Ranson

Department of Medical Oncology, Christie Hospital NHS Trust, Manchester, United Kingdom

Correspondence: Malcolm Ranson, M.D., Department of Medical Oncology, Christie Hospital NHS Trust, Wilmslow Road, Manchester, UK, M20 4BX. Telephone: 44-0-161-446-3000; Fax: 44-0-161-446-3299; e-mail: malcolm.ranson{at}man.ac.uk


   LEARNING OBJECTIVES
Top
 Learning Objectives
Abstract
 Introduction
 Conclusion
 References
 
After completing this course, the reader will be able to:

  1. Recognize the basic biology and importance of the erbB family of growth factor receptors.
  2. Explain the current status of clinical development of ZD1839 in solid tumors other than non-small cell lung cancer (NSCLC).
  3. Appreciate some of the future directions for clinical research for this class of anti-tumor agent.

Access and take the CME test online and receive one hour of AMA PRA category 1 credit at CME.TheOncologist.com


   ABSTRACT
Top
 Learning Objectives
 Abstract
Introduction
 Conclusion
 References
 
ZD1839 (IressaTM) is an orally active, selective epidermal growth factor receptor tyrosine kinase inhibitor that blocks signal transduction pathways involved in cell proliferation. Preclinical studies demonstrated that ZD1839 is a promising agent for the treatment of a wide range of tumors and has additive-to-synergistic effects when combined with radiation or chemotherapy in various cell lines and xenografts. Phase I clinical trials have reported that ZD1839 has acceptable tolerability and antitumor activity. In addition to non-small cell lung cancer, phase II/III studies are currently investigating ZD1839 as monotherapy or in combination therapy against prostate, breast, head and neck, gastric, and colorectal tumors.

Key Words. ZD1839 (IressaTM) • Breast cancer • Prostate cancer • Head and neck cancer • Colorectal cancer


   INTRODUCTION
Top
 Learning Objectives
 Abstract
 Introduction
Conclusion
 References
 
At the beginning of the new millennium, there were over 10 million new cancer cases, 6.2 million cancer deaths and 22.4 million people living with cancer worldwide [1]. The most common cancers in terms of new cases were lung (1.2 million), breast (1.05 million), colorectal (945,000), stomach (876,000), and liver (564,000), and it is estimated that, in 2020, there will be 15 million new cases and 10 million deaths [1]. Current anticancer treatments include surgery, radiotherapy, chemotherapy, and endocrine therapy. However, many of the available treatment options have significant toxicity with limited efficacy, and these limitations emphasize the need for development of innovative strategies to combat the disease, provide maintenance therapy, and enhance quality of life.

The epidermal growth factor receptor (EGFR) is one of a family of four closely related receptors that use tyrosine kinase activity as the signal transduction trigger: EGFR (or erbB1), HER2/neu (erbB2), HER3 (erbB3), and HER4 (erbB4) [2]. EGFR is commonly expressed in many human tumors, including non-small cell lung cancer (NSCLC), prostate, breast, colorectal, head and neck, ovarian, gastric, and pancreatic cancers [3]. The EGFR pathway contributes to a number of processes involved in tumor survival and growth including cell proliferation, inhibition of apoptosis, angiogenesis, and metastasis, thus making it an attractive target for anticancer therapies [4]. This is described in detail elsewhere in this supplement [5]. There are several agents in development that target the EGFR, and two of the most promising approaches currently under clinical investigation are the small-molecule tyrosine kinase inhibitors (TKIs) and the monoclonal antibodies. Other approaches include bispecific antibodies, EGFR-directed vaccine approaches, and antisense oligonucleotides [6]. These agents have an advantage over conventional chemotherapeutic agents in that they selectively block specific deregulated pathways in tumor cells while having minimal effects on normal cell function. ZD1839 (IressaTM) is the most advanced EGFR-TKI in clinical development.

The use of ZD1839 in lung cancer is covered elsewhere in this supplement [7]. This article concentrates on the potential of this targeted agent in other tumor types and of combining ZD1839 with standard chemotherapy, hormonal therapy, or ionizing radiation.

ZD1839: An Orally Active Inhibitor of EGFR Signaling
ZD1839 is a novel, low molecular weight, synthetic anilinoquinazoline (4-(3-chloro-4-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline) [8] (Fig. 1Go). It is an orally active, selective EGFR-TKI that blocks signal transduction processes implicated in the proliferation and survival of cancer cells. ZD1839 is highly selective, with minimal activity against other tyrosine kinases and serine/threonine kinases (Table 1Go) [9]. In addition to NSCLC cells, ZD1839 shows in vitro growth inhibition against a range of other human tumor cells including head and neck [10], oral [9], bladder [11], prostate, breast, ovarian, and colon cells [12], with concentrations that cause 50% inhibition (IC50s) that range from 0.05 to 10 µM depending on the cell type. ZD1839 has also shown antitumor activity against a range of human tumor xenografts, including prostate, colon, and breast [13–16].



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  		Figure 1. Chemical structure of ZD1839.

 

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  		Table 1. IC50 values of ZD1839 for different kinases [9]
 
Further studies have demonstrated notable activity for ZD1839 in combination with chemotherapeutic agents against tumor cell lines that express EGFR. ZD1839 in combination with cisplatin, carboplatin, oxaliplatin, docetaxel, etoposide, doxorubicin, topotecan, and raltitrexed showed enhanced growth inhibition in cell lines from human lung, colon, breast, and ovarian cancers [12, 16, 17]. Increasing experimental evidence also suggests enhancement of the antitumor activity of ionizing radiation and hormonal therapy [18–20].

Phase I trials of ZD1839 monotherapy in healthy volunteers and patients with advanced disease have shown that ZD1839 has good bioavailability and is generally well tolerated at doses of 500 mg/day or less [21–25]. ZD1839 has also shown promising clinical activity, particularly in patients with NSCLC [21, 22, 24, 25]. Phase II/III studies are currently investigating ZD1839 monotherapy against prostate, breast, head and neck, colorectal, and renal tumors. In addition, a program of combination therapy trials is ongoing in many tumor types, including NSCLC, prostate, breast, colorectal, head and neck, ovarian, glioma, renal, bladder, and cervical cancers.

ZD1839 in Prostate Cancer Treatment
Most patients with advanced prostate cancer are initially responsive to hormonal manipulation; however, once a patient has progressive disease, treatment options are limited. Understanding the mechanisms involved in the progression from normal prostate epithelium to androgen-responsive tumor, and finally to androgen-independent/hormone-refractory carcinoma, could aid the search for novel therapeutic regimens to target malignant disease.

There has been extensive research into the cellular mechanisms underlying the development of resistance to hormonal manipulation; autocrine production of growth-stimulating factors may be involved [26]. High levels of EGFR expression have been observed in prostate tumors [3], and preclinical data suggest that non-steroid-hormone signal transduction pathways, such as the EGFR signaling pathway, can activate the androgen receptor in the environment of clinical androgen deprivation (Fig. 2Go). Abnormal activation of the EGFR signaling pathway could result from high levels of EGFR expression, autocrine stimulation with overproduction of ligands, reduced dephosphorylation of tyrosine kinase, or constitutive activation of a mutant receptor [26]. Recognition of the interaction between growth factor signaling and the androgen-receptor pathway suggests that inhibition of this signaling could convert androgen-independent prostate cancer back to a hormone-sensitive state [26].



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  		Figure 2. Diagram of aberrant EGFR signaling in prostate cancer cells. Abnormal activation of the EGFR signaling pathway could occur from high levels of EGFR expression, autocrine stimulation with overproduction of ligands, reduced dephosphorylation of tyrosine kinase, or constitutive activation of a mutant receptor. Abbreviations: AR = androgen receptor; CDK = cyclin-dependent kinase; EGFR = epidermal growth factor receptor; TGF-{alpha} = transforming growth factor-{alpha}.

 
ZD1839 is currently undergoing preclinical and clinical evaluation for the treatment of androgen-independent prostate cancer, having been shown to inhibit growth in human prostate cancer cell lines [12, 27]. In one study, ZD1839 caused dose- and time-dependent growth inhibition of androgen-responsive and androgen-independent prostate cancer cell lines [27]. The antiproliferative effect of ZD1839 in this study was mainly cytostatic and was associated with a block in the G0/G1 phase of the cell cycle, which was evident after approximately 9 h treatment. In androgen-responsive and androgen-independent prostate cancer cell lines, a dose-dependent additive increase in growth inhibition was also observed when ZD1839 was used in combination with the antiandrogen flutamide [27]. In athymic nude mice, daily oral administration of single-agent ZD1839 caused reductions in the growth of hormone-resistant prostate xenografts [28]. A further study demonstrated growth inhibition of both androgen-dependent and -independent xenografts when treated with ZD1839 [29]. In a prostate cell line, ZD1839 combined with paclitaxel showed enhanced antitumor activity compared with either drug alone (Fig. 3Go) [28]. Overall, these preclinical findings suggest that blockade of EGFR signaling is a promising novel therapeutic strategy for the treatment of prostate cancer. The underlying molecular mechanisms responsible for these effects require further investigation, but the results support clinical evaluation of ZD1839 in prostate cancer.



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  		Figure 3. Antitumor activity of ZD1839 in hormone-refractory prostate cancer: potentiation of the effects of paclitaxel in the PC3 cell line [28]. Reprinted by permission from Clinical Cancer Research 2000;6:4885-4892. ©2000 American Association for Cancer Research.

 
Phase I studies have demonstrated activity of ZD1839 in patients with advanced prostate cancer. Nineteen patients, three of whom had prior chemotherapy, were recruited into phase I trials [26]. A total of 14 patients were evaluable for prostate-specific antigen (PSA) response (defined as >=50% PSA decrease for at least 6 weeks), and there were two responders, with durations of response of 2.5 and 6.5 months. Disease-related symptom improvement was observed in 8 of 12 evaluable patients, with durations ranging from 1.5 to 6.5 months. Phase II monotherapy studies are ongoing.

Ongoing phase I/II pilot studies are investigating the effects of ZD1839 in combination with mitoxantrone and prednisone, and with docetaxel and estramustine, on hormone-refractory prostate cancer. In one such study, 30 patients received ZD1839 250 or 500 mg/day in combination with docetaxel and estramustine [30]. A PSA response (PSA decline of >=50% lasting >=4 weeks) was observed in 11/30 patients and to date no unexpected or additive toxicity has been observed. The most frequent grade 3/4 adverse events were leukopenia, neutropenia, and diarrhea. This ongoing study suggests that the combination of ZD1839 with docetaxel and estramustine is feasible, with an acceptable tolerability profile and a promising PSA response rate, for the treatment of hormone-refractory prostate cancer.

ZD1839 in Breast Cancer Treatment
Survival rates for breast cancer patients have improved in recent years [1]. However, not all patients respond well to current therapies, and survival rates remain poor for patients with metastatic breast cancer. Agents that can inhibit the growth of both hormone-dependent and -independent tumor cells are required to improve treatment for breast cancer patients. Evidence suggests that cross-talk between the estrogen receptor (ER) and the EGFR/HER2 pathway is associated with endocrine resistance (Fig. 4Go) [31, 32]. Thus, EGFR-targeted therapies such as ZD1839 may be valuable in the treatment of ER-negative tumors and endocrine-resistant ER-positive tumors. Interestingly, Massarweh et al. [33] have shown that ZD1839 can restore tamoxifen sensitivity in endocrine-resistant HER2-overexpressing breast tumors. In another study, treatment of tamoxifen-sensitive cells in vitro with tamoxifen and ZD1839 enhanced apoptosis and decreased proliferative activity, leading to an outgrowth of resistant cells [34]. Furthermore, Wakeling et al. [35] found that ZD1839 treatment of tamoxifen-resistant MCF-7 cells blocked mitogen-activated protein kinase activity, and that treatment of wild-type MCF-7 cells with tamoxifen and ZD1839 prevented development of tamoxifen resistance. These results support the clinical use of ZD1839 in tamoxifen-resistant breast cancer, and suggest that early use of ZD1839 in combination with antiestrogenic agents, such as tamoxifen or fulvestrant (FaslodexTM), may prevent resistance.



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  		Figure 4. Diagram of aberrant EGFR signaling in breast cancer cells. Cross-talk between the ER and the EGF/HER2 receptor pathway is associated with endocrine resistance. Tamoxifen is linked to increased cellular signaling via the EGFR and with sensitivity to EGFR inhibitors. Combining tamoxifen with ZD1839 has been found to delay the development of endocrine resistance in breast cancer models. Abbreviations: CDK = cyclin-dependent kinase; EGFR = epidermal growth factor receptor; ER = estrogen receptor; TGF-{alpha} = transforming growth factor-{alpha}.

 
Ductal carcinoma in situ (DCIS) of the breast is recognized as a potential precursor of invasive breast cancer, and treatment at this stage may prevent progression of the disease [36]. In xenografts of surgically removed DCIS breast tissue, ZD1839 inhibited proliferation and increased apoptosis, whereas trastuzumab, a monoclonal antibody directed against HER2, had no effect [13]. In addition, ZD1839 inhibits proliferation in both ER-positive and ER-negative DCIS, suggesting that EGFR-TKIs could be important in treating high-risk DCIS and breast cancer [37]. ZD1839 inhibits the proliferation of human breast cancer cells in a dose- and time-dependent manner, even in cells that express low levels of EGFR [38, 39].

Ongoing phase II studies are investigating ZD1839 treatment in advanced/metastatic EGFR-positive breast cancer, ER-negative/EGFR-positive breast cancer, and in recurrent tamoxifen-resistant disease and DCIS. ZD1839 is also being studied in combination with anastrozole (ArimidexTM), fulvestrant, trastuzumab, and chemotherapy.

ZD1839 in Colorectal Cancer Treatment
EGF is a potent mitogen for several human epithelial cell types, and enhanced EGF expression has been detected in human colon carcinomas [3]. In addition, EGFRs are expressed at varying levels on malignant colon epithelial cells [3], making colorectal cancer a potential target for EGFR-TKI therapy. As a single agent, ZD1839 has been shown to inhibit growth of colon cancer cell lines and xenografts [12, 16]. Apoptosis induced by ZD1839 alone was found to be further enhanced by a combination of ZD1839 and cytotoxic drugs in GEO colon carcinoma cells [12] and, in nude mice bearing GEO colon tumor xenografts, ZD1839 enhanced the growth inhibition produced by paclitaxel, topotecan, or raltitrexed [13]. This led to almost complete regression and produced a significant increase in survival compared with a cytotoxic drug or ZD1839 alone. Supra-additive antitumor activity was observed in colon cancer xenografts treated with the combination of ZD1839, protein kinase A antisense, and the novel taxane IDN5109 [40].

In the clinical setting, a phase I/II pharmacokinetic, pharmacodynamic, and biologic activity study is investigating ZD1839 750 mg/day in patients with colorectal cancer [41]. Eight out of 24 evaluable patients had stable disease after ZD1839 treatment (median duration 2.2 months); five of these had tumor shrinkage. Preliminary tumor biopsy data suggest activity, as indicated by decreased levels of Ki67, p-EGFR, p-AKT, and p-ERK following treatment, and ZD1839 appears to be generally well tolerated. ZD1839 is also being investigated in combination with other therapies. Inhibition of EGFR-TK activity by ZD1839 has been shown to reverse resistance to the active metabolite of irinotecan, SN-38, in human colon tumor cells, thus supporting clinical investigation of ZD1839 combined with irinotecan in patients with SN-38-resistant colorectal cancer [42]. Trials with this combination are ongoing in patients with advanced colorectal cancer. Continuous oral administration of ZD1839 in combination with 5-fluorouracil (5-FU)/leucovorin (LV) has been shown in a feasibility/pharmacokinetic study to have an acceptable tolerability profile in patients with advanced colorectal cancer [43]. Furthermore, data of best tumor response showed that one patient had a complete response, five had a partial response, and 12 had stable disease. No significant change in exposure of ZD1839 or 5-FU/LV was observed when the two agents were given in combination. Additional trials in patients with advanced colorectal cancer are currently investigating ZD1839 in combination with different regimens and doses of 5-FU/LV.

ZD1839 in Head and Neck Cancer Treatment
EGFR appears important in the biology of squamous-cell carcinoma (SCC) of the head and neck, and EGFR expression correlates with disease prognosis and reduced survival [3]. Indeed, in human head and neck SCC, ZD1839 has been shown to induce G1 arrest; this is associated with an upregulation of p27KIP1 cyclin-dependent kinase inhibitor [44]. In addition, preclinical studies in head and neck cancer cell lines have suggested additive antitumor activity of ZD1839 with 5-FU and/or cisplatin [45]. In preclinical investigations, ZD1839 was also effective against intracranial tumors expressing high levels of EGFR [46]. ZD1839 might prove effective for the treatment of gliomas and may also have broader applicability for cancers that metastasize to the brain.

In phase I studies investigating ZD1839, encouraging antitumor activity has been observed in head and neck cancer [24]. Furthermore, a phase II study has treated patients with recurrent SCC of the head and neck with ZD1839 500 mg/day as monotherapy [47]. From a total of 52 patients recruited into the study, 47 were assessed. Half of these patients have progressive disease and 85% had prior chemotherapy exposure. The overall tumor response rate was 11% and the disease control rate, including partial responses, complete responses and stable disease, was reported as 53% of the 47 patients assessed in the study. The median time to disease progression was 3.5 months, and median survival extended beyond the 6 months expected for this patient population to a reported 11 months. Toxicity was acceptable, with only one patient discontinuing therapy due to a grade 2 acneiform rash. Three patients had their doses of ZD1839 reduced to 250 mg/day after experiencing mild to moderate diarrhea. These results suggest that ZD1839 monotherapy is active and has an acceptable tolerability profile in patients with recurrent or metastatic SCC of the head and neck.

ZD1839 in Ovarian Cancer Treatment
Approximately 30%-70% of ovarian cancers express high levels of EGFR [48]. Preclinical studies of ZD1839 in ovarian cancer cell lines have shown promising results, revealing increased growth inhibition when ZD1839 is used in combination with chemotherapy drugs (cisplatin, carboplatin, oxaliplatin, paclitaxel, docetaxel, doxorubicin, etoposide, topotecan, and raltitrexed) versus either agent alone [12]. Furthermore, ZD1839 inhibited the growth of the ovarian cancer cell line 2008, which expresses high levels of EGFR (IC50 = 3.2 µM), and, in this cell line, acted synergistically with clinically relevant cytotoxic drugs [48]. These preclinical findings support the rational use of ZD1839 in combination with chemotherapy for ovarian cancer.

Future Directions: Radiosensitization by EGFR Blockade
Radiation therapy plays a primary role in the treatment of many epithelial tumors. However, proliferation of tumor cells during radiation treatment has been identified as a factor that affects tumor response and local control [49]. One method of counteracting tumor repopulation and resistance is the use of hyperfractionation and intensified radiation treatment regimens delivered over a shorter period of time. Unfortunately, this approach has practical and cost implications and may be accompanied by a marked increase in acute toxicity.

To reduce tumor cell repopulation during treatment, agents such as ZD1839 could be administered to slow or inhibit tumor cell proliferation. Indeed, studies have reported that cell survival and repopulation following radiotherapy in epithelial tumors may be regulated by the activation and expression of EGFR that is induced following radiation [50, 51]. Furthermore, activation of downstream effectors of the EGFR signaling pathway has been shown to increase cellular resistance to ionizing radiation, suggesting that EGFR blockade may lead to a reduction in tumor cell repopulation by inhibition of tumor cell growth and/or modulation of cellular radiosensitivity (Fig. 5Go).



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  		Figure 5. Diagram demonstrating radiosensitization by EGFR blockade. EGFR inhibition induces an accumulation of cells particularly in the G1 phase of the cell cycle. In addition, the cellular ability to undertake DNA repair following irradiation is reduced by blockade of EGFR. The combined effect is to increase the pro-apoptotic effects of irradiation. Abbreviations: EGFR = epidermal growth factor receptor; TGF-{alpha} = transforming growth factor-{alpha}.

 
Additive-to-synergistic interactions have been observed in in vitro studies of ZD1839 in combination with radiation [20]. Furthermore, a cooperative antiproliferative and pro-apoptotic effect was obtained when human NSCLC, colon, ovarian, and breast cancer cell lines were treated with ionizing radiation followed by ZD1839 [52]. Xenograft models have also demonstrated benefits of the combination of ZD1839 with radiation therapy. In one human colon carcinoma xenograft model, ZD1839 was shown to enhance the therapeutic effect of radiotherapy, both single and fractionated doses (Fig. 6Go) [18]. Long-term growth regression of human GEO colon cancer xenografts followed treatment with ionizing radiation in combination with ZD1839 [52]. In addition, significant antiangiogenic effects, as determined by immunohistochemical count of neovessels, were observed with these tumors.



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  		Figure 6. ZD1839 enhances the efficacy of single-dose and fractionated-dose radiotherapy in LoVo xenografts [18]. Reprinted by permission from the British Journal of Cancer 2002;86:1157-1161. ©2002 Nature Publishing Group.

 
These studies provide a strong rationale for clinical investigation of the combination of radiation therapy and ZD1839 treatment. It will be important to determine whether the addition of ZD1839 increases the therapeutic index of radiation therapy. Interestingly, a recent study investigated whether EGFR expression and in vivo radiocurability of murine tumors are related [53]. The levels of EGFR correlated inversely with radiation-induced apoptosis, suggesting that the lack of sensitivity to apoptosis induction was a major mechanism responsible for radioresistance of tumors with high levels of EGFR. Furthermore, the relationship between EGFR expression and radiosensitivity suggests that the pretreatment assessment of EGFR expression could predict radiotherapy outcome and assist in selecting an effective radiotherapeutic approach to radioresistant tumors.


   CONCLUSION
Top
 Learning Objectives
 Abstract
 Introduction
 Conclusion
References
 
Recently reported phase II clinical studies (IDEAL 1 and IDEAL 2) have demonstrated that ZD1839 monotherapy in patients with advanced NSCLC, who have previously received prior treatment with cytotoxic chemotherapy, is well tolerated and provides clinically significant antitumor activity and symptom relief [54–57]. However, agents that target the EGFR, such as ZD1839, have potential in a wide range of tumors, including prostate, breast, head and neck, gastric, and colorectal tumors, and from early to advanced/hormone-independent disease, either as monotherapy or in combination with standard chemotherapy, hormonal therapy, or radiotherapy. Phase I studies and preliminary results from phase II clinical trials have demonstrated that ZD1839 has acceptable tolerability and evidence of activity against a variety of malignancies. In addition to NSCLC, phase II/III studies are currently investigating ZD1839 in a wide range of tumors.


   ACKNOWLEDGMENT
Top
 Learning Objectives
 Abstract
 Introduction
 Conclusion
 References
 
Dr. Malcolm Ranson is a speaker non grata for AstraZeneca. At the time of publication, this paper discusses the investigational and unlabeled usage of ZD1839.


   REFERENCES
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 Learning Objectives
 Abstract
 Introduction
 Conclusion
 References
 

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Received June 26, 2002; accepted for publication July 25, 2002.




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