Gefitinib (Iressa) is a novel targeted therapy that inhibits the tyrosine kinase activity of the epidermal growth factor receptor by competitively blocking the ATP binding site. In preclinical studies gefitinib has shown potent activity in a number of tumor models, including several lung cancer cell lines and xenografts. Two large randomized Phase II studies (IDEAL 1 and IDEAL 2) in pretreated non-small cell lung cancer reported a response rate approaching 20% in second-line patients and ∼10% in those pretreated with two or more chemotherapy regimens. The median survival in these two studies approached 6–8 months. As a first-line therapy, gefitinib has been assessed in combination with two different chemotherapy regimens in two large randomized studies (INTACT 1 and INTACT 2). Both studies failed to show an improvement in survival on a total patient accrual of >1000 patients in each study. Other end points (e.g., time to progression and response rate) were also not improved by the addition of gefitinib. Additional studies are indicated to assess the possible role of gefitinib in the maintenance of patients who received chemotherapy or chemoradiotherapy. Studies investigating gefitinib as first-line monotherapy are also required.

The majority of patients with non-small cell lung cancer (NSCLC) eventually develop metastatic disease or disease that is not amenable to local therapies only and are potential candidates for systemic therapies. Although chemotherapy can improve survival in patients with advanced disease, the advantage is only ∼2 months over best supportive care, and this is at the cost of substantial adverse effects. The search for new agents that are at least as active as chemotherapy but better tolerated is of paramount importance. A number of novel agents that act specifically against select targets present on cancer cells, such as the epidermal growth factor receptor (EGFR), are being tested in advanced NSCLC. Thus far, primarily patients with advanced NSCLC have been assessed, but there is a good rationale to investigate several of these agents in earlier disease settings, where some of the targeted genetic abnormalities are already present (1).

EGFR is highly expressed in a variety of solid tumors, including NSCLC. EGFR is highly expressed in most (∼80%) lung squamous cell carcinomas, and approximately half of all lung adenocarcinomas and large-cell carcinomas. Activation of the EGFR in cancer cells has been shown to promote processes involved in tumor cell proliferation, angiogenesis, invasion, and metastasis, and to inhibit apoptosis (2, 3, 4). EGFR (erbB1 or HER1) is a member of the erbB receptor family, which also includes erbB2 (HER2), erbB3 (HER3), and erbB4 (HER4). It is a transmembrane glycoprotein composed of an extracellular ligand-binding domain, a transmembrane domain, and an intracellular signal-transducing domain with tyrosine kinase activity. After binding of a physiological ligand such as epidermal growth factor, the EGFR dimerizes with either another EGFR monomer or another member of the erbB family (5). This leads to activation of tyrosine kinase, autophosphorylation of tyrosine, and initiation of signaling cascades that ultimately result in various downstream responses such as cell proliferation. Moreover, EGFR expression in tumors has been associated with a poor response to therapy, development of cytotoxic drug resistance, disease progression, and poor survival (6, 7, 8, 9). Other mechanisms of increased EGFR signaling that might be involved in tumor cell proliferation include increased levels of extracellular ligand, heterodimerization of EGFR, and EGFR mutation. The most common form of mutated EGFR in tumors is EGFRvIII, which is found in up to 39% of NSCLC cases (10). EGFRvIII carries a deletion mutation from amino acids 6 to 273 in the extracellular binding domain and exhibits constitutive tyrosine kinase activity that is independent of extracellular ligand binding (11).

Structure and Mechanism of Action.

Gefitinib [4-(3-chloro-4-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline, C22H24ClFN4O3; ZD1839, Iressa] is a synthetic anilinoquinazoline compound. Gefitinib acts by inhibiting EGFR signal transduction pathways. Gefitinib selectively binds to the EGFR-tyrosine kinase domain, preventing ATP from binding and blocking subsequent receptor autophosphorylation, which results in the inhibition of signal transduction.

Preclinical in Vitro Studies.

As a single agent and in combination with various chemotherapy agents, gefitinib has been shown to exert antitumor activity, including effects on cell proliferation, apoptosis, and angiogenesis, in a variety of human cancer cell lines known to express EGFR (12, 13, 14). Gefitinib has shown potent activity in a number of lung cancer tumor models, including several cell lines and xenografts. In general, however, the preclinical activity is mainly represented by inhibition of tumor proliferation (15), although in some specific tumor models apoptosis has also been observed, such as in the A341 cell line. This cell line has an extraordinarily high expression of EGFR and is exquisitely sensitive to EGFR inhibitors. Gefitinib (0.1–10 μmol/liter) dose-dependently inhibited growth in several NSCLC cell lines; this effect was evident in NSCLC cells with high (H226), moderate (A549, H157), and low (H322) EGFR expression (16). Interestingly, the expression level of EGFR is not directly correlated with the potency of this agent in preclinical models. In preclinical models, combinations of gefitinib and several chemotherapeutic agents, such as paclitaxel, cisplatin, and 5-fluorouracil, have been demonstrated to have additive or even synergistic efficacy. Also, radiotherapy had additive or synergistic activity in combination with gefitinib in several tumor models. In in vivo models, the antitumor activity may partly result from inhibition of angiogenesis, because vascular endothelial growth factor and interleukin 8 production can be inhibited in these models, as well as tumor neovascularization.

As combination therapy, gefitinib plus paclitaxel or vinorelbine showed synergy in reducing NSCLC cell growth. The findings with gefitinib plus cisplatin were less clear, with both additive and antagonistic effects on cell growth seen. Administration of gefitinib 24 h before radiotherapy (2–6 Gy) resulted in a synergistic to additive effect in NSCLC cells (16). In keeping with the findings from in vivo studies, gefitinib alone and in combination with various chemotherapeutic agents (e.g., platinum and taxanes) showed significant antitumor activity against human NSCLC tumor xenografts in immunodeficient mice (14, 16). Gefitinib also enhanced effects of radiotherapy in human A549 and SK-LC-16 NSCLC tumor xenografts (17, 18).

Phase I Studies.

Four open-label Phase I studies have evaluated the tolerability, pharmacokinetics, and pharmacodynamics of gefitinib in 254 patients with heavily pretreated solid tumors, including 100 patients with NSCLC (19, 20, 21, 22). Escalating doses of gefitinib (50–1000 mg/day) were administered orally. Gefitinib was well tolerated: the most common adverse events were grade 1/2 (mild/moderate) skin rash, diarrhea, nausea, vomiting, and anorexia; grade 3/4 adverse events were uncommon. The maximum tolerated dose was determined to be 700 mg/day, with reversible grade 3 diarrhea being the predominant dose-limiting toxicity. Doses >700 mg/day were in fact associated with substantial toxicity, which required dose reduction or treatment interruptions in a significant proportion of patients. The most frequent side effect of gefitinib and the class of EGFR inhibitors is skin toxicity (50–60%). This develops as an acneiform rash, especially pronounced in the skin of the face and upper trunk. In more severe cases, skin toxicity may extend to the lower body. Both diarrhea (35–55%) and skin toxicities are dose dependent and transient. There is really not much one can do to prevent or treat the skin toxicity, although some efficacy has been observed with the use of antiacne medications. Other less-frequent side effects are transient transaminitis and nausea. Infrequent side effects, sometimes severe, are interstitial lung pneumonitis and hematuria. Interstitial lung pneumonitis has been observed in ∼1% of treated patients (2% in Japan and 0.3% in the United States). The median time of onset was 24 days in Japan and 42 days in the United States experience, and one-third of occurrences were fatal. Patients often presented with acute onset of dyspnea, with or without cough and a low-grade fever (23).

Antitumor activity was reported in all 4 of the trials, with 10 of 100 patients with advanced NSCLC achieving a partial response and another 12 patients having stable disease. Responses and stable disease were reported across the dose range of 150–700 mg/day with no greater efficacy at the higher doses. Thus, gefitinib appears to be effective at doses lower than its maximum tolerated dose. As a result of these studies, 250 mg/day and 500 mg/day were the doses selected for additional investigation in Phase II and III studies.

Phase II Studies.

The use of second-line chemotherapy has increased markedly, and nowadays a number of patients undergoing chemotherapy also receive therapy at relapse. Docetaxel is the only agent approved thus far for the indication of second-line chemotherapy in advanced NSCLC. This agent achieved a response rate of only 7%, but nevertheless increased significantly survival over a best supportive care arm or two other chemotherapy agents (11, 24). Docetaxel is, however, rather toxic, and a dose of 75 mg/m2 rather than the full dose of 100 mg/m2 is indicated in second-line treatment of NSCLC. Clearly, better-tolerated treatment is needed in this setting.

Two large randomized Phase II studies in pretreated NSCLC have been conducted recently (IDEAL 1 and IDEAL 2). Because no clear correlation has been observed between EGFR expression and sensitivity to gefitinib in preclinical models, no patient selection was performed in these studies; however, an attempt was made to obtain paraffin-embedded material from most patients to enable retrospective assessment of EGFR expression in relation to response to therapy. Patients were randomized to receive 250 or 500 mg of gefitinib daily until progression. Both IDEAL trials recruited patients with stage III/IV NSCLC (incurable with surgery or radiotherapy) for whom previous chemotherapy had failed. IDEAL 1 recruited 209 patients from Australia, Europe, South Africa, and Japan who had failed 1 or 2 prior chemotherapy regimens (at least 1 of which was platinum-based; Ref. 25), whereas IDEAL 2 recruited 216 patients from the United States who had failed ≥2 prior chemotherapy regimens (involving at least 1 platinum agent and docetaxel, administered concurrently or as separate regimens; Ref. 26). Prognoses for patients in IDEAL 2 were poorer than for those in IDEAL 1; IDEAL 2 patients were required to be symptomatic at trial entry.

Gefitinib 250 mg/day showed antitumor activity (tumor shrinkage and stable disease) in >40% of patients with previously treated advanced NSCLC. The objective tumor response rates were 18.4% in IDEAL 1 and 11.8% in IDEAL 2 (25). The disease control rates (defined as the best tumor response of complete response, partial response, or stable disease, confirmed and sustained for ≥4 weeks) in IDEAL 1 and IDEAL 2 were 54.4% and 42.2%, respectively. Median overall survival times were 7.6 months and 6.5 months, respectively (27).

Interestingly, there was no difference in response rate between 250 and 500 mg/day. A significant improvement in disease-related symptoms was observed in patients with a response or stable disease. The symptom improvement findings from IDEAL 2 are supported by IDEAL 1, in which 67 of 104 of patients receiving gefitinib 250 mg/day were symptomatic at trial entry. In these patients, symptom improvement rate was 40.3%. In both trials, symptom improvement was rapid, the median time to improvement being 8–10 days (27).

Although both doses of gefitinib were well tolerated, the 500 mg/day regimen had significantly more skin toxicity and diarrhea and required more dose reductions and treatment delays. Therefore, the standard dose of gefitinib has become 250 mg in this setting. There was no correlation between response to gefitinib and EGFR expression in a retrospective analysis presented recently (28). Also, in another study (29), no correlation was described between EGFR expression and response to gefitinib in >40 patients treated within the expanded access gefitinib program, in which the dose of 250 mg/day has been chosen. In the IDEAL studies there was also apparently no correlation between efficacy and the degree of skin toxicity. However, women, those with adenocarcinoma histology and never-smokers had a higher chance to respond to gefitinib (25). The median survival in these two studies approaches 6–8 months, which is similar to the docetaxel studies and longer than best supportive care by ∼2 months; randomized studies will, however, be necessary to prove that gefitinib is superior to best supportive care. Two randomized studies are comparing gefitinib versus best supportive care with survival and improvement of pulmonary symptoms as primary end points, respectively.

Gefitinib has been approved in Japan and the United States for relapsing patients with advanced NSCLC based on the results of these two Phase II studies (23).

Phase III Studies.

In first-line therapy, gefitinib has been assessed in combination with two different chemotherapy regimens in two large randomized studies (INTACT 1 and INTACT 2) for which results have been reported recently. Patients were randomized to receive either gefitinib (250 mg/day or 500 mg/day) or placebo in combination with cisplatin/gemcitabine (INTACT 1, n = 1093) or carboplatin/paclitaxel (INTACT 2, n = 1037; Refs. 30, 31). Both studies failed to show an improvement in survival. The other end points (time to progression, response rate, and so forth) were also not improved by the addition of gefitinib. These major negative results cast doubts on the preclinical models that showed synergy or additive effects of several combinations of chemotherapy with gefitinib. The lack of patient selection could partially explain these negative findings. Alternative explanations are the possibility that gefitinib acts as a cytostatic agent and, therefore, may potentially reduce the effect of chemotherapy when the drugs are given concomitantly. In both of these studies there was some indication that after 5–6 months of therapy, the gefitinib arms did fare slightly better in time to progression, although this did not reach statistical significance. In an exploratory subset analysis, it was shown that there was a trend in INTACT 2 toward increased survival with gefitinib of patients with adenocarcinoma who had received chemotherapy for ≥90 days (31). These observations suggest that gefitinib may have a role as maintenance after chemotherapy. Additional studies are indicated to assess the possible role of gefitinib in the maintenance of patients who received chemotherapy or chemoradiotherapy. One such study is being launched by the European Organization for Research and Treatment of Cancer Lung Cancer Group and another by the Southwest Oncology Group (SWOG S0023). The European Organization for Research and Treatment of Cancer study randomizes nonprogressing advanced-stage NSCLC patients to receive gefitinib or placebo after four cycles of platinum-based chemotherapy. The Southwest Oncology Group study randomizes stage IIIA/B NSCLC patients to gefitinib or placebo as maintenance after combined chemoradiation therapy. Furthermore, studies investigating gefitinib in front-line as a single agent are also required. These studies are being planned or are being performed at this time. A large randomized study investigating gefitinib in the adjuvant treatment of radically resected NSCLC is presently running in North America, with the National Cancer Institute of Canada leading this study.

In conclusion, gefitinib does appear to be a breakthrough in the treatment of advanced NSCLC. It is likely that its use will rapidly move from advanced late-stage disease to earlier and less-advanced stages in the near future. Studies in the neoadjuvant and adjuvant settings are in fact also underway.

Dr. Mark Socinski: In many ways the INTACT trials was a test of two versus three drugs. That has not been a successful strategy historically in this disease setting. Do you think there is a role for EGFR drugs in doublet combinations, platinum plus one of these of these agents?

Dr. Giaccone: The dogma that two versus three is never going to work is, I think, just a dogma. In other diseases, three is better than two, and I cannot believe that non-small cell lung cancer is so different. I think we should first understand why this combination does not work, and if there is antagonism, then what is provoking it, because the published preclinical data do not show antagonism.

Dr. Geoffrey Shapiro: This question of whether there is antagonism is very important and is a major issue when trying to combine signal transduction inhibitors with chemotherapy. It is a recurrent theme not only with gefitinib but now with ISIS 3521. Cells that are not programmed to undergo apoptosis are not going to die when the signaling pathways are turned off, but rather they may undergo cell cycle arrest. Cell cycle arrest induced by a signal transduction inhibitor could theoretically prevent responses to a DNA or microtubule-damaging agent. The sequence and interval of chemotherapy and signal transduction inhibitors may be critical when combinations are explored.

Dr. Roman Perez-Soler: There are at least 100 different tyrosine kinases in the body. We have been told that these agents are extremely selective for one tyrosine kinase, but I think that these drugs do many things, and when the cells die, it is not because the EGFR is blocked.

Dr. David Gandara: Regarding potential antagonism, there are similar data with erlotinib and chemotherapy. This raises the issues about whether the models that were looked at with high levels of EGFR are particularly sensitive tumors, representing a small subset that is not reflective of the clinical population.

Dr. Giaccone: Going back to the combination with chemotherapy, I think we should be cautious now, at least with the small molecules, because they do not do what we expected. The monoclonal antibodies probably work differently, although the target is the same. Monoclonal antibodies have a long half-time, whereas small molecules do not. There should be more work done on sequence and timing before we do more trials in combining small molecules with chemotherapy.

Dr. Gandara: We should be exploring the concept of pulse dosing of EGFR tyrosine kinase inhibitors, even though the paradigm has been continuous suppression. In the original erlotinib data, they pulsed the dose up to 1600 mg and saw clinical responses with a single dose.

Dr. Socinski: The INTACT trials to me do not say that this is not an important class of drugs; they say gefitinib doesn’t add to the efficacy of platinum-based therapy. It was the wrong question to ask. Now that seems pretty evident, but it is also true of other drugs, so I think the message has to be enrichment of the study population with the appropriate trial design and identifying the appropriate first-line patients to receive this drug

Dr. Joan Schiller: The message for me was a very sobering thought that these preclinical models turn out often not to be very predictive. We have been talking about how we need to do preclinical studies to design the clinical trials, and yet we did the preclinical studies with gefitinib and they didn’t predict the clinical trials.

Dr. Paul Bunn: The preclinical trials show A431 as an aberrant cell line, and they showed that 15% of lung cancer cells in vitro have a great response to gefitinib, and that’s the same as the trial response rate. The preclinical models aren’t as bad as you’re saying

Dr. Schiller: In retrospect it is easy to go back and say, “Oh you picked the wrong cell line,” but at the time nobody was saying that and we proceeded with those clinical trials. So I am afraid if we do sequencing studies to come up with more clinical trials, maybe we’ll go back and say again, “Oh, wrong cell line.” We do have some clinical clues here, however, about when these drugs will be effective, such as the gender issue, if that turns out to be a true and pertinent observation. We should be exploring those clinical observations to figure out how these agents work.

Dr. Eric Rowinsky: I agree with Dr. Bunn. I think that we did see the models, we did know that A431 responds dramatically. We have had robust data. I don’t think we have really analyzed and used that data correctly.

Dr. Fadlo Khuri: Clearly, there is nothing simple about the design of these combination trials, and there are pure monotherapy trials that we would like to do that get blocked. We need a concerted educational effort on drug development and trial design in this country and in Europe. What we are discussing today needs to be disseminated to a broader audience.

Presented at the First International Conference on Novel Agents in the Treatment of Lung Cancer, October 17–18, 2003, Cambridge, Massachusetts.

Requests for reprints: Giuseppe Giaccone, Vrije Universiteit Medical Center, Department of Medical Oncology, 1117 De Boelelaan, HV 1081 Amsterdam, the Netherlands. Phone: 31-20-444-4321; Fax: 31-20-444-4079; E-mail: [email protected]

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