The Oncologist, Vol. 7, Suppl 4, 25-30,
August 15, 2002
© 2002 AlphaMed Press
ZD1839 (IressaTM): What’s in It for the Patient?
Ronald B. Natale,
Susan L. Zaretsky
Cedars-Sinai Comprehensive Cancer Center, Los Angeles, California, USA
Correspondence:
Ronald B. Natale, M.D., Cedars-Sinai Comprehensive Cancer Center, 8700 Beverly Boulevard, Suite C2000, Los Angeles, California 90048-1804, USA. Telephone: 310-423-1101; Fax: 310-652-8759; e-mail: rnatale{at}csccc.com
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LEARNING OBJECTIVES
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After completing this course, the reader will be able to:- Identify the available survey instruments for measuring the quality of life (QOL) of patients with lung cancer.
- Appreciate the importance of symptom management to cancer patients.
- Learn how QOL measurements are being assessed in clinical trials in lung cancer.
- Recognize the global burden of lung cancer.
Access and take the CME test online and receive one hour of AMA PRA category 1 credit at CME.TheOncologist.com
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ABSTRACT
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Although cytotoxic chemotherapy has had a significant impact on the treatment of some malignancies, its impact against most solid tumors is limited. This is especially true in the case of non-small cell lung cancer (NSCLC) in which about 90% of patients ultimately die from metastatic disease. Although chemotherapy has produced modest improvements in response rates and survival in a subset of patients with advanced NSCLC, its primary objective remains to provide palliation of disabling disease-related symptoms. It is hoped that the introduction of new, rationally designed anticancer agents, with greater specificity and less toxicity, will improve the outcome for patients with a range of tumor types, including NSCLC.
ZD1839 (IressaTM) is the first of a new class of epidermal growth factor receptor tyrosine kinase inhibitors. The results of two large phase II trials have shown that ZD1839 provides clinically significant symptom relief for many patients with extensively pretreated advanced NSCLC. Moreover, this improvement in disease-related symptoms correlated with improved survival and tumor response. ZD1839 also had an acceptable tolerability profile: most drug-related adverse events were mild and reversible and quite different from those typically associated with cytotoxic agents. Some patients also experienced improved quality of life, particularly those with a partial response or stable disease. Thus, ZD1839 offers a new treatment option providing meaningful symptom relief for many patients with advanced NSCLC.
Key Words. ZD1839 (IressaTM) • NSCLC
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INTRODUCTION
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Despite major advances in the treatment of cancer over the past few decades, some forms of the disease are still associated with substantial morbidity and mortality. The GLOBOCAN registry, which provides estimates of cancer incidence and mortality worldwide, shows that in the year 2000 there were more than 10 million new cases of cancer, and over 6 million cancer deaths [1, 2]. This represents an increase of approximately 23% in cancer incidence and mortality since 1990. Although cytotoxic chemotherapy has had a major impact on the treatment of some malignancies, such as childhood acute lymphoblastic leukemia, germ cell malignancies, lymphoma, and trophoblastic tumors, its impact against most solid tumors has been limited. The introduction of rationally designed, target-based therapeutic agents might improve the outcome for patients with a range of tumor types.
Many cancers are associated with severe disease-related symptoms, which cause a great deal of distress to the patient. This is compounded by the fact that, with traditional chemotherapies, the adverse effects associated with the treatment may partially or wholly offset the symptomatic benefits derived from tumor regression/stabilization. Quality of life (QOL), therefore, is increasingly recognized as an important end point of cancer treatment, particularly for those patients receiving palliative care. Therefore, the Oncologic Drugs Advisory Committee of the U.S. Food and Drug Administration has recommended that beneficial effects on QOL and/or survival should be the basis for approval of new anticancer drugs [3]. New, rationally designed anticancer agents are expected to have greater specificity and lower toxicity than traditional cytotoxic chemotherapy, which should translate into QOL benefits.
ZD1839 (IressaTM) is the first in a new class of agents: it is an orally active, selective epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI). ZD1839 blocks EGFR autophosphorylation and subsequently signal transduction pathways implicated in proliferation, metastasis, angiogenesis, and the inhibition of apoptosis. The mechanism of action of EGFR-TKIs is discussed in this issue by Baselga [4]. In the present review, the results of two large phase II trials of ZD1839 in pretreated patients with advanced non-small cell lung cancer (NSCLC) are used to illustrate some of the patient benefits of new anticancer agents.
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UNMET PATIENT NEEDS IN NSCLC
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Worldwide, lung cancer is the leading cause of cancer death, with an estimated 1.1 million lung-cancer-related deaths in the year 2000: it kills more people every year than breast and prostate cancer combined [1]. For patients with advanced or metastatic NSCLC, median survival has improved by only about 2 months over the past 3 decades [5]. Most patients with NSCLC present with advanced stages of the disease and subsequently experience substantial symptomatic distress [6]. Further progress is needed to decrease the morbidity associated with uncontrolled symptoms.
The most common symptoms of advanced NSCLC are dyspnea, cough, pain, loss of appetite, and hemoptysis, which are reported by 87%, 86%, 75%, and 41% of patients, respectively, at presentation [7]. Weight loss is also an associated symptom. These symptoms of NSCLC are generally frequent and severe, and worsen in the final months of life [8].
In recent years there has been an increase in the use of chemotherapy in advanced NSCLC, partly as a result of a modest survival advantage compared with best supportive care demonstrated in patients treated with platinum-based regimens [9]. With increased use of these drugs, the number of patients seeking second-line therapy after relapse on first-line treatment has increased. Second-line therapies are limited, and patients with tumor progression at this stage generally have a very poor prognosis and severe disease-related symptoms. Resistance to platinum-based drugs develops in many tumors, and cumulative toxicities may necessitate treatment withdrawal. Studies on the use of third-line, primarily palliative, chemotherapy in advanced NSCLC have not yet been performed.
It is clear that both the symptoms of NSCLC and the approaches used to treat it can impact a patient’s QOL. As noted above, traditional cytotoxic chemotherapy agents are often associated with significant toxicity, which has a detrimental effect on a patient’s QOL. Such toxicity might mean that a patient would rather not receive chemotherapy. In a recent study assessing the treatment preferences of patients with lung cancer, only 22% of patients said that they would choose chemotherapy over best supportive care for a 3-month improvement in survival, while the majority (68%) would choose chemotherapy if it substantially reduced symptoms even without an improvement in survival [10]. The toxicity burden of chemotherapy also means that many patients, such as the elderly, who may tolerate chemotherapy poorly because of impaired organ function and comorbidities, are often not considered for cytotoxic chemotherapy.
Furthermore, clinical analyses have shown that symptoms and QOL at diagnosis are strong prognostic factors of survival for patients with lung cancer [11, 12]; one study that included 82 patients with lung cancer demonstrated that symptom distress alone was a significant predictor of survival [13]. There is, therefore, a clear need for new agents with improved efficacy, in terms of survival and/or symptom relief, and reduced toxicity for the treatment of NSCLC. The therapeutic aim in this population is disease control without compromising overall QOL.
Assessment of Disease-Related Symptoms and QOL in Clinical Trials of New Anticancer Agents
During the past decade, a variety of lung-cancer-specific instruments have been developed to assess various aspects of QOL, including disease-specific symptoms. One such instrument is the Functional Assessment of Cancer Therapy for Lung Cancer (FACT-L, version 4), which contains the Lung Cancer Subscale (LCS) that assesses disease-specific symptoms.
The FACT-L is a reliable and comprehensive, yet relatively brief and sensitive, means of assessing QOL domains relevant to patient values [14–16]. Within the five components of the FACT-L scale are 34 items, each of which is scored from 0-4 (maximum total score 136), with a higher total score indicating better QOL (Fig. 1
). This instrument was validated in a trial of almost 600 patients with advanced NSCLC conducted by the Eastern Cooperative Oncology Group (ECOG) [15]. In phase II studies of ZD1839, the FACT-L questionnaire was completed at baseline, at the end of each 28-day treatment period (before assessments and before patients were given information about the status of their disease), and at the time of withdrawal (Table 1). Those patients with an increase in total FACT-L score of at least six points sustained for at least 4 weeks were considered to have an improved QOL.
The LCS, a subscale of the FACT-L, has been shown to provide reliable, independently validated information about the symptoms experienced by lung cancer patients, and is sensitive to clinical changes in these patients [14, 15]. It is a seven-item questionnaire that covers shortness of breath, weight loss, clear thinking, coughing, appetite, tightness in chest, and ease of breathing (Fig. 1
). Each item is rated on a five-point scale (from 0, worst, to 4, best), with a total score ranging from 0 (most symptomatic) to 28 (asymptomatic). In simple terms, the LCS provides a means of quantifying the routine questions asked by physicians at patients’ bedsides as a part of usual care.
In the above-mentioned study, changes in the LCS were anchored to clinically relevant end points, such as objective response, time to progression, survival, and increases in performance status and body weight. A mean LCS score improvement of 2.4 points from baseline to 12 weeks correlated strongly with response to treatment and positive outcomes in other clinical parameters; the LCS score did not change (mean difference of 0.0) for patients with progressive disease (Fig. 2). Similarly, 12-week LCS score changes for early progressing patients were 3.1 points worse than those of later progressing patients. Therefore, a 2-3 point difference on the LCS was indicated as the minimum change associated with clinical significance [15]. In phase II studies of ZD1839, disease-related symptoms were assessed approximately weekly using a diary card consisting of the LCS (Table 1). Those patients with an increase of at least two points in LCS score, sustained for a minimum of 4 weeks, with no worsening at any interim weekly time points, were considered to have meaningful symptom improvement.
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Figure 2. Symptom improvement by objective response in patients with advanced NSCLC [15]. Reprinted by permission from Journal of Clinical Epidemiology 2002;55:285-295. ©2002 Elsevier Science, Inc. Abbreviations: CR = complete response; PR = partial response; SD = stable disease; PD = progressive disease.
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PHASE II CLINICAL TRIAL RESULTS OF ZD1839 IN PATIENTS WITH ADVANCED NSCLC
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The preliminary data from two large phase II trials of ZD1839 monotherapy, IressaTM Dose Evaluation in Advanced Lung cancer (IDEAL) 1 [17, 18] and 2 [19, 20], were recently reported at the American Society for Clinical Oncology. These results demonstrate the importance of having improvements in symptoms and QOL as objectives for clinical trials of novel cancer therapies in advanced NSCLC. Inclusion criteria were similar for the two studies, although patients recruited for IDEAL 2 had poorer prognoses. Patients enrolled in IDEAL 2 had to have received at least two chemotherapy regimens including a platinum-based agent and docetaxel, while those enrolled in IDEAL 1 must have received one or two previous chemotherapy regimens, at least one of which had included a platinum-based agent. The IDEAL 2 protocol required patients to have disease-related symptoms at baseline with a score of 
24 on the LCS. This was not a requirement of entry to IDEAL 1, but only patients with an LCS score of 24 were evaluable for symptom and QOL improvements.
In both of these trials, patients were randomized to either 250 or 500 mg/day ZD1839 (Fig. 3). The results showed that there were no differences in response between the two doses in either study and that the lower dose level was better tolerated; therefore, 250 mg/day has been chosen as the recommended dose, and data for this dose only are presented here. Patient demographics are provided in Table 2.
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Table 2. Demography and disease characteristics of patients treated with 250 mg/day ZD1839 in IDEAL 1 and IDEAL 2
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SYMPTOM RELIEF
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Many patients had a prospectively defined improvement in disease-related symptoms: the symptom improvement rates were 40% in IDEAL 1 and 43% in IDEAL 2. Symptom relief was rapid: the median time to improvement was 8 days in IDEAL 1 and 10 days in IDEAL 2 (the times of the first post-baseline assessment for each study).
Further, the LCS data correlated with objective tumor response rates: there was a clinically significant improvement in disease-related symptoms in most patients with a partial/complete response or stable disease in both studies, whereas those patients with progressive disease showed relatively little symptom improvement. For example, 69% and 100% of patients experiencing an objective response had symptom improvement in IDEAL 1 and 2, respectively [17, 19]. An improvement in disease-related symptoms was also associated with an increase in overall and progression-free survival in both trials [17, 19].
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QOL
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Overall QOL (as shown by FACT-L total score) improved in 24% and 34% of patients in IDEAL 1 and IDEAL 2, respectively. The median time to improvement was 29 days in IDEAL 1 and 30 days in IDEAL 2 (the approximate times of the first post-baseline assessments). Most patients who had a partial/complete response or stable disease also had an improvement in their QOL [17, 19].
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TOLERABILITY
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ZD1839 was generally well tolerated. The majority of adverse events were mild, reversible National Cancer Institute common toxicity criteria (CTC; version 2.0) grade 1/2 diarrhea and skin reactions (rash, pruritus, dry skin, and acne). Across the two trials there was only one drug-related grade 3/4 skin reaction, which was grade 3 rash, and one incidence of grade 3 diarrhea [18, 20]. Overall grade 3/4 drug-related adverse events occurred in only 9% of patients in IDEAL 1 and 7% of patients in IDEAL 2. Further, ZD1839 was not associated with typical cytotoxic adverse events such as alopecia, neuropathy, neutropenia, or other hematologic toxicity.
What Do These Results Mean for the Patient?
The IDEAL 1 and 2 results suggest that for patients with advanced NSCLC who have previously received platinum-based chemotherapy, ZD1839 offers a new treatment option with the potential of providing meaningful symptom relief in many patients, particularly those who experience an objective response or stable disease. Symptom relief is an important outcome for these patients because many experience frequent and severe symptoms. The results also suggest that survival is longer in patients who have an improvement in their disease-related symptoms compared with those who show no symptom response.
Patients may also experience improvement in their QOL, especially those who experienced an objective response or stable disease. For example, in IDEAL 2, symptom improvements translated into tangible QOL benefits: one elderly patient who was bedridden 50% of the time prior to ZD1839 therapy now walks two miles a day [19].
The novel mechanism of action of ZD1839 has led to a tolerability profile distinct from that of cytotoxic chemotherapy, with major patient benefits. In IDEAL 1 and 2, the overwhelming majority of patients found that diarrhea or skin reactions were tolerable, improved over time, or were manageable with brief interruption of treatment (less than 14 days) [21]. In some cases, simple interventions were helpful, such as the use of loperamide or other antidiarrheals, or the short-term use of a topical or oral antibiotic for pustular skin lesions. ZD1839 was not associated with typical cytotoxic adverse events such as alopecia, neutropenia, or other hematologic toxicity. While alopecia is a distressing side effect of chemotherapy for many patients, neutropenia can be severe or life-threatening and may require hospitalization. In addition, chemotherapy-associated anemia is strongly linked with fatigue, and loss of activity and overall QOL. The favorable adverse-event profile of ZD1839 may enable its use in patients who are considered unfit for chemotherapy or refuse chemotherapy because of its toxicity.
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CONCLUSIONS AND FUTURE DIRECTIONS
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Data from IDEAL 1 and 2 demonstrate that ZD1839 offers extensively pretreated patients with advanced NSCLC the chance of a clinically significant improvement of their disease-related symptoms and an improvement in their QOL in the later stages of their disease. The favorable tolerability profile of ZD1839 may also extend its use to patients who are unable or unwilling to accept the toxicity of traditional cytotoxic chemotherapy.
The distinct mechanism of action and acceptable tolerability profile of ZD1839 may confer improved efficacy when used in combination with chemotherapy, particularly with respect to tumor regression and improved survival. Phase III trials of ZD1839 in combination with standard chemotherapy regimens (gemcitabine/cisplatin or paclitaxel/carboplatin) as first-line treatment for advanced NSCLC are nearing completion after preliminary studies suggested promising antitumor activity with no increases in any significant clinical toxicity [22, 23]. Studies showing the importance of EGFR in the pathogenesis of lung cancer [24] have provided the rationale for a multi-institutional Specialized Program in Research Excellence phase III chemoprevention trial of ZD1839 versus placebo in former/current smokers with a previous history of lung cancer. It is hoped that the results of these trials will reveal clinically relevant outcomes for patients with NSCLC, and the potential of ZD1839 in the chemoprevention of lung cancer. Further, the results of ongoing trials of ZD1839 as monotherapy or in combination therapy in patients with a range of solid tumors will reveal whether benefits will apply to patients with other tumor types.
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ACKNOWLEDGMENT
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Dr. Ronald B. Natale receives research support from AstraZeneca, Eli Lilly, Pfizer, and Aventis. At the time of publication, this paper discusses the investigational and unlabeled usage of ZD1839.
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REFERENCES
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- Natale RB, Skarin AT, Maddox A-M et al. Improvement in symptoms and quality of life for advanced non-small-cell lung cancer patients receiving ZD1839 (‘Iressa’) in IDEAL 2. Proc Am Soc Clin Oncol 2002;21:292a (A1167).
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- Ranson M, Hammond L, Ferry D et al. ZD1839 (‘Iressa’), a selective oral EGFR-TKI (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]
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Received July 2, 2002;
accepted for publication July 25, 2002.
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Abstract
