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Gefitinib (‘Iressa’): a new therapy for advanced non-small-cell lung cancer
ARTICLE IN PRESS Respiratory Medicine (2005) 99, 298–307
Gefitinib (‘Iressa’): a new therapy for advanced non-small-cell lung cancer Martin Reck,1, Ulrich Gatzemeier2 Department of Thoracic Oncology, Hospital Grosshansdorf, Woehrendamm 80, Grosshansdorf 22927, Germany Received 9 March 2004; accepted 10 August 2004
KEYWORDS Non-small-cell lung cancer (NSCLC); Epidermal growth factor receptor (EGFR); EGFR tyrosine kinase inhibitor; Gefitinib; ‘Iressa’
Summary Patients with advanced non-small-cell lung cancer (NSCLC) have a poor prognosis and suffer many disease-related symptoms. Treatments should therefore aim to palliate these symptoms as well as improve overall quality of life. Gefitinib (‘Iressa’) is a novel epidermal growth factor receptor tyrosine kinase inhibitor that targets cell signaling involved in tumor growth and differentiation. In Phase II trials in recurrent NSCLC, gefitinib provided objective responses and symptom relief, and was generally well tolerated. Now approved for the treatment of advanced NSCLC in over 25 countries, including Japan and the USA, gefitinib has demonstrated significant clinical benefit in a disease area with limited treatment options. & 2004 Elsevier Ltd. All rights reserved.
Introduction Lung cancer is a significant public health problem. It is one of the most common forms of cancer—1.2 million new cases of lung cancer were diagnosed worldwide in 2000—followed by breast cancer (1.05 million new cases) and colorectal cancer (945,000 new cases).1 The disease is a leading cause of cancer death in both men and women Corresponding author. Tel.: +49-4102-601-261; fax: +49-4102601-247. E-mail address: [email protected] (M. Reck). 1 Reck has received honoraria from AstraZeneca, Bristol-Myers Squibb, Lilly, Chugai Pharma, and Pierre Fabre. 2 Gatzeineier has been a consultant for AstraZeneca and Lilly, and has received honoraria from Bristol-Myers Squibb and Pierre Fabre.
worldwide, accounting for an estimated 1.1 million deaths in 2000,1 and approximately 80% of all lung cancer cases are non-small-cell lung cancer (NSCLC).
Symptoms of NSCLC Evaluation of the signs and symptoms of lung cancer can provide important information regarding a patient’s disease stage and prognosis. In general, lung cancer patients initially present with a wide variety of symptoms, often related to the respiratory tract, such as cough, dyspnea, chest pain, hemoptysis, and hoarseness.2 More general symptoms include fever, bone pain, weakness, weight loss, anorexia, neuropathic pain, headache, confusion, and ataxia.
0954-6111/$ - see front matter & 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.rmed.2004.08.009
ARTICLE IN PRESS Gefitinib: a new therapy for advanced NSCLC A centrally located tumor or one arising in the large airways can produce local symptoms, including cough, localized wheezing, hemoptysis, or dyspnea.3 Locally advanced tumors will usually generate systemic symptoms, such as fatigue, weight loss, and fever. Individual symptoms may provide more specific information; for example, hoarseness can result from mediastinal invasion of the recurrent laryngeal nerve. Distant metastatic disease may also cause symptoms that aid evaluation and prognosis. Metastases from lung cancer have been found in every organ; however, the four most common sites of metastases are the adrenal glands, liver, central nervous system, and bone. Disease-related symptoms cause a great deal of distress to the patient and, together with the general psychologic and social impact of cancer, can seriously compromise overall quality of life (QoL). It is increasingly recognized that improvement in symptoms and QoL are important endpoints in the evaluation of new anticancer treatments.
Treatment options for advanced NSCLC Surgery is the treatment of choice for early stage (I and II) NSCLC, while a multidisciplinary approach, combining surgery, chemotherapy, and radiotherapy, offers the best chance of a cure for locally advanced disease (IIIa and IIIb). Approximately half of all patients with early stage or locally advanced NSCLC are treated non-surgically, either because they are unable to tolerate surgical resection, or because their tumor is considered to be unresectable (stage III disease). Platinum-based chemotherapy combinations are well-established first-line treatments for patients with advanced NSCLC (stage IV disease); however, chemotherapy is associated with significant toxicity and limited efficacy. A high proportion of patients relapse and only docetaxel is the only chemotherapy agent currently approved for second-line therapy.4,5 Despite improvements in the treatment of NSCLC, approximate 5-year survival rates are: 65% (stage I disease); 40% (stage II disease); 15% (stage III disease); 5% (stage IV disease).6 The 1-year survival rate for patients with advanced recurrent NSCLC is also poor: for those patients receiving best supportive care after at least one chemotherapy regimen, 1-year survival is 16%7 and a retrospective analysis of patients receiving third- and fourth-line chemotherapy reported 5.5% 1-year survival.8 There is an urgent need for more effective and less toxic treatments for patients with advanced NSCLC.
299 Novel biologic agents are currently being investigated for the treatment of NSCLC. These rationally designed therapeutics offer hope that bettertolerated treatment options, which provide clinical benefit, may be found. The current status of development of a selection of these new therapeutic agents is summarized in Table 1.9–36 The epidermal growth factor receptor (EGFR) is an important therapeutic target. This cell membrane receptor has intrinsic tyrosine kinase (TK) activity and exists as a monomer that dimerizes following ligand binding. Dimerization activates the intrinsic TK domain, resulting in tyrosine autophosphorylation and the initiation of numerous downstream signaling pathways.37–40 The EGFR mediates cell signaling associated with tumor development, such as increased cell proliferation and decreased apoptosis.37–40 Furthermore, expression or high expression of the EGFR is seen in a wide variety of human tumors, including most NSCLCs.41–44 The EGFR has therefore been implicated in the pathogenesis of several human tumors and forms a key target for novel anticancer therapies. A number of promising agents have been designed to antagonize EGFR function,45 such as monoclonal antibodies (cetuximab [Erbitux]) and small-molecule EGFR-TK inhibitors (EGFR-TKIs) (gefitinib [‘Iressa’] and erlotinib [Tarceva]). Current clinical investigations of gefitinib encompass a variety of human malignancies such as head and neck, breast, and colorectal cancer.46 However, gefitinib is furthest advanced in clinical development for the treatment of NSCLC: to date, approximately 150,000 patients have received gefitinib worldwide and it is the first EGFR-TKI to have been licensed. The indication in Japan is for inoperable or recurrent disease. In the USA and Australia, gefitinib monotherapy has recently been approved for the treatment of locally advanced or metastatic NSCLC after the failure of both platinum-based and docetaxel chemotherapies.
Gefitinib Gefitinib is an orally active EGFR-TKI that blocks signal transduction pathways implicated in the proliferation and survival of cancer cells, and other host-dependent processes promoting cancer cell growth.38 Gefitinib has an intracellular mechanism of action. It competes with ATP for binding to the EGFR, thus directly inhibiting EGFR autophosphorylation. In vitro studies have demonstrated that gefitinib reduces cell proliferation, increases apoptosis, and inhibits angiogenesis.47,48 In preclinical studies, gefitinib demonstrated tumor growth in-
300
Table 1
Examples of novel biologic agents in clinical development for the treatment of NSCLC.
Drug
Mechanism of action
Current status of development in NSCLC
References
Gefitinib (‘Iressa’)
EGFR-TKI
Fukuoka et al.9, Kris et al.10
Erlotinib (Tarceva, OSI-774)
EGFR-TKI
Cetuximab (Erbitux, IMC-C225)
Anti-EGFR monoclonal antibody
Approved in over 25 countries (see text for indications) Phase III as single agent and in combination with standard chemotherapy Phase III in combination with standard chemotherapy Phase I/II in combination with standard chemotherapy Phase I/II as single agent and in combination with erlotinib Phase III in combination with taxanes Phase I/II as single agent and in combination with standard chemotherapy
Bexarotene (Targretin, LGD1069)
ISIS 3521 (Affinitac, LY-900003)
Binds nuclear hormone receptors and directly mediates gene expression
Protein kinase Ca antisense
Bcl-2 antisense
Phase III in combination with standard chemotherapy Phase I/II as single agent and in combination with standard chemotherapy Phase III in combination with standard chemotherapy Phase I/II in combination with standard chemotherapy Phase III in combination with docetaxel
EGFR, epidermal growth factor receptor; EGFR-TKI, EGFR tyrosine kinase inhibitor; VEGF, vascular endothelial growth factor.
Kelly et al.14, Kim et al.15, Robert et al.16, Rosell et al.17 Langmuir et al.18, Novotny et al.19, Sandler et al.20 Data not yet available Adjei et al.21, Hurwitz et al.22, Khuri et al.23, Kim et al.24, Lipton et al.27, Pierson et al.26, Sprague et al.28, Zaknoen et al.25 Data not yet available
Jacobs et al.29, Khuri et al.30, Rizvi et al.31, Yocum et al.32 Lynch et al.33 Moore et al.34, Ritchs et al.35 Yuen et al.36 Data not yet available
M. Reck, U. Gatzemeier
Oblimersen (Genasense, G-3139)
Humanized anti-VEGF monoclonal antibody Farnesyl-transferase inhibitor
Data not yet available
ARTICLE IN PRESS
Bevacizumab (Avastin, rhuMabVEGF) Lonafarnib (Sarasar, SCH 66336)
Herbst et al.11, Gatzemeier et al.12, Shepherd et al.13
ARTICLE IN PRESS Gefitinib: a new therapy for advanced NSCLC hibition in a wide range of tumor cell lines and human tumor xenograft models, including lung, breast, colon, and prostate cancers.47,49–52 These results supported the clinical development of gefitinib as an anticancer agent. Four large, multicenter, Phase I trials investigated the dose escalation of gefitinib up to 1000 mg/day in 254 patients with a range of solid malignancies.53–56 Encouraging antitumor activity was observed, particularly in NSCLC: 10 out of 100 patients with NSCLC experienced a partial response across a range of doses. These trials demonstrated the acceptable tolerability profile and ease of administration of gefitinib. Adverse events were mostly mild (grade 1/2); the most common were rash/acne and diarrhea. Dose-limiting toxicity was observed at 700–1000 mg/day, while responses occurred from 150–700 mg/day. These data supported the selection of 250 and 500 mg/day doses for Phase II trials of gefitinib. Two large, randomized, double-blind, Phase II studies continued the investigation of gefitinib monotherapy for the treatment of NSCLC. The ‘Iressa’ Dose Evaluation in Advanced Lung cancer (IDEAL) 1 and 2 trials each recruited approximately 200 patients with locally advanced or metastatic NSCLC and compared gefitinib doses of 250 and 500 mg/day.9,10 In IDEAL 1, patients had received one or two prior chemotherapy regimens, while patients enrolled in IDEAL 2 had received at least two previous chemotherapy regimens and were required to be symptomatic for NSCLC at baseline. Although this was not a requirement for IDEAL 1, 64% and 69% of patients in the 250 and 500 mg/day groups were symptomatic for NSCLC at trial entry. In both trials, key endpoints included objective response rate, symptom relief, QoL, safety profile, and survival. Symptom improvement in Phase II trials Gefitinib demonstrated significant improvement in disease-related symptoms in both IDEAL 1 and 2, as assessed by the Lung Cancer Subscale (LCS) of the Functional Assessment of Cancer Therapy–Lung (FACT-L)57,58 (Fig. 1 and Table 2). The LCS and FACT-L have been independently validated and shown to provide clinically meaningful information about symptoms commonly experienced by lung cancer patients and their QoL.57,58 A total of 356 patients in IDEAL 1 and 2 were evaluable for symptom improvement, with median baseline LCS scores of 16–18. Symptom improvement was demonstrated in 40% and 43% of evaluable patients at 250 mg/day, and 37% and 35% of patients at 500 mg/day, in IDEAL 1 and 2, respectively.9 At both dose levels, symptom improvement
301
Figure 1 Functional Assessment of Cancer Therapy-Lung (FACT-L), showing the Trial Outcome Index (TOI) and the Lung Cancer Subscale (LCS) items.
was rapid, with a median time to improvement of 8–10 days in both trials.59 Furthermore, LCS responses were durable, with median durations of symptom improvement of 5.1 months (IDEAL 1) and 5.4 months (IDEAL 2) observed in the 500 mg/day dose group (not yet reached at data cut-off for the 250 mg/day group in both trials). Analysis of improvements in individual LCS items showed that high proportions of patients reported improvements in pulmonary symptoms (IDEAL 2 data shown in Fig. 2; similar results were seen in IDEAL 1). The LCS items of difficulty breathing and shortness of breath showed the greatest improvement in IDEAL 2: these items were both improved in 89% of patients with LCS improvement at 250 mg/ day. Comparison of individual LCS item scores at baseline with on-study best scores showed marked increases in the proportion of patients reporting individual items as asymptomatic, together with fewer items reported as very symptomatic (eg. IDEAL 2 data shown in Fig. 3). The LCS data showed a positive correlation with objective tumor response. The majority of patients with a partial/complete response (69% in IDEAL 1 and 100% in IDEAL 2 at 250 mg/day) or with stable disease (70% in IDEAL 1 and 81% in IDEAL 2 at 250 mg/day) experienced clinically significant improvement in disease-related symptoms, whereas for patients with progressive disease, the symptomimprovement rate was relatively low (12% in both IDEAL 1 and 2 at 250 mg/day). Furthermore, patients with symptom improvement had longer overall and progression-free survival: for example, in IDEAL 2 at 250 mg/day, median overall survival in patients with symptom improvement was 13.6 months compared with 3.7 months in patients who did not experience symptom improvement.
ARTICLE IN PRESS 302 Table 2
M. Reck, U. Gatzemeier Assessment of disease-related symptoms and QoL.
Method of assessment
Disease-related symptoms
QoL
LCS, a subscale of the validated QoL instrument, the FACT-L questionnaire57
FACT-L questionnaire, validated with respect to its psychometric properties and sensitivity to clinical changes57
The 7 LCS items: (1) (2) (3) (4) (5) (6) (7)
Shortness of breath Cough Tightness in chest Difficulty breathing Loss of appetite Weight loss Lack of clear thinking
TOI measures the more physical aspects of FACT-L shown to be sensitive to chemotherapy
TOI covers: (1) Symptoms (LCS) (2) Physical wellbeing (3) Functional wellbeing
Frequency of assessment
Patients completed a weekly diary card, rating each item on a scale of 0–4
Maximum (best; asymptomatic) score attainable
LCS: 28
Prospectively defined clinically meaningful improvement
X2-point improvement for X4 weeks, with no worsening at any interim timepoints58
FACT-L was completed at baseline, and on day 28 of each treatment period (before clinical assessment and before patients were informed of their disease status) TOI: 84 FACT-L: 136 X6-point improvement for X4 weeks
FACT-L, Functional Assessment of Cancer Therapy-Lung; LCS, Lung Cancer Subscale; QoL, quality of life; TOI, Trial Outcome Index.
Figure 2 Specific symptom improvement in all patients with Lung Cancer Subscale improvement (IDEAL 2, 250 mg/day).
These results provide further evidence of the clinical relevance of symptom improvement as a trial endpoint, in addition to the clear benefit experienced by the patient.
QoL in Phase II trials The complete FACT-L questionnaire evaluated QoL and its subset, the Trial Outcome Index (TOI), assessed the more physical aspects of FACT-L57,58
ARTICLE IN PRESS Gefitinib: a new therapy for advanced NSCLC
303
Figure 3 Comparison of individual Lung Cancer Subscale item scores at baseline and on-study best score (IDEAL 2, 250 mg/day).
Table 3
QoL improvement rates (250 mg/day). IDEAL 1 (n ¼ 67)
IDEAL 2 (n ¼ 102)
Response (%)
TOI
FACT-L
TOI
FACT-L
Improved No change Worsened Othera
20.9 26.9 9.0 43.3
23.9 14.9 19.4 41.8
33.3 14.7 5.9 46.1
34.3 12.7 6.9 46.1
a Patients to whom a response could not be assigned, e.g. due to missing data. FACT-L, Functional Assessment of Cancer Therapy-Lung; IDEAL, ‘Iressa’ Dose Evaluation in Advanced Lung cancer; QoL, quality of life; TOI, Trial Outcome Index.
(Fig. 1 and Table 2). In both IDEAL 1 and 2, patients had compromised QoL at trial entry. Compared with maximum (asymptomatic) scores of 84 for the TOI and 136 for FACT-L, the median baseline scores were 53 and 49 (TOI) and 85 and 86 (FACT-L) in IDEAL 1 and 2, respectively. Gefitinib treatment resulted in QoL FACT-L improvement in 24% and 34% of patients at 250 mg/day (IDEAL 1 and 2, respectively) (Table 3). As observed with the LCS symptom data, improvements in QoL were associated with tumor response: 54% and 92% of patients with an objective response in IDEAL 1 and 2, respectively, showed improvement in overall FACT-L scores. Objective tumor response in Phase II trials Gefitinib treatment resulted in clinically meaningful antitumor activity in both trials, assessed
using the Southwest Oncology Group-modified International Union Against Cancer/World Health Organization criteria. Objective response rates were 18% and 19% in IDEAL 1, and 12% and 9% in IDEAL 2 at 250 and 500 mg/day, respectively. In addition to the patients who experienced objective tumor responses, approximately 30% of patients in both trials achieved stable disease, resulting in disease control rates of 54% and 51% in IDEAL 1, and 42% and 36% in IDEAL 2 at 250 and 500 mg/day, respectively. Median overall survival times in the 250 and 500 mg/day groups were 7.6 and 7.9 months (IDEAL 1), and 6.5 and 5.9 months (IDEAL 2), respectively. The estimated 1-year survival rates were 35% and 29% (IDEAL 1) and 29% and 24% (IDEAL 2) for the 250 and 500 mg/day dose groups, respectively. These results demonstrated no difference in efficacy between the two doses of gefitinib.
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Safety/tolerability in Phase II trials Gefitinib was generally well tolerated in both IDEAL 1 and 2. The most common adverse events were mild: National Cancer Institute Common Toxicity Criteria (version 2.0) grade 1/2 gastrointestinal and skin-related adverse events. Fewer patients had grade 3/4 adverse events with 250 mg/day than with 500 mg/day (8.7% versus 30.2% in IDEAL 1 and 6.9% versus 17.5% in IDEAL 2, respectively). Overall, the 250 mg/day dose was better tolerated than 500 mg/day and this, combined with similar results for efficacy endpoints with the two doses, makes 250 mg/day the recommended dose for patients with NSCLC who have previously received chemotherapy. This dissociation of dose–response and dose–toxicity relationships was forecast for biologic agents such as gefitinib.60 Direct targeting of malignant cells was expected to reduce toxicity at clinically effective doses. In this model, assessment of the maximum tolerated dose is not an appropriate endpoint and concepts such as the optimal biologic dose are more meaningful. This alternative outcome aims to elucidate the dose that provides maximum efficacy while maintaining a favorable tolerability profile. Evidence from the IDEAL trials suggests that gefitinib conforms to this model and that 250 mg/day is the optimal biologic dose of gefitinib in NSCLC.
(both as expected from previous studies of gefitinib), and hematologic (as expected from the toxicity profiles of gemcitabine/cisplatin and paclitaxel/carboplatin). The frequency of adverse events was similar across all treatment arms, except for diarrhea, rash, and acne, which showed a gefitinib dose–response relationship. The incidence of pulmonary adverse events, including interstitial lung disease (ILD)-type events, was generally similar in treatment arms in INTACT 1 and 2 (Table 4). It is unclear why the combination of gefitinib with standard doublet chemotherapy failed to show survival benefits in the first-line setting. Possible explanations include a pharmacodynamic antagonism between the drugs, or that treatment with chemotherapy sensitizes tumors to EGFR-targeted therapy, so that gefitinib is more effective in pretreated patients. These results reinforce the need for better understanding of the activity of gefitinib in a wider range of tumor types, treatment strategies, and patient subgroups. Erlotinib, another EGFR-TKI, has also been investigated in combination with standard chemotherapy in patients with metastatic NSCLC in the first-line setting in two Phase III trials. As with gefitinib, overall survival (the primary endpoint) was not improved.
Phase III trails Two large, randomized, double-blind, placebocontrolled, Phase III trials, each of approximately 1000 previously untreated patients with NSCLC, investigated gefitinib in combination with gemcitabine/cisplatin (the ‘Iressa’ NSCLC Trial Assessing Combination Treatment [INTACT] 1), or carboplatin/paclitaxel (INTACT 2).61,62 Despite showing no additional benefit in efficacy, there was no worsening of chemotherapy-associated toxicities, thus confirming the favorable tolerability of gefitinib in the placebo-controlled setting. The most common adverse events were gastrointestinal, skin related
Compassionate-use program More than 44,000 patients worldwide have received gefitinib as part of a compassionate-use program. These patients have advanced (inoperable stage III or IV) NSCLC, do not qualify for clinical trials, and have exhausted other treatment options. As well as providing patients with earlier access to this novel therapy for NSCLC, this program has imparted a considerable amount of valuable clinical information on the use of gefitinib. Gefitinib has demonstrated clinical activity in terms of objective tumor response, disease control, and overall survival.63–66 In addition, tumor response has been related to
Table 4
Incidence of pulmonary adverse events in INTACT 1 and 2.
Dyspnea, n (%) Cough, n (%) Pneumonia, n (%) ILD event, n (%)
Gefitinib 500 mg/day (n ¼ 700)
Gefitinib 250 mg/day (n ¼ 704)
Placebo
181 (25.9) 146 (20.9) 43 (6.1) 8 (1.1)
189 (26.8) 159 (22.6) 48 (6.8) 8 (1.1)
193 (27.7) 148 (21.3) 46 (6.6) 6 (0.9)
INTACT, ‘Iressa’ NSCLC Trial Assessing Combination Treatment; ILD, interstitial lung disease.
(n ¼ 696)
ARTICLE IN PRESS Gefitinib: a new therapy for advanced NSCLC symptomatic benefit. A final analysis of more than 21,000 patients who took part in this compassionate-use program in the USA recently reported a 1year survival rate of 29.9%, which is consistent with the IDEAL trial results.63 Tolerability data have generally been consistent with previous studies, with most adverse events observed being mild skinrelated or gastrointestinal disorders. In this wide compassionate-use program, the incidence of ILD is approximately 0.3%. In comparison, the incidence of ILD in Japanese patients treated with gefitinib has been reported as 1.7%.67 However, in approximately 140,000 patients worldwide treated with gefitinib, the overall incidence of ILD is less than 1%. It is difficult to determine the exact cause for this condition in these patients, as these events may have been due to progression of the lung cancer, prior therapy, or gefitinib treatment. Hence, a direct relationship between gefitinib and ILD is unclear in many cases. Potential prognostic factors For a variety of NSCLC treatment strategies, many research efforts have focused on investigating clinical and biologic factors that may predict which patients will benefit from treatment. Emerging data have identified specific somatic EGFR mutations in patients with dramatic responses to gefitinib.68,69 This provides an exciting insight into why some patients experience such dramatic responses to gefitinib and also confirms that this is a targeted therapy. However, the role of these mutations in other clinical benefits seen with gefitinib such as disease stabilization and/or symptom improvement is not yet known and further molecular studies are ongoing to explain the mechanisms responsible for these benefits.
Conclusions Patients with NSCLC often present with pulmonary symptoms; therefore, treatment strategies should aim to provide disease-related symptom relief and improved QoL. These are important endpoints in the clinical evaluation of novel therapies for cancer, and this is further supported by their observed correlation with objective tumor response and survival. In recent trials, the oral EGFR-TKI gefitinib has demonstrated improvement in pulmonary symptoms and QoL in pretreated patients with advanced NSCLC. In addition, gefitinib monotherapy resulted in clinically significant antitumor activity and displayed a favorable tolerability profile. The combination of gefitinib with
305 platinum-based chemotherapy doublets in the firstline setting for NSCLC produced no additional survival benefit. A large-scale compassionate-use program has provided extensive clinical experience with gefitinib therapy. Gefitinib has demonstrated antitumor activity and good tolerability in these patients and further results from this program are awaited with interest. To conclude, treatment with gefitinib has demonstrated significant clinical benefit for patients with advanced NSCLC and, in particular, provides rapid relief from the pulmonary symptoms that are commonly associated with this disease. ‘Iressa’ is a trademark of the AstraZeneca group of companies.
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307 56. Nakagawa K, Tamura T, Negoro S, et al. Phase I pharmacokinetic trial of the selective oral epidermal growth factor receptor tyrosine kinase inhibitor gefitinib (‘Iressa’, ZD1839) in Japanese patients with solid malignant tumours. Ann Oncol 2003;14:922–30. 57. Cella DF, Bonomi AE, Lloyd SR, Tulsky DS, Kaplan E, Bonomi P. Reliability and validity of the Functional Assessment of Cancer Therapy-Lung (FACT-L) quality of life instrument. Lung Cancer 1995;12:199–220. 58. Cella D, Eton DT, Fairclough DL, et al. What is a clinically meaningful change on the Functional Assessment of Cancer Therapy-Lung (FACT-L) Questionnaire? Results from Eastern Cooperative Oncology Group (ECOG) Study 5592. J Clin Epidemiol 2002;55:285–95. 59. Herbst RS, Fukuoka M, Schiller J, et al. ZD1839 (‘Iressa’) in pretreated patients with advanced non-small-cell lung cancer (NSCLC): results of phase II trials (IDEAL 1 and 2). Poster PI5 presented at the 1st International Symposium on Signal Transduction Modulators in Cancer Therapy, Amsterdam, The Netherlands, September 23–25, 2002. 60. Rowinsky EK. The pursuit of optimal outcomes in cancer therapy in a new age of rationally designed target-based anticancer agents. Drugs 2000;60(Suppl 1):1–14. 61. Giaccone G, Johnson DH, Manegold C, et al. A phase III clinical trial of ZD1839 (‘Iressa’) in combination with gemcitabine and cisplatin in chemotherapy-naive patients with advanced non-small-cell lung cancer (INTACT 1). Ann Oncol 2002;13(Suppl 5):2 (abs. 4). 62. Johnson DH, Herbst R, Giaccone G, et al. ZD1839 (‘‘Iressa’’) in combination with paclitaxel & carboplatin in chemotherapy-naive patients with advanced non-small-cell lung cancer (NSCLC): results from a phase III clinical trial (INTACT 2). Ann Oncol 2002;13(Suppl 5):127 (abs. 4680). 63. Ochs J, Grous JJ, Warner KL. Final survival and safety results for 21,064 non-small-cell lung cancer (NSCLC) patients who received compassionate use gefitinib in a U.S. expanded access program (EAP). Proc Am Soc Clin Oncol 2004;23:628 (abs. 7060). 64. Coplin MA, Kommareddy A, McLeod H, et al. Gefitinib (‘Iressa’, ZD1839) shows activity and is well tolerated in elderly patients with non-small-cell lung cancer (NSCLC). Poster 3048 presented at ASCO, Chicago, IL, USA, May 31–June 3, 2003. 65. Janne PA, Ostler PA, Lucca J, et al. ZD1839 (‘Iressa’) shows antitumor activity in patients with recurrent non-small-cell lung cancer treated on a compassionate use protocol. Poster 1274 presented at ASCO, Orlando, FL, USA, May 18–21, 2002. 66. Lo ´pez Martin A, Constenla M, Martı´n Algarra S, et al. Gefitinib (‘Iressa’, ZD1839) in advanced non-small-cell lung cancer patients after progression on chemotherapy. Poster 2695 presented at ASCO, Chicago, IL, USA, May 31–June 3, 2003. 67. Inoue A, Saijo Y, Maemondo M, et al. Severe acute interstitial pneumonia and gefitinib. Lancet 2003; 361:137–9. 68. 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;350:2129–39. 69. Paez JG, Ja ¨nne PA, Lee JC, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 2004;304:1497–500.
Gefitinib (‘Iressa’): a new therapy for advanced non-small-cell lung cancer Martin Reck,1, Ulrich Gatzemeier2 Department of Thoracic Oncology, Hospital Grosshansdorf, Woehrendamm 80, Grosshansdorf 22927, Germany Received 9 March 2004; accepted 10 August 2004
KEYWORDS Non-small-cell lung cancer (NSCLC); Epidermal growth factor receptor (EGFR); EGFR tyrosine kinase inhibitor; Gefitinib; ‘Iressa’
Summary Patients with advanced non-small-cell lung cancer (NSCLC) have a poor prognosis and suffer many disease-related symptoms. Treatments should therefore aim to palliate these symptoms as well as improve overall quality of life. Gefitinib (‘Iressa’) is a novel epidermal growth factor receptor tyrosine kinase inhibitor that targets cell signaling involved in tumor growth and differentiation. In Phase II trials in recurrent NSCLC, gefitinib provided objective responses and symptom relief, and was generally well tolerated. Now approved for the treatment of advanced NSCLC in over 25 countries, including Japan and the USA, gefitinib has demonstrated significant clinical benefit in a disease area with limited treatment options. & 2004 Elsevier Ltd. All rights reserved.
Introduction Lung cancer is a significant public health problem. It is one of the most common forms of cancer—1.2 million new cases of lung cancer were diagnosed worldwide in 2000—followed by breast cancer (1.05 million new cases) and colorectal cancer (945,000 new cases).1 The disease is a leading cause of cancer death in both men and women Corresponding author. Tel.: +49-4102-601-261; fax: +49-4102601-247. E-mail address: [email protected] (M. Reck). 1 Reck has received honoraria from AstraZeneca, Bristol-Myers Squibb, Lilly, Chugai Pharma, and Pierre Fabre. 2 Gatzeineier has been a consultant for AstraZeneca and Lilly, and has received honoraria from Bristol-Myers Squibb and Pierre Fabre.
worldwide, accounting for an estimated 1.1 million deaths in 2000,1 and approximately 80% of all lung cancer cases are non-small-cell lung cancer (NSCLC).
Symptoms of NSCLC Evaluation of the signs and symptoms of lung cancer can provide important information regarding a patient’s disease stage and prognosis. In general, lung cancer patients initially present with a wide variety of symptoms, often related to the respiratory tract, such as cough, dyspnea, chest pain, hemoptysis, and hoarseness.2 More general symptoms include fever, bone pain, weakness, weight loss, anorexia, neuropathic pain, headache, confusion, and ataxia.
0954-6111/$ - see front matter & 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.rmed.2004.08.009
ARTICLE IN PRESS Gefitinib: a new therapy for advanced NSCLC A centrally located tumor or one arising in the large airways can produce local symptoms, including cough, localized wheezing, hemoptysis, or dyspnea.3 Locally advanced tumors will usually generate systemic symptoms, such as fatigue, weight loss, and fever. Individual symptoms may provide more specific information; for example, hoarseness can result from mediastinal invasion of the recurrent laryngeal nerve. Distant metastatic disease may also cause symptoms that aid evaluation and prognosis. Metastases from lung cancer have been found in every organ; however, the four most common sites of metastases are the adrenal glands, liver, central nervous system, and bone. Disease-related symptoms cause a great deal of distress to the patient and, together with the general psychologic and social impact of cancer, can seriously compromise overall quality of life (QoL). It is increasingly recognized that improvement in symptoms and QoL are important endpoints in the evaluation of new anticancer treatments.
Treatment options for advanced NSCLC Surgery is the treatment of choice for early stage (I and II) NSCLC, while a multidisciplinary approach, combining surgery, chemotherapy, and radiotherapy, offers the best chance of a cure for locally advanced disease (IIIa and IIIb). Approximately half of all patients with early stage or locally advanced NSCLC are treated non-surgically, either because they are unable to tolerate surgical resection, or because their tumor is considered to be unresectable (stage III disease). Platinum-based chemotherapy combinations are well-established first-line treatments for patients with advanced NSCLC (stage IV disease); however, chemotherapy is associated with significant toxicity and limited efficacy. A high proportion of patients relapse and only docetaxel is the only chemotherapy agent currently approved for second-line therapy.4,5 Despite improvements in the treatment of NSCLC, approximate 5-year survival rates are: 65% (stage I disease); 40% (stage II disease); 15% (stage III disease); 5% (stage IV disease).6 The 1-year survival rate for patients with advanced recurrent NSCLC is also poor: for those patients receiving best supportive care after at least one chemotherapy regimen, 1-year survival is 16%7 and a retrospective analysis of patients receiving third- and fourth-line chemotherapy reported 5.5% 1-year survival.8 There is an urgent need for more effective and less toxic treatments for patients with advanced NSCLC.
299 Novel biologic agents are currently being investigated for the treatment of NSCLC. These rationally designed therapeutics offer hope that bettertolerated treatment options, which provide clinical benefit, may be found. The current status of development of a selection of these new therapeutic agents is summarized in Table 1.9–36 The epidermal growth factor receptor (EGFR) is an important therapeutic target. This cell membrane receptor has intrinsic tyrosine kinase (TK) activity and exists as a monomer that dimerizes following ligand binding. Dimerization activates the intrinsic TK domain, resulting in tyrosine autophosphorylation and the initiation of numerous downstream signaling pathways.37–40 The EGFR mediates cell signaling associated with tumor development, such as increased cell proliferation and decreased apoptosis.37–40 Furthermore, expression or high expression of the EGFR is seen in a wide variety of human tumors, including most NSCLCs.41–44 The EGFR has therefore been implicated in the pathogenesis of several human tumors and forms a key target for novel anticancer therapies. A number of promising agents have been designed to antagonize EGFR function,45 such as monoclonal antibodies (cetuximab [Erbitux]) and small-molecule EGFR-TK inhibitors (EGFR-TKIs) (gefitinib [‘Iressa’] and erlotinib [Tarceva]). Current clinical investigations of gefitinib encompass a variety of human malignancies such as head and neck, breast, and colorectal cancer.46 However, gefitinib is furthest advanced in clinical development for the treatment of NSCLC: to date, approximately 150,000 patients have received gefitinib worldwide and it is the first EGFR-TKI to have been licensed. The indication in Japan is for inoperable or recurrent disease. In the USA and Australia, gefitinib monotherapy has recently been approved for the treatment of locally advanced or metastatic NSCLC after the failure of both platinum-based and docetaxel chemotherapies.
Gefitinib Gefitinib is an orally active EGFR-TKI that blocks signal transduction pathways implicated in the proliferation and survival of cancer cells, and other host-dependent processes promoting cancer cell growth.38 Gefitinib has an intracellular mechanism of action. It competes with ATP for binding to the EGFR, thus directly inhibiting EGFR autophosphorylation. In vitro studies have demonstrated that gefitinib reduces cell proliferation, increases apoptosis, and inhibits angiogenesis.47,48 In preclinical studies, gefitinib demonstrated tumor growth in-
300
Table 1
Examples of novel biologic agents in clinical development for the treatment of NSCLC.
Drug
Mechanism of action
Current status of development in NSCLC
References
Gefitinib (‘Iressa’)
EGFR-TKI
Fukuoka et al.9, Kris et al.10
Erlotinib (Tarceva, OSI-774)
EGFR-TKI
Cetuximab (Erbitux, IMC-C225)
Anti-EGFR monoclonal antibody
Approved in over 25 countries (see text for indications) Phase III as single agent and in combination with standard chemotherapy Phase III in combination with standard chemotherapy Phase I/II in combination with standard chemotherapy Phase I/II as single agent and in combination with erlotinib Phase III in combination with taxanes Phase I/II as single agent and in combination with standard chemotherapy
Bexarotene (Targretin, LGD1069)
ISIS 3521 (Affinitac, LY-900003)
Binds nuclear hormone receptors and directly mediates gene expression
Protein kinase Ca antisense
Bcl-2 antisense
Phase III in combination with standard chemotherapy Phase I/II as single agent and in combination with standard chemotherapy Phase III in combination with standard chemotherapy Phase I/II in combination with standard chemotherapy Phase III in combination with docetaxel
EGFR, epidermal growth factor receptor; EGFR-TKI, EGFR tyrosine kinase inhibitor; VEGF, vascular endothelial growth factor.
Kelly et al.14, Kim et al.15, Robert et al.16, Rosell et al.17 Langmuir et al.18, Novotny et al.19, Sandler et al.20 Data not yet available Adjei et al.21, Hurwitz et al.22, Khuri et al.23, Kim et al.24, Lipton et al.27, Pierson et al.26, Sprague et al.28, Zaknoen et al.25 Data not yet available
Jacobs et al.29, Khuri et al.30, Rizvi et al.31, Yocum et al.32 Lynch et al.33 Moore et al.34, Ritchs et al.35 Yuen et al.36 Data not yet available
M. Reck, U. Gatzemeier
Oblimersen (Genasense, G-3139)
Humanized anti-VEGF monoclonal antibody Farnesyl-transferase inhibitor
Data not yet available
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Bevacizumab (Avastin, rhuMabVEGF) Lonafarnib (Sarasar, SCH 66336)
Herbst et al.11, Gatzemeier et al.12, Shepherd et al.13
ARTICLE IN PRESS Gefitinib: a new therapy for advanced NSCLC hibition in a wide range of tumor cell lines and human tumor xenograft models, including lung, breast, colon, and prostate cancers.47,49–52 These results supported the clinical development of gefitinib as an anticancer agent. Four large, multicenter, Phase I trials investigated the dose escalation of gefitinib up to 1000 mg/day in 254 patients with a range of solid malignancies.53–56 Encouraging antitumor activity was observed, particularly in NSCLC: 10 out of 100 patients with NSCLC experienced a partial response across a range of doses. These trials demonstrated the acceptable tolerability profile and ease of administration of gefitinib. Adverse events were mostly mild (grade 1/2); the most common were rash/acne and diarrhea. Dose-limiting toxicity was observed at 700–1000 mg/day, while responses occurred from 150–700 mg/day. These data supported the selection of 250 and 500 mg/day doses for Phase II trials of gefitinib. Two large, randomized, double-blind, Phase II studies continued the investigation of gefitinib monotherapy for the treatment of NSCLC. The ‘Iressa’ Dose Evaluation in Advanced Lung cancer (IDEAL) 1 and 2 trials each recruited approximately 200 patients with locally advanced or metastatic NSCLC and compared gefitinib doses of 250 and 500 mg/day.9,10 In IDEAL 1, patients had received one or two prior chemotherapy regimens, while patients enrolled in IDEAL 2 had received at least two previous chemotherapy regimens and were required to be symptomatic for NSCLC at baseline. Although this was not a requirement for IDEAL 1, 64% and 69% of patients in the 250 and 500 mg/day groups were symptomatic for NSCLC at trial entry. In both trials, key endpoints included objective response rate, symptom relief, QoL, safety profile, and survival. Symptom improvement in Phase II trials Gefitinib demonstrated significant improvement in disease-related symptoms in both IDEAL 1 and 2, as assessed by the Lung Cancer Subscale (LCS) of the Functional Assessment of Cancer Therapy–Lung (FACT-L)57,58 (Fig. 1 and Table 2). The LCS and FACT-L have been independently validated and shown to provide clinically meaningful information about symptoms commonly experienced by lung cancer patients and their QoL.57,58 A total of 356 patients in IDEAL 1 and 2 were evaluable for symptom improvement, with median baseline LCS scores of 16–18. Symptom improvement was demonstrated in 40% and 43% of evaluable patients at 250 mg/day, and 37% and 35% of patients at 500 mg/day, in IDEAL 1 and 2, respectively.9 At both dose levels, symptom improvement
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Figure 1 Functional Assessment of Cancer Therapy-Lung (FACT-L), showing the Trial Outcome Index (TOI) and the Lung Cancer Subscale (LCS) items.
was rapid, with a median time to improvement of 8–10 days in both trials.59 Furthermore, LCS responses were durable, with median durations of symptom improvement of 5.1 months (IDEAL 1) and 5.4 months (IDEAL 2) observed in the 500 mg/day dose group (not yet reached at data cut-off for the 250 mg/day group in both trials). Analysis of improvements in individual LCS items showed that high proportions of patients reported improvements in pulmonary symptoms (IDEAL 2 data shown in Fig. 2; similar results were seen in IDEAL 1). The LCS items of difficulty breathing and shortness of breath showed the greatest improvement in IDEAL 2: these items were both improved in 89% of patients with LCS improvement at 250 mg/ day. Comparison of individual LCS item scores at baseline with on-study best scores showed marked increases in the proportion of patients reporting individual items as asymptomatic, together with fewer items reported as very symptomatic (eg. IDEAL 2 data shown in Fig. 3). The LCS data showed a positive correlation with objective tumor response. The majority of patients with a partial/complete response (69% in IDEAL 1 and 100% in IDEAL 2 at 250 mg/day) or with stable disease (70% in IDEAL 1 and 81% in IDEAL 2 at 250 mg/day) experienced clinically significant improvement in disease-related symptoms, whereas for patients with progressive disease, the symptomimprovement rate was relatively low (12% in both IDEAL 1 and 2 at 250 mg/day). Furthermore, patients with symptom improvement had longer overall and progression-free survival: for example, in IDEAL 2 at 250 mg/day, median overall survival in patients with symptom improvement was 13.6 months compared with 3.7 months in patients who did not experience symptom improvement.
ARTICLE IN PRESS 302 Table 2
M. Reck, U. Gatzemeier Assessment of disease-related symptoms and QoL.
Method of assessment
Disease-related symptoms
QoL
LCS, a subscale of the validated QoL instrument, the FACT-L questionnaire57
FACT-L questionnaire, validated with respect to its psychometric properties and sensitivity to clinical changes57
The 7 LCS items: (1) (2) (3) (4) (5) (6) (7)
Shortness of breath Cough Tightness in chest Difficulty breathing Loss of appetite Weight loss Lack of clear thinking
TOI measures the more physical aspects of FACT-L shown to be sensitive to chemotherapy
TOI covers: (1) Symptoms (LCS) (2) Physical wellbeing (3) Functional wellbeing
Frequency of assessment
Patients completed a weekly diary card, rating each item on a scale of 0–4
Maximum (best; asymptomatic) score attainable
LCS: 28
Prospectively defined clinically meaningful improvement
X2-point improvement for X4 weeks, with no worsening at any interim timepoints58
FACT-L was completed at baseline, and on day 28 of each treatment period (before clinical assessment and before patients were informed of their disease status) TOI: 84 FACT-L: 136 X6-point improvement for X4 weeks
FACT-L, Functional Assessment of Cancer Therapy-Lung; LCS, Lung Cancer Subscale; QoL, quality of life; TOI, Trial Outcome Index.
Figure 2 Specific symptom improvement in all patients with Lung Cancer Subscale improvement (IDEAL 2, 250 mg/day).
These results provide further evidence of the clinical relevance of symptom improvement as a trial endpoint, in addition to the clear benefit experienced by the patient.
QoL in Phase II trials The complete FACT-L questionnaire evaluated QoL and its subset, the Trial Outcome Index (TOI), assessed the more physical aspects of FACT-L57,58
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303
Figure 3 Comparison of individual Lung Cancer Subscale item scores at baseline and on-study best score (IDEAL 2, 250 mg/day).
Table 3
QoL improvement rates (250 mg/day). IDEAL 1 (n ¼ 67)
IDEAL 2 (n ¼ 102)
Response (%)
TOI
FACT-L
TOI
FACT-L
Improved No change Worsened Othera
20.9 26.9 9.0 43.3
23.9 14.9 19.4 41.8
33.3 14.7 5.9 46.1
34.3 12.7 6.9 46.1
a Patients to whom a response could not be assigned, e.g. due to missing data. FACT-L, Functional Assessment of Cancer Therapy-Lung; IDEAL, ‘Iressa’ Dose Evaluation in Advanced Lung cancer; QoL, quality of life; TOI, Trial Outcome Index.
(Fig. 1 and Table 2). In both IDEAL 1 and 2, patients had compromised QoL at trial entry. Compared with maximum (asymptomatic) scores of 84 for the TOI and 136 for FACT-L, the median baseline scores were 53 and 49 (TOI) and 85 and 86 (FACT-L) in IDEAL 1 and 2, respectively. Gefitinib treatment resulted in QoL FACT-L improvement in 24% and 34% of patients at 250 mg/day (IDEAL 1 and 2, respectively) (Table 3). As observed with the LCS symptom data, improvements in QoL were associated with tumor response: 54% and 92% of patients with an objective response in IDEAL 1 and 2, respectively, showed improvement in overall FACT-L scores. Objective tumor response in Phase II trials Gefitinib treatment resulted in clinically meaningful antitumor activity in both trials, assessed
using the Southwest Oncology Group-modified International Union Against Cancer/World Health Organization criteria. Objective response rates were 18% and 19% in IDEAL 1, and 12% and 9% in IDEAL 2 at 250 and 500 mg/day, respectively. In addition to the patients who experienced objective tumor responses, approximately 30% of patients in both trials achieved stable disease, resulting in disease control rates of 54% and 51% in IDEAL 1, and 42% and 36% in IDEAL 2 at 250 and 500 mg/day, respectively. Median overall survival times in the 250 and 500 mg/day groups were 7.6 and 7.9 months (IDEAL 1), and 6.5 and 5.9 months (IDEAL 2), respectively. The estimated 1-year survival rates were 35% and 29% (IDEAL 1) and 29% and 24% (IDEAL 2) for the 250 and 500 mg/day dose groups, respectively. These results demonstrated no difference in efficacy between the two doses of gefitinib.
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Safety/tolerability in Phase II trials Gefitinib was generally well tolerated in both IDEAL 1 and 2. The most common adverse events were mild: National Cancer Institute Common Toxicity Criteria (version 2.0) grade 1/2 gastrointestinal and skin-related adverse events. Fewer patients had grade 3/4 adverse events with 250 mg/day than with 500 mg/day (8.7% versus 30.2% in IDEAL 1 and 6.9% versus 17.5% in IDEAL 2, respectively). Overall, the 250 mg/day dose was better tolerated than 500 mg/day and this, combined with similar results for efficacy endpoints with the two doses, makes 250 mg/day the recommended dose for patients with NSCLC who have previously received chemotherapy. This dissociation of dose–response and dose–toxicity relationships was forecast for biologic agents such as gefitinib.60 Direct targeting of malignant cells was expected to reduce toxicity at clinically effective doses. In this model, assessment of the maximum tolerated dose is not an appropriate endpoint and concepts such as the optimal biologic dose are more meaningful. This alternative outcome aims to elucidate the dose that provides maximum efficacy while maintaining a favorable tolerability profile. Evidence from the IDEAL trials suggests that gefitinib conforms to this model and that 250 mg/day is the optimal biologic dose of gefitinib in NSCLC.
(both as expected from previous studies of gefitinib), and hematologic (as expected from the toxicity profiles of gemcitabine/cisplatin and paclitaxel/carboplatin). The frequency of adverse events was similar across all treatment arms, except for diarrhea, rash, and acne, which showed a gefitinib dose–response relationship. The incidence of pulmonary adverse events, including interstitial lung disease (ILD)-type events, was generally similar in treatment arms in INTACT 1 and 2 (Table 4). It is unclear why the combination of gefitinib with standard doublet chemotherapy failed to show survival benefits in the first-line setting. Possible explanations include a pharmacodynamic antagonism between the drugs, or that treatment with chemotherapy sensitizes tumors to EGFR-targeted therapy, so that gefitinib is more effective in pretreated patients. These results reinforce the need for better understanding of the activity of gefitinib in a wider range of tumor types, treatment strategies, and patient subgroups. Erlotinib, another EGFR-TKI, has also been investigated in combination with standard chemotherapy in patients with metastatic NSCLC in the first-line setting in two Phase III trials. As with gefitinib, overall survival (the primary endpoint) was not improved.
Phase III trails Two large, randomized, double-blind, placebocontrolled, Phase III trials, each of approximately 1000 previously untreated patients with NSCLC, investigated gefitinib in combination with gemcitabine/cisplatin (the ‘Iressa’ NSCLC Trial Assessing Combination Treatment [INTACT] 1), or carboplatin/paclitaxel (INTACT 2).61,62 Despite showing no additional benefit in efficacy, there was no worsening of chemotherapy-associated toxicities, thus confirming the favorable tolerability of gefitinib in the placebo-controlled setting. The most common adverse events were gastrointestinal, skin related
Compassionate-use program More than 44,000 patients worldwide have received gefitinib as part of a compassionate-use program. These patients have advanced (inoperable stage III or IV) NSCLC, do not qualify for clinical trials, and have exhausted other treatment options. As well as providing patients with earlier access to this novel therapy for NSCLC, this program has imparted a considerable amount of valuable clinical information on the use of gefitinib. Gefitinib has demonstrated clinical activity in terms of objective tumor response, disease control, and overall survival.63–66 In addition, tumor response has been related to
Table 4
Incidence of pulmonary adverse events in INTACT 1 and 2.
Dyspnea, n (%) Cough, n (%) Pneumonia, n (%) ILD event, n (%)
Gefitinib 500 mg/day (n ¼ 700)
Gefitinib 250 mg/day (n ¼ 704)
Placebo
181 (25.9) 146 (20.9) 43 (6.1) 8 (1.1)
189 (26.8) 159 (22.6) 48 (6.8) 8 (1.1)
193 (27.7) 148 (21.3) 46 (6.6) 6 (0.9)
INTACT, ‘Iressa’ NSCLC Trial Assessing Combination Treatment; ILD, interstitial lung disease.
(n ¼ 696)
ARTICLE IN PRESS Gefitinib: a new therapy for advanced NSCLC symptomatic benefit. A final analysis of more than 21,000 patients who took part in this compassionate-use program in the USA recently reported a 1year survival rate of 29.9%, which is consistent with the IDEAL trial results.63 Tolerability data have generally been consistent with previous studies, with most adverse events observed being mild skinrelated or gastrointestinal disorders. In this wide compassionate-use program, the incidence of ILD is approximately 0.3%. In comparison, the incidence of ILD in Japanese patients treated with gefitinib has been reported as 1.7%.67 However, in approximately 140,000 patients worldwide treated with gefitinib, the overall incidence of ILD is less than 1%. It is difficult to determine the exact cause for this condition in these patients, as these events may have been due to progression of the lung cancer, prior therapy, or gefitinib treatment. Hence, a direct relationship between gefitinib and ILD is unclear in many cases. Potential prognostic factors For a variety of NSCLC treatment strategies, many research efforts have focused on investigating clinical and biologic factors that may predict which patients will benefit from treatment. Emerging data have identified specific somatic EGFR mutations in patients with dramatic responses to gefitinib.68,69 This provides an exciting insight into why some patients experience such dramatic responses to gefitinib and also confirms that this is a targeted therapy. However, the role of these mutations in other clinical benefits seen with gefitinib such as disease stabilization and/or symptom improvement is not yet known and further molecular studies are ongoing to explain the mechanisms responsible for these benefits.
Conclusions Patients with NSCLC often present with pulmonary symptoms; therefore, treatment strategies should aim to provide disease-related symptom relief and improved QoL. These are important endpoints in the clinical evaluation of novel therapies for cancer, and this is further supported by their observed correlation with objective tumor response and survival. In recent trials, the oral EGFR-TKI gefitinib has demonstrated improvement in pulmonary symptoms and QoL in pretreated patients with advanced NSCLC. In addition, gefitinib monotherapy resulted in clinically significant antitumor activity and displayed a favorable tolerability profile. The combination of gefitinib with
305 platinum-based chemotherapy doublets in the firstline setting for NSCLC produced no additional survival benefit. A large-scale compassionate-use program has provided extensive clinical experience with gefitinib therapy. Gefitinib has demonstrated antitumor activity and good tolerability in these patients and further results from this program are awaited with interest. To conclude, treatment with gefitinib has demonstrated significant clinical benefit for patients with advanced NSCLC and, in particular, provides rapid relief from the pulmonary symptoms that are commonly associated with this disease. ‘Iressa’ is a trademark of the AstraZeneca group of companies.
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