Departments of 1 Thoracic Oncology and 2 Biometrics, The Netherlands Cancer Institute, Amsterdam, The Netherlands
Received 22 September 2003; revised 13 January 2004; accepted 20 January 2004
![]() |
ABSTRACT |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
We describe 16 months single-institution experience with gefitinib (Iressa, ZD1839) used as ultimum refugium for pretreated non-small-cell lung cancer (NSCLC) patients.
Patients and methods:
Toxicity, response and survival data of NSCLC patients participating in a compassionate-use program with gefitinib were reviewed. Documented disease progression and confirmation of the absence of other treatment options were requested. Oral gefitinib at a dose of 250 mg/day was given until disease progression, unacceptable toxicity or death. Coxs proportional hazards model was used to analyze relationships between factors and probability of survival.
Results:
Rapid disease precluded treatment in eight cases. Of 92 evaluable patients, one-third had a baseline performance status (PS) of 2. The main side-effects of gefitinib were grade 12 diarrhea and skin rash. A disease control rate of 46% (objective response rate 8.7%) and 1-year survival of 29% were documented. Histology (adenocarcinoma) and a never-smoking history were predictive of response. Number of previous chemotherapy regimens, gender, time since diagnosis and time since last chemotherapy lacked such an association. Radiotherapy during gefitinib treatment was well tolerated and was associated with prolonged survival in a patient with multiple brain metastases. Multivariate analyses revealed a significant impact of PS on survival. A never-smoking history, adenocarcinoma/bronchoalveolar-cell carcinoma and female gender showed a trend towards better survival outcomes.
Conclusion:
Gefitinibs single-agent activity in a group consisting of pretreated NSCLC patients is confirmed. Side-effects of gefitinib were mild. Prolonged survival was associated with good PS and less significantly with a never-smoking history, female gender and histology. Additional studies on mechanisms of tumor control and selection of target populations for this remarkable new drug are warranted.
Key words: non-small-cell lung cancer, NSCLC, gefitinib, Iressa, EGRA tyrosine kinase inhibitor, ZD183g, bronchoalveolar-cell carcinoma
![]() |
Introduction |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
The epidermal growth factor receptor (EGFR) has been found to be expressed or highly expressed in a variety of solid tumors, including NSCLC [6, 7]. Molecular studies have revealed abnormal signal transduction in lung cancer cells and high EGFR expression levels have been associated with an unfavorable clinical outcome, making the receptor a promising target for anticancer therapy [8, 9].
Gefitinib, a synthetic anilinoquinazoline, is an orally available inhibitor of the tyrosine kinase domain of the EGFR [10]. The therapeutic efficacy of this molecule was first observed during phase I evaluation [1113]. Partial responses in NSCLC patients have been documented and some of these responses continued for >9 months. Antitumor activity was observed at doses lower than the maximum tolerated dose of 700 mg/day. Two phase II randomized trials comparing gefitinib at dose levels of 250 and 500 mg/day in patients with previously treated NSCLC have recently confirmed the important single-agent activity of gefitinib and revealed that 250 mg/day was as effective as, but less toxic than, 500 mg/day [14, 15]. Here, we present a review of our 16 months experience with gefitinib.
![]() |
Patients and methods |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Baseline assessment included medical history (including prior anticancer therapy), smoking history, physical examination and vital signs, PS, complete blood cell count and blood biochemistry, chest X-ray and tumor assessment (X-rays or computed tomography scans). At follow-up (every 46 weeks), interval history, chest X-ray, tumor assessment, complete blood count and biochemistry were collected. Compliance with study medication and data regarding symptomatic benefit (pulmonary symptoms) and concomitant therapy were extracted from the patient records. All chest X-rays were reviewed to confirm the objective response rate and obtain a picture of any potential pulmonary toxicity elicited by gefitinib [16, 17]. Treatment-related toxicity was graded according to the National Cancer Institute Common Toxicity Criteria [18].
Statistical methods
Retrospective analyses were made for response, survival and toxicity. Responses were measured according to RECIST (Response Evaluation Criteria in Solid Tumors; EORTC) [19]. Disease control was defined as the best tumor response of complete response (CR), partial response (PR) or stable disease (SD) confirmed and sustained for 4 weeks. Response rates between subgroups were compared using Fishers exact test. Survival and progression-free survival were defined as the period from the date of commencing gefitinib treatment to the date of death or disease progression, respectively, or last follow-up. Survival curves were constructed using the KaplanMeier method. Cox proportional hazard analysis was performed to explore the combined effects of variables in relation to survival. Six variables were included in the model: four patient (age, gender, PS and smoking history) and two tumor (stage and histology) characteristics. All analyses were performed using SAS® 8.2 software and S-PLUS® 6 software. Figures were created with programmes developed by Harrell [20]. The model was verified for its regression assumptions (proportional hazards, linearity, additivity) via examination of the residuals. Differences were considered significant if P <0.05.
![]() |
Results |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
|
Overall, the toxicity of gefitinib was modest (Table 2). Common side-effects were grade 12 skin rash and diarrhea in 34% and 22% of patients, respectively. Less prominent were nausea/vomiting, anorexia and desquamation/itching. Gefitinib-related toxicity became apparent after 24 weeks of treatment and was swiftly reversible upon treatment discontinuation.
|
|
|
|
|
![]() |
Discussion |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Interstitial lung disease (ILD) attributed to gefitinib has recently attracted attention [16, 17]. Retrospectively, we diagnosed ILD in one patient. The interstitial abnormalities discovered were asymptomatic and transient. Other patients with interstitial pulmonary abnormalities had obvious tumor progression (lymphangitis). ILD is a complex entity that accompanies different disorders such as cardiac failure, pulmonary metastases/lymphangitis and infections and is seen relatively frequently following chemotherapy and radiotherapy [22, 23]. Therefore, a causal relationship between ILD and gefitinib cannot be easily made. Recently analyzed trials (Iressa NSCLC Trial Assessing Combination Treatment; INTACT 1 and 2) studying the addition of gefitinib to standard chemotherapy showed a low incidence of ILD in both the gefitinib (1.1%) and placebo arms (0.9%) [24, 25]. Our data, and more importantly the experience with 37 000 patients in the AstraZeneca global Expanded Access Program, also revealed a low percentage (0.36%) of potential pulmonary complications, suggesting that the first report on ILD might have overestimated this problem [16].
Initially patients were advised to stop gefitinib therapy when palliative radiotherapy for brain or bone metastases was judged appropriate. Later in the program, discontinuation of gefitinib was avoided in those patients, who still had symptomatic benefit or intrathoracic disease control while developing metastases. With the combination gefitinib and radiotherapy, excellent symptomatic responses were seen without significant extra- or intracranial toxicity. For example, one patient with isolated brain recurrence is responding >9 months after radiotherapy (plus gefitinib). Other studies, including phase I experience in children with glioblastoma multiforme, also suggest that the response on radiotherapy is enhanced by gefitinib. At the same time an increasing number of observations indicate that gefitinib alone is also effective in NSCLC patients with brain metastases [2630]. Recent experimental studies have provided evidence for release of growth factor activity by ionizing radiation and an enhanced antitumor effect if ionizing radiation was followed by gefitinib, for which inhibition of growth factors and DNA repair are being held responsible [3136]. These observations call for larger trials designed to evaluate and define the role of gefitinib in the treatment of brain metastases in NSCLC patients, either as single agent or in combination with radiation therapy.
An objective response rate of almost 9% and a disease control rate of >45% in a group of NSCLC patients with poor prognostic characteristics confirms the important single-agent activity of gefitinib. Our population was not restricted to patients with PS 02 or a life expectancy of >12 weeks. In a univariate analysis, adenocarcinoma and a non-smoking history were predictive for response, which partly confirms observations by others, who found BAC histology and non-smoking history to be predictive of response [37]. We noted the longest survival among the (small) subgroup of patients with BAC. Erlotinib, another EGFR inhibitor, has also shown prominent activity in patients with BAC [38]. Given the fact that EGFR expression is strongest in squamous-cell carcinomas, this is an intriguing observation, suggesting that mechanisms other than receptor blocking may provide clues about successful treatment with gefitinib. The IDEAL (Iressa Dose Evaluation in Advanced Lung cancer) 1 study that identified adenocarcinoma as a prognostic factor received a similar comment [39]. HER2 co-expressing with EGFR may be the underlying mechanism for prominent effects of gefitinib in BAC [40]. However, our group of patients suggests that the effect of histology on survival is less important than PS, and confirms that prolonged symptom and disease control is possible without response. Thus, efficacy cannot be determined by response status alone, and the identification of a validated marker of gefitinib activity will be a leap forward in the use of this remarkable drug in daily practice.
Docetaxel, with a response rate of 7% and a survival gain of 7 weeks (median survival 7.5 months versus 4.6 months with best supportive care alone) in pretreated patients with a PS 02, has been accepted as a standard second-line treatment for NSCLC [41]. Our data suggest that gefitinib, when given to patients failing on platinum-based chemotherapy with a reasonable performance status, might have similar efficacy. This underlines the need for a randomized comparison of these two drugs.
In conclusion, gefitinibs single-agent activity and mild toxicity profile are confirmed in a NSCLC population for whom no other treatment options existed. Efficacy was especially prominent in patients with adenocarcinoma (BAC) and no smoking history. Asymptomatic, transient interstitial pulmonary abnormalities were observed in one patient, and additional data are needed to validate the relationship between gefitinib and ILD. Excellent results with gefitinib given concurrently with radiotherapy merit additional studies on combined treatment.
![]() |
Acknowledgements |
---|
![]() |
FOOTNOTES |
---|
![]() |
REFERENCES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
2. Non-small Cell Lung Cancer Collaborative Group. Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials. BMJ 1995; 311: 899909.
3. Herbst RS, Dang NH, Skarin AT. Chemotherapy for advanced non-small cell lung cancer. Hematol Oncol Clin North Am 1997; 11: 473517.[ISI][Medline]
4. Ganz PA, Figlin RA, Haskell CM et al. Supportive care versus supportive care and combination chemotherapy in metastatic non-small cell lung cancer. Does chemotherapy make a difference? Cancer 1989; 63: 12711278.[ISI][Medline]
5. Schiller JH, Harrington D, Belani CP et al. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med 2002; 346: 9298.
6. Salomon DS, Brandt R, Ciardiello F, Normanno N. Epidermal growth factor-related peptides and their receptors in human malignancies. Crit Rev Oncol Hematol 1995; 19: 183232.[CrossRef][ISI][Medline]
7. Franklin WA, Veve R, Hirsch FR et al. Epidermal growth factor receptor family in lung cancer and premalignancy. Semin Oncol 2002; 29: 314.
8. Meert AP, Martin B, Delmotte P et al. The role of EGF-R expression on patient survival in lung cancer: a systematic review with meta-analysis. Eur Respir J 2002; 20: 975981.
9. Ciardiello F. An update of new targets for cancer treatment: receptor-mediated signals. Ann Oncol 2002; 13: 2938.
10. Lawrence DS, Niu J. Protein kinase inhibitors: the tyrosine-specific protein kinases. Pharmacol Ther 1998; 77: 81114.[CrossRef][ISI][Medline]
11. Ranson M, Hammond LA, Ferry D et al. ZD1839, a selective oral epidermal growth factor receptor-tyrosine kinase inhibitor, is well tolerated and active in patients with solid, malignant tumors: results of a phase I trial. J Clin Oncol 2002; 20: 22402250.
12. Herbst RS, Maddox AM, Rothenberg ML et al. Selective oral epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 is generally well-tolerated and has activity in non-small-cell lung cancer and other solid tumors: results of a phase I trial. J Clin Oncol 2002; 20: 38153825.
13. Negoro S, Nakagawa K, Fukuoka M et al. Final results of a Phase I intermittent dose-escalation trial of ZD1839 (Iressa) in Japanese patients with various solid tumors. Proc Am Soc Clin Oncol 2001; 20: 324a (Abstr 1292).
14. Fukuoka M, Yano S, Giaccone G et al. Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer. J Clin Oncol 2003; 21: 22372246.
15. Kris MG, Natale RB, Herbst RS et al. A Phase II trial of ZD1839 (Iressa) in advanced non-small-cell lung cancer (NSCLC) patients who had failed platinum- and docetaxel-based regimes (IDEAL 2). Proc Am Soc Clin Oncol 2002; 21: 292a (Abstr 1166).
16. Inoue A, Saijo Y, Maemondo M et al. Severe acute interstitial pneumonia and gefitinib. Lancet 2003; 361: 137139.[CrossRef][ISI][Medline]
17. Okamoto I, Fujii K, Matsumoto M et al. Diffuse alveolar damage after ZD1839 therapy in a patient with non-small cell lung cancer. Lung Cancer 2003; 40: 339342.[CrossRef][ISI][Medline]
18. CTC2 updates and utilities, available at: http://ctep.info.nih.gov (19 February 2003, date last accessed).
19. Gehan EA, Tefft MC. Will there be resistance to the RECIST (Response Evaluation Criteria in Solid Tumors)? J Natl Cancer Inst 2000; 92: 179181.
20. Harrell FE. Regression Modeling Strategies. New York: Springer-Verlag 2001.
21. Albanell J, Rojo F, Averbuch S et al. Pharmacodynamic studies of the epidermal growth factor receptor inhibitor ZD1839 in skin from cancer patients: histopathologic and molecular consequences of receptor inhibition. J Clin Oncol 2002; 20: 110124.
22. Movsas B, Raffin TA, Epstein AH, Link CJ Jr. Pulmonary radiation injury. Chest 1997; 111: 10611076.
23. Foucher P, Biour M, Blayac JP et al. Drugs that may injure the respiratory system. Eur Respir J 1997; 10: 265279.
24. 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: 2 (Abstr 4).
25. Johnson DH, Herbst R, Giaccone G et al. ZD1839 (Iressa) in combination with paclitaxel and 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: 127 (Abstr 468).
26. Ceresoli GL, Gregorc V, Cappuzzo F et al. ZD1839 in non-small cell lung cancer (NSCLC) patients with brain metastases (BM). Proc Am Soc Clin Oncol 2003; 22: 674 (Abstr 2709).
27. Gelibter A, Pino MS, Ceribelli M et al. Results from compassionate use of ZD1839 in pre-treated non small cell lung cancer (NSCLC): Our experience. Proc Am Soc Clin Oncol 2003; 22: 232 (Abstr 929).
28. Chiu CH, Tsai CM, Chiang SC et al. Effect of ZD 1839 (Iressa) on metstatic brain lesions in patients with advanced non-small cell lung cancer. Lung Cancer 2003; 41: 251 (Abstr 631).
29. Chakravarti A, Seiferheld W, Robbins I et al. Phase I results from RTOG BR-0211, a phase I/II study of an oral epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), ZD 1839 (Iressa), with radiation therapy in glioblastoma multiforme (GBM). Int J Radiat Oncol Biol Phys 2003; 57 (2 Suppl): S329.
30. Katz A, Zalewski P. Quality-of-life benefits and evidence of antitumour activity for patients with brain metastases treated with gefitinib. Br J Cancer 2003; 89 (Suppl 2): S15S18.
31. Dent P, Reardon DB, Park JS et al. Radiation-induced release of transforming growth factor alpha activates the epidermal growth factor receptor and mitogen-activated protein kinase pathway in carcinoma cells, leading to increased proliferation and protection from radiation-induced cell death. Mol Biol Cell 1999; 10: 24932506.
32. Bianco C, Tortura G, Bianco R et al. Enhancement of antitumor activity of ionizing radiation by combined treatment with the selective epidermal growth factor receptor-tyrosine kinase inhibitor ZD 1839 (Iressa). Clin Cancer Res 2002; 8: 32503258.
33. Huang S, Li J, Armstrong EA, Harari PM. Modulation of radiation response and tumor-induced angiogenesis after epidermal growth factor receptor inhibition by ZD1839 (Iressa). Cancer Res 2002; 62: 43004306.
34. Heimberger AB, Learn CA, Archer GE et al. Brain tumors in mice are susceptible to blockade of epidermal growth factor receptor (EGFR) with the oral, specific, EGFR-tyrosine kinase inhibitor ZD1839 (Iressa). Clin Cancer Res 2002; 8: 34963502.
35. Stea B, Falsey R, Kislin K et al. Time and dose-dependent radiosensitization of the glioblastoma multiforme U251 cells by the EGF receptor tyrosine kinase inhibitor ZD 1839 (Iressa). Cancer Lett 2003; 202: 4351.[CrossRef][ISI][Medline]
36. Shintani S, Li C, Mihara M et al. Enhancement ot tumor radioresponse by combined treatment with gefitinib (Iressa, ZD 1839), an epidermal growth factor receptor tyrosine kinase inhibitor, is accompanied by inhibition of DNA damage repair and cell growth in oral cancer. Int J Cancer 2003; 197: 10301037.[CrossRef]
37. Shah NT, Miller VA, Kris MG et al. Bronchioalveolar histology and smoking history predict response to gefitinib. Proc Am Soc Clin Oncol 2003; 22: 628 (Abstr 2524).
38. Miller VA, Patel J, Shah N et al. The epidermal growth factor receptor tyrosine kinase inhibitor erlotinib (TarcevaTM, OSI-774) shows promising activity in patients with bronchioloalveolar cell carcinoma (BAC): preliminary results of a Phase II trial. Proc Am Soc Clin Oncol 2003; 22: 619 (Abstr 2491).
39. Johnson DH, Arteaga CL. Gefitinib in recurrent non-small-cell lung cancer: an IDEAL trial? J Clin Oncol 2003; 21: 22272229.
40. Cappuzzo F, Gregorc V, Meastri A et al. Correlation between efficacy of ZD1839 and HER-2 expression in locally advanced or metastatic NSCLC: a phase III trial. Ann Oncol 2002; 13: 148 (Abstr 544).
41. Shepherd FA, Fossella FV, Lynch T et al. Docetaxel (Taxotere) shows survival and quality-of-life benefits in the second-line treatment of non-small cell lung cancer: a review of two phase III trials. Semin Oncol 2001; 28: 49.