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Commentary on ZD1839 (Iressa) in non small cell lung cancer
Lung Cancer 40 (2003) 77 /78 www.elsevier.com/locate/lungcan
Commentary on ZD1839 (Iressa) in non small cell lung cancer M. Ranson *, N. Thatcher CR-UK Department of Medical Oncology, Christie Hospital NHS Trust, University of Manchester, Wilmslow Road, Manchester M20 4BX, UK Received 25 November 2002; accepted 29 November 2002
1. Introduction
2. Who to treat
The case report of Fujiwara and colleagues describes a patient with stage IV non-small cell lung cancer who had received two prior chemotherapy regimens. Although close to death and dependent on oxygen the patient achieved a rapid dramatic radiological and clinical response to ZD1839. With treatment the patient improved sufficiently to be discharged from hospital and was able to subsequently return to work. The therapeutic efficacy of ZD1839 in refractory NSCLC was first observed during early phase I evaluation [1 /4]. Partial responses occurred in ten of 100 patients with advanced pre-treated NSCLC treated in phase I trials and in some cases tumour response was durable for over 9 months. In phase I trials evidence of antitumour activity was observed at doses well below the maximal tolerated dose of 700 /1000 mg/day. Two randomised phase II trials comparing 250 with 500 mg/ day (IDEAL 1 and 2) identified that 250 mg/day was just as effective but less toxic than 500 mg/day [5 /8]. This led to the approval of ZD1839 in relapsed NSCLC in Japan and South Korea in July 2002. Licensing applications are underway in other countries. As in this case report, the onset of symptomatic improvement may sometimes be rapid. During IDEAL 1 and 2 trials lung cancer symptoms (LCS) were evaluated weekly using the seven-item LCS subscale of the FACT-L questionnaire. The median time to LCS scale improvement was just 8/10 days, very close to the timing of the first LCS assessment. The low intrinsic toxicity of ZD1839 and the potential for rapid symptom’s improvement facilitated ZD1839 use in this case despite the multiple adverse clinical features at the outset of treatment.
Phase I and phase II trials have indicated that ZD1839 has promising activity even in heavily pretreated patients. In phase I and II trials patients were not selected, based upon EGFR expression. The data from the phase II trials suggests that, the response rate in women, and in patients with adenocarcinoma is higher than in men, or those with squamous tumours. Such observations require confirmation in other studies. The patient in this case report was both female and had adenocarcinoma with a bilateral infiltrative pattern of lung involvement. Interestingly, the relative expression of EGFR does not appear to closely parallel responsiveness to ZD1839 in vitro. Defining the molecular profile of responding versus non-responding patients may result in a more bespoke use of EGFR inhibitors and the achievement of higher response rates than the 11 /18% response rates reported in phase II trials. Unlike the paradigm of STI-571 in GIST where patients exhibit a relatively homogeneous phenotype that can be therapeutically exploited by STI-571, there is no easily identified NSCLC phenotype with a universal, strong EGFR dependence. The collection and study of biopsy material in trials must, therefore, remain a priority.
* Corresponding author. Tel.: /44-161-446-3000; fax: /44-161446-3299. E-mail address: [email protected] (M. Ranson).
3. Single agent or combination EGFR-targeted drugs such as ZD1839 are effective in relapsed advanced NSCLC but how do we best incorporate them into our treatment strategy? Sadly there is no randomised comparison of ZD1839 versus docetaxel in second-line treatment of advanced NSCLC. Thus in good performance status patients where docetaxel would normally be considered, there remains uncertainty about the optimal approach. There are ongoing trials to compare monotherapy ZD1839 with the doublet of docetaxel and ZD1839. However, this does not answer the question of whether sequential treatment
0169-5002/03/$ - see front matter # 2003 Published by Elsevier Science Ireland Ltd. doi:10.1016/S0169-5002(03)00041-2
78
M. Ranson, N. Thatcher / Lung Cancer 40 (2003) 77 /78
would be preferable for these patients. Docetaxel also has activity in relapsed NSCLC but is too toxic for many patients in this setting. ZD1839 with its relatively favourable toxicity profile would be a potential option for patients unsuitable for docetaxel or for those patients who prefer a lower toxicity approach. We also lack data on ZD1839 monotherapy as a first line therapy. In this setting it deserves to be studied in patients unsuitable for chemotherapy. In addition, EGFR inhibitors may improve the efficacy of radiotherapy and well-designed randomised trials are required in this area [9]. Two large, randomised, double blind trials of ZD1839 in combination with chemotherapy (INTACT 1 and 2) have been performed and the results were reported at ESMO 2002 [10,11]. The chemotherapy regimen in INTACT 1 was gemcitabine/cisplatin and in INTACT 2 was paclitaxel/carboplatin. Patients were randomised to either placebo, 250 mg/day ZD1839 or 500 mg/day ZD1839 tablets in addition to chemotherapy. Patients continued with ZD1839 or placebo until disease progression. These trials were completed rapidly and enrolled over 2000 patients in 10 months. Mature data conclusively demonstrated that ZD1839 did not produce additional therapeutic benefit over chemotherapy alone. At first sight this may seem a surprising result given the promising data for ZD1839 as a single agent in relapsed patients and the reports of synergy with chemotherapy drugs in pre-clinical models [9]. However, triplet drug regimens have not been reliably superior to doublets in advanced NSCLC and the INTACT trials may be another example of this. It remains to be seen whether a doublet of a cytotoxic drug with ZD1839 may be better than a single agent. The INTACT trials involved the concurrent administration of cytotoxic chemotherapy with ZD1839 and it is possible that its concurrent use with cytotoxics negates the activity of ZD1839. Perhaps a more successful approach would to use sequential therapy.
4. What about patients with poor performance status The case presented by Fujiwara is a patient with poor performance status. Such patients are widely excluded from clinical trials of anticancer agents. As a result research attention has focussed on developing treat-
ments for patients with good performance status. The rapid and dramatic response in this case report serves to emphasise that there now is scope for trials with novel agents such as ZD1839 in patients with poor performance status in both first line and relapsed settings.
References [1] Ranson H, Hammond L, Ferry D, et al. ZD1839, a selective oral EGFR-TKI (epidermal growth factor receptor tyrosine kinase inhibitor) is well tolerated and active in patients with solid, malignant tumours: results of a phase I trial. J Clin Oncol 2002;20:2240 /50. [2] Negoro S, Nakagawa K, Fukuoka M, et al. Final results of a phase I intermittent dose-escalation trial of ZD1839 in Japanese patients with various solid tumours. Proc Am Soc Clin Oncol 2001;20:324a. [3] Baselga J, Rischin D, Ranson M, et al. Phase I phamacokinetic and pharmacodynamic trial of ZD1839 (Iressa), a selective oral epidermal growth factor receptor tyrosine kinase inhibitor, in patients with five selected solid tumor types. J Clin Oncol 2002;20:4292 /302. [4] Kris M, Herbst R, Rischin D, et al. Objective regressions in nonsmall cell lung cancer patients treated in phase I trials of oral ZD1839, a selective tyrosine kinase inhibitor that blocks the epidermal growth factor receptor. Lung Cancer 2000;29(Suppl. 1):72. [5] Fukuoka M, Yano S, Giaccone G, et al. Final results from a phase II trial of ZD1839 (Iressa) for patients with advanced nonsmall cell lung cancer. Proc Am Soc Clin Oncol 2002;21:1188a. [6] Douillard JY, Skarin A, Baselga J, et al. Improvement in diseaserelated symptoms and quality of life for advanced non-small cell lung cancer (NSCLC) patients treated with ZD1839 in IDEAL 1 and 2. Ann Oncol 2002;13(Suppl. 5):480a. [7] Kris M, Natale R, Herbst R, et al. A phase II trial of ZD1839 (Iressa) in advanced non-small cell lung cancer who had tailed platinum and docetaxel-based regimens (IDEAL 2). Proc Am Soc Clin Oncol 2002;21:1166a. [8] Natale RB, Skarin AT, Maddox AM, 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;21:1167a. [9] Ranson M, Mansoor W, Jayson G. ZD1839 (Iressa): a selective EGFR-TK inhibitor. Expert Rev Anticancer Ther 2002;2:161 /8. [10] Giaccone G, Johnson DH, Manegold C, et al. A phase III clinical trial of ZD1839 (Iressa) in combination with gemcitabine and cisplatin in chemotherapy-naı¨ve patients with advanced non-small cell lung cancer (INTACT 1). Ann Oncol 2002;13(Suppl. 5):40a. [11] Johnson DH, Herbst R, Giaccone G, et al. ZD1839 (Iressa) in combination with paclitaxel and carboplatin in chemotherapynaı¨ve patients with advanced non-small cell lung cancer (NSCLC): results from a phase III clinical trial (INTACT 2). Ann Oncol 2002;13(Suppl. 5):468a.
Commentary on ZD1839 (Iressa) in non small cell lung cancer M. Ranson *, N. Thatcher CR-UK Department of Medical Oncology, Christie Hospital NHS Trust, University of Manchester, Wilmslow Road, Manchester M20 4BX, UK Received 25 November 2002; accepted 29 November 2002
1. Introduction
2. Who to treat
The case report of Fujiwara and colleagues describes a patient with stage IV non-small cell lung cancer who had received two prior chemotherapy regimens. Although close to death and dependent on oxygen the patient achieved a rapid dramatic radiological and clinical response to ZD1839. With treatment the patient improved sufficiently to be discharged from hospital and was able to subsequently return to work. The therapeutic efficacy of ZD1839 in refractory NSCLC was first observed during early phase I evaluation [1 /4]. Partial responses occurred in ten of 100 patients with advanced pre-treated NSCLC treated in phase I trials and in some cases tumour response was durable for over 9 months. In phase I trials evidence of antitumour activity was observed at doses well below the maximal tolerated dose of 700 /1000 mg/day. Two randomised phase II trials comparing 250 with 500 mg/ day (IDEAL 1 and 2) identified that 250 mg/day was just as effective but less toxic than 500 mg/day [5 /8]. This led to the approval of ZD1839 in relapsed NSCLC in Japan and South Korea in July 2002. Licensing applications are underway in other countries. As in this case report, the onset of symptomatic improvement may sometimes be rapid. During IDEAL 1 and 2 trials lung cancer symptoms (LCS) were evaluated weekly using the seven-item LCS subscale of the FACT-L questionnaire. The median time to LCS scale improvement was just 8/10 days, very close to the timing of the first LCS assessment. The low intrinsic toxicity of ZD1839 and the potential for rapid symptom’s improvement facilitated ZD1839 use in this case despite the multiple adverse clinical features at the outset of treatment.
Phase I and phase II trials have indicated that ZD1839 has promising activity even in heavily pretreated patients. In phase I and II trials patients were not selected, based upon EGFR expression. The data from the phase II trials suggests that, the response rate in women, and in patients with adenocarcinoma is higher than in men, or those with squamous tumours. Such observations require confirmation in other studies. The patient in this case report was both female and had adenocarcinoma with a bilateral infiltrative pattern of lung involvement. Interestingly, the relative expression of EGFR does not appear to closely parallel responsiveness to ZD1839 in vitro. Defining the molecular profile of responding versus non-responding patients may result in a more bespoke use of EGFR inhibitors and the achievement of higher response rates than the 11 /18% response rates reported in phase II trials. Unlike the paradigm of STI-571 in GIST where patients exhibit a relatively homogeneous phenotype that can be therapeutically exploited by STI-571, there is no easily identified NSCLC phenotype with a universal, strong EGFR dependence. The collection and study of biopsy material in trials must, therefore, remain a priority.
* Corresponding author. Tel.: /44-161-446-3000; fax: /44-161446-3299. E-mail address: [email protected] (M. Ranson).
3. Single agent or combination EGFR-targeted drugs such as ZD1839 are effective in relapsed advanced NSCLC but how do we best incorporate them into our treatment strategy? Sadly there is no randomised comparison of ZD1839 versus docetaxel in second-line treatment of advanced NSCLC. Thus in good performance status patients where docetaxel would normally be considered, there remains uncertainty about the optimal approach. There are ongoing trials to compare monotherapy ZD1839 with the doublet of docetaxel and ZD1839. However, this does not answer the question of whether sequential treatment
0169-5002/03/$ - see front matter # 2003 Published by Elsevier Science Ireland Ltd. doi:10.1016/S0169-5002(03)00041-2
78
M. Ranson, N. Thatcher / Lung Cancer 40 (2003) 77 /78
would be preferable for these patients. Docetaxel also has activity in relapsed NSCLC but is too toxic for many patients in this setting. ZD1839 with its relatively favourable toxicity profile would be a potential option for patients unsuitable for docetaxel or for those patients who prefer a lower toxicity approach. We also lack data on ZD1839 monotherapy as a first line therapy. In this setting it deserves to be studied in patients unsuitable for chemotherapy. In addition, EGFR inhibitors may improve the efficacy of radiotherapy and well-designed randomised trials are required in this area [9]. Two large, randomised, double blind trials of ZD1839 in combination with chemotherapy (INTACT 1 and 2) have been performed and the results were reported at ESMO 2002 [10,11]. The chemotherapy regimen in INTACT 1 was gemcitabine/cisplatin and in INTACT 2 was paclitaxel/carboplatin. Patients were randomised to either placebo, 250 mg/day ZD1839 or 500 mg/day ZD1839 tablets in addition to chemotherapy. Patients continued with ZD1839 or placebo until disease progression. These trials were completed rapidly and enrolled over 2000 patients in 10 months. Mature data conclusively demonstrated that ZD1839 did not produce additional therapeutic benefit over chemotherapy alone. At first sight this may seem a surprising result given the promising data for ZD1839 as a single agent in relapsed patients and the reports of synergy with chemotherapy drugs in pre-clinical models [9]. However, triplet drug regimens have not been reliably superior to doublets in advanced NSCLC and the INTACT trials may be another example of this. It remains to be seen whether a doublet of a cytotoxic drug with ZD1839 may be better than a single agent. The INTACT trials involved the concurrent administration of cytotoxic chemotherapy with ZD1839 and it is possible that its concurrent use with cytotoxics negates the activity of ZD1839. Perhaps a more successful approach would to use sequential therapy.
4. What about patients with poor performance status The case presented by Fujiwara is a patient with poor performance status. Such patients are widely excluded from clinical trials of anticancer agents. As a result research attention has focussed on developing treat-
ments for patients with good performance status. The rapid and dramatic response in this case report serves to emphasise that there now is scope for trials with novel agents such as ZD1839 in patients with poor performance status in both first line and relapsed settings.
References [1] Ranson H, Hammond L, Ferry D, et al. ZD1839, a selective oral EGFR-TKI (epidermal growth factor receptor tyrosine kinase inhibitor) is well tolerated and active in patients with solid, malignant tumours: results of a phase I trial. J Clin Oncol 2002;20:2240 /50. [2] Negoro S, Nakagawa K, Fukuoka M, et al. Final results of a phase I intermittent dose-escalation trial of ZD1839 in Japanese patients with various solid tumours. Proc Am Soc Clin Oncol 2001;20:324a. [3] Baselga J, Rischin D, Ranson M, et al. Phase I phamacokinetic and pharmacodynamic trial of ZD1839 (Iressa), a selective oral epidermal growth factor receptor tyrosine kinase inhibitor, in patients with five selected solid tumor types. J Clin Oncol 2002;20:4292 /302. [4] Kris M, Herbst R, Rischin D, et al. Objective regressions in nonsmall cell lung cancer patients treated in phase I trials of oral ZD1839, a selective tyrosine kinase inhibitor that blocks the epidermal growth factor receptor. Lung Cancer 2000;29(Suppl. 1):72. [5] Fukuoka M, Yano S, Giaccone G, et al. Final results from a phase II trial of ZD1839 (Iressa) for patients with advanced nonsmall cell lung cancer. Proc Am Soc Clin Oncol 2002;21:1188a. [6] Douillard JY, Skarin A, Baselga J, et al. Improvement in diseaserelated symptoms and quality of life for advanced non-small cell lung cancer (NSCLC) patients treated with ZD1839 in IDEAL 1 and 2. Ann Oncol 2002;13(Suppl. 5):480a. [7] Kris M, Natale R, Herbst R, et al. A phase II trial of ZD1839 (Iressa) in advanced non-small cell lung cancer who had tailed platinum and docetaxel-based regimens (IDEAL 2). Proc Am Soc Clin Oncol 2002;21:1166a. [8] Natale RB, Skarin AT, Maddox AM, 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;21:1167a. [9] Ranson M, Mansoor W, Jayson G. ZD1839 (Iressa): a selective EGFR-TK inhibitor. Expert Rev Anticancer Ther 2002;2:161 /8. [10] Giaccone G, Johnson DH, Manegold C, et al. A phase III clinical trial of ZD1839 (Iressa) in combination with gemcitabine and cisplatin in chemotherapy-naı¨ve patients with advanced non-small cell lung cancer (INTACT 1). Ann Oncol 2002;13(Suppl. 5):40a. [11] Johnson DH, Herbst R, Giaccone G, et al. ZD1839 (Iressa) in combination with paclitaxel and carboplatin in chemotherapynaı¨ve patients with advanced non-small cell lung cancer (NSCLC): results from a phase III clinical trial (INTACT 2). Ann Oncol 2002;13(Suppl. 5):468a.