Effect of re-treatment with gefitinib (‘Iressa’, ZD1839) after acquisition of resistance

A 70-year-old man with adenocarcinoma of the lung developed pulmonary metastases 7 months after middle and lower lobectomy of the right lung in October 1998. He received four courses of first-line chemotherapy with docetaxel/irinotecan from June to September 1999. The best response was stable disease and, after 6 months of treatment, there was evidence of progressive disease with increase in size and number of pulmonary metastases. Therefore, we recommended enrollment in a phase I study of gefitinib ('Iressa') [1.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: 324aGoogle Scholar], an orally active epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor.The patient began to take gefitinib 700 mg/day in March 2000. Remarkable tumor regression was immediately achieved in April 2000 (Figure 1). This response lasted for 18 months. However, pulmonary metastases again developed (considered to be progressive disease), and gefitinib was discontinued in October 2001. The patient received a combination of nedaplatin, a second-generation platinum complex with high antitumor activity against non-small-cell lung cancer [2.Kameyama Y. Okazaki N. Nakagawa M. et al.Nephrotoxicity of a new platinum compound, 254-S, evaluated with rat kidney cortical slices.Toxicol Lett. 1990; 52: 15-24Crossref PubMed Scopus (75) Google Scholar], and gemcitabine in November 2001. Significant tumor regression was achieved, and a total of six courses from November to April 2002 were administered. Pulmonary metastases progressed again and pulmonary effusion developed in August 2002. Although progressed, he had few symptoms, and was considered to have a performance status of 0. We planned to use a chemotherapy regimen that had not previously been used for this patient, but instead commenced re-treatment with gefitinib at the patient's request on September 3, 2002 (gefitinib 250 mg/day had by this time been approved for use in Japan). One month later, a significant response had been achieved (Figure 1).This is an interesting case in which acquired resistance to gefitinib could be overcome. There are some possible explanations. First, resistance to gefitinib might naturally change over time, but there is no report of this so far. Secondly, because platinum-based cytotoxic chemotherapy was administered after the first treatment with gefitinib, the proportion of sensitive or resistant cells might have been modified. Thirdly, treatment with cytotoxic chemotherapy might produce genetic changes in EGFR or other unknown associated genes that regulate resistance to gefitinib. Saltz et al. reported that a combination of the EGFR inhibitor cetuximab (C225) and irinotecan produced a 22.5% partial response in patients with irinotecan-refractory colorectal cancer with high EGFR expression [3.Saltz L. Rubin M. Hochster H. et al.Cetuximab (IMC-C225) plus irinotecan (CPT-11) is active in CPT-11-refractory colorectal cancer (CRC) that express epidermal growth factor receptor (EGFR).Proc Am Soc Clin Oncol. 2002; 20: 3aGoogle Scholar]. In contrast to that report, cytotoxic agents have the possibility of modifying resistance to cytostatic agents. Recently, two large phase III studies to compare concurrent use of conventional platinum-based chemotherapy (carboplatin/paclitaxel or cisplatin/gemcitabine) and gefitinib with conventional chemotherapy alone were reported [4.Giaccone G. Johnson D.H. 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: 2Abstract Full Text PDF Google Scholar, 5.Johnson D.H. 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: 127Abstract Full Text PDF PubMed Google Scholar]. No differences in overall survival were found. These results suggested that gefitinib and chemotherapy may be targeting the same cells with the possibility of overlapping activity. If cytotoxic agents altered sensitivity to gefitinib by genetic modification, chemotherapy followed by gefitinib might be superior to concurrent use. Gefitinib is a very promising agent, but little knowledge is available concerning the types of cases for which gefitinib should be administered, or how gefitinib should be combined with conventional cytotoxic agents. Further investigations are needed to answer these questions. A 70-year-old man with adenocarcinoma of the lung developed pulmonary metastases 7 months after middle and lower lobectomy of the right lung in October 1998. He received four courses of first-line chemotherapy with docetaxel/irinotecan from June to September 1999. The best response was stable disease and, after 6 months of treatment, there was evidence of progressive disease with increase in size and number of pulmonary metastases. Therefore, we recommended enrollment in a phase I study of gefitinib ('Iressa') [1.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: 324aGoogle Scholar], an orally active epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor. The patient began to take gefitinib 700 mg/day in March 2000. Remarkable tumor regression was immediately achieved in April 2000 (Figure 1). This response lasted for 18 months. However, pulmonary metastases again developed (considered to be progressive disease), and gefitinib was discontinued in October 2001. The patient received a combination of nedaplatin, a second-generation platinum complex with high antitumor activity against non-small-cell lung cancer [2.Kameyama Y. Okazaki N. Nakagawa M. et al.Nephrotoxicity of a new platinum compound, 254-S, evaluated with rat kidney cortical slices.Toxicol Lett. 1990; 52: 15-24Crossref PubMed Scopus (75) Google Scholar], and gemcitabine in November 2001. Significant tumor regression was achieved, and a total of six courses from November to April 2002 were administered. Pulmonary metastases progressed again and pulmonary effusion developed in August 2002. Although progressed, he had few symptoms, and was considered to have a performance status of 0. We planned to use a chemotherapy regimen that had not previously been used for this patient, but instead commenced re-treatment with gefitinib at the patient's request on September 3, 2002 (gefitinib 250 mg/day had by this time been approved for use in Japan). One month later, a significant response had been achieved (Figure 1). This is an interesting case in which acquired resistance to gefitinib could be overcome. There are some possible explanations. First, resistance to gefitinib might naturally change over time, but there is no report of this so far. Secondly, because platinum-based cytotoxic chemotherapy was administered after the first treatment with gefitinib, the proportion of sensitive or resistant cells might have been modified. Thirdly, treatment with cytotoxic chemotherapy might produce genetic changes in EGFR or other unknown associated genes that regulate resistance to gefitinib. Saltz et al. reported that a combination of the EGFR inhibitor cetuximab (C225) and irinotecan produced a 22.5% partial response in patients with irinotecan-refractory colorectal cancer with high EGFR expression [3.Saltz L. Rubin M. Hochster H. et al.Cetuximab (IMC-C225) plus irinotecan (CPT-11) is active in CPT-11-refractory colorectal cancer (CRC) that express epidermal growth factor receptor (EGFR).Proc Am Soc Clin Oncol. 2002; 20: 3aGoogle Scholar]. In contrast to that report, cytotoxic agents have the possibility of modifying resistance to cytostatic agents. Recently, two large phase III studies to compare concurrent use of conventional platinum-based chemotherapy (carboplatin/paclitaxel or cisplatin/gemcitabine) and gefitinib with conventional chemotherapy alone were reported [4.Giaccone G. Johnson D.H. 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: 2Abstract Full Text PDF Google Scholar, 5.Johnson D.H. 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: 127Abstract Full Text PDF PubMed Google Scholar]. No differences in overall survival were found. These results suggested that gefitinib and chemotherapy may be targeting the same cells with the possibility of overlapping activity. If cytotoxic agents altered sensitivity to gefitinib by genetic modification, chemotherapy followed by gefitinib might be superior to concurrent use. Gefitinib is a very promising agent, but little knowledge is available concerning the types of cases for which gefitinib should be administered, or how gefitinib should be combined with conventional cytotoxic agents. Further investigations are needed to answer these questions.