Evaluation of safety and efficacy of gefitinib ('iressa', zd1839) as monotherapy in a series of Chinese patients with advanced non-small-cell lung cancer: experience from a compassionate-use programme

Platinum-based combination chemotherapy is the standard first-line treatment for patients with advanced non-small-cell lung cancer (NSCLC). Although meta-analysis of clinical trials proved that combination chemotherapy for advanced NSCLC is superior to best supportive care [1] and new cytotoxic agents have been developed over the past decade, the 5-year survival rate for these patients remains <1% [2]. The pace of progress is too slow and new therapeutic approaches are required. Based on our increasing understanding of the biology of NSCLC, targeted therapy is providing some promising new agents. Targeted therapy is usually aimed at a key protein implicated in tumour cell proliferation, survival, invasion or resistance to conventional treatments but spares the normal cells, thereby producing less toxicity than conventional therapies [3].

Many solid tumours express or highly express the epidermal growth factor receptor (EGFR). In lung cancer, deregulation of EGFR is seen mainly in NSCLC: EGFR is highly expressed in NSCLC at levels varying from 32–80% [4‐6]. Abnormal signal transduction arising from the receptor is implicated in the growth and proliferation of these tumours. Thus, disruption of the EGFR signal transduction pathway is an ideal target for anticancer therapy.

Gefitinib is an orally active small molecule EGFR tyrosine kinase inhibitor (EGFR-TKI). The tolerability and efficacy of gefitinib have been explored extensively in the West and Japan. In a Phase I trial, Nakagawa et al compared the safety profile, pharmacokinetic parameters and antitumour activity of gefitinib in patients with solid malignant tumours in Japan, the USA and Europe, and no significant difference was found for ethnicity [7]. However, severe interstitial pneumonia related to gefitinib therapy was more common in the Japanese population [8, 9]. In IDEAL ('Iressa' Dose Evaluation in Advanced Lung cancer) 1, which included 102 Japanese patients with advanced NSCLC, the response rate of Japanese patients taking gefitinib was significantly higher than that of non-Japanese patients but bias of baseline factors between strata, not ethnicity, was thought to account for the difference [10]. But Owing to the paucity of current data on gefitinib between defferent races, the possibility of differences in the toxicity and efficacy of gefitinib for ethnicity cannot be excluded. At present, there are few data regarding the tolerability and efficacy of gefitinib in Chinese patients.

Patients with advanced NSCLC who had no alternative therapeutic options have been able to receive gefitinib treatment in a worldwide compassionate-use programme. Here we report the outcome of treatment with oral gefitinib 250 mg/day in Chinese patients with advanced NSCLC participating in the compassionate-use programme at Peking Union Medical College Hospital.

A daily oral 250 mg dose of gefitinib was well tolerated in this series of Chinese patients with advanced NSCLC, who received gefitinib as part of a compassionate-use programme. AEs were mild and reversible and different to those associated with conventional chemotherapy, such as neutropenia, thrombocytopenia and neuropathy. No haematological or neural toxicity was observed in the study. As with prior clinical trials evaluating the toxicity of gefitinib, the most frequently reported AEs were acneform rash and diarrhoea (grade 1 or 2). Four patients developed grade 1 or 2 stomatitis during treatment, which has previously been associated with gefitinib treatment in 7.8% of patients in IDEAL 1 but was not reported in IDEAL 2 [17].

Severe acute interstitial pneumonia is the most serious AE that has been linked with gefitinib therapy. Inoue et al recently reported that 4 of 18 patients receiving gefitinib in their clinic developed severe acute interstitial pneumonia [8]. The authors stated that 291 of 17,500 patients (1.7%) treated with gefitinib in Japan had developed suspected interstitial pneumonia or acute lung injury. In contrast to the higher incidence of interstitial pneumonia, this severe AE was lower in the rest of the world [9]. The worldwide frequency of interstitial lung disease to date in ~92,750 patients who have received gefitinib is <1.0% [18]. The ethnicity between Chinese and Japanese people is probably similar, but we saw no evidence of interstitial pneumonia in the series of patients. Although no patients developed acute interstitial pneumonia, the possibility of drug-related interstitial lung disease could not be excluded because of the small number of patients in our series.

The response rate (35.5%) was higher than that of recently presented Phase II trials (18.4% and 11.8% in patients receiving gefitinib 250 mg/day in IDEAL 1 and 2, respectively). The DCRs were 54.4% and 42% for the 250 mg/day dose in IDEAL 1 and 2, respectively, in contrast to 58.1% in our study. Unlike IDEAL 2, which was performed in the USA, IDEAL 1 was a global trial that recruited patients from 43 centres across Europe, Australia, South Africa and Japan and included a total of 102 Japanese patients with advanced NSCLC. The response rate for Japanese patients was higher than that of non-Japanese patients (27.5% versus 10.45%; odds ratio 3.72; p = 0.0023). However, the difference in response rate for ethnicity was not verified using multivariate logistical regression analysis. The difference in response rate between Japanese and non-Japanese patients was attributed to bias of baseline predictive factors of patients (gender, PS and histology) [19, 10].

QoL is an important endpoint for assessment of gefitinib treatment and has been included in some phase I and phase II trials. In these trials, the Functional Assessment of Cancer Therapy – Lung questionnaire was used to assess QoL and symptoms. Its validation and sensitivity were verified. Significant improvements in symptoms and QoL were observed in IDEAL 1 and 2. In IDEAL 1, symptom and QoL improvement with a dose of 250 mg/day were 40.3% and 23.9%, respectively, and in IDEAL 2 they were 43.1% and 34.3%, respectively. In both trials, improvements in symptoms and QoL correlated well with tumour response [20].

In our patient series, the EORTC QLQ-C30 and its supplement module QLQ-LC13 were used for assessment of QoL and symptoms. Together, they are thought to be one of the best developed instruments for lung cancer assessment [21]. The questionnaires have been translated into >20 languages and validation of the standard Chinese version has been verified [22]. In our series of patients, mean scores of four functioning scales (physical, role, emotional and social functioning) and global QoL increased significantly after 8 weeks of treatment and were associated with high response from 56–88%. Mean score of cognitive functioning also increased, from 66 at baseline to 76 at the end of second cycle with response of 72% (not statistically significant; p = 0.08). General and disease-related symptom scores increased from 44% to 84%. Importantly, improvement of symptoms and QoL correlated with objective tumour response. Patients with objective tumour response had higher rates of symptom and QoL response. The results indicate that placebo effect is unlikely to explain completely the improvement in symptoms and QoL with gefitinib, though there is no placebo control in our patient series or the EAP. Emotional functioning response was observed in all patients with objective tumour response, but this was not statistically significant when compared with nonresponders (100% versus 79%; p = 0.23). As emotional functioning contained more subjective questions, such as "Did you feel tense?", "Did you worry?", "Did you feel irritable?" and "Did you feel depressed?", the limited difference of emotional functioning response between responders and nonresponders with gefitinib cannot completely exclude the possibility of placebo effect. Thus, a placebo control group should be included in future studies of QoL and symptom improvement with gefitinib.

In conclusion, the data from this patient series show that an oral dose of gefitinib 250 mg/day is well tolerated and has significant antitumour activity in Chinese patients with advanced NSCLC who had failed previous chemotherapy and for whom no other treatment options were available. Although clinical trials are needed to confirm these positive findings, the data suggest that treatment with gefitinib may be beneficial for some Chinese patients who do not respond to chemotherapy and have poor prognosis.

'Iressa' is a trademark of the AstraZeneca group of companies