Gefitinib as a Last Treatment Option for Non-Small Lung Cancer: Durable Disease Control in a Subset of Patients
Abstract & Commentary
Synopsis: Gefitinib’s 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.
Source: Haringhuizen A, et al. Ann Oncol. 2004;15:786-792.
Non-small lung cancer (NSCLC) is the leading cause of cancer death worldwide and the majority of patients present with advanced, incurable disease. Combination chemotherapy regimens using cisplatin have provided a modest survival advantage but outcomes after disease program is very poor. Newer therapies are clearly needed. The epidermal growth factor receptor (EGFR) has been shown to be expressed in a variety of solid tumors including NSCLC. High EGFR expression levels have been associated with an unfavorable clinical outcome, making this a promising target for anticancer therapy. Gefitinib (Iressa) is an orally available inhibitor of the tyrosine kinase domain of the EGFR. Partial responses in NSCLC patients have been documented. Two phase II trials of gefitinib have compared doses of 250 mg/d and 500 mg/d in patients previously treated for NSCLC have demonstrated single agent activity of 250 mg/d but less toxic than the higher dose. The present study reports a retrospective analysis of patients with pathologically proven NSCLC who were enrolled in an expanded access program at the Netherlands Cancer Institute to allow compassionate use of gefitinib.
Comment by Stuart M. Lichtman, MD
This paper presents data from the expanded access program from May 2001 to September 2002. One hundred patients were offered gefitinib as a last treatment after failure of previous chemotherapy or if no other treatment options were available. Brain metastases were an exclusion criterion, but patients with performance status > 2 and short life expectancy were allowed to enter the program. The drug was given at 250 mg/d. The drug was supplied for an indefinite period until disease progression, unacceptable toxicity, or death. Retrospective analyses were made for response, survival and toxicity. Ninety-two patients were evaluable. The median age was 58 years (range, 33-76). One third of the patients had a performance status of > 2 and 86% had stage IV disease and 62% had adenocarcinoma including 6 patients with bronchoalveolar-cell carcinoma (BAC). Eighty-five (92.5%) of the patients had received chemotherapy with 94% receiving a cisplatin combination and 31% received more than one regimen. In total, 1478 weeks were analyzed (median, 10.7; range, 0.4-75.3). The objective response rate was 8.7% and the duration of the response ranged from 1.2 to 15.8+ months. Thirty-four (37%) experienced stable disease (confirmed for > 4 weeks). Responses were documented in patients with adenocarcinoma only and were more frequent among never smokers and did not show any relation to gender, age, number of prior chemotherapy regimens, time since last chemotherapy, time since diagnosis or stage of disease. After a median followup of 8 months, the median survival was 4.9 months and 1-year survival was 29%. Multivariate regression modeling showed only that patients with PS 2-4 had a significantly worse prognosis, while there was a trend toward better survival for females, never smokers and patients with adenocarcinoma/BAC. Age and disease stage were not significantly associated with overall survival. Treatment toxicity was modest with common side effects being grade 1-2 skin rash and diarrhea in 34% and 22% of patients respectively. One asymptomatic patient developed interstitial pulmonary changes during the first 4 weeks of treatment unrelated to tumor progression or infection. Upon prolongation of gefitinib therapy the radiographic changes disappeared and an objective response was observed.
This study demonstrates that gefitinib has a clear palliative role in the therapy of patients with previously treated NSCLC. Its activity compares favorably with other salvage treatments and the one-year survival rate of 29% also is remarkable when compared to standard chemotherapy regimens.1 The low toxicity observed in this previously treatment population makes a clear alternative to further chemotherapy. The one possible patient with interstitial lung disease and the lower incidence in larger databases (~1%) should lessen fears of this complication.2 Palliative radiotherapy was administered with the patients continuing to receive gefitinib with excellent palliative benefit without added toxicity. The longest survival was among the small subgroup of patients with BAC and no responses were seen in squamous cell patients despite that EGFR receptor expression is strongest in this subtype. However, the analysis of the patients in this report demonstrated that the effect of histology on survival is less important than PS and also confirms that prolonged symptom and disease control is possible without response. Haringhuizen and colleagues conclude that efficacy cannot be determined by response status alone. Therefore gefitinib’s single agent activity and mild toxicity are confirmed in a NSCLC population for whom no other treatment options existed. The disease stabilization and survival data observed compares favorable to salvage chemotherapy regimens with less toxicity.3
1. Schiller JH, et al. N Engl J Med. 2002;346:92-98.
2. Inoue A, et al. Lancet. 2003;361:137-139.
3. Shepherd FA, et al. Semin Oncol. 2001;28:4-9.
Stuart M. Lichtman, MD, FACP, Associate Professor of Medicine, NYU School of Medicine, Division of Oncology; Don Monti Division of Medical Oncology, North Shore University Hospital, Manhasset, NY, is on the Editorial Board of Clinical Oncology Alert.