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Gefatinib (Iressa) as First-line Therapy for Advanced NSCLC in Patients with Poor Performance
Abstract & Commentary
By William B. Ershler, MD
Synopsis: In a phase II trial of gefitinib for patients with advanced NSCLC, demonstrable EGFR mutation, and poor performance status (PS 2-4), Inoue et al report a median survival of 17.8 months. In addition to a high-response and disease-control rates (66% and 90%, respectively), improvement in performance status was observed in 78% of the patients.
Source: Inoue A, et al. First-line gefitinib for patients with advanced non-small cell lung cancer harboring epidermal growth factor receptor mutations without indication for chemotherapy. J Clin Oncol. 2009;27:1394-1400.
The percentage of patients with newly diagnosed non-small-cell lung cancer (NSCLC) who present with poor performance status is remarkably high, perhaps reflecting advanced age, existing comorbidities, and/or the functional impact of this malignancy. For example, from a series of more than 500 patients with NSCLC, Lilenbaum et al found that the prevalence of poor performance status (Eastern Cooperative Oncology Group [ECOG] PS 2 to 4) was 34% when estimated by practitioners and 48% when determined by patients themselves.1 This is indeed of relevance because the optimal treatment for advanced stage patients with PS2 is quite controversial2-5 and there remains a prevalent sense that for those with PS3 or PS4, treatment beyond supportive care is of no value.6
Gefitinib (Iressa; AstraZeneca), an orally active, epidermal growth-factor receptor (EGFR) tyrosine-kinase inhibitor (TKI), has shown novel antitumor activity in patients with advanced NSCLC.7,8 Because the toxicity of gefitinib is less than that of cytotoxic agents, its utility as first-line treatment for patients with NSCLC having poor PS was addressed by Inoue et al from Japan. An earlier study, also from Japan, suggested that gefitinib should not be used in unselected, poor-performance NSCLC patients due to its low efficacy and toxicity (particularly in the development of interstitial lung disease).9 However, Inoue et al developed a method10 enabling them to determine EGFR mutation status and, thereby, select individuals with the greatest likelihood of responding to TKI therapy.
Thus, the current multicenter, phase II study was undertaken to investigate the efficacy and feasibility of gefitinib for patients with advanced NSCLC harboring EGFR mutations without indication for chemotherapy as a result of poor PS. For this, chemotherapy-naïve patients with poor PS (patients 20 to 74 years of age with ECOG PS 3 to 4, 75 to 79 years of age with PS 2 to 4, and > 80 years of age with PS 1 to 4) who had EGFR mutations were enrolled and received gefitinib (250 mg/d) alone.
Between February 2006 and May 2007, 30 patients with NSCLC and poor PS, including 22 patients with PS 3-4, were enrolled. The overall response rate was 66% (90% CI, 51% to 80%), and the disease control rate was 90%. PS improvement rate was 79% (p < .00005); in particular, 68% of the 22 patients improved from > PS 3 at baseline to < PS 1. The median progression-free survival, median survival time, and one-year survival rate were 6.5 months, 17.8 months, and 63%, respectively. No treatment-related deaths were observed. It was notable that a clinically valuable improvement in performance status was evident in the majority of treated patients and that EGFR mutations were observed in a diverse group of NSCLC patients, not necessarily female, non-smokers with adenocarcinoma histology.
These are exceptionally positive results considering the dismal prognosis experienced by poor PS NSCLC patients treated with chemotherapy or supportive care. The question, of course, is just how applicable they will be to the population of patients in the United States or Europe. In Japan, EGFR mutations are found in up to 40% of NSCLC cases, whereas in the United States, the rate is more like 10%. Nonetheless, the findings would support an effort to determine EGFR status in all patients with advanced NSCLC and a trial to assess whether similar results could be observed in that segment of the overall NSCLC patients, especially those with poor PS.
1. Lilenbaum RC, et al. Prevalence of poor performance status in lung cancer patients: Implications for research. J Thorac Oncol. 2008;3:125-129.
2. The Elderly Lung Cancer Vinorelbine Italian Study Group. Effects of vinorelbine on quality of life and survival of elderly patients with advanced non-small-cell lung cancer. J Natl Cancer Inst. 1999;91:66-72.
3. Free CM, et al. Lung cancer outcomes at a UK cancer unit between 1998-2001. Lung Cancer. 2007;57:222-228.
4. Langer C, et al. Randomized phase II trial of paclitaxel plus carboplatin or gemcitabine plus cisplatin in Eastern Cooperative Oncology Group performance status 2 non-small-cell lung cancer patients: ECOG 1599. J Clin Oncol. 2007;25(4):418-23.
5. Lilenbaum RC, et al. Single-agent versus combination chemotherapy in advanced non-small-cell lung cancer: the cancer and leukemia group B (study 9730). J Clin Oncol. 2005;23:190-196.
6. Pfister DG, et al. American Society of Clinical Oncology treatment of unresectable non-small-cell lung cancer guideline: update 2003. J Clin Oncol. 2004;22:330-353.
7. Fukuoka M, et al. Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer (The IDEAL 1 Trial) [corrected]. J Clin Oncol. 2003;21:2237-2246.
8. Kris MG, et al. Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer: a randomized trial. JAMA. 2003;290:2149-2158.
9. Hotta K, et al. Gefitinib should be cautiously administered to poor performance status patients with non-small-cell lung cancer: results from a prospective feasibility study. Lung Cancer. 2005;50:413-415.
10. Nagai Y, et al. Genetic heterogeneity of the epidermal growth factor receptor in non-small cell lung cancer cell lines revealed by a rapid and sensitive detection system, the peptide nucleic acid-locked nucleic acid PCR clamp. Cancer Res. 2005;65:7276-7282.