The challenges of targeting EGFR in Asia
Tony Mok
Professor
Department of Clinical Oncology
The Chinese University of Hong Kong

The human epidermal growth factor receptor (EGFR) is overexpressed in 40–80% of primary NSCLC tumours and was proposed as a target for NSCLC treatment based on its important role in cellular growth and proliferation. EGFR tyrosine kinase inhibitors compete with ATP to bind the EGFR TK domain and prevent downstream signalling. Extensive studies were performed in the past decade confirming its role in management of advanced NSCLC, and more specifically lung cancer with activating EGFR mutation.

Four large, randomised phase III trials comparing EGFR TKIs in combination with chemotherapy with chemotherapy alone and there were no survival advantage. Only subsequently, we recognize that the somatic mutations in the kinase domain of EGFR are responsible for the dramatic and durable tumor response to EGFR TKIs. Multiple phase II studies conducted in Asia showed that clinically selected population with high incidence of EGFR mutation benefit from EGFR TKI as first line therapy. Lee et al reported tumor response rate of 69% to gefitinib in a population of non-smoking Korean women with adenocarcinoma.  Similar results in clinical efficacy were noted in a Spanish Lung Cancer group trial with EGFR mutation-positive patients who received erlotinib monotherapy. Tumour biopsies were obtained from 2312 patients and a total of 307 patients had EGFR mutations. A median survival of 24 months and an ORR of 73% was noted in 165 patients with EGFR mutation-positive tumours who received erlotinib as either first- or second-line therapy. The early observation is confirmed in a recent randomized phase III study in Asia.  In the IPASS 1217 patients from 9 countries in Asia were randomised to gefitinib (n=609) or carboplatin/taxol (n=608).  Gefitinib demonstrated superior PFS compared with C/P (HR 0.74; 95% CI 0.65-0.85; p<0.0001).  The improvement is potentially driven by differences in the subgroups with EGFR mutation + and - tumours. Tumor response rate was significantly higher (43% vs 32.2%; odds ratio [OR] 1.59; 95% CI 1.25-2.01 p=0.0001).  Quality of life improvement rate was higher with gefitinib (FACT-L 48% vs 41%; OR 1.34: 95% CI 1.06-1.69; p=0.0148). PFS in EGFR mutation + pts was longer for geftinib than chemotherapy (HR 0.48: 95% CI 0.36-0.64; p<0.0001); in EGFR mutation   pts PFS was longer with chemotherapy than geftinib (HR 2.85: 95% CI 2.05-3.98; p<0.0001). EGFR mutation is a potent predictor of treatment outcome to EGFR TKI. Patients should have EGFR mutation analysis for decision of first line therapy if tissue sample is available. A phase III trial (EURTAC) selected patients with EGFR mutation and randomized to either erlotinib or chemotherapy. Results from these studies will potentially define the optimal molecular predictors of response to EGFR TKI as first line therapy.

Alternative way is to combine chemotherapy and EGFR TKI in sequential manner. The FAST-ACT trial, a placebo-control randomised phase II study of 150 patients from Asia and Australia was designed to determine if a sequential combination of erlotinib and chemotherapy could improve clinical outcomes in patients with advanced NSCLC. Patients received gemcitabine and carboplatin on Days 1 and 8 followed by erlotinib or placebo from Days 15–28. All patients received erlotinib or placebo as maintenance therapy. The RR was 36.8% for the erlotinib arm versus 24.4% for the placebo arm. Median progression-free survival (PFS) was 7.2 months with erlotinib versus 5.5 months with placebo; HR=0.57 (95% CI 0.38; 0.84), P=0.005. A phase III trial (FASTACT II) evaluating this treatment regimen will be initiated in first quarter of 2009.

Patients with negative or unknown EGFR mutation should receive chemotherapy as first line therapy. Most patients eventually experience disease progression, usually within a median of 3–6 months of initiation of first-line therapy. The  currently approved second-line treatment regimens include two cytotoxic chemotherapy agents docetaxel (Taxotere) and pemetrexed (Alimta), and the molecular-targeted EGFR TKI, including gefitinib and erlotinib. In the pivotal trial for erlotinib, BR.21, 731 patients with advanced-stage NSCLC were treated with erlotinib monotherapy or placebo. A significant survival benefit was observed with erlotinib versus placebo; a median OS of 6.7 months with erlotinib, compared with 4.7 months in patients treated with placebo (P<0.001).  The INTEREST study (an open-label phase III trial of gefitinib versus docetaxel as second- or third-line therapy) met one of its primary endpoints of demonstrating noninferiority of gefitinib relative to docetaxel. The OS times were similar for the two treatment arms; median OS was 7.6 months for gefitinib and 8.0 months for docetaxel (HR 1.020; 96% confidence interval [CI], 0.905–1.150); one-year survival rates were 32% with gefitinib treatment and 34% with docetaxel. The RR was slightly higher with gefitinib (9.1%) than docetaxel (7.6%), although this difference was not significant (P=0.32).39 Gefitinib had a more favourable tolerability profile and improved QoL compared to docetaxel. The Japanese trial, V15-32, did not demonstrate noninferiority in OS with gefitinib compared to docetaxel (HR 1.12; 95.24% CI, 0.89–1.4, P=0.33). The ISEL trial failed to show a significant overall increase in survival with gefitinib monotherapy compared to placebo in patients with advanced disease (5.6 months for gefitinib and 5.1 months for placebo; HR 0.89, 95% CI 0.77–1.02, P= 0.087). A pre-planned subgroup analysis of 342 Asian patients in ISEL, however, demonstrated a 4-month survival advantage for gefitinib compared with placebo; median OS in Asian patients was 9.5 months for gefitinib versus 5.5 months for placebo (P=0.01).

In summary, EGFR mutation is a strong biomarker predictor of tumor response and PFS to EGFR TKI in first line therapy for advanced NSCLC. For patient with negative or unknown EGFR mutation, chemotherapy remains the first line and EGFR TKI could be used as 2nd or 3rd line therapy.