Gefitinib in the First-Line Setting

Platinum-based doublet chemotherapy is the standard of care for the first-line treatment of patients with metastatic NSCLC and good performance status (8). Among patients who are not candidates for platinum-based therapy due to age or performance status, the use of sequential single agents is an option (9). With conventional chemotherapy regimens, response rates (RRs) remain at 20% to 40% and median survival is typically 8 to 10 months. Attempts to improve efficacy by adding cytotoxic agents to the standard platinum-based doublet regimen have resulted in increased toxicity without improved survival (10). This has led to increased interest in the use of molecularly targeted agents in the first-line setting.

Various trials with gefitinib as a first line treatment:

Gefitinib showed promising results as a single agent in refractory NSCLC in 2 phase 2 studies known as IDEAL (Iressa Dose Evaluation in Advanced Lung cancer) 1 and 2. In IDEAL 1, 210 pretreated patients were randomized to receive gefitinib at 250 or 500 mg/day (6). The overall response rate (ORR)- tumour shrinkage was 18.4% and 19% and overall survival (OS) was 7.6 months and 8.0 months for the lower dose and the higher dose groups, respectively. In IDEAL 2, 216 patients who had relapsed after platinum and docetaxel regimens were randomized to receive gefitinib 250 or 500 mg/day (7). Efficacy results were similar between the dosing groups; the ORR was 12% and the 1-year survival rate was 25%. In both studies, grade 3-4 adverse events (AEs) such as acneiform rash and diarrhea were more frequent with the higher dose (6,7).

A phase 2 study evaluated gefitinib 250 mg daily in 42 chemotherapy-naive patients with advanced NSCLC (11). Gefitinib showed some activity with an ORR of 30%, but the investigators observed an unacceptably high rate of grade 5 interstitial lung disease (4 patients). Another phase 2 study conducted in 37 patients with advanced NSCLC who were never-smokers evaluated the same dose of gefitinib, finding a 69% partial response (PR) rate and an 11% standard deviation (SD) rate. The estimated 1-year survival rate was 73% (12).

More recently, an open-label, randomized, parallel-group study called IPASS (Iressa Pan-ASia Study) evaluated gefitinib versus carboplatin/paclitaxel as first-line treatment in 1217 chemotherapy-naive patients in Asia whose tumors were of adenocarcinoma histology and who had either never smoked or were former light smokers (ceased smoking at least 15 years prior to study enrollment and had ≤ 10 pack-years exposure) (13). The study demonstrated that gefitinib had superior progression-free survival (PFS), that is, the lapse of time a person lives without his/her tumour progressing compared with carboplatin/paclitaxel in this population of clinically selected patients (25% with no progression after 1 year in the gefitinib arm versus 7% in the carboplatin/paclitaxel arm; hazard ratio (HR) 0.74; P<.0001).

Overall, treatment with gefitinib elicited a superior ORR (43% versus32%; P=.0001) and improvement in patient quality of life compared with chemotherapy (48% versus 41%; P=.0148 for Functional Assessment of Cancer Therapy - Lung [FACT-L] total score). Gefitinib had a more favorable tolerability profile and AEs (13).

Furthermore the IPASS trial showed that NSCLC patients with a mutation in the EGFR gene appear to be more likely to benefit from gefitinib (Iressa) than from conventional chemotherapy (14,15). Among patients with EGFR mutations, median progression-free survival was 9.5 months with gefitinib and 6.3 months with carboplatin/paclitaxel. Patients without EGFR mutations experienced a median progression free survival of 5.5 months with carboplatin/paclitaxel and 1.5 months with gefitinib (13). Hence EGFR mutation status was a strong predictive biomarker in this clinically selected first-line setting indicating that a molecularly defined population will benefit most from first-line Gefitinib (16,17).

Subsequently, the phase 3 INTEREST (Iressa Non-small-cell lung cancer Trial Evaluating REsponse and Survival against Taxotere) trial, conducted 1466 patients with NSCLC who had received 1 or 2 prior chemotherapy regimens, and found gefitinib to be non-inferior for survival (median OS of 7.6 months; 1-year survival of 32%) compared with docetaxel, and offered improved tolerability and patient quality of life (18). Preplanned subgroup analyses found one significant difference between the treatment groups: patients who had received 2 prior chemotherapy regimens had better survival with docetaxel than with gefitinib (P=.031). Overall, among patients taking gefitinib, 2.2% had grade 3/4 hematologic AEs, whereas docetaxel-treated patients had a 58.2% incidence of grade 3/4 neutropenia and a 42.3% incidence of grade 3/4 leucopenia (19,20).

In their recently published work the iTARGET trial (A phase II trial to assess the response to gefitinib in epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer tumors), Sequist and colleagues studied the use of gefitinib in chemotherapy-naive patients with identified EGFR mutations. 98 patients from 11 centres were prospectively screened for EGFR mutations and subsequently treated with an EGFR TKI once such mutations were identified. 34 patients (35%) with EGFR mutations were identified (21). Three of the 98 samples (4%) were inadequate for EGFR testing. Of the 34 samples with EGFR mutations, the most common genomic changes were exon 19 deletions (18 patients, 53%) and the L858R point mutation of exon 21 (9 patients, 26%). Thirty-one of 34 patients were begun on gefitinib 250mg daily; one patient chose not to proceed with treatment, while 2 others were not started on gefitinib due to the presence of mutations associated with gefitinib resistance. With a median follow-up of 12.3 months, median PFS for the 31 treated patients was reported as 9.2 months (95% CI, 6.2-11.8 months), and median overall survival was 17.5 months (95% CI, 13.5-21.3 months) (21).

This trial is significant for several reasons. First, it demonstrates that prospective genetic testing prior to initiation of first-line therapy is feasible.

Second, the trial provides prospective confirmation of the results from prior studies in which mutation status was assessed. Namely, rates of response and disease control are high, and median times to progression and overall survival have been encouraging (16,17).

The trial also provides some additional evidence about the impact of some resistance mutations, such as T790M and MET amplification. Patients harboring these mutations in their pretreatment specimen tended to do poorly with gefitinib therapy, consistent with prior preclinical and clinical evidence (22,23).