Mutations in EGFR Gene Confer Beneficial Response to Oral TKI Gefitinib in NSCLC

Gefitinib, an oral tyrosine kinase inhibitor (TKI), is highly effective in patients with non-small-cell lung cancer (NSCLC) who harbor mutations of the EGFR gene (mEGFR), as demonstrated by a pooled analysis of four phase III studies and a separate phase III study presented at the ECCO 15 – ESMO 34 Joint Congress.

Gefitinib (Iressa), an oral tyrosine kinase inhibitor (TKI), is highly effective in patients with non-small-cell lung cancer (NSCLC) who harbor mutations of the EGFR gene (mEGFR), as demonstrated by a pooled analysis of four phase III studies and a separate phase III study presented at the ECCO 15 — ESMO 34 Joint Congress.

The pooled analysis of four phase III trials comparing gefitinib monotherapy (250 mg orally per day) versus chemotherapy (docetaxel alone or carboplatin/docetaxel) showed marked efficacy of the oral TKI in NSCLC patients with mEGFR. As in previous trials, the benefits of gefitinib in prolonging progression-free survival (PFS) were even greater in Asians with mutations than in non-Asians with mutations.

“This analysis suggests that EGFR testing should be performed in NSCLC patients to select for therapy,” stated J.Y. Douillard, MD, Centre Rene Gauducheau, Nantes, France, who presented the pooled analysis of the ISEL, V-15-32, INTEREST, and IPASS studies.

Of the 4864 patients enrolled in these four trials, mEGFR status was obtained on 1006 (21%). The pooled objective response rate (ORR) with gefitinib was 65% (range, 37% to 71%) in those with mEGFR versus 3% (range, 0-6.6%) in those without mutations. In the active comparator arms, the pooled ORR in mutation-positive patients was 30% for docetaxel alone and 47% for carboplatin/docetaxel; and 9% and 24%, respectively, for those without mEGFR.

In each study, the ORR was numerically superior for gefitinib than for comparator chemotherapy in mEGFR-positive patients, and similar or poorer than comparator chemotherapy in those without mutations. The trend was similar for PFS or time to treatment failure, with the longest disease-free interval observed in patients with mutations (range, 7-11 months).

A literature review subsequently conducted by Dr Douillard and his colleagues replicated these findings. Among a total of 5241 patients treated with gefitinib monotherapy, a consistent benefit was observed for patients with mEGFR (mean ORR 69%) versus comparators (mean ORR 39%). Improved outcomes were seen in Asians versus non-Asians with mEGFR, a finding that has been previously reported. The PFS benefit of gefitinib in mEGFR-positive patients was constant regardless of whether the drug was used as first-line or second-line therapy, and in studies where previous lines of therapy were unknown.

WJTOG 3405 Trial

PFS was significantly prolonged by gefitinib compared with cisplatin/docetaxel in a randomized, open-label, phase III trial of patients with advanced, metastatic, or recurrent NSCLC harboring mEGFR.

“This study met its primary endpoint, PFS. Results are consistent with previous studies showing PFS of about 10 months with gefitinib and 5.6 months with chemotherapy,” stated Junji Tsurutani, MD, Kinki University School of Medicine in Osaka, Japan.

The study enrolled and randomized 177 patients with locally advanced, metastatic, or recurrent NSCLC plus mEGFR to either gefitinib 250 mg daily until disease progression or up to 6 cycles of cisplatin 80 mg/m2 plus docetaxel 60 mg/m2 on day 1 given every 21 days (1 cycle).

Treatment arms were well balanced for demographic and disease-related characteristics. About 50% of patients were age 65 years and older, 74% were female, and 75% were non-smokers. Median PFS was significantly prolonged with gefitinib compared with chemotherapy: 9.2 months versus 6.3 months, respectively (P <.001). Grade 3 and 4 hematologic and non-hematologic toxicities were more frequent in the chemotherapy arm, while liver dysfunction and rash were more common in those treated with gefitinib.

The results of this Japanese trial are similar to two other recent Phase III trials: NEJ002 and FIRST SIGNAL. In all three of these Phase III trials, a clear benefit with gefitinib was observed for patients with mEGFR, while PFS in patients treated with chemotherapy did not differ according to EGFR mutation status.

ECCO/ESMO Abstracts O-9003 and O-9002