Citation: European Journal of Cancer Supplements, Vol 7 No 2, September 2009, Page 505

M. Kris¹, T. Mok², E. Kim³, J.Y. Douillard⁴, M. Fukuoka⁵, N. Thatcher<sup>6

1</sup>Memorial Sloan-Kettering Cancer Center, New York, USA
²The Chinese University of Hong Kong, Hong Kong, China
³The University of Texas M.D. Anderson Cancer Center, Houston, USA
⁴Centre René Gauducheau, Nantes, France
⁵Kinki University School of Medicine, Osaka, Japan
⁶Christie Hospital, Manchester, United Kingdom

Background: Gefitinib (Iressa®) inhibits tyrosine kinase activity of the epidermal growth factor receptor (EGFR). The EGFR kinase can be constitutively activated by mutations in exon 19 or 21 of the EGFR gene. Cells harboring these mutations are “addicted” to EGFR signaling and are exquisitely sensitive to blockade of the kinase. These mutations are often found in the tumors of patients (pts) with marked benefit to gefitinib. We reviewed results of phase III trials of gefitinib monotherapy, focusing on pts with known EGFR mutation status.
Methods: Of the 4864 pts enrolled on the ISEL, INTEREST, IPASS, and V-15–32 trials of gefitinib 250 mg orally daily vs a comparator, we obtained EGFR mutation status on 1006 (21%).
Results: Across the different studies, the pooled objective response rate (ORR) with gefitinib in EGFR mutation positive pts was 65% [114/176, 95% CI 58% to 71%], range 38% to 71%. In EGFR mutation negative pts, it was 3% [11/324, 95% CI 2% to 6%], range 0% to 7%. For active comparators, ORRs in EGFR mutation positive pts were 30% [9/30 pooled] for docetaxel alone and 47% [61/129] for carboplatin/paclitaxel. For mutation negative patients, ORRs were 9% [12/132 pooled] with docetaxel alone and 24% [20/85] with carboplatin/paclitaxel. In every study, ORR was numerically better for gefitinib than comparator in EGFR mutation positive pts, and similar or poorer than comparator in EGFR mutation negative pts. For pts with EGFR mutations, the ORR with gefitinib was 71% when used initially and ranged from 38% to 67% in studies where gefitinib was given after chemotherapy. A trend similar to ORR was observed for progression-free survival (PFS) or time to treatment failure, with longest median values in gefitinib-treated EGFR mutation positive pts (range 7–11 months). The results of these 4 studies are consistent with the published data in pts with known EGFR mutation status.
Conclusions: For pts with tumors with EGFR mutations: 1) ORR with gefitinib was higher in EGFR mutation-positive than -negative pts in every study, 2) This ORR was higher on gefitinib than comparator in every study, 3) Median PFS tended to be longer on gefitinib than comparators. 4) ORR was 38% or greater regardless of line of therapy. For pts with tumors without EGFR mutations: ORR and median PFS tended to be similar to or poorer for gefitinib than comparators. These results justify pretreatment determination of EGFR mutation status at the time of diagnosis to select therapy with higher response and improved PFS.