Combining the Anti-EGFR Agent Gefitinib With Chemotherapy in Non–Small-Cell Lung Cancer: How Do We Go From INTACT to Impact? (2004)

In this issue of the Journal of Clinical Oncology are the final results of two large phase III randomized controlled trials of the anti– epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor gefitinib in combination with chemotherapy in untreated patients with advanced non–smallcell lung cancer (NSCLC) [1,2]. In these two trials, with more than 2,000 patients combined, the addition of gefitinib to chemotherapy failed to meet either the primary end point of survival or the secondary end points of time to disease progression or response rates. There was not even a suggestion of a nonsignificant trend in any of these end points in favor of gefitinib. In addition, a similar absence of benefit of two comparable phase III studies in NSCLC with erlonitib, another EGFR tyrosine kinase inhibitor, has been recently reported. The two gefitinib trials, INTACT 1 and 2, were well designed, adequately powered, and well conducted. The conclusion that concomitant gefitinib administration does not add clinical benefit to conventional chemotherapy in NSCLC seems, therefore, irrefutable. These results would not have been readily anticipated a priori for a series of reasons: first, gefitinib has demonstrated well-documented activity as a single agent in the initial phase I studies that included a large number of patients with NSCLC, and the antitumor activity of gefitinib has been confirmed in two large phase II studies in the secondand third-line setting, with response rates ranging from 9% to 18%, depending on the study and the dose [3,4]. Second, unlike with triplet chemotherapy combinations, full doses of chemotherapy could be given in combination with gefitinib, because no overlapping toxicities between gefitinib and chemotherapy have been observed in the phase I studies with these combinations. Third, available preclinical data for gefitinib combined with chemotherapy were impressively additive [5,6]. Given the outcome of the INTACT trials, it is obvious that some of these observations were incorrect or that some additional key determinants had not been taken into account. The first criticism of these trials is the lack of selection of the subset of patients likely to respond to gefitinib. Unlike trastuzumab, there are not available predictive markers of sensitivity to anti-EGFR agents; in fact, there is evidence of a lack of correlation between EGFR expression levels in the tumor and response to anti-EGFR agents, and a retrospective analysis of tumor samples from the gefitinib phase II single agent studies in NSCLC has confirmed this lack of correlation with gefitinib as well [7,8]. It is, therefore, possible that in a situation in which the responding phenotype to gefitinib has not been yet characterized, the molecular heterogeneity of lung cancer could have resulted in a false-negative result in the overall study population [9]. Although there was no evidence of patient enrichment in the phase II studies in favor of treatment sensitive subtypes or a suggestion of a negative effect in nonresponders, it would have been extremely important to have collected tumor samples to allow for post hoc clinical correlations, assuming a molecular signature of receptor sensitivity is identified. However, let us go back to the trastuzumab comparison. The initial pivotal studies with trastuzumab showed single-agent activity and improvement in survival when combined with chemotherapy in a suboptimal population because, in addition to patients with 3 HER2 overexpressing tumors, patients with 2 HER2 ovexpressing tumors were also included [10,11]; it is now known that 2 HER2 overexpressing, fluorescence in situ hybridization–negative tumors do not respond to trastuzumab [12]. The consequence was that the combined response rate in 2 and 3 HER2 overexpressing breast tumors to single agent trastuJOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 22 NUMBER 5 MARCH 1 2004