Does Gefitinib Shorten Lung Cancer Survival? Chaos Redux
Authors: Vicki L. Keedy, Carlos L. Arteaga, David H. Johnson
Journal: Journal of Clinical Oncology (2008)

In this issue, Kelly et al present the results of a Southwest Oncology Group (SWOG) phase III study (S0023) designed to prospectively determine the value of maintenance gefitinib after chemoradiotherapy in patients with locally advanced non–small-cell lung cancer (NSCLC). The trial was suspended before completing its target accrual for an unplanned interim analysis based on the negative results of a separate phase III trial (known as the Iressa Survival Evaluation in Lung Cancer) comparing gefitinib with a placebo in recurrent NSCLC. The overall survival in the gefitinib arm of S0023 was statistically inferior to that observed in the placebo arm (hazard ratio 0.633; 95% CI, 0.44 to 0.91; P .013). Of possible relevance to the negative outcome, patients participating in S0023 were not preselected on the basis of any of the known putative molecular markers of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) activity. This is certainly not the first time that the untargeted use of an EGFR inhibitor has proved ineffective in the treatment of NSCLC.EGFR-TKIshavebeencombinedwithplatinum-basedchemotherapy in patients with advanced disease with no observed survival benefit. However, in none of the previous studies was a statistically significant survival disadvantage observed in the EGFR-TKI arm. The results of S0023 seem counterintuitive to our professed knowledge of how EGFR-TKIs supposedly work. How then do we explain these rather surprising and disappointing results? When an investigational treatment yields an unexpected detrimental outcome, the prospect of excessive toxicity caused by the treatment is an obvious consideration. One distinct possibility in this particular trial is an increase in the number of treatment-related pulmonary deaths. Preclinical data suggest that the EGFR pathway is important in DNA double-strand break repair mechanisms, and thus, inhibition of this pathway presumably enhances the effectiveness of radiotherapy. However, if repair of sublethal damage in normal tissues was impaired by EGFR blockade, then the resultant increase in host toxicities might adversely impact long-term survival. As is well known, both radiotherapy and docetaxel can cause pulmonary fibrosis, and interstitial lung disease has been observed after gefitinib therapy. In addition, interstitial lung disease seems to be even more problematic after gefitinib therapy in individuals with pre-existing pulmonary fibrosis. Thus, one might suppose that the combination of these therapies would be a near perfect situation for causing significant pulmonary toxicity. Importantly, however, overall grade 3 to 4 toxicities were modest in both the placebo and gefitinib arms, and the toxic death rates were minimal (2% for gefitinib v 0% for placebo); the difference in toxic death rate seems hardly sufficient to account for the observed outcome. Moreover, the overall frequency of pulmonary complications in this trial seems to be consistent with what others have reported. Notably, in head and neck cancers at least, the concurrent use of irradiation and EGFR blockade does not seem to increase acute or late toxicity. Thus, the combination of irradiation and EGFR blockade seems to be relatively well tolerated regardless of the sequencing of these therapies. Accordingly, excess toxicity caused by an adverse interaction between EGFR blockade and irradiation does not seem to be the explanation for the S0023 results. Another possible explanation is an imbalance in known (or potentially unrecognized) prognostic factors leading to an altered outcome not necessarily related to treatment effect per se. However, this seems unlikely because there were no obvious differences in wellestablished prognostic factors among the two arms despite the early termination of the study before the desired accrual was achieved. Conversely, a number of potentially important patient and tumor characteristics were not recorded at baseline including smoking history, tumor EGFR status (including EGFR mutational status or gene amplification), and K-ras mutational status. Potentially, a chance and unrecognized imbalance in one of these factors could have influenced the study’s outcome. For example, compared with individuals with tumors containing wild-type EGFR, patients with tumors harboring an EGFR mutation seem to have a better overall prognosis irrespective of their treatment. In addition, a negative smoking history has been associated with a higher likelihood of the patient’s tumor harboring an EGFR mutation and a greater probability of benefit with EGFR-TKI therapy. By contrast, the presence of a K-ras mutation, found almost exclusively in smokers, is associated with resistance to these drugs and a less favorable outcome. If any of these parameters was disproportionately distributed between the two arms, it could account for a survival differential. Although we agree with the authors that such an imbalance in any of these uncaptured characteristics seems highly unlikely, it remains an open question without full knowledge of the frequency and distribution of these prognostic and predictive parameters among the randomly assigned population. Perhaps this concern diminishes in light of mounting evidence suggesting that EGFR gene mutation status and EGFR amplification or overexpression may not reliably predict for improved survival with the use of EGFR inhibitors. As mentioned previously, several trials have evaluated EGFR inhibitors in combination with chemotherapy with negative results. JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 26 NUMBER 15 MAY 2