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Originally published as JCO Early Release 10.1200/JCO.2008.18.5462 on September 8 2008 © 2008 American Society of Clinical Oncology.
In Reply
University of Kansas Medical Center, Kansas City, KS
Southwest Oncology Group Statistical Center, Seattle, WA
University of California, Davis, Sacramento, CA We appreciate the comments and considerations raised by the recent letters of Bhutani et al and Stewart regarding the results of the Southwest Oncology Group S0023 clinical trial. Our article1 and the accompanying editorial by Keedy et al2 detail potential explanations for why the trial did not demonstrate a positive effect for gefitinib maintenance, but also address the more cogent question of why the trial was actually negative (ie, gefitinib actually decreased patient survival when compared with placebo). Bhutani et al suggest that molecular heterogeneity of reported predictive factors of benefit from epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) could have masked a potential survival benefit for gefitinib, particularly because the majority of tumors do not possess favorable survival predictors such as EGFR mutations or fluorescent in situ hybridization (FISH) positivity. They suggest that we should have accounted for this molecular variability in our trial. I must remind the authors that S0023 was activated in the year 2000, before knowledge of the molecular predictive factors for EGFR TKIs in lung cancer, and that anti-EGFR therapy and targeted therapy in general were in their infancy at that time. Furthermore, a survival advantage was demonstrated in the BR21 monotherapy trial of erlotinib versus placebo where the same unknown molecular heterogeneity existed.3 In the molecular outcome analysis of that study, EGFR immunohistochemical expression and high FISH copy number significantly prolonged survival in the univariate analysis, but EGFR mutations did not.4 However, in the multivariate analysis, none of the molecular markers were independent predictors of prolonged survival for patients treated with erlotinib. These data, among others, suggest that, although the response is most dramatic in patients with tumors with EGFR activating mutations, survival gain with erlotinib is possible in patients with wild-type EGFR and perhaps greatest in those patients with EGFR FISH–positive tumors. Overall, only approximately 10% of non–small-cell lung cancer tumor specimens are negative for EGFR protein expression, FISH, and activating mutation. This patient subset also seems more likely to have KRAS mutations, another unfavorable survival group.5 In a subsequent analysis of BR21 evaluating the role of KRAS, Tsao et al6 showed that 15% of patients with KRAS mutant tumors did not derive any survival benefit from erlotinib but cautioned that the sample size was small. Thus, we agree that molecular heterogeneity for a survival effect with gefitinib exists but believe that the majority of profiles are favorable with a chance to produce at least a small survival benefit.7 Therefore, this would not have changed our statistical approach. On the basis of these considerations, we would have predicted that, in the worst scenario, gefitinib would have exhibited a neutral effect in the great majority of patients (ie, the survival curves would have been similar between patients randomly assigned to gefitinib or placebo). Instead, an unexplained significantly worse survival outcome was observed for the gefitinib arm of S0023. Bhutani et al also hypothesize that, because KRAS mutant tumors also do not respond to chemotherapy, the previous chemoradiotherapy treatment enriched the population for these resistant tumors, resulting in a decreased survival time. If so, it is most likely that this effect would have led to early disease progression and ineligibility for random assignment to gefitinib or placebo maintenance. In fact, in S0023, 69% of patients on the gefitinib arm achieved an objective response to the definitive treatment regimen, which does not lend support for an enriched KRAS mutant population. Moreover, univariate analysis of KRAS mutation in BR21 did not show a significant survival difference between patients with KRAS-mutated tumors receiving erlotinib versus placebo (P = .31), although treated patients had a shorter survival.5 Thus, although we agree that a small minority of patients may have benefited from gefitinib in the S0023 trial, we believe that this effect was masked by a larger group who actually was harmed. Furthermore, decreased survival did not seem to be the result of gefitinib toxicity because the toxic death rate from gefitinib was only 2%. Stewart raises an intriguing hypothesis for the lack of benefit with gefitinib. He suggests that a reduction in membrane transporters from prior chemoradiotherapy conferred temporary drug resistance, rendering gefitinib ineffective. Although this effect is theoretically possible, it would not explain the negative impact of gefitinib in S0023. The in-depth analysis of the shape of the published survival curve may be misleading because there remain quite a few censored observations on this part of the curve. Only 54 of 124 patients on the placebo arm and 71 of 117 patients on the gefitinib arm had actually died at the time of publication. With mature follow-up data, we predict that the curves will smooth out. The growing list of explanations for the outcome observed in S0023 undeniably highlights our limited understanding of the molecular biology of lung cancer and the dynamic influences of treatment on tumor biology, as Keedy et al2 point out. The heterogeneity of stage III non–small-cell lung cancer further complicates interpretation of the data. Definitely, a biologic black hole exists for stage III disease. To our knowledge, S0023 was the first randomized trial in stage III lung cancer to collect tumor samples and serial blood samples, and molecular analysis testing for EGFR pathways and KRAS expression is planned. Stay tuned. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: Karen Kelly, AstraZeneca (C); David R. Gandara, AstraZeneca (C) Stock Ownership: None Honoraria: None Research Funding: None Expert Testimony: None Other Remuneration: None NOTES published online ahead of print at www.jco.org on September 8, 2008 REFERENCES
1. Kelly K, Chansky K, Gaspar LE, et al: Phase III trial of maintenance gefitinib or placebo after concurrent chemoradiotherapy and docetaxel consolidation in inoperable stage III non–small-cell lung cancer: SWOG S0023. J Clin Oncol 26:2450-2456, 2008 2. Keedy VL, Arteaga CL, Johnson DH: Does gefitinib shorten lung cancer survival? Chaos redux. J Clin Oncol 26:2428-2430, 2008 3. Shepherd FA, Pereira JR, Ciuleanu T, et al: Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 353:123-132, 2005 4. Tsao MS, Sakurada A, Cutz JC, et al: Erlotinib in lung cancer: Molecular and clinical predictors of outcome. N Engl J Med 353:133-144, 2005 5. Massarelli E, Varella-Garcia M, Tang X, et al: KRAS mutation is an important predictor of resistance to therapy with epidermal growth factor receptor tyrosine kinase inhibitors in non-small cell lung cancer. Clin Cancer Res 13:2890-2896, 2007 6. Tsao M, Zhu C, Sakurada A, et al: An analysis of the prognostic and predictive importance of K-ras mutation status in the National Cancer Institute of Canada Clinical Trials Group BR.21 study of erlotinib versus placebo in the treatment of non–small-cell lung cancer. J Clin Oncol 24:365s, 2006 (suppl; abstr 7005) 7. Hirsch FR, Varella-Garcia M, Bunn PA Jr, et al: Molecular predictors of outcome with gefitinib in a phase III placebo-controlled study in advanced non–small-cell lung cancer. J Clin Oncol 24:5034-5042, 2006
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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