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Originally published as JCO Early Release 10.1200/JCO.2008.16.0374 on March 31 2008 © 2008 American Society of Clinical Oncology.
Does Gefitinib Shorten Lung Cancer Survival? Chaos Redux
Division of Hematology and Oncology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN In this issue, Kelly et al1 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.2 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.3 This is certainly not the first time that the untargeted use of an EGFR inhibitor has proved ineffective in the treatment of NSCLC. EGFR-TKIs have been combined with platinum-based chemotherapy in patients with advanced disease with no observed survival benefit.4-7 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.8 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,9,10 and interstitial lung disease has been observed after gefitinib therapy.11 In addition, interstitial lung disease seems to be even more problematic after gefitinib therapy in individuals with pre-existing pulmonary fibrosis.11 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.12 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.13 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 well-established 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.6,14 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.15,16 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.17,18 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.6,7,14,19 As mentioned previously, several trials have evaluated EGFR inhibitors in combination with chemotherapy with negative results.4-7 In a subset analysis of one of these trials,6 patients with wild-type EGFR seemed to have a worse survival when treated with an EGFR-TKI plus chemotherapy compared with chemotherapy alone. Gandara and Gumerlock20 have suggested that this is because EGFR-TKIs cause a G1 cell cycle arrest in cancer cell lines with wild-type EGFR as opposed to induction of apoptosis in cell lines with mutant EGFR. However, this explanation does not explain the outcomes in this particular setting because gefitinib was administered after chemotherapy. Gandara et al21 also reported that lung cancer cell lines possessing wild-type EGFR with K-ras mutations demonstrated significantly increased apoptosis when treated with docetaxel followed by gefitinib. The results of the trial by Kelly et al1 seem contradictory to these preclinical data. Of note, patients with a history of prior thoracic radiotherapy seem to be less responsive to gefitinib,11 and perhaps the prior exposure to irradiation renders these preclinical data irrelevant in this setting. Finally, the surprising outcome of S0023 also raises the disquieting possibility that gefitinib somehow stimulated tumor growth either directly or indirectly. To our knowledge, there are no examples in the preclinical literature using cancer cell lines, xenografts, or transgenic models of lung cancer that would predict this result. However, gefitinib and related quinazolines have been shown to induce EGFR homodimers and EGFR–HER-2 and EGFR–HER-3 heterodimers.22-24 Although these dimers are inactive under the experimental conditions shown in these studies, this property raises the possibility that gefitinib can stabilize ErbB receptor oligomers and indirectly enhance EGFR-independent signaling by kinases present in those protein complexes. In addition, there is a suggestion that NSCLCs with K-ras mutations do worse when treated with the EGFR-TKI erlotinib.25 This again raises the question of the K-ras gene status of the tumors in the SWOG study. Is it possible that chemoradiotherapy selected for an enriched K-ras mutant tumor cell population that did less well when subsequently treated with gefitinib? In the absence of additional mechanistic data in support of a tumor stimulatory effect of gefitinib, we can only speculate about possible biologic explanations for the negative outcome observed. We should point out, however, that the lung cancer cell lines and models used in preclinical studies with EGFR antagonists such as gefitinib may not mirror the lung cancers in this study because they had been modified by the primary therapy. Like most TKIs, gefitinib affects other protein and lipid kinases in addition to EGFR.26 It is entirely possible that some of these kinases and off-target interactions are inhibitory to cancer cells, which, on exposure to gefitinib, would be then positively stimulated. In light of the results of the SWOG study, these possibilities should be investigated further. In ancient Greek, khaos or chaos means "gaping void." The results of S0023 illustrate the ongoing gaping void in our understanding of lung cancer biology and the importance of continued bench to bedside to bench investigations. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. AUTHOR CONTRIBUTIONS Collection and assembly of data: Vicki L. Keedy, Carlos L. Arteaga, David H. Johnson Manuscript writing: Vicki L. Keedy, Carlos L. Arteaga, David H. Johnson Final approval of manuscript: Vicki L. Keedy, Carlos L. Arteaga, David H. Johnson NOTES published online ahead of print at www.jco.org on March 31, 2008. REFERENCES
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Herbst RS, Giaccone G, Schiller JH, et al: Gefitinib in combination with paclitaxel and carboplatin in advanced non-small-cell lung cancer: A phase III trial—INTACT 2. J Clin Oncol 22:785-794, 2004 6. Herbst RS, Prager D, Hermann R, et al: TRIBUTE: A phase III trial of erlotinib hydrochloride (OSI-774) combined with carboplatin and paclitaxel chemotherapy in advanced non–small-cell lung cancer. J Clin Oncol 23:5892-5899, 2005 7. Gatzemeier U, Pluzanska A, Szczesna A, et al: Phase III study of erlotinib in combination with cisplatin and gemcitabine in advanced non–small-cell lung cancer: The Tarceva Lung Cancer Investigation Trial. J Clin Oncol 25:1545-1552, 2007 8. Rodemann HP, Dittmann K, Toulany M: Radiation-induced EGFR-signaling and control of DNA-damage repair. Int J Radiat Biol 83:781-791, 2007[CrossRef][Medline] 9. Mehta V: Radiation pneumonitis and pulmonary fibrosis in non-small-cell lung cancer: Pulmonary function, prediction, and prevention. 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Bell DW, Lynch TJ, Haserlat SM, et al: Epidermal growth factor receptor mutations and gene amplification in non–small-cell lung cancer: Molecular analysis of the IDEAL/INTACT gefitinib trials. J Clin Oncol 23:8081-8092, 2005 15. Miller VA, Kris MG, Shah N, et al: Bronchioloalveolar pathologic subtype and smoking history predict sensitivity to gefitinib in advanced non–small-cell lung cancer. J Clin Oncol 22:1103-1109, 2004 16. Pao W, Miller V, Zakowski M, et al: EGF receptor gene mutations are common in lung cancers from "never smokers" and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci U S A 101:13306-13311, 2004 17. Pao W, Wang TY, Riely GJ, et al: KRAS mutations and primary resistance of lung adenocarcinomas to gefitinib or erlotinib. PLoS Med 2:e17, 2005[CrossRef][Medline] 18. 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 19. Douillard J-Y, Kim E, Hirsh V, et al: Gefitinib (IRESSA) versus docetaxel in patients with locally advanced or metastatic non-small-cell lung cancer pre-treated with platinum based chemotherapy: A randomized, open-label phase III study (INTEREST). J Thorac Oncol 2:S305, 2007 (suppl) 20. Gandara DR, Gumerlock PH: Epidermal growth factor receptor tyrosine kinase inhibitors plus chemotherapy: Case closed or is the jury still out? J Clin Oncol 23:5856-5858, 2005 21. Gandara DR, Davies AM, Gautschi O, et al: Epidermal growth factor receptor inhibitors plus chemotherapy in non-small-cell lung cancer: Biologic rationale for combination strategies. Clin Lung Cancer 8:S61-S67, 2007 (suppl 2)[CrossRef][Medline] 22. Arteaga CL, Ramsey TT, Shawver LK, et al: Unliganded epidermal growth factor receptor dimerization induced by direct interaction of quinazolines with the ATP binding site. J Biol Chem 272:23247-23254, 1997 23. Anido J, Matar P, Albanell J, et al: ZD1839, a specific epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, induces the formation of inactive EGFR/HER2 and EGFR/HER3 heterodimers and prevents heregulin signaling in HER2-overexpressing breast cancer cells. Clin Cancer Res 9:1274-1283, 2003 24. Lichtner RB, Menrad A, Sommer A, et al: Signaling-inactive epidermal growth factor receptor/ligand complexes in intact carcinoma cells by quinazoline tyrosine kinase inhibitors. Cancer Res 61:5790-5795, 2001 25. Eberhard DA, Johnson BE, Amler LC, et al: Mutations in the epidermal growth factor receptor and in KRAS are predictive and prognostic indicators in patients with non–small-cell lung cancer treated with chemotherapy alone and in combination with erlotinib. 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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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