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Originally published as JCO Early Release 10.1200/JCO.2005.05.030 on July 25 2005 © 2005 American Society of Clinical Oncology.
Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors Plus Chemotherapy: Case Closed or Is the Jury Still Out?University of California Davis Cancer Center, Sacramento, CA The cases for and against giving combinations of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) such as gefitinib and erlotinib concurrently with chemotherapy for first-line treatment of advanced-stage non–small-cell lung cancer (NSCLC) have just become even more complex. In this issue of the Journal of Clinical Oncology are two additional pieces of evidence—one favoring the prosecution's case (EGFR TKIs plus concurrent chemotherapy is a bad idea: "guilty as charged") and one for the defense (the evidence against the combination is all "circumstantial": this is a case of the defendant, erlotinib, being "in the wrong place at the wrong time"). Let's examine the evidence from these two studies.1,2 Herbst et al present data from the TRIBUTE trial of paclitaxel/carboplatin plus concurrent erlotinib or placebo, showing that erlotinib added nothing to chemotherapy for any outcome measure in the overall study population. These data are strikingly reminiscent of those published previously in the gefitinib-based INTACT (Iressa NSCLC Trial Assessing Combination Treatment) trials and the similarly designed TALENT trial of gemcitabine/cisplatin plus or minus erlotinib.3-5 Altogether, these four trials testing the concept of chemotherapy plus concurrent EGFR TKI account for 4,421 patients, a substantial investment of patient resources. While erlotinib added nothing to efficacy, it did contribute to toxicity. The authors report 48 deaths attributable to an adverse event: 32 (10.2%) of 322 deaths in the erlotinib arm versus 15 (4.4%) of 340 in the placebo arm. So the question at hand is why were TRIBUTE and TALENT negative studies? Similarly, why did gefitinib not add benefit to chemotherapy in INTACT 1 and INTACT 2? After all, we know that chemotherapy by itself produces objective responses and prolongs survival in NSCLC when compared with supportive care alone.6,7 In a recently reported trial in patients with NSCLC failing chemotherapy (BR21) erlotinib monotherapy resulted in objective responses and prolonged survival when compared with placebo.8 Thus, it is logical to conclude that the antitumor activity of these agents should be at least additive (ie, 1 + 1 should equal 2). (Personal communication, Alisha and Zachary Stickney, April 18, 2005.) However, in the four large clinical trials cited above, 1 + 1 appears to equal only 1. How could this be? Although there are a number of possible explanations, two hypotheses that seem most likely have been proposed: (1) Lack of patient selection for the target (EGFR) explains the results; or (2) Chemotherapy and EGFR TKIs, given concurrently, result in a negative interaction (antagonism?) in at least a subset of patients treated. The first hypothesis, that negative results are explained by failure to "enrich" the study population(s) by a biomarker predictive of response, clearly has merit. One need only look back to the clinical trials of trastuzumab plus chemotherapy in breast cancer to see the rationale for predetermining a sensitive population most likely to benefit from such a combination.9 Mathematical probability suggests that if trastuzumab plus chem-otherapy had been tested in a nonselected population, no benefit of trastuzumab would have been discernable. In favor of this explanation, the authors of TRIBUTE report a survival benefit for the combination in patients categorized as "never-smokers," a group previously reported to have a higher response rate to erlotinib or gefitinib as single agents, and as noted below, a group with a higher likelihood of harboring an EGFR-activating mutation.10 It is here that the study by Eberhard et al describing EGFR and KRAS mutations in a subset of 274 patient tumors from TRIBUTE becomes relevant. A large number of potential biomarkers for sensitivity or resistance to EGFR TKIs have been proposed, including protein expression of EGFR by immunohistochemistry, gene copy number determined by fluorescence in situ hybridization (FISH), mutations of EGFR or KRAS, and expression levels of downstream pathway markers such as phosphorylated (p) AKT or p-MAPK.11 About this time last year, two groups simultaneously reported that activating mutations in the EGFR tyrosine kinase domain were associated with the dramatic responses to gefitinib and erlotinib occasionally observed by clinicians.12,13 In the analysis by Eberhard in this issue of the Journal, EGFR mutations were detected in 13% of patients and were more common in the never-smoking group, as previously described. Within the limitations of a subset analysis such as this, the authors report several findings pertinent to the hypotheses raised above. Of interest, EGFR mutations conferred a good prognosis, regardless of treatment received (ie, those patients with EGFR mutations receiving chemotherapy plus placebo lived longer). More importantly, comparative analysis of four patient subsets, those with mutant EGFR or wild type (wt) EGFR treated with erlotinib plus chemotherapy or chemotherapy alone, is informative. While patients with mutant EGFR treated with the combination had a trend toward a higher response rate than those receiving chemotherapy alone (53% v 23%, respectively; P = ns), they fared significantly better than those patients with wt EGFR treated with the combination (response rate, 18%; P < .01). Moreover, this same subset, those with wt EGFR treated with the combination, shows the highest rate of progressive disease (52%). These data are in support of hypothesis 2, that chemotherapy plus erlotinib results in a negative interaction in those patients with wt EGFR. The authors point out that other outcome measures, such as time to progression (TTP) and overall survival, may be better end points from which to draw conclusions about the interactions of erlotinib and chemotherapy. Realizing the limitations of small subgroup analysis, none of the differences in TTP or survival reached statistical significance. However, it is the subgroup with wt EGFR treated with erlotinib plus chemotherapy that numerically, if not statistically, demonstrated the worst results for both TTP and overall survival. Providing a rationale for these findings are recent preclinical studies demonstrating that EGFR TKIs result primarily in a G1 cell cycle arrest in cancer cell lines with wt EGFR, versus induction of apoptosis in cell lines with mutant EGFR.14 Furthermore, combination studies in vitro and in vivo have shown that in some models, G1 arrest resulting from pretreatment with EGFR TKIs blocks subsequent effects of chemotherapy, and that continuous concurrent administration of the combination is less effective than intermittent or sequential pulse delivery.15,16 Lastly, the authors report that KRAS mutations, found 21% of specimens tested, were largely mutually exclusive from EGFR mutations, and that patients with mutant KRAS tumors showed poorer clinical outcomes when treated with erlotinib and chemotherapy. Eberhard et al conclude that although patients with EGFR mutant tumors have a higher response rate to erlotinib plus chemotherapy than those with wt tumors, the relevance in selecting patients for erlotinib therapy remains unclear, and further studies are needed to confirm the findings of this retrospective subset analysis. Whether EGFR mutations or other biomarkers such as gene copy number assessed by FISH will ultimately prove to be the better predictor of clinical outcome from these TKIs remains controversial, and was a subject of discussion at the 2005 Annual Meeting of the American Society of Clinical Oncology.17 While certainly not conclusive, these data also suggest that for patients with wt EGFR, who make up the vast majority of the NSCLC population in the United States, caution should be observed in recommending such a combination strategy outside of a protocol setting. Since prospective trials now in development will repeat the TRIBUTE approach by treating NSCLC populations enriched for the likelihood of EGFR mutations (such as never-smokers and adenocarcinomas) with an erlotinib-chemotherapy combination, the hypotheses raised above will be put directly to the test. Alternatively, other studies are testing delivery of chemotherapy and EGFR TKIs by intermittent dosing schedules designed to achieve pharmacodynamic separation, and thus avoid possible negative consequences of concurrent use.18 So while the two studies in this issue of the Journal provide additional insight regarding the merit or lack of merit of EGFR TKIs plus concurrent chemotherapy, the jury is still out. Authors' Disclosures of Potential Conflicts of Interest Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. 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.
Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C)
REFERENCES
1. Herbst RS, Prager D, Hermann R, et al: TRIBUTE: A phase III trial of erlotinib HCl (OSI-774) combined with carboplatin and paclitaxel chemotherapy in advanced non–small-cell lung cancer. J Clin Oncol 23:5892-5899, 2005
2. 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. J Clin Oncol 23:5900-5909, 2005
3. 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
4. Giaccone G, Herbst RS, Manegold C, et al: Gefitinib in combination with gemcitabine and cisplatin in advanced non-small-cell lung cancer: A phase III trial–INTACT 1. J Clin Oncol 22:777-784, 2004
5. Gatzemeier U, Pluzanska A, Szczesna A, et al: Results of a phase III trial of erlotinib (OSI-774) combined with cisplatin and gemcitabine (GC) chemotherapy in advanced non-small cell lung cancer (NSCLC). J Clin Oncol 22:617, 2004 (suppl, abstr 7010) 6. Rapp E, Pater JL, Willan A, et al: Chemotherapy can prolong survival in patients with advanced non-small cell lung cancer: Report of a Canadian multicenter randomized trial. J Clin Oncol 6:633-641, 1988[Abstract]
7. Cullen MH, Billingham LJ, Woodroffe CM, et al: Mitomycin, ifosfamide, and cisplatin in unresectable non–small-cell lung cancer: Effects on survival and quality of life. J Clin Oncol 17:3188-3194, 1999 8. Shepherd F, Pereira J, Ciuleanu TE, et al: A randomized placebo-controlled trial of erlotinib in patients with advanced non-small cell lung cancer following failure of 1st or 2nd line chemotherapy: A National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) trial. J Clin Oncol 22:18, 2004 (suppl, abstr 7022)
9. Slamon DJ, Leyland-Jones B, Shak S, et al: Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 344:783-792, 2001
10. Pao W, Miller V, Zakowski M, et al: EGF receptor gen mutations are common in lung cancer 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 11. Gandara DR, West H, Chansky K, et al: Bronchioloalveolar carcinoma: A model for investigating the biology of EGFR inhibition. Clin Cancer Res 10:4205s-4209s, 2004
12. Paez JG, Janne PA, Lee JC, et al: EGFR mutations in lung cancer: Correlation with clinical response to gefitinib therapy. Science 304:1497-1500, 2004
13. Lynch TJ, Bell DW, Sordella R, et al: Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small cell lung cancer to gefitinib. N Engl J Med 350:2129-2139, 2004
14. Tracy S, Mukohara T, Hansen M, et al: Gefitinib induces apoptosis in the EGFRL858R non-small-cell lung cancer cell line H3255. Cancer Res 64:7241-7244, 2004 15. Gumerlock PH, Pryde BJ, Kimura T, et al: Enhanced cytotoxicity of docetaxel OSI-774 combination in non-small cell lung carcinoma (NSCLC). Proc Am Soc Clin Oncol 22:662, 2003 (abstr 2661)
16. Solit DB, She Y, Moasser M, et al: Pulsatile administration of the epidermal growth factor receptor inhibitor gefitinib is significantly more effective than continuous dosing for sensitizing tumors to paclitaxel. Clin Cancer Res 11:1983-1989, 2005 17. Hirsch F, Gandara DR, McCoy J, et al: Increased egfr gene copy number detected by fish is associated with increased sensitivity to gefitinib in patients with bronchioloalveolar carcinoma (BAC) (S0126). Proc Am Soc Clin Oncol 23: 628s, 2005 (abstr 7030) 18. Davies AM, Lara PN, Lau D, et al: Intermittent erlotinib in combination with docetaxel (DOC): Phase I schedules designed to achieve pharmacodynamic separation. J Clin Oncol 24:630s, 2005 (suppl, abstr 7038)
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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