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Originally published as JCO Early Release 10.1200/JCO.2009.23.0029 on August 31 2009 © 2009 American Society of Clinical Oncology.
Reply to D. Tassinari et alNational Kyushu Cancer Center, Fukuoka, Japan
Kinki University School of Medicine, Osaka, Japan
Centre René Gauducheau, Nantes, France
AstraZeneca, Macclesfield, United Kingdom
The University of Texas M. D. Anderson Cancer Center, Houston, TX Tassinari et al1 raise some questions regarding the validity and translation of noninferiority study data into clinical practice. In particular, they consider the INTEREST study, which established the noninferiority of gefitinib compared with docetaxel in terms of overall survival,2 the regulatory gold standard and prespecified primary end point. Tassinari et al queried the assumption that 75 mg/m2 of docetaxel once every 3 weeks is the gold standard for second-line treatment in non–small-cell lung cancer (NSCLC). Although only 55 patients were treated with this dose in the TAX-317 study, median survival was significantly longer with docetaxel compared with best supportive care (BSC; 7.5 v 4.6 months; log-rank test, P = .010).3 Furthermore, data from subsequent studies, including INTEREST and the phase III JMEI study of pemetrexed versus docetaxel, have been consistent with TAX-317, with median survival of 7 to 8 months reported for docetaxel.2,4–6 Docetaxel is the most commonly prescribed drug in second-line NSCLC and is a recognized standard of care in this setting.7 Tassinari et al state that "the key question that remains without any answer is who gets benefit" from the INTEREST data. Previous studies and clinical practice have indicated that in some subgroups of patients, defined by either clinical or molecular parameters, gefitinib has a greater degree of antitumor activity than others, for example, female patients, those of Asian racial origin, those with adenocarcinoma histology, never/light smokers, and patients with tumors with high epidermal growth factor receptor gene copy number (by fluorescent in situ hybridization) or activating mutations of epidermal growth factor receptor. The differential antitumor activity of gefitinib in most of these subgroups was clearly evident in the INTEREST study. However, in both INTEREST and V-15-32,8 the same heterogeneity in antitumor activity was observed with docetaxel; that is, patients from these subgroups did better on both treatments. Tassinari et al grouped the results of four noninferiority studies and stated, "All but the V-15-32 study showed noninferiority of the novel drug (pemetrexed, oral topotecan, and gefitinib) versus docetaxel 75 mg/m2." However, the different methodology and patient populations used in these four studies makes cross-study comparisons difficult. We believe that the INTEREST results are not "controversial"; noninferiority was met according to an appropriate prespecified margin9,10 and required gefitinib 250 mg to retain at least 50% of the historical docetaxel 75 mg/m2 survival effect over BSC. This margin allows a clinically important loss of efficacy (5% in 1-year survival or 1 month in median survival) to be excluded. Although the noninferiority margin was established from the small TAX-317 study using estimated information, and the upper CI limit of the hazard ratio (HR) in the analysis of overall survival in INTEREST was fairly close to the noninferiority margin, the methodology allowed for the uncertainty in the historical data, the estimated HR, and standard error. In addition, the most conservative population, the per-protocol population, was used for the noninferiority analyses, as this tends to increase differences between treatments and is recommended in the International Conference on Harmonisation E9 guideline.11 Furthermore, the HR in INTEREST was 1.020, the Kaplan-Meier curves clearly overlap, and the upper CI limit of 1.154 was below that of 1.20 observed in the JMEI study of pemetrexed versus docetaxel,5 thus providing additional reassurance that there is no clinically important difference in survival between gefitinib and docetaxel. Furthermore, the INTEREST overall survival data in conjunction with the historical docetaxel data compared with BSC provide strong evidence (P = .0137) that gefitinib is an active agent in this setting. The JMEI study mentioned previously did not prove that survival of pemetrexed was statistically noninferior to docetaxel (HR, 0.99; 95% CI, 0.82 to 1.20; P = .226) according to the original specified noninferiority margin (on the basis of the upper bound of the CI for the HR being < 1.11), although noninferiority was achieved with a subsequently defined 50% effect retention margin (upper bound of 95% CI for HR < 1.21). INTEREST showed that in the unlikely worst-case scenario (on the basis of the upper CI limit), there is a smaller potential disadvantage for gefitinib compared with docetaxel (upper CI limit, 1.15) than observed in the JMEI study for pemetrexed compared with docetaxel (upper CI limit, 1.20). Pemetrexed was approved for use in this treatment setting in September 2004 on the basis of the JMEI study and although its label was subsequently narrowed (May 2008) to patients with nonsquamous histology on the basis of later subgroup findings, the choice of noninferiority margin and acceptability of the degree of potential loss in the overall population has not been refuted. Therefore, we believe the original noninferiority assessment of pemetrexed compared with docetaxel on the basis of the JMEI study is still highly relevant to the noninferiority assessment of gefitinib compared with docetaxel on the basis of the INTEREST study. In the V-15-32 study (n = 489), statistical noninferiority of gefitinib relative to docetaxel in terms of overall survival was not proven (HR, 1.12; 95.24% CI, 0.89 to 1.40; noninferiority margin, 1.25).8 However, imbalances in postdiscontinuation therapies complicated the interpretation of the overall survival result, with more docetaxel-treated patients receiving additional anticancer therapy. In contrast, in the much larger INTEREST study (n = 1,466), subsequent therapies after randomly assigned treatments were well balanced between the gefitinib and docetaxel groups. In V-15-32, importantly, secondary end points, largely unaffected by the effects of subsequent therapy, showed similar or superior efficacy for gefitinib compared with docetaxel. Differences in postdiscontinuation treatments in the V-15-32 study may have contributed to noninferiority in overall survival not being proven. We thank the correspondents for their deliberations; however, we would question their description of the results of the ISEL (Iressa Survival in Lung Cancer) phase III study and their discussion of the "paradox" of the INTEREST and ISEL studies. Although ISEL did not meet its primary objective (statistically significant survival advantage for gefitinib compared with placebo) in the total population (HR, 0.89; 95% CI, 0.77 to 1.02; P = .087) or in patients with adenocarcinoma (HR, 0.84; 95% CI, 0.68 to1.03; P = .089), positive results were achieved in preplanned subgroup analyses, with significantly longer survival with gefitinib than with placebo in never-smokers (HR, 0.67; 95% CI, 0.49 to 0.92; P = .012) and patients of Asian origin (HR, 0.66; 95% CI, 0.48 to 0.91; P = .01).12 ISEL recruited patients who were refractory to or intolerant of their latest chemotherapy regimen; therefore, a high proportion of patients (90%) were refractory to their most recent therapy, whereas in INTEREST, only 58% were refractory. Likewise, the other phase III studies discussed (JMEI and TAX-317), did not have this refractory inclusion criteria. We believe the different patient populations of these studies signify that data comparison is both difficult and perhaps inappropriate, with the refractory nature of the ISEL population being the most likely explanation for failure to reach statistical significance. The results of the INTEREST study should not be understated; to our knowledge, it is the first ever study to establish equivalent efficacy between an oral targeted therapy and intravenous chemotherapy in advanced NSCLC. In conclusion, we strongly support the robust statistical design of INTEREST and its result of noninferiority of gefitinib compared with docetaxel for overall survival. We thank the correspondents for their interest in our studies. 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: Mark Sellers, AstraZeneca (C); Alison Armour, AstraZeneca (C) Consultant or Advisory Role: Jean-Yves Douillard, AstraZeneca (C), sanofi-aventis (C) Stock Ownership: Mark Sellers, AstraZeneca; Alison Armour, AstraZeneca Honoraria: Yukito Ichinose, Chugai Pharmaceutical, Kyowa, AstraZeneca, sanofi-aventis; Masahiro Fukuoka, AstraZeneca, Chugai Pharmaceutical, Takeda Pharmaceutical, Astellas Pharma; Jean-Yves Douillard, AstraZeneca, sanofi-aventis Research Funding: None Expert Testimony: None Other Remuneration: None REFERENCES
1. Tassinari D, Lazzari-Agli L, Tomebesi P, et al: I am no one. No one is perfect...therefore I am perfect. J Clin Oncol 27:e128–e129, 2009. 2. Kim ES, Hirsh V, Mok T, et al: Gefitinib versus docetaxel in previously treated non–small-cell lung cancer (INTEREST): A randomised phase III trial. Lancet 372:1809–1818, 2008.[CrossRef][Medline] 3. Shepherd FA, Dancey J, Ramlau R, et al: Prospective randomized trial of docetaxel versus best supportive care in patients with non–small-cell lung cancer previously treated with platinum-based chemotherapy. J Clin Oncol 18:2095–2103, 2000. 4. Cufer T, Vrdoljak E, Gaafar R, et al: Phase II, open-label, randomized study (SIGN) of single-agent gefitinib (IRESSA) or docetaxel as second-line therapy in patients with advanced (stage IIIb or IV) non–small-cell lung cancer. Anticancer Drugs 17:401–409, 2006.[CrossRef][Medline] 5. Hanna N, Shepherd FA, Fossella FV, et al: Randomized phase III trial of pemetrexed versus docetaxel in patients with non–small-cell lung cancer previously treated with chemotherapy. J Clin Oncol 22:1589–1597, 2004. 6. Ramlau R, Gervais R, Krzakowski M, et al: Phase III study comparing oral topotecan to intravenous docetaxel in patients with pretreated advanced non–small-cell lung cancer. J Clin Oncol 24:2800–2807, 2006. 7. Pfister DG, Johnson DH, Azzoli CG, et al: American Society of Clinical Oncology treatment of unresectable non–small-cell lung cancer guideline: Update 2003. J Clin Oncol 22:330–353, 2004. 8. Maruyama R, Nishiwaki Y, Tamura T, et al: Phase III study, V-15-32, of gefitinib versus docetaxel in previously treated Japanese patients with non–small-cell lung cancer. J Clin Oncol 26:4244–4252, 2008. 9. Carroll KJ: Active-controlled, non-inferiority trials in oncology: Arbitrary limits, infeasible sample sizes, and uninformative data analysis—Is there another way? Pharm Stat 5:283–293, 2006.[CrossRef][Medline] 10. Rothmann M, Li N, Chen G, et al: Design and analysis of non-inferiority mortality trials in oncology. Stat Med 22:239–264, 2003.[CrossRef][Medline] 11. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. 2004 http://www.ich.org. 12. Thatcher N, Chang A, Parikh P, et al: Gefitinib plus best supportive care in previously treated patients with refractory advanced non–small-cell lung cancer: Results from a randomised, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer). Lancet 366:1527–1537, 2005.[CrossRef][Medline]
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Copyright © 2009 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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