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Setting the Bar for Therapeutic Trials in Non–Small-Cell Lung Cancer: How Low Can We Go? David H. Johnson, University of Texas Southwestern School of Medicine, Dallas, TX See accompanying article on page 1407

Despite the progress achieved in the early diagnosis and treatment of lung cancer over the last 40 years, more than 220,000 US citizens will receive a lung cancer diagnosis in 2014, the vast majority of whom will die as a result of their disease within a few months.1 Fortunately, the pace of discovery has quickened and produced greater insight into lung cancer biology, which in turn has yielded new potential therapeutic targets.2,3 In fact, today there are more than 120 drugs in development for lung cancer,4 in contrast with just 25 years ago, when thoracic oncologists were limited to fewer than a dozen chemotherapy agents to treat advanced disease.5 However, getting these newer drugs to the clinic as quickly as possible is a daunting task that has elicited much debate pertaining to the design and interpretation of phase III clinical trials.6-9 To investigate how the design and interpretation of clinical trials conducted in advanced non–small-cell lung cancer (NSCLC) may have changed over time, Sacher et al10 undertook a review of all phase III therapeutic studies performed between 1980 and 2010. In the article that accompanies this editorial, each of the 203 unique clinical trials evaluated by Sacher et al was assessed for its design, primary outcome, reported statistical difference, and the magnitude of survival benefit. For the purposes of their analysis, a trial was deemed to be “positive” if the authors of the original report “recommended the new treatment arm be adopted” on any basis or if “further study” of the experimental arm was recommended. In addition, if the authors of the original report “explicitly stated that the study agent was either equal in efficacy or noninferior to the control arm,” Sacher et al classified the study as “asserting noninferiority.”10 Several noteworthy trends were identified in this three-decade retrospective analysis. First, the number of advanced NSCLC phase III trials increased from 32 in the 1980s to more than 100 studies executed between 2001 and 2010. Second, sample size increased over time from a median enrollment of approximately 150 to more than 400 participants per study. Third, there was a change in the make-up of therapeutic strategies under investigation, from primarily multiagent triplet chemotherapy regimens in the 1980s to mainly doublet chemotherapy regimens in the 1990s, and most recently, to an increase in the number of trials (approximately one in five studies) involving targeted therapies in the 2000s. Fourth, coincident with the change in therapeutic strategies, there was a shift in primary trial end point from an exclusive use of overall survival (OS) in the 1980s and 1990s to more frequent use of progression-free-survival (PFS) after 2000. Fifth, a statistically significant trend toward more positive interpretations of Journal of Clinical Oncology, Vol 32, No 14 (May 10), 2014: pp 1389-1391

trial results was noted after 2000, compared with the decades 1980 through 2000, although the fraction of studies meeting their preplanned primary statistical end point remained essentially unchanged. Finally, over time, the magnitude of survival benefit deemed “clinically relevant” progressively diminished, from a median of 3.9 months in the 1980s to just 0.9 months after 2000 (P ⬍ .001).10 Interestingly, only before 1990 were studies deemed to be “negative” on the basis of an insignificant magnitude of survival benefit, despite statistical significance. Sacher et al10 suggest their data “raise questions regarding the design and interpretation of phase III trials in NSCLC.” In reflecting on these trends, it seems doubtful that many oncologists or victims of lung cancer would lament the increase in the overall number of NSCLC phase III trials, given the magnitude of this public health problem. Relatedly, the increase in sample size can be viewed as a welcome development that represents a positive response to previous criticisms regarding lack of adequate power required to detect clinically meaningful survival differences in the National Cancer Institute–sponsored trials that were conducted between 1973 and 1994.11 Likewise, the shift away from exclusive chemotherapy-based therapeutic questions toward more trials of targeted therapies undoubtedly reflects advances in our knowledge of tumor biology and the investigation of new, less toxic cytotoxic and targeted therapies (eg, pemetrexed, erlotinib, and crizotinib).2 None of these developments seems particularly problematic. By contrast, the shift toward PFS as a preferred primary end point in NSCLC clinical trials is more controversial.6,7,12-16 The motivation to use PFS as a preferred end point, as opposed to OS, stems in part from an understandable desire to reduce the duration and cost of cancer clinical trials.6,7 However, unlike colon cancer, for instance,17 a surprisingly small amount of data supports the role of PFS as a surrogate for OS in advanced lung cancer trials.13-17 Recently, Laporte et al18 attempted to settle this deficit by way of a meta-analysis using individual patient data derived from five randomized trials that compared front-line docetaxel-based chemotherapy with vinorelbine-based chemotherapy. Unfortunately, the results of this analysis offered at best only modest support for using PFS in lieu of OS, at least in the conventional chemotherapy setting, leading some thoracic oncology experts to urge continued use of OS as the preferred primary end point in future lung cancer trials.13 However, in circumstances in which active drugs are available for recurrent or progressive disease, as is now the case with NSCLC,19,20 PFS is viewed by some experts as an appropriate primary © 2014 by American Society of Clinical Oncology

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study end point because it is thought to be less influenced by subsequent therapy than OS.12,15,21 Interestingly, the increase in the use of PFS as a primary end point in NSCLC trials identified by Sacher et al10 occurred around the same time that docetaxel received initial US Food and Drug Administration approval on the basis of a positive survival benefit in the setting of recurrent disease.22 Additionally, in the early 2000s, the US Food and Drug Administration approved PFS as a surrogate end point for advanced lung cancer studies, despite acknowledged limitations.21,23 Thus, the increased use of PFS in recent NSCLC studies is likely a result of the availability of multiple active second- and third-line agents, combined with the US Food and Drug Administration’s official imprimatur. Parenthetically, in its formal guidance to industry, the agency recommended that if PFS is used, the observed magnitude of effect should be “substantial and robust,” but did not define “substantial and robust.”21 To this end, some experts have suggested that only treatments with a PFS risk reduction of at least 50% would be expected to meaningfully affect OS.18 A more worrisome trend is the recent increase in the number of trials deemed to be positive despite their failure to meet a preplanned primary statistical end point. This tendency was most evident post 2000, after which a substantial percentage of trials were said to be positive on the basis of a nonsignificant trend in the primary end point, an improvement in a secondary trial end point (eg, toxicity), or a claim of noninferiority in trials that were not designed to assess noninferiority.10 Although many factors could account for this trend, undoubtedly a desire to salvage something positive out of an otherwise negative study played a major role. In any case, this trend is hardly unique to lung cancer trials, and potential solutions have been proffered. For example, Ocana and Tannock24 recently recommended restricting the term positive to describe only those trials in which there is a statistically significant survival difference that equals or exceeds a clinically important value that is prespecified in the protocol. This proposal is not without critics, and the approach has not been universally embraced.25-27 Moreover, what constitutes a clinically important survival benefit depends on whom one asks and is customarily determined by the individuals who specialize in the disease and design the clinical trial. Before 1990, in an era dominated by chemotherapy questions, a 2-month improvement in median survival was considered clinically meaningful.9 Going forward, this estimate may no longer be adequate or appropriate, given what we now know about lung cancer biology and heterogeneity.2 Also disquieting is the tendency of investigators to impute clinically meaningful value to progressively lower survival benefits. Unabated, such a trend could lead to an ever increasing number of trials achieving so-called statistically significant results that turn out to be clinically irrelevant and costly.28 To counter this trend, Sobrero and Bruzzi have argued for a need to “raise the bar of efficacy for drug approval” 29(p5868) by restricting regulatory approval to treatments they deem “paradigm changing.” 29(p5870) In the case of a difficult to treat cancer like NSCLC, a paradigm-changing treatment would be expected to double PFS and result in at least a 50% increment in median or 2-year survival rates, at a minimum,29 a stance supported by Sacher et al.10 However, this position has been challenged as impractical and even risky because it could result in missed opportunities afforded by larger sample sizes (eg, failure to recognize subsets of responsive patients not anticipated pretreatment).30 Critics also suggest that such an approach might adversely affect future 1390

© 2014 by American Society of Clinical Oncology

investments from venture capitalists and pharmaceutical companies in oncology research.30 In summary, the work of Sacher et al10 nicely outlines the evolution of NSCLC phase III trial design and interpretation over the last three decades and also highlights some of the ongoing challenges that confront clinical trialists. The authors’ desire to establish and endorse “clear standards of acceptable minimal clinical differences in advanced NSCLC and appropriate clinically relevant outcomes” is laudable. However, the recommendation seems rooted in traditional frequentist statistical methodology that may not be ideally suited to the current era of clinical investigation.25-27 As others have noted, moving away from the traditional clinical development approach that is based on sequential, distinct phases toward a more integrated view that uses adaptive design tools to increase flexibility and maximize the use of accumulated knowledge could play an important role in improving the speed and cost-effectiveness of drug development.26,27 To this end, both the US Food and Drug Administration and the European Medicines Agency have encouraged the adoption of novel clinical trial designs, including statistical methods such as adaptive design, although, to date, uptake of newer trial designs has been remarkably slow.27,31 Given the size, expense, and low success rates achieved with traditional phase III trial design, this needs to change. AUTHOR’S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The author(s) indicated no potential conflicts of interest. REFERENCES 1. Siegel R, Ma J, Zou Z, et al: Cancer statistics, 2014. CA Cancer J Clin 64:9-29, 2014 2. Johnson DH, Schiller JH, Bunn PA Jr: Recent clinical advances in lung cancer management. J Clin Oncol [epub ahead of print on February 24, 2014] 3. Patel JD, Krilov L, Adams S, et al: Clinical cancer advances 2013: Annual report on progress against cancer from the American Society of Clinical Oncology. J Clin Oncol 32:129-160, 2014 4. Grogan K: Nearly 1,000 cancer drugs in development in USA. PharmaTimes Online, 2012. http://www.pharmatimes.com/article/12-06-01/Nearly_1_ 000_cancer_drugs_in_development_in_USA.aspx 5. Johnson DH: Evolution of cisplatin-based chemotherapy in non-small cell lung cancer: A historical perspective and the Eastern Cooperative Oncology Group experience. Chest 117:133S-137S, 2000 (4 suppl 1) 6. Booth CM, Eisenhauer EA: Progression-free survival: Meaningful or simply measurable? J Clin Oncol 30:1030-1033, 2012 7. Korn EL, Freidlin B, Abrams JS: Overall survival as the outcome for randomized clinical trials with effective subsequent therapies. J Clin Oncol 29:2439-2442, 2011 8. Rothenberg ML, Carbone DP, Johnson DH: Improving the evaluation of new cancer treatments: Challenges and opportunities. Nat Rev Cancer 3:303309, 2003 9. Horwitz RI, Abell JE, Christian JB, et al: Right answers, wrong questions in clinical research. Sci Transl Med 6:221fs5, 2014 10. Sacher AG, Le LW, Leighl NB: Shifting patterns in the interpretation of phase III clinical trial outcomes in advanced non–small-cell lung cancer: The bar is dropping. J Clin Oncol 32:1407-1411, 2014 11. Breathnach OS, Freidlin B, Conley B, et al: Twenty-two years of phase III trials for patients with advanced non–small-cell lung cancer: Sobering results. J Clin Oncol 19:1734-1742, 2001 12. Buyse M, Sargent DJ, Saad ED: Survival is not a good outcome for randomized trials with effective subsequent therapies. J Clin Oncol 29:47194720, 2011; author reply 4720-4721 13. Cheema PK, Burkes RL: Overall survival should be the primary endpoint in clinical trials for advanced non-small-cell lung cancer. Curr Oncol 20:e150-e160, 2013 14. Hotta K, Fujiwara Y, Matsuo K, et al: Time to progression as a surrogate marker for overall survival in patients with advanced non-small cell lung cancer. J Thorac Oncol 4:311-317, 2009 15. Soria JC, Massard C, Le Chevalier T: Should progression-free survival be the primary measure of efficacy for advanced NSCLC therapy? Ann Oncol 21:2324-2332, 2010 JOURNAL OF CLINICAL ONCOLOGY

Information downloaded from jco.ascopubs.org and provided by at Univ of Calgary on October 4, 2014 from Copyright © 2014 American Society of Clinical Oncology. All rights reserved. 136.159.235.223

Editorial

16. Pilz LR, Manegold C, Schmid-Bindert G: Statistical considerations and endpoints for clinical lung cancer studies: Can progression free survival (PFS) substitute overall survival (OS) as a valid endpoint in clinical trials for advanced non-small-cell lung cancer? Transl Lung Cancer Res 1:26-35, 2012 17. Johnson KR, Ringland C, Stokes BJ, et al: Response rate or time to progression as predictors of survival in trials of metastatic colorectal cancer or non-small-cell lung cancer: A meta-analysis. Lancet Oncol 7:741-746, 2006 18. Laporte S, Squifflet P, Baroux N, et al: Prediction of survival benefits from progression-free survival benefits in advanced non-small-cell lung cancer: Evidence from a meta-analysis of 2334 patients from 5 randomised trials. BMJ Open 3, 2013 19. Gridelli C, Ardizzoni A, Ciardiello F, et al: Second-line treatment of advanced non-small cell lung cancer. J Thorac Oncol 3:430-440, 2008 20. Langer CJ, Mok T, Postmus PE: Targeted agents in the third-/fourth-line treatment of patients with advanced (stage III/IV) non-small cell lung cancer (NSCLC). Cancer Treat Rev 39:252-260, 2013 21. US Department of Health and Human Services, US, Food and Drug Administration, Center for Drug Evaluation and Research, et al: Guidance for industry: Clinical trial endpoints for the approval of non-small cell lung cancer drugs and biologics. Silver Spring, MD, US Food and Drug Administration, 2011 22. 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 18:20952103, 2000 23. Pazdur R: Endpoints for assessing drug activity in clinical trials. Oncologist 13:19-21, 2008 (suppl 2) 24. Ocana A, Tannock IF: When are “positive” clinical trials in oncology truly positive? J Natl Cancer Inst 103:16-20, 2011 25. Lee JJ: Demystify statistical significance: Time to move on from the P value to Bayesian analysis. J Natl Cancer Inst 103:2-3, 2011 26. Berry DA: Bayesian clinical trials. Nat Rev Drug Discov 5:27-36, 2006 27. Berry DA: Adaptive clinical trials in oncology. Nat Rev Clin Oncol 9:199-207, 2012 28. Fojo T, Grady C: How much is life worth: Cetuximab, non-small cell lung cancer, and the $440 billion question. J Natl Cancer Inst 101:1044-1048, 2009 29. Sobrero A, Bruzzi P: Incremental advance or seismic shift? The need to raise the bar of efficacy for drug approval. J Clin Oncol 27:5868-5873, 2009 30. Berger ML, Eck S, Ruberg SJ: Raising the bar of efficacy for drug approval requires an understanding of patient diversity. J Clin Oncol 28:e343-e344, 2010; author reply e5 31. DeMets DL, Califf RM: A historical perspective on clinical trials innovation and leadership: Where have the academics gone? JAMA 305:713-714, 2011

DOI: 10.1200/JCO.2014.55.1929; published online ahead of print at www.jco.org on March 31, 2014

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Setting the bar for therapeutic trials in non-small-cell lung cancer: how low can we go?

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