PERSPECTIVES Box1 Potential mechanisms of resistance to targeted therapies fit from or be re tan ment.Perhaps ba Mutation at drug binding site Downstream pathway mutation and/or activation .Feedbackupregulation of target Parallel pathway activatio r vity of cet indngsg ents with KRA Oncology to issue apro clinica effectiveness of both the test and the drug. The use of biomarkers to identify patients EGFR-directed in who are most likely to PetkconmemcdyhcBokg well.The NCIC Clinical strategy for Group BR cepted by】 rope atech,OSI Pharn euticals)in the APP 0 anced NSCLC The trial uggests thi The obective of this approach is to facilitate he acc nt com cebo,le e rker ep other c cted as pa n patients ncedcolorectal cer treatm ent the as mus by patients in thetrial ermined that ate suppo est.a p subgroup analy CA$120.0 mor ts w t is prop or phosphatas an tensin homolog(PTEN)mutations ar aswell as approve the test for id ntifying ver,the Box2 Challenges of the targeted therapy era of the assay is that the More druas More disease of More use of placebo controls test and the drug in the biomarker. egativ More use of randomized screening trial pop The okings Institution pane time to reach end point bursement byinsurersfor off-abel us of atory complexit NATURE REVIEWSIDRUG DISCOVERY VOLUME 9 MAY 2010 365 2010 Marmillan Publishers Limited All rightsand drugs occur in different divisions of the agency (that is, the Center for Devices and Radiological Health, and the Center for Drug Evaluation and Research, respec￾tively) that apply separate review processes and have different approval standards. Investigators and sponsors may find it challenging to design clinical trials that are acceptable to both divisions and to provide conclusive evidence of the safety and effectiveness of both the test and the drug. Recently, a group of clinical investigators, scientists, drug developers and regulatory experts, convened by the Brookings Institution, proposed a novel strategy for drug and biomarker co-development designated “Targeted Approval” (Accelerating Development and Approval of Targeted Cancer Therapies; see Further Information). The objective of this approach is to facilitate the accelerated development and approval of a cancer therapy that is used in a population defined by a specific biomarker test. The proposed criteria for targeted approval are that the drug must be indicated for use in cancer treatment; the assay must be analytically validated; and the drug must demonstrate, in a population defined by the test, a prespecified statistically significant change in a clinical end point that is reason￾ably likely to predict clinical benefit. Under such circumstances, it is proposed that the FDA would approve the drug for use in the population identified by the biomarker test, as well as approve the test for identifying the patient population for treatment with the drug. However, the caveat of approval of the assay is that the test has not been proved useful to identify patients with expected lack of benefit from the drug. Post-marketing studies would be necessary and required to establish the utility of the test and the drug in the biomarker-negative population. The Brookings Institution panel proposed that, in these circumstances, reim￾bursement by insurers for off-label use of the drug would not occur until completion of the post-marketing studies. At present, it is not clear whether or not this proposal will be accepted by the FDA, or any other regulatory authority. What is clear is that revisions to regulatory policies and procedures are essential to enable a more rapid development of targeted anticancer therapies and the biomarker assays that are essential for their optimal use. personalized care to reduce cost The use of biomarkers to identify patients who are most likely to respond or be resistant to treatment has significant cost implications as well. The NCIC Clinical Trials Group BR.21 trial demonstrated the clinical utility of erlotinib (Tarceva; Genentech, OSI Pharmaceuticals) in the treatment of advanced NSCLC27,28. The trial, which found an improvement in median overall survival of 2 months for erlotinib treatment compared with placebo, led to the marketing approval of the drug in the United States and other countries. An eco￾nomic analysis conducted as part of the clinical trial assessed resource utilization by patients in the trial and determined that the incremental cost-effectiveness ratio for erlotinib treatment was CA$94,638 per life-year gained. However, subgroup analy￾ses revealed that the drug is much more cost-effective if used in non-smokers or in patients whose tumours have a high EGFR copy number28. The clinical development and use of cetuximab further illustrates the complexity and value of biomarker-based drug develop￾ment. Perhaps based on the experience with trastuzumab, initial clinical trials with cetuximab were limited to patients with EGFR-overexpressing colorectal tumours. Indeed, the FDA-approved label for cetuxi￾mab limits its use to this patient population. Post-marketing studies demonstrated simi￾lar activity of cetuximab in patients with low or non-expressing tumours, suggesting that the level of EGFR expression was irrelevant to the clinical effectiveness of the drug. Recently, a series of studies have clearly demonstrated that colorectal tumours that harbour KRAS mutations fail to respond to cetuximab and related treatments, and that patients with KRAS-mutated tumours do not benefit from such treatment29–32. These findings led the American Society of Clinical Oncology to issue a provisional clinical opinion recommending against the use of EGFR-directed monoclonal antibodies in patients whose colorectal tumours harbour KRAS mutations33 — a recommendation recently accepted by regulatory authorities in the United States and in Europe. The revised drug labelling translates into a more limited commercial market for these drugs, and a recent estimate suggests that the US health-care system could save as much as US$700 million annually in drug costs by limiting the use of these drugs to patients with KRAS wild-type tumours34. A formal economic analysis of cetuximab treatment in patients with advanced colorectal cancer demonstrated an incremental cost-effective￾ness ratio of cetuximab treatment compared with best supportive care of CA$199,742 per life-year gained35. This could be reduced to CA$120,061 by limiting use of the drug to patients with KRAS wild-type tumours. Recent data suggest that colorectal tumours with BRAF or phosphatase and tensin homolog (PTEN) mutations are Box 1 | potential mechanisms of resistance to targeted therapies The mechanismslisted below contribute to the challengesin identifying clinically useful biomarkersthat can be used to select patients who are mostlikely to benefitfrom or be resistant to treatment: • Mutation at drug binding site • Downstream pathway mutation and/or activation • Feedback upregulation oftarget • Parallel pathway activation • Pharmacologicalresistance Box 2 | Challenges of the targeted therapy era As more epigenetic targets are identified, and with more than 800 anticancer therapeutics in clinical development, the obstaclesto targeted therapy include the following: • More drugs • More diseases • More use of placebo controls • More use ofrandomized screening trials • Longertime to reach end points • More expensive documentation • Multiple effective lines oftherapy • Greaterregulatory complexity Pers P ectives NATURE REvIEWS | Drug Discovery vOLUME 9 | MAY 2010 | 365 © 2010 Macmillan Publishers Limited. 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