On May 23, 2017, the US Food and Drug Administration (FDA) granted accelerated approval to pembrolizumab (Keytruda, Merck & Co) for patients with unresectable or metastatic, microsatellite instable-high (MSI-H) or mismatchrepair-deficient(dMMR)solidtumorsthathaveprogressedonpriortherapyandhavenosatisfactorytreatment options. This approval is, to date, the first drug authorized for use based on a molecular biomarker rather than a traditional histopathologic diagnosis. The approval bridges several themes in modern oncologic drug development: the rapidtranslationofhigh-qualitybasicscience,tailoringtherapybasedongeneticsubgroups,andaflexibilityonthepart oftheFDAtoauthorizedrugsbasedonearly,favorabledata.Expertshavehailedtheapprovalasrealizingthepromise of precision oncology, and some have wondered if traditional classification of cancers by site of origin will be supplanted. Adam Feuerstein, a senior biotechnology reporter, asked, "How soon before we no longer refer to breast,lung,coloncancer,butinsteadonlydescribegenetic makeup of cancer?" 1 Indeed, there are other drugs followinginpembrolizumab'sfootsteps.Larotrectinib(LOXO-101, Loxo Oncology)isakinaseinhibitorthathasdemonstrated very high response rates (a measure of tumor shrinkage) in patients with diverse cancers who share a fusion of the tropomyosin receptor kinase (TRK) gene. 2 Although there is much reason for enthusiasm, we believe that broad, tissue-agnostic cancer drug approvals raise 4 considerations for physicians, patients, and payers.First, genetic approvals come with sizable uncertainty as to whether the drug works equally well among all the tumor types that it will be applied to. The approval of pembrolizumab for solid cancers was based on 59 patients treated in a series of uncontrolled phase 2 trials, 3 demonstrating a 46% (27 of 59) objective response rate. Among these 59 patients, 14 cancers were represented. Only 2 had more than 10 patients represented in the sample (endometrial cancer, and biliary cancer), and 7 of 14 cancers had just 1 patient with that particular tumor, including breast and prostate cancer-common malignant abnormalities without prior immunotherapy approval. In the Figure, we contrast the broad scope of the MSI-H approval against the limited number of patients on which it is based. Prior to the approval, drugs like pembrolizumab were already available for the treatment of 34% of cancer patients in America. With the approval, this percentage has expanded, though only 12% of cancer patients were represented by more than 5 patients in the pivotal data; 21% were represented by just 1 to 5 patients, and 24% of patients were not represented at all. Thenumberofpatientsincludedwitheachtumortype isimportantowingtothepotentialinteractionbetweenthe biomarker and the tissue type. Consider the oncogenic

The ability to identify medical reversals and other low-value medical practices is an essential prerequisite for efforts to reduce spending on such practices. Through an analysis of more than 3000 randomized controlled trials (RCTs) published in three leading medical journals (the Journal of the American Medical Association, the Lancet, and the New England Journal of Medicine), we have identified 396 medical reversals. Most of the studies (92%) were conducted on populations in high-income counties, cardiovascular disease was the most common medical category (20%), and medication was the most common type of intervention (33%).

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ObjectiveTo determine the differences between recommendations by the National Comprehensive Cancer Network (NCNN) guidelines and Food and Drug Administration approvals of anticancer drugs, and the evidence cited by the NCCN to justify recommendations where differences exist.DesignRetrospective observational study.SettingNational Comprehensive Cancer Network and FDA.Participants47 new molecular entities approved by the FDA between 2011 and 2015.Main outcome measuresComparison of all FDA approved indications (new and supplemental) with all NCCN recommendations as of 25 March 2016. When the NCCN made recommendations beyond the FDA’s approvals, the recommendation was classified and the cited evidence noted.Results47 drugs initially approved by the FDA between 2011 and 2015 for adult hematologic or solid cancers were examined. These 47 drugs were authorized for 69 FDA approved indications, whereas the NCCN recommended these drugs for 113 indications, of which 69 (62%) overlapped with the 69 FDA approved indications and 44 (39%) were additional recommendations. The average number of recommendations beyond the FDA approved indications was 0.92. 23% (n=10) of the additional recommendations were based on evidence from randomized controlled trials, and 16% (n=7) were based on evidence from phase III studies. During 21 months of follow-up, the FDA granted approval to 14% (n=6) of the additional recommendations.ConclusionThe NCCN frequently recommends beyond the FDA approved indications even for newer, branded drugs. The strength of the evidence cited by the NCCN supporting such recommendations is weak. Our findings raise concern that the NCCN justifies the coverage of costly, toxic cancer drugs based on weak evidence.

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