Precision Medicine 2030

REALIZING THE PROMISE OF PRECISION MEDICINE Precision medicine, in the context of pharmacotherapy, typically relates to the use of predictive tools, such as biomarkers to select treatments, tailor dosing, or monitor response. The mainstays of precision medicine, which are now second nature, include therapeutic drug monitoring and managing drug therapy in the setting of organ dysfunction, interacting drugs, or other factors that influence concentrations and/or response. Technologies like genomic testing have given clinicians access to new tools, but these tools essentially serve the same function as traditional measures—to shift the probability of a certain outcome for a subgroup of patients through altered dosing or treatment. However, much hope and hype has surrounded the promise of modern precision medicine approaches, resulting in high expectations for predictive value and clinical utility. Despite healthy skepticism, the pace of translating new technologies to the clinic over the past decade has been impressive, most notably with respect to the broader use of next-generation sequencing technologies, availability of more US Food and Drug Administration (FDA)–authorized tests for novel biomarkers, and new treatments for monogenic diseases and various cancer subtypes. Efforts to bring precision medicine principles to the clinic in the past 10 years faced challenges but ultimately established some boundaries for translation. Testing for pharmacogene variants, like CYP450 enzymes, might have been among the most immediate uses of modern genomic technologies in the clinic. However, evidence for pharmacogenetic interactions was often derived from observational studies or clinical pharmacokinetic data, which resulted in calls to demonstrate a test’s impact on outcomes in controlled trials. This high standard was successfully accomplished for abacavir and HLA-B*5701 testing; such evidence indeed hastened the uptake of testing, and lack of such evidence hindered adoption of testing for other well-characterized gene–drug interactions (e.g., CYP2C19 for clopidogrel). In contrast, prospective testing for ostensibly predictive biomarkers became routine in drug development, often because of a mechanistic link between the drug’s pharmacology and the disease’s molecular pathology. Building upon hormone receptor testing for breast cancer treatments, trastuzumab for HER2positive breast cancer persisted as the archetype for contemporary targeted drug development long after its approval in 1998. It took several years for imatinib to increase the numerator of biomarker-based approvals. The paradigm seemed to shift a couple years later in 2008 with post hoc clinical trial findings that panitumumab and cetuximab were less effective for KRAS mutation-positive colorectal cancers. These findings prompted rapid adoption of KRAS testing in practice, but also drove extensive debate around the challenges of relying retrospective studies for regulatory decisions. All of these early cases served to clarify the basic evidentiary considerations for biomarker-based prescribing. Over the ensuing years, the drugdiagnostic codevelopment pathway became well established and paved the way for continued innovation in clinical drug development. In the early 2010s, new treatments for certain patients with lung cancer (ALK-positive and EGFR mutation-positive tumors), melanoma (BRAF mutation-positive tumors), and breast and ovarian cancer (BRCA mutation-positive tumors) showed significant tumor responses or delayed disease progression in clinical trials and were approved along with companion in vitro diagnostic tests. More recently (over the past 3 years), approximately half of novel cancer drugs were initially approved for a subset of patients with a given tumor type. Cancer is now routinely thought of in a molecular context, and biomarker-centric (i.e., tissue agnostic) rather than histology-centric drug development approaches have been successfully pursued (e.g., pembrolizumab and larotrectinib). As biomarker testing has evolved, so too have the clinical trials and complex and innovative trial designs arose out of a need for