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QuestionÌý What is the validity of the molecular targets and clinical benefits of US Food and Drug Administration–approved genome-targeted cancer drugs based on the results of pivotal clinical trials?

FindingsÌý In this cohort study, 50 molecular-targeted drugs covering 84 indications were identified. Using an international grading system to evaluate molecular targetability strength (European Society for Medical Oncology Scale for Clinical Actionability of Molecular Targets) and a scale to assess clinical benefit in genome-targeted cancer therapies (European Society for Medical Oncology Magnitude of Clinical Benefit Scale), 24 indications (29%) supported high-benefit genomic-based cancer treatments.

MeaningÌý The therapeutic benefit grading frameworks used in this study can help stakeholders identify therapies with the greatest clinical potential.

ImportanceÌý The number of new genome-targeted cancer drugs has increased, offering the possibility of personalized therapy, often at a very high cost.

ObjectiveÌý To assess the validity of molecular targets and therapeutic benefits of US Food and Drug Administration–approved genome-targeted cancer drugs based on the outcomes of their corresponding pivotal clinical trials.

Design and SettingsÌý In this cohort study, all genome-targeted cancer drugs that were FDA-approved between January 1, 2015, and December 31, 2022, were analyzed. From FDA drug labels and trial reports, key characteristics of pivotal trials were extracted, including the outcomes assessed.

Main Outcomes and MeasuresÌý The strength of evidence supporting molecular targetability was assessed using the European Society for Medical Oncology (ESMO) Scale for Clinical Actionability of Molecular Targets (ESCAT). Clinical benefit for their approved indications was evaluated using the ESMO–Magnitude of Clinical Benefit Scale (ESMO-MCBS). Substantial clinical benefit was defined as a grade of A or B for curative intent and 4 or 5 for noncurative intent. Molecular targets qualifying for ESCAT category level I-A and I-B associated with substantial clinical benefit by ESMO-MCBS were rated as high-benefit genomic-based cancer treatments.

ResultsÌý A total of 50 molecular-targeted drugs covering 84 indications were analyzed. Forty-five indications (54%) were approved based on phase 1 or phase 2 pivotal trials, 45 (54%) were supported by single-arm pivotal trials, and 48 (57%) were approved on the basis of subgroup analyses. By each indication, 46 of 84 primary end points (55%) were overall response rate (median [IQR] overall response rate, 57% [40%-69%]; median [IQR] duration of response, 11.1 [9.2-19.8] months). Among the 84 pivotal trials supporting these 84 indications, 38 trials (45%) had I-A ESCAT targetability, and 32 (38%) had I-B targetability. Overall, 24 of 84 trials (29%) demonstrated substantial clinical benefit via ESMO-MCBS. Combining these ratings, 24 of 84 indications (29%) were associated with high-benefit genomic-based cancer treatments.

Conclusions and RelevanceÌý The results of this cohort study demonstrate that among recently approved molecular-targeted cancer therapies, fewer than one-third demonstrated substantial patient benefits at approval. Benefit frameworks such as ESMO-MCBS and ESCAT can help physicians, patients, and payers identify therapies with the greatest clinical potential.