Clinical Value of Molecular Targets and FDA-Approved Genome-Targeted Cancer Therapies

Abstract

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

Objective: 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 settings: 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 measures: 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.

Results: 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 relevance: 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.

Figure 1.. Flow Chart Showing Search Results

Figure 2.. ESCAT Class Distribution of Molecular Targets

This figure shows the European Society for Medical Oncology Scale for Clinical Actionability of Molecular Targets (ESCAT) class distribution of the molecular targets of genome-targeted drugs approved by the US Food and Drug Administration from 2015 to 2022. Class I-C evidence was connected to basket trials showing similar clinical benefits across tumor types, and class II-A represents drugs approved based on retrospective studies alone. The pivotal trial supporting an indication is the trial or cohort reported in section 14 of the labeling (A). Data points included pivotal trials, supplemental trials, and subgroup analyses (B).

Figure 3.. ESCAT Class Distribution of Molecular Targets by High Benefit vs Low Benefit

This figure shows the European Society for Medical Oncology Scale for Clinical Actionability of Molecular Targets (ESCAT) class distribution of the molecular targets of genome-targeted drugs approved by the US Food and Drug Administration from 2015 to 2022 stratified by high-benefit vs low-benefit classifications. The pivotal trial supporting an indication is the trial or cohort reported in section 14 of the labeling (A). Data points included pivotal trials, supplemental trials, and subgroup analyses (B).