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Published on: July 25, 2020
Clinical Value of Molecular Targets and FDA-Approved Genome-Targeted Cancer Therapies
Ariadna Tibau1,2, Thomas J Hwang1,3,4, Consolacion Molto5
1Program on Regulation, Therapeutics, and Law (PORTAL), Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
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.
Insights
Fewer than one-third of recently approved genome-targeted cancer drugs showed substantial patient benefits. Frameworks like ESMO-MCBS and ESCAT help identify high-benefit cancer treatments for better clinical decisions.
Area of Science:
- Oncology
- Genomics
- Clinical Pharmacology
Background:
- The increasing number of genome-targeted cancer drugs offers personalized therapy options.
- These targeted therapies are often associated with high costs, necessitating rigorous evaluation of their clinical utility.
Purpose of the Study:
- To evaluate the validity of molecular targets and therapeutic benefits of FDA-approved genome-targeted cancer drugs.
- To assess these benefits based on pivotal clinical trial outcomes.
Main Methods:
- A cohort study analyzed 50 genome-targeted drugs approved by the FDA between 2015 and 2022.
- The European Society for Medical Oncology (ESMO) Scale for Clinical Actionability of Molecular Targets (ESCAT) and ESMO-Magnitude of Clinical Benefit Scale (ESMO-MCBS) were used to assess targetability and clinical benefit.
Main Results:
- Of 84 indications analyzed, 29% demonstrated substantial clinical benefit.
- Many approvals (54%) were based on phase 1/2 trials, single-arm trials (54%), or subgroup analyses (57%).
- Only 29% of indications were rated as high-benefit genomic-based cancer treatments.
Conclusions:
- A significant proportion of recently approved molecular-targeted cancer therapies showed limited substantial patient benefits at the time of approval.
- Benefit assessment frameworks like ESMO-MCBS and ESCAT are crucial tools for physicians, patients, and payers.
- These frameworks aid in identifying cancer treatments with the highest clinical potential and value.
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