Study: Few FDA-approved targeted cancer drugs meet ESMO benefit benchmarks

Fewer than one-third of molecularly targeted cancer drugs recently approved by the US Food and Drug Administration (FDA) meet established European benchmarks for clinical benefits, according to a study published April 4 in JAMA Oncology.

For the study, researchers examined drugs approved by the FDA between 1 January 2015 and 31 December 2022, and found 50 molecularly-targeted drugs for solid tumors with a combined 84 new and supplemental labeled targeted indications.

One key finding in the study was that of the total indications, only 24 (29%) were deemed to reflect substantial clinical benefit, based on pivotal trial data and their rating on the European Society of Medical Oncology (ESMO) Magnitude of Clinical Benefit Score (ESMO-MCBS).

In recent years, genomic testing sharply increased, and the number of molecularly targeted approvals accounted for 40% of all solid cancer indications during the study period – but the strength and quality of supporting evidence has been variable, wrote study researchers, who are affiliated with the Program on Regulation, Therapeutics and Law (PORTAL) at Brigham and Women’s Hospital and Harvard Medical School.

Supporting drug trials for targeted oncology drugs often use surrogate endpoints, including disease-free survival (DFS) and progression-free survival (PFS), and several FDA approvals were granted based on expansion cohorts of phase I studies or basket trials, noted Ariadna Tibau, MD, PhD, a medical oncologist at the Hospital Sant Pau in Barcelona, and colleagues.

“This new paradigm for agents that have shown promising efficacy in early clinical development, raises questions about the clinical benefits of the drugs,” the authors wrote.

Scoring clinical benefits

Developed in 2015 and adapted since then, the ESMO-MCBS is intended for use in improving the critical appraisal of drugs and as a tool for value-based planning and resource allocation.

“Next-generation sequencing technology defining the sequence variation status of hundreds of genes in a single test has rapidly expanded as an important component of cancer care,” Tibau and colleagues wrote. “However, the safety and effectiveness of several US Food and Drug Administration (FDA)-approved molecular- targeted drugs have not necessarily matched their biochemical target profiles.”

Among other factors, a clinical benefit score reflects survival and response rates, toxicities, and quality of life. Substantial benefit is signified by an A or B grade for curative therapies or a 4-5 score for non-curative therapies.

“While a high ESMO-MCBS score does not automatically imply high value (that depends on the price), the scale can be used to frame such considerations and can help public policymakers advance ‘accountability for reasonableness’ in resource allocation deliberations,” according to ESMO.

The ESMO Scale for Clinical Actionability of Molecular Targets (ESCAT), which was released in 2018, is a classification system measuring the validity of genomic markers for use in guiding targeted oncology therapies. A class 1-A designation means the target is supported by evidence of a survival benefit in a prospective randomized trial, while class 1-B reflects PFS and other surrogate endpoints in a prospective randomized trial, and class 1-C is given when evidence comes from tissue-agnostic basket trials.

Missing the ESMO mark

For the new JAMA Oncology study, Tibau and colleagues searched FDA@drugs database for approvals and analyzed drug labels and clinical trial reports for clinical evidence. The authors acknowledged as a limitation that they only included post-approval clinical studies for accelerated approvals that were converted to regular approvals during the study period.

Researchers identified 22 genes and 48 genomic alterations used in guiding 84 indications in 84 pivotal trials. Highlights of their findings on the 84 indications include the following:

Forty-five (54%) were approved based on phase 1 or phase 2 pivotal trials.
Forty-five (54%) were supported by single-arm pivotal trials.
Forty-eight (57%) were approved based on subgroup analyses.
Forty-six of 84 primary endpoints (55%) were overall response rate.
Only seven indications (8%) were supported by trials demonstrating an improvement in overall survival.
Of fully approved indications, 16% were given based on single-arm trials, many with small sample sizes or stemming from exploratory analyses.
More than half of single-arm trials present moderate and promising yet unconfirmed clinical benefits before approval.

On ESCAT targetability, researchers reported that 38 trials (45%) were I-A and 32 (38%) were I-B. When ESCAT targetability and ESMO-MCBS, were combined, 24 of 84 indications (29%) were associated with high-benefit genomic-based cancer treatments.

Tibau and colleagues wrote that the ESMO-MCBS and ESCAT frameworks help identify molecular therapies and targets with high value and prioritize access.

“However, we found that drug indications supported by these characteristics represent a minority of cancer drug approvals in recent years.”

Furthermore, they asked, given the uncertainties, should prices be lower?

“These data reinforce the need for continued engagement of all stakeholders in generating adequate data to enable high-value cancer care for patients,” the authors concluded.

Study

Study: Few FDA-approved targeted cancer drugs meet ESMO benefit benchmarks

Related topics

Recommended content

Welcome to the new RAPS Digital Experience