Among the 198 new oncology drugs approved by the U.S. Food and Drug Administration (FDA) between 1998 and 2022, approximately 43% of them were precision therapies, according to a recent study published by Suehnholz et al in Cancer Discovery.
Background
Precision oncology therapies often require genomic biomarker screening for patient selection; whereas for molecularly targeted therapies, the mechanism of action is known, but these drugs do not require biomarker testing for patient selection.
“For this study, we mark the beginning of the field of precision oncology as 1998 with the approval of trastuzumab, one of the first molecularly targeted therapies indicated for HER2-positive breast cancer. Since then, the field has exponentially grown with the discovery of novel biomarkers and corresponding drug approvals—thanks in part to a progressive decrease in the cost of genomic sequencing and improvements in sequencing technology,” highlighted senior study author Debyani Chakravarty, PhD, an assistant attending molecular geneticist in the Department of Pathology and Laboratory Medicine and a lead scientist of the OncoKB at Memorial Sloan Kettering Cancer Center. “To our knowledge, there has not been a systematic assessment of how much this field has grown and the extent to which its expansion has benefitted patients with cancer,” she continued.
Study Methods and Results
In the new study, investigators reviewed and classified the oncology drugs approved by the FDA from 1998 to 2022 in order to quantify the expansion and impact of precision oncology.
“We defined a precision oncology therapy as a drug that is most effective in a molecularly defined subset of patients and for which pretreatment molecular profiling is required for optimal patient selection,” said lead study author Sarah P. Suehnholz, PhD, a senior scientist of the OncoKB at Memorial Sloan Kettering Cancer Center.
Among the 198 new oncology drugs approved by the FDA during the study period, 82.8% (n = 164) of them were classified as molecularly targeted therapies and 43.4% (n = 86) of them were classified as precision oncology drugs such as kinase inhibitors, monoclonal antibodies, small-molecule inhibitors, antibody-drug conjugates, and immune checkpoint inhibitors.
The analysis also showed a slow expansion in the rate of FDA approvals of precision oncology therapies from 1998 to 2017 and a rapid increase from 2017 to 2022.
“The highest number was registered in 2020, with 12 FDA approvals, and the number appears to drop in 2021 and 2022—suggesting that we may have reached the peak of single biomarker-based precision oncology therapies,” noted Dr. Chakravarty. “This finding also emphasizes the need for innovative combination approaches that can address multiple genomic alterations as well as targeted therapies effective in patients whose tumors are driven by alterations in common tumor suppressor genes or transcription factors,” she emphasized.
Further, the investigators classified precision oncology therapies into four categories based on the novelty of their mechanism of action to assess the innovation in the field. They found that 42% of the drugs worked through a similar mechanism of action as a previously approved therapy or targeted resistance to an existing drug.
“The majority of these therapies target only seven biomarkers, highlighting the narrow scope of precision oncology drug development during this period. Several targets have remained undruggable since 1998. We are now making inroads with some, for example, targeting specific KRAS [alterations], but we need to continue to expand the number of actionable genetic alterations,” stressed Dr. Chakravarty.
In the second portion of the study, the investigators used two versions of the precision oncology knowledge base OncoKB—deployed in 2017 and 2022—to assess the clinical actionability of the genetic alterations detected by the MSK-IMPACT sequencing assay in a set of 47,271 solid tumor samples.
The investigators examined whether a certain tumor mutation, which was considered predictive of response to an investigational drug approved in 2017, was then recognized as a biomarker predictive of response to a drug approved in 2022.
They determined that the fraction of patient samples carrying genomic alterations that made them eligible for treatment with standard-of-care precision oncology therapies or for enrollment in a clinical trial with promising clinical data nearly doubled from 18.1% in 2017 to 35.9% in 2022. They also noted an almost 50% decrease from 44.2% in 2017 to 22.8% in 2022 in the fraction of samples with oncogenic alterations currently deemed nonactionable.
Conclusions
“Despite the dramatic growth of the field, the clinical impact of precision oncology is still debated. By thoroughly and systematically mapping out the landscape of precision oncology, our study revealed that these therapies are a mainstay of current oncology care,” suggested Dr. Chakravarty. “Unfortunately, these drugs can be extremely expensive, and insurance coverage often dictates whether a patient will receive them. Our findings support that coverage of precision oncology therapies is essential and should not be available to only a select few,” she reiterated.
The investigators underlined the significance of universal genetic testing to aid in the development of treatments targeting rare genomic alterations regardless of the site of tumor origin.
According to the investigators, one limitation of their analysis was that they did not include information on whether patients actually received the precision therapy for which they were found to be eligible. As for further limitations, the investigators reported that they did not acquire information on germline mutations that determine eligibility for certain targeted therapies, and the patient population involved in their study had limited diversity. In addition, the analysis was based on FDA approvals, and different countries may have different regulatory status and approaches to precision oncology.
“Eligible patients may not receive a precision oncology drug for several reasons related to their disease or to our current health-care landscape. It is … important to note that not all patients treated with a genomic-matched therapy will benefit equally,” stated Dr. Chakravarty.
Disclosure: The research in this study was funded by the National Institutes of Health, OncoKB commercial licensing fees, the Prostate Cancer Foundation Challenge Award, and the Marie-Josée and Henry R. Kravis Center for Molecular Oncology. For full disclosures of the study authors, visit aacrjournals.org.
