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Quality of biomarker defined subgroups in FDA approvals of PD-1/PD-L1 inhibitors 2014 to 2020
Myung S Kim1, Alexander Xu2, Alyson Haslam3
1Division of Hematology and Medical Oncology, Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon, USA.
Abstract:
PD-L1 expression is associated with differential response in cancers treated with checkpoint inhibitors. Clinical trials for Food and Drug Administration (FDA) approvals of programmed death receptor-1 (PD-1)/programmed death ligand-1 (PD-L1) inhibitors include limited subgroup analyses based on PD-L1 expression. We aimed to define the characteristics of PD-L1 defined subgroups of clinical trials leading to FDA approvals for new indications of PD-1/PD-L1 inhibitors. FDA approvals for PD-1/PD-L1 inhibitors from January 2014 to December 2020 were identified and the clinical trials leading to each drug approval were reviewed. We collected key variables from publicly available information on FDA website and peer-reviewed publications of clinical trials. We assessed regulatory characteristics (approval date, approved drug[s], cancer type, line of therapy and biomarker-restricted approval criteria) of each approval. Clinical trials leading to approvals were reviewed for trial design (RCT vs single arm study, primary endpoint) and PD-L1 defined subgroup design (no subgroup analysis, single threshold 2-group analysis, nested subgroups and adjacent subgroups). We then compared regulatory and trials characteristics (trial design, primary endpoint and biomarker approval criteria) between studies with nested and adjacent subgroups. There were 60 approvals for PD-1/PD-L1 inhibitors between January 2014 and December 2020. Twelve of 60 (20%) did not include any PD-L1 subgroups. Twenty-five of 60 (42%) approvals reported only two subgroups, 14 (23%) included adjacent subgroups and 9 (15%) had nested subgroups. Twenty-five of 60 trials (42%) are single arm studies. Comparison of characteristics between trials with nested subgroup design and adjacent subgroup design did not show differences. We conclude that approvals for new indications of PD-1/PD-L1 inhibitors are based on studies that do not include comprehensive reporting of outcomes by PD-L1 biomarker subgroups.
Insights
Most cancer drug approvals using PD-1/PD-L1 inhibitors lack detailed subgroup analyses for programmed death ligand-1 (PD-L1) expression. This limits understanding of differential treatment responses in specific patient groups.
Area of Science:
- Oncology
- Immunotherapy
- Clinical Trial Analysis
Background:
- Programmed death-ligand 1 (PD-L1) expression influences patient response to PD-1/PD-L1 inhibitors in cancer.
- Regulatory approvals for these immunotherapies often involve limited subgroup analyses based on PD-L1 expression.
Purpose of the Study:
- To characterize PD-L1 defined subgroups within clinical trials leading to FDA approvals for new indications of PD-1/PD-L1 inhibitors.
- To assess how PD-L1 subgroup analyses have evolved in trials supporting regulatory approvals.
Main Methods:
- Reviewed FDA approvals for PD-1/PD-L1 inhibitors (January 2014-December 2020).
- Collected data on regulatory and trial characteristics, including subgroup analysis design (none, 2-group, nested, adjacent).
- Compared trial designs and biomarker criteria between nested and adjacent subgroup studies.
Main Results:
- Out of 60 approvals, 20% lacked PD-L1 subgroups, 42% had only two subgroups, 23% used adjacent subgroups, and 15% used nested subgroups.
- 42% of trials were single-arm studies.
- No significant differences were found between nested and adjacent subgroup trial designs.
Conclusions:
- FDA approvals for new indications of PD-1/PD-L1 inhibitors are frequently based on trials lacking comprehensive outcome reporting across PD-L1 biomarker subgroups.
- This highlights a gap in fully understanding treatment efficacy across diverse patient populations defined by PD-L1 status.
