UCSF

INTRODUCTION: First-line trials evaluating programmed cell death protein 1/programmed-death ligand 1 inhibitors (PDI) are often preceded by FDA approvals of PDI in second-line settings; however, many control-arm patients in these first-line trials do not receive PDI at disease progression. We performed a systematic analysis of trials evaluating upfront use of PDI in metastatic solid tumours to (1) quantify the number of control-arm patients that receive PDI upon disease progression and (2) the timing difference between FDA approval for a PDI in the second-line setting and (3) enrolment period for the same drug in a first-line trial. METHODS: Using the Drugs@FDA website, we evaluated all approvals for first-line and second-line PDI in metastatic solid tumours through December 2021. From corresponding trials, we calculated the timing difference between second-line approval of a PDI and start/end of accrual of first-line trials and management of disease progression for control-arm patients. RESULTS: 25/32 approvals for upfront PDI were preceded by approval of a PDI in the second-line of the same disease and included in this analysis. First-line trials start of accrual preceded approval of a PDI by a mean of 4 months, median 6 months and ended accrual by a mean and median of 14 after second-line approval. A mean of 51% of control-arm patients received subsequent therapy, with a mean of 33% of these patients receiving a PDI. CONCLUSION: This analysis shows that many control-arm patients in the included trials did not receive a PDI with already established efficacy at any point during their recorded treatment. This underscores a need to standardise the approach to disease progression for control-arm patients to reflect evolving standards of care. This analysis is limited by a lack of individual patient-level data, heterogeneity of included trials and exclusion of first-line PDI trials that did not meet their primary endpoint.