Pauline Corbaux1, Mévidette El-Madani2, Michel Tod1, Julien Péron3, Denis Maillet4, Jonathan Lopez5, Gilles Freyer4, Benoit You6. 1. Faculty of Medicine Lyon-Sud, Claude Bernard University Lyon 1, EMR UCBL/HCL 3738, University of Lyon, Lyon, France. 2. Faculty of Medicine Lyon-Sud, Claude Bernard University Lyon 1, EMR UCBL/HCL 3738, University of Lyon, Lyon, France; Pharmacology Department, National Research Centre, Cairo, Egypt. 3. Faculty of Medicine Lyon-Sud, Claude Bernard University Lyon 1, EMR UCBL/HCL 3738, University of Lyon, Lyon, France; Biometry and Evolutionary Biology Laboratory, Health and Biostatistics Team, CNRS UMR 5558, Claude Bernard University Lyon 1, University of Lyon, Lyon, France. 4. Faculty of Medicine Lyon-Sud, Claude Bernard University Lyon 1, EMR UCBL/HCL 3738, University of Lyon, Lyon, France; Department of Medical Oncology, Cancerology Institute of Hospices Civils de Lyon (IC-HCL), CITOHL, Lyon-Sud Hospital, Lyon, France. 5. Department of Biochemistry and Molecular Biology, Lyon-Sud Hospital, Hospices Civils de Lyon, Lyon, France. 6. Faculty of Medicine Lyon-Sud, Claude Bernard University Lyon 1, EMR UCBL/HCL 3738, University of Lyon, Lyon, France; Department of Medical Oncology, Cancerology Institute of Hospices Civils de Lyon (IC-HCL), CITOHL, Lyon-Sud Hospital, Lyon, France. Electronic address: benoit.you@chu-lyon.fr.
Abstract
BACKGROUND: Determining the optimal biological dose (OBD) has been described as an alternative strategy to the maximum tolerated doses (MTDs) for identifying the recommended phase II trial doses (RP2Ds) of phase I anti-cancer therapies. However, the clinical relevance is still unknown. An extensive review was performed to assess if the OBDs defined in early-phase trials were useful for subsequent drug development and approvals. METHODS: All the molecular targeted therapies approved by the Food and Drug Administration (FDA) in solid oncology or in haematological malignancies before July 2018 were listed through the National Cancer Institute Database. The early-phase trial publications investigating these drugs as single agents were retrieved and analysed to identify the drugs for which OBDs were reported. The publications of subsequent pivotal efficacy clinical trials leading to the approvals were retrieved, and OBDs compared with the final labelled doses and dosing schedules. RESULTS: A total of 87 early-phase trial publications were analysed, corresponding to 81 FDA-approved targeted therapies. OBDs were reported for 40% (32/81) of these drugs (19 small molecules, 13 monoclonal antibodies). MTDs were not identified for 59% (19/32) of molecules. When the OBDs were selected as the RP2Ds (18/32 molecules), the final FDA-approved doses were consistent with the OBDs for 83% of the drugs, which is much higher than the previously reported 58% rate when MTDs were chosen as the RP2Ds. CONCLUSION: Although still poorly investigated, the OBD may be a relevant and complementary end-point for early-phase trials of targeted therapies.
BACKGROUND: Determining the optimal biological dose (OBD) has been described as an alternative strategy to the maximum tolerated doses (MTDs) for identifying the recommended phase II trial doses (RP2Ds) of phase I anti-cancer therapies. However, the clinical relevance is still unknown. An extensive review was performed to assess if the OBDs defined in early-phase trials were useful for subsequent drug development and approvals. METHODS: All the molecular targeted therapies approved by the Food and Drug Administration (FDA) in solid oncology or in haematological malignancies before July 2018 were listed through the National Cancer Institute Database. The early-phase trial publications investigating these drugs as single agents were retrieved and analysed to identify the drugs for which OBDs were reported. The publications of subsequent pivotal efficacy clinical trials leading to the approvals were retrieved, and OBDs compared with the final labelled doses and dosing schedules. RESULTS: A total of 87 early-phase trial publications were analysed, corresponding to 81 FDA-approved targeted therapies. OBDs were reported for 40% (32/81) of these drugs (19 small molecules, 13 monoclonal antibodies). MTDs were not identified for 59% (19/32) of molecules. When the OBDs were selected as the RP2Ds (18/32 molecules), the final FDA-approved doses were consistent with the OBDs for 83% of the drugs, which is much higher than the previously reported 58% rate when MTDs were chosen as the RP2Ds. CONCLUSION: Although still poorly investigated, the OBD may be a relevant and complementary end-point for early-phase trials of targeted therapies.
Authors: Antje-Christine Walz; Arthur J Van De Vyver; Li Yu; Marc R Birtwistle; Nevan J Krogan; Mehdi Bouhaddou Journal: Pharmacol Ther Date: 2022-02-18 Impact factor: 13.400