Project Confirm: Accelerated Drug Approvals for CML—Response
Authors: Kendra L. Sweet, Jorge E. Cortes, Jane F. Apperley, Mel Mann, Michael J. Mauro, Vivian G. Oehler, Cristina Ruiz, Charles A. Schiffer, Lori A. Ehrlich, Gulsum E. Pamuk, Joseph Wynne, Gautam U. Mehta, Olanrewaju O. Okusanya, R. Angelo de Claro, Marc R. Theoret, B. Douglas Smith, Kelly J. Norsworthy
Journal: Clinical Cancer Research (2024)

We thank Beumer and Salamone for their interest in our perspective piece (1). We note that they agree with our assertion that it is unlikely most patients with chronic myeloid leukemia (CML) require the maximum tolerated dose (MTD) of tyrosine kinase inhibitors (TKI). However, the authors expressed concerns about the scope of Project Optimus and inadequate reliance on therapeutic drug monitoring (TDM) for TKI dose optimization.The authors noted that Project Optimus only recommends shifting a single dose. However, the stated purpose of Project Optimus is to "reform the dose optimization and dose selection paradigm in oncology drug development." The current dose selection paradigm—based on cytotoxic chemotherapeutics—leads to doses and schedules of molecularly targeted therapies that are frequently inadequately characterized before initiating registration trials (2). Notably, while most drugs in oncology have targeted a single fixed or weight/BSA-based dose, Project Optimus does not preclude the use of TDM in certain clinical scenarios.Consistent with the goal of Project Optimus, TDM aims to prospectively improve the benefit/risk balance of a therapy. In contrast, drug development targeting the MTD is typically reliant on a short observation period and does not prospectively identify an optimized dosage. Identifying an optimized dosage does not preclude TDM, as exemplified by the revised dosing approaches for warfarin that initiate doses based on genomic markers prior to TDM (3). The TDM approach has been applied in oncology for drugs such as busulfan and methotrexate. A 2021 FDA analysis identified 11 FDA-approved drugs recommending TDM in their prescribing information aiming to optimize efficacy, reduce safety concerns, and/or manage pharmacokinetic drug interactions (4). Thus, there are circumstances where TDM may be recommended, particularly for drugs with a narrow therapeutic window or multiple drug–drug interactions.Beumer and colleagues previously articulated the challenges with TDM, such as the absence of randomized trials or availability of practical and efficient bioanalytical tools (5). Additional research in well-planned, prospective studies is needed before these approaches can be broadly incorporated into practice. Elements such as interpatient variability, intrapatient variability, and frequency of monitoring need to be established. In addition, care must be taken to utilize appropriate testing that has been sufficiently validated to inform clinical care. Testing should also be widely available. Potential dangers of use of TDM with unvalidated and understudied assays are covered in FDA's Guidance for Industry on Recommendations for Premarket Notifications for Lamotrigine and Zonisamide Assays (6).Ultimately, a more dynamic approach will be needed. More than pharmacokinetics based, this will require an integrative approach, including pharmacokinetics, pharmacodynamics, efficacy, and safety data, and in some cases, modeling and simulation. We encourage active conversation around development of novel approaches to optimize dosages of drugs for CML, not just for the indicated population, but for the individual patient.See the original Letter to the Editor, p. 235K.L. Sweet reports personal fees from Novartis, Bristol Meyers Squibb, and Pfizer during the conduct of the study; other support from BeiGene; personal fees from Nkarta, Karyopharm, BerGenBio, and Curis; grants and personal fees from Jazz; and grants from Incyte outside the submitted work. J.E. Cortes reports grants and personal fees from Novartis, Pfizer, Sun Pharma, and Takeda; personal fees from Tern Pharma; and grants from Ascentage outside the submitted work. J.F. Apperley reports grants and personal fees from Incyte and Pfizer and personal fees from Novartis outside the submitted work. M.J. Mauro reports personal fees and other support from Novartis, Bristol Myers Squibb, Takeda, TERNS, and Enliven; personal fees from Pfizer and AbbVie; and other support from Sun Pharma/SPARC during the conduct of the study. V.G. Oehler reports grants and other support from Pfizer, Inc; other support from Novartis and Ascentage outside the submitted work. C. Ruiz reports personal fees and non-financial support from Pfizer Inc. and Novartis outside the submitted work. B.D. Smith reports other support from Novartis, Pfizer, BMS, and Servier outside the submitted work. No disclosures were reported by the other authors.