In Reply We thank Drs Baa and Rastogi for their comments regarding our recent Brief Report.1 First, they commented on the starting dose of 45 mg/m2 of doxorubicin in the phase 1 component and the 3 + 3 design, correctly pointing out that a more traditional approach would have been to dose escalate the novel component to a fixed-dose standard of care. However, pembrolizumab lacks a traditional dose-response/toxic effects curve. Dosing is based on translational models and measurement. Maximum serum target engagement occurs with trough concentrations of 1 mg/kg. To our knowledge, a maximally tolerated dose has never been identified, and toxic effects have not been linked to dosing at clinically relevant levels.2 In designing the trial,1 our major concern was worsening of anthracycline-mediated cardiac toxic effects by the addition of a programmed cell death 1 inhibitor. Because doxorubicin has a traditional dose-response association with respect to both efficacy and toxic effects, we elected to escalate the doxorubicin dose. Although 45 mg/m2 is not considered a standard initial dose, it has established clinical activity.3 The 3 + 3 approach allowed us to quickly escalate to the phase 2 doses of 75 mg/m2 of doxorubicin and 200 mg of pembrolizumab every 3 weeks, the accepted monotherapy doses for each drug.2
Wagner MJ, Cranmer LD, Pollack SM. Combination Doxorubicin and Pembrolizumab in Patients With Advanced Anthracycline-Naive Sarcoma—Reply. JAMA Oncol. 2021;7(3):465–466. doi:10.1001/jamaoncol.2020.7873
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