Combination Doxorubicin and Pembrolizumab in Patients With Advanced Anthracycline-Naive Sarcoma—Reply

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