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Abstract Bintrafusp alfa, a first‐in‐class bifunctional fusion protein composed of the extracellular domain of TGF‐βRII (a TGF‐β “trap”) fused to a human IgG1 mAb blocking PD‐L1, is being evaluated for efficacy and safety in solid tumor indications as monotherapy and in combination with small‐molecule drugs. We evaluated the perpetrator drug–drug interaction (DDI) potential of bintrafusp alfa via cytochrome P4503A4 (CYP3A4) enzyme modulation, which is responsible for the metabolism of a majority of drugs. The holistic approach included (1) evaluation of longitudinal profiles of cytokines implicated in CYP3A4 modulation and serum 4β‐hydroxycholesterol, an endogenous marker of CYP3A4 activity, in a phase I clinical study, and (2) transcriptomics analysis of the CYP3A4 mRNA levels vs the TGFB gene expression signature in normal hepatic tissues. Bintrafusp alfa was confirmed not to cause relevant proinflammatory cytokine modulation or alterations in 4β‐hydroxycholesterol serum concentrations in phase I studies. Transcriptomics analyses revealed no meaningful correlations between TGFB gene expression and CYP3A4 mRNA expression, supporting the conclusion that the risk of CYP3A4 enzyme modulation due to TGF‐β neutralization by bintrafusp alfa is low. Thus, bintrafusp alfa is not expected to have DDI potential as a perpetrator with co‐administered drugs metabolized by CYP3A4; this information is relevant to clinical evaluations of bintrafusp alfa in combination settings.