Optimizing ADC and TCE Combination Therapy: A QSP Approach 

ADC Therapeutics was planning a  new clinical trial to test the efficacy of combinations of the ADC, loncastuximab tesirine-lpyl (lonca), with TCEs, such as mosunetuzumab (mosun), glofitamab (glofit), and epcoritamab (epcor). In the absence of prior clinical studies with these combinations, key questions included: (1) whether the combinations would lead to enhanced efficacy over the monotherapy treatments, (2) whether ADC dose-reductions would affect efficacy, and (3) how assessment of the combination effect would depend on treatment evaluation time.

MetrumRG developed an integrated quantitative systems pharmacology (QSP) model capable of describing pharmacokinetic and efficacy data from clinical studies of ADC and TCE monotherapies (including mosun, glofit, and epcor).  Given its basic foundation on mechanistic cell biology, the model was well suited for the prediction of the anti-tumor effects of these combinations under different scenarios. Simulations assessed the impact of various combination dosing schedules, reduced magnitude of ADC dose, and other clinical factors, such as lymphopenia, on the expected therapeutic outcomes.

Results: The integrated QSP model revealed key insights into the ADC + TCE combination therapy:

• All combination therapies were predicted to outperform the monotherapies, providing supportive evidence for the potential benefits of combining ADCs with TCEs.
• In the dose ranges studied, the efficacy of the combination regimens was largely independent of the cumulative ADC dose, with the total number of treatment cycles being the most significant factor influencing tumor growth inhibition (TGI).

It was determined that reducing the ADC dose would not negatively impact the efficacy of the combination therapy and that extending the treatment period may be advantageous. For example, a lower dose of lonca maintained over more dose cycles is preferable to skipping doses due to adverse events (AEs). This collaboration provided valuable insights into optimizing combination therapy, setting the stage to inform dosing decisions, the design of future studies, and entire development strategies.