Abstract
Objective
Checkpoint inhibitors that target PD-1 or PD-L1 have had a profound effect in a variety of cancers, both as a single therapy and in combinations [1]. Currently, four anti-PD-1 and three anti-PD-L1 monoclonal antibodies (mAbs) are FDA-approved [2]. Meta-analyses suggest that anti-PD-1 mAbs may yield better survival outcomes [3, 4], however these conclusions are limited by a lack of direct clinical comparisons between anti-PD-1 and anti-PD-L1 mAbs. A model-based meta-analysis comparing the level of PD-1:PD-L1 complex inhibition these mAbs achieve at their clinical doses can provide insights into their efficacy profiles and identify scenarios where targeting PD-1 could be preferential to PD-L1 or vice-versa.
Conclusions
- High levels of PD-1:PD-L1 complex inhibition are achieved by the approved molecules
at their clinical doses. - Anti-PD-L1 mAbs achieve slightly higher inhibition than anti-PD-1 mAbs – effect on
clinical outcomes is unclear. - In contrast, literature meta-analysis and [3,4] indicate higher efficacy for anti-PD-1
mAbs. - The model suggests that the relative efficacy of anti-PD-1 to anti-PD-L1 mAbs is not
determinable based on PD-1:PD-L1 complex inhibition alone, and perhaps other
biological mechanisms not included in the model (e.g., the PD-1:PD-L2 axis as
suggested in [3]) could explain the higher efficacy of anti-PD-1 mAbs seen in literature
meta-analyses. - Which drug class is better depends on multiple factors including receptor expression,
target half-lives, and drug affinities, but the overall better efficacy of anti-PD-1 mAbs
can't be predicted from a model that doesn't include the presence of other PD-1 binding
targets such as PD-L2.