Pembrolizumab, a humanized IgG4 monoclonal antibody targeting the PD-1 receptor, revolutionized cancer immunotherapy by blocking PD-L1/PD-L2 interactions, thereby reactivating T-cells to attack tumors. Marketed as Keytruda by MSD, it is approved for numerous indications and currently the worldwide best selling drug. This presentation chronicles pembrolizumab's development from its inception in 2005 at Organon as an immunology project, through pivots to oncology amid corporate acquisitions, near-cancellations, and resurrections driven by strong sponsorship.

Quantitative Systems Pharmacology (QSP) modeling played a pivotal role in accelerating development, enabling dose optimization without traditional sequential trials. Key contributions included PK-PD modeling in cynomolgus monkeys to establish exposure-response curves, tumor size modeling to debunk phantom dose-responses linked to baseline tumor burden, and translational QSP from syngeneic mouse models to humans, enabling selection of 2 mg/kg Q3W as the optimal dose. These efforts supported the 2014 FDA approval via a single clinical study (KEYNOTE-001) and five modeling reports, outpacing competitors.

The pembrolizumab story underscores how QSP integrates mechanistic insights—from target binding to tumor inhibition—to overcome hurdles, embrace innovative paradigms, and expedite regulatory pathways. It highlights the fluidity of drug development under pressure, emphasizing personal motivation, interdisciplinary collaboration, and robust science to bring novel mechanisms to market efficiently.