Exposure-Response (E-R) Analysis Of Efficacy Of Pegvorhyaluronidase Alfa (Pegph20) In Combination With Nab-Paclitaxel Plus Gemcitabine (Ag) In Patients (Pts) With Metastatic Pancreatic Ductal Adenocarcinoma.

e15746 Background: PEGPH20 depolymerizes extracellular matrix hyaluronan (HA) and is an investigational agent for the treatment of pts with HA-accumulating tumors. HALO-109-202 (260 pts) was conducted to evaluate the effect of PEGPH20 + AG in pts with mPDA. Methods: E-R models were developed to evaluate the relationship between PEGPH20 exposure and efficacy, including time to PFS, time to OS, and overall response (OR). Results: The final E-R PFS model was a Cox proportional hazards model that included effects of PEGPH20 C max and baseline tumor biopsy HA (high or low). Higher PEGPH20 C max was associated with a lower risk of radiological progression. Pts with baseline HA≥ 50% (HA-high) tumor biopsy were at a lower risk of radiological progression with PEGPH20 treatment. A similar E-R model evaluated the effect of PEGPH20 on OS, including effects of dose-adjusted PEGPH20 concentration 7 days postdose (D7 Conc), liver metastases, and baseline tumor burden. The model-predicted influence of PEGPH20 D7 Conc on risk of death indicated that with increasing PEGPH20 D7 Conc, the predicted risk of death decreases. Pts with liver metastases and higher baseline tumor burden were predicted to have a higher risk of death. The final E-R efficacy model for OR probability was a linear function of dose-adjusted PEGPH20 AUC in Cycle 1, where increasing exposure was related to a higher predicted OR probability. Conclusions: The E-R analyses demonstrate that improvements in PFS and OS with PEGPH20 + AG is PEGPH20 exposure-dependent, supporting 3 µg/kg as an appropriate dose for further development and emphasizing the need for sufficient PEGPH20 exposure for improved therapeutic effect. Clinical trial information: NCT01839487. [Table: see text]