Palbociclib in combination with sunitinib exerts a synergistic anti-cancer effect in patient-derived xenograft models of various human cancers types

Abstract

The efficacy/safety of combining palbociclib (a CDK4/6 inhibitor) and sunitinib (a multi-targeted receptor tyrosine kinase inhibitor) was evaluated, using patient-derived xenograft (PDX) models. Twenty-three PDX mice models were developed from patients with various solid tumors. The mice were randomized to 4 groups (5-6 mice in each): control/palbociclib (100 mg/kg)/sunitinib (50 mg/kg)/combination. Drugs were administered orally, 5 days/week. In 17/23 PDX models (74%), the combination demonstrated a synergistic inhibitory effect vs the monotherapies ("responder" models) with no unexpected toxicities. In 13/17 responder models, where standard-of-care (SOC) was an additional comparator, the combination was more effective than SOC in 7 models, as effective in 4, and less effective in 2. The mean ± SEM experiment duration in 15/17 responder models (2/17 were excluded due to technical issues) was 86 ± 12 and 31 ± 5 days for the combination and control groups, respectively (p = 0.0002). The effect of the combination was dose-dependent. Cell-viability experiments in A549/MDA-MB-231/HT-29 cell lines and experiments using tumor-derived primary cell spheroids supported the PDX findings. In conclusion, combination of palbociclib and sunitinib exerts a synergistic anti-tumor effect without adding unexpected toxicity. A clinical trial assessing this combination is underway.

Keywords: Efficacy; PDX models; Palbociclib; Sunitinib; Synergy.