Introduction: Treatment for cancer, particularly in later lines, is often inadequate. Combinational therapies targeting several signaling pathways simultaneously are considered a promising approach, with limited clinical evidence. Effectiveness of such combinations can be explored in patient-derived xenograft (PDX) tumor models, which more accurately represent human tumor biology, drug responsiveness, and treatment-related toxicity than standard xenograft models derived from established human cancer cell lines.
Objectives: To evaluate, in PDX models, the anti-tumor effect and safety of combinational therapy including a CDK4/6 inhibitor (palbociclib) plus a multi-targeted receptor tyrosine kinase inhibitor (mtRTKI; sunitinib).
Methods: Overall, 20 PDX models were developed from patients with various solid tumors. For each, tumor was implanted subcutaneously in immune-deficient mice (NRG or NSG). The mice were randomized to 4 treatment groups: vehicle as control, palbociclib (100 mg/kg), sunitinib (50 mg/kg), or combination thereof. Each treatment group included 5-6 mice (18/20 models). Drugs were administered orally, 5 days per week. Tumor volume was monitored twice a week with digital caliper. Mice body weight and clinical signs were examined twice a week to evaluate toxicity.
Results: The mean experiment time (all experiments) was 66 days (SEM, 10 days; range, 15-170 days). In 14 of the 20 evaluated models (70%), including those for cholangiocarcinoma, breast, lung, pancreas, colon, stomach, and ovarian cancer, combinational therapy with palbociclib and sunitinib had significantly superior anti-cancer activity compared to either drug alone, without any unexpected toxicity. Mean duration of response in these 14 models was 72 days (SEM, 12 days). The combination of palbociclib and sunitinib prevented tumor growth, and in 3 models reduced tumor size. In the 2 PDX models developed from patients with palbociclib-resistant disease, the combination overcame tumor resistance to palbociclib. In 5 of the models which demonstrated synergy between palbociclib and sunitinib, the effect of administrating 2-fold lower doses of both drugs was evaluated. The lower doses were shown to suppress tumor growth in a dose-response manner.
Conclusions: These PDX results suggest that the combination of palbociclib and sunitinib exert a synergistic anti-tumor effect on multiple tumor types without adding unexpected toxicity.
Citation Format: Neta Moskovits, Idit Peretz, Eva Chausky, Raisa Meerson, Ella Itzhaki, Noga Marsiano, Nofar Shmuel, Ranny Yaffe, Natalia Edison, Tal Goldman, Salomon Stemmer. Synergistic anti-cancer activity of palbociclib in combination with sunitinib in patient-derived xenograft (PDX) models of various human cancers types [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5054.
