Cabozantinib (C) is a tyrosine kinase inhibitor against VEGFR2, RET, MET and AXL that has demonstrated clinical activity in RCC and 2L HCC and has been shown to promote an immune-permissive environment. C is undergoing clinical trials in combination with immune checkpoint inhibitors (ICI). The objectives of this preclinical study were to determine systemic cytokine profile changes induced by the combination with αPD1 and to assess cooperativity in anti-tumoral effects.
Syngeneic colon (CT26, Colon38) and bladder (MBT2) tumor models were established in BALB/C, C57Bl6 or C3H/HEJ mice. C (10 or 30 mg/kg po qd) and αPD1 (10 mg/kg ip 2x weekly) were given for up to 30 days simultaneously or with a delay for αPD1, and serum was collected.
Serum cytokines & chemokines were assessed after coadministration of C (30 mg/kg) and αPD1 for 30 days, or when αPD1 was administered 14 days after C. VEGFA, IL3, GM-CSF, MIP1beta, IL17, CCL5, IFNγ, IL10 and IL5 were elevated in the former with a median of 72x (range 39-1207x), as compared to αPD1 or C administered alone with a median of 3.7x (1.4-135x) and 1.0x (0.5-1.9x), respectively, relative to vehicle-treated animals. Delayed treatment of αPD1 did not exhibit the same increase in analyte levels as seen with the simultaneous administration (median of 1.74x (1-9.9x). For anti-tumor efficacies, two C doses were explored in CT26 (T/C10/30 67/38% - tumor growth inhibition T/C ratios at 10 or 30 mg/kg), MBT2 (T/C10/30 37/14%) and Colon38 (T/C10/30 21/12%) models. C at 30 mg/kg led to strong anti-tumor efficacy in MBT2 and Colon38, limiting any ICI combinatorial impact to the post-treatment tumor expansion. For CT26 (30 mg/kg) and MBT2 (10 mg/kg), simultaneous dosing of C and αPD1 showed greater anti-tumor effects than single agents despite only limited effects of αPD1 alone. C + αPD1 more than doubled the treatment-specific time that tumors required to reach 1000mm3 compared to C alone.
Together, these results indicate that simultaneous treatment of C with αPD1 lead to strong systemic increases in key cytokines & chemokines and can result in robust anti-tumor efficacy. Our results support the clinical exploration of C + ICI combinations and the potential of this TKI for use in further clinical settings.
Ipsen Innovation SAS.
Ipsen Innovation.
S. Rolland, J. Nahkle, R. Delille: Employee of Ipsen. S.G. Klinz, F. Meyer-Losic: Employee and stock owner: Ipsen. All other authors have declared no conflicts of interest.