Cabozantinib in combination with anti-PD1 immune checkpoint inhibitor in syngeneic tumour mouse models

Abstract Background Cabozantinib (C), a tyrosine kinase inhibitor against VEGFR2, RET, MET and Axl, has demonstrated clinical activity in RCC and 2L HCC, and has been shown to promote an immune-permissive environment. C is being investigated in clinical trials in combination with immune checkpoint inhibitors (ICI). This preclinical study aimed to determine systemic cytokine profile changes induced by the combination of C + αPD1 and assess cooperativity in anti-tumoral effects. Methods Syngeneic colon (CT26, Colon38) and bladder (MBT2) tumour 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 administered either simultaneously for up to 30 days or with a 14-day delay for αPD1, and serum was collected. Results After 30 days' coadministration of C (30 mg/kg) and αPD1, serum cytokines and chemokines (VEGFA, IL3, GM-CSF, MIP1beta, IL17, CCL5, IFNγ, IL10, IL5) were elevated with a median of 72x (range 39–1207x), as compared to 30-days' single administration of αPD1 or C with a median of 3.7x (1.4–135x) and 1.0x (0.5–1.9x), respectively, relative to vehicle-treated animals. Delayed treatment with αPD1 did not result in the same increase in analyte levels as coadministration (median of 1.74x [1–9.9x]). For anti-tumour efficacies, two C doses were explored in CT26 (T/C10/30 67/38% - tumour 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-tumour efficacy in MBT2 and Colon38, limiting any ICI combinatorial impact to the post-treatment tumour expansion. For CT26 (30 mg/kg) and MBT2 (10 mg/kg), simultaneous dosing of C and αPD1 showed greater anti-tumour effects than single agents despite only limited effects of αPD1 alone. C + αPD1 more than doubled the treatment-specific time that tumours required to reach 1000mm3 compared to C alone. Conclusions The results indicate that simultaneous treatment of C + αPD1 leads to strong systemic increases in key cytokines and chemokines and can result in robust anti-tumour efficacy. Our results support the clinical exploration of C + ICI combinations and the potential of this TKI for use in further clinical settings. Editorial acknowledgement Isabelle Kaufmann, PhD of Oxford PharmaGenesis, Oxford, UK for provided medical writing support, which was sponsored by Ipsen, Abingdon, UK. Legal entity responsible for the study Ipsen. Funding Ipsen. Disclosure R. Sparks: Full / Part-time employment: Ipsen. S. Rolland: Full / Part-time employment: Ipsen. S. Klinz: Full / Part-time employment: Ipsen. F. Meyer-Losic: Full / Part-time employment: Ipsen. J. Nakhle: Full / Part-time employment: Ipsen. R. Delille: Full / Part-time employment: Ipsen. M. Hillairet de Boisferonc: Research grant / Funding (institution), Contractual obligation: Ipsen.