Abstract
Background Cabozantinib is an orally available inhibitor of tyrosine kinases including VEGFR2 and c-MET. We performed a post hoc analysis to find associations between select plasma biomarkers and treatment response in patients (pts) with metastatic castration resistant prostate cancer (mCRPC) who received cabozantinib 100 mg daily as part of a phase 2 non-randomized expansion cohort (NCT00940225).Methods Plasma samples were collected at baseline, 6 weeks and at time of maximal response from 81 mCRPC pts with bone metastases, of which 33 also had measurable soft-tissue disease. Levels of 27 biomarkers were measured in duplicate using enzyme-linked immunosorbent assay. Spearman correlation coefficients were calculated for the association between biomarker levels or their change on treatment and either bone scan response (BSR) or soft tissue response according to RECIST.ResultsA BSR and RECIST response were seen in 66/81 pts (81 %) and 6/33 pts (18 %) respectively. No significant associations were found between any biomarker at any time point and either type of response. Plasma concentrations of VEGFA, FLT3L, c-MET, AXL, Gas6A, bone-specific alkaline phosphatase, interleukin-8 and the hypoxia markers CA9 and clusterin significantly increased during treatment with cabozantinib irrespective of response. The plasma concentrations of VEGFR2, Trap5b, Angiopoietin-2, TIMP-2 and TIE-2 significantly decreased during treatment with caboznatinib.ConclusionsOur data did not reveal plasma biomarkers associated with response to cabozantinib. The observed alterations in several biomarkers during treatment with cabozantinib may provide insights on the effects of cabozantinib on tumor cells and on tumor micro-environment and may help point to potential co-targeting approaches.
Highlights
Cabozantinib is an orally available inhibitor of tyrosine kinases including vascular endothelial growth factor (VEGF) receptor 2 (VEGFR2) and c-MET
The waterfall plot of the bone scan response of the 81 patients included in this analysis and the soft tissue response of the 33 patients with measurable disease are depicted in Fig. 1, showing that 66 of 81 pts (81 %) had a decrease in bonescan lesion area (BSLA) of more than 30 %, and 6 of 33 pts (18 %) had a partial soft tissue response according to response evaluation criteria in solid tumors (RECIST)
Our primary underlying hypothesis in this study was that hypoxia-related markers would be associated with response to cabozantinib; but similar to others, we did not find any significant associations between plasma biomarkers at any time point or their change throughout treatment and either bone scan response or soft tissue response to cabozantinib
Summary
Cabozantinib is an orally available inhibitor of tyrosine kinases including VEGFR2 and c-MET. The receptor tyrosine kinase c-MET, known to exert a major role in tumor formation and progression, has been shown to be induced in hypoxic cancers in general [7], and in advanced or androgen-receptorindependent prostate cancer in particular [8], especially in bone metastases [9]. MET and VEGFR2 were recently shown to dimerize [10], and VEGF blockade was shown to restore and increase MET activity in GBM cells in a hypoxia-independent manner, while inducing a program reminiscent of EMT [10]. These observations suggest that co-targeting of these receptors may be necessary in order to abrogate their effects on the tumour
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