Modulation of soluble c-Met, bone turnover markers, angiogenic factors, and c-Met in men with mCRPC treated with cabozantinib.
Background: Cabozantinib (cabo) is a multi-TKI against c-Met and VEGFR2. Cabo elicits striking changes in bone scans (BS), reductions in soft-tissue mets, and improves bone pain in mCRPC. This unique response is unlinked from PSA and suggests that targets of Cabo reside in the bone microenvironment. To explore the underlying mechanisms of Cabo activity, we examined changes in soluble c-Met, angiogenic factors, bone specific alkaline phosphatase (BAP), and tumor specific c-Met signaling in men on Cabo. Methods: A phase II cohort of docetaxel pretreated men with mCRPC received Cabo. Response was assessed q6 wks by BS and CT scan. Blood and trans-iliac bone marrow biopsies (BMs) were collected pretreatment and at wk 6. Soluble c-Met was measured by ELISA, angiogenic factors by multiplex immunoassay, and tumor c-Met/phospho c-Met expression by IHC. Results: 21 patients with bony mets were evaluated; 38% also had soft tissue mets. 13/21 (62%) pts experienced an improvement (PRs + CRs) in BS and 2/8 (25%) achieved a PR in soft tissue mets. 12/20 (60%) pts had reductions in BAP on therapy (median reduction 48.5%). VEGFR2 levels decreased in response to therapy (p 5% tumor involvement (median 80%) were evaluable for 10 patients, 9 of whom also had a 6 wk BM. High intensity, tumor-specific expression of c-Met was detectable in 8/10 (80%) of pretreatment tumors (median involvement 60%) and increased in 4/9 (45%) pts at 6 wks (median increase 30%). Activated phospho c-Met was detectable in 9/10 (90%) of pretreatment tumors (median involvement 80%) and decreased in 5/9 (56%) pts (median reduction 30%) at 6 wks. Conclusions: The results of our study suggest that changes in soluble markers of c-Met, bone turnover, and angiogenesis are linked to Cabo activity. Analyses of BMs demonstrate high c-Met activation in pretreatment mets and suggest Cabo-mediated inhibition at 6 wks. These data support the hypothesis that c-Met contributes to “driver” signaling networks in mCRPC and suggest that biomarkers of stromal cell function should be prioritized for further study.
The interesting thing here is the bone biopsy result. Baseline measurement confirmed high levels of cMET and phospho-cMET. After Cabo treatment cMET expression increased somewhat, but activated cMET expression decreased somewhat. Not really a smoking gun or a serious Aha! moment, but it adds to the body of knowledge and contributes to the understanding of the biology occurring in the bone microenvironment. Incidentally, the 21 patients treated had treatment efficacy results consistent with those previously reported in other studies. This study appears to be NCT01428219 which would make it the first 60mg dose data we have seen.