Hepatocyte growth factor (HGF) and its receptor (MET) are activated in UC. In translational studies, cabozantinib, a receptor tyrosine kinase inhibitor primarily targeting MET and VEGFR2, reversed HGF-driven UC cell growth and invasion.
In this phase II study, pts received cabozantinib 60 mg/day in 28-day cycles in 3 cohorts: 1) mUC, 2) bone-only mUC, and 3) metastatic rare bladder histology. Primary objective was overall response rate (ORR) by RECIST v1.1. In cohort 1, we also report on the tumor responses by site of metastases (mets). Secondary objectives were to assess the progression-free survival (PFS) and overall survival (OS) in all cohorts.
Of 67 pts enrolled, 70% of male, median age: 63 (22–82), KPS 80% in 73% pts. Primary sites: 69% bladder, 25% upper tract, 6% both. No. prior therapies: 1/2/3/ ≥ 4 (range 1–6) in 34/39/16/9% of pts, respectively. Of 41 evaluable pts in cohort 1, there was 1 complete response (CR), 7 partial responses (PR) (ORR = 19.5%; 95% CI: 8.8–34.9%), 18 stable disease (SD), and 15 progressive disease (PD). Median progression-free survival (mPFS): 3.7 mos(95% CI: 2.3–6.5); 6-month PFS: 38.0%(95% CI: 23.3–52.6%). Median overall survival (mOS): 8.2 mos (95% CI: 5.2–10.3); 6-month OS: 65.1%(95% CI: 48.3–77.6%); 12-month OS: 25.7% (95% CI: 13.0–40.3%). ORR in cohort 1 was evaluated by site of mets in 63 target-lesions: 25.3%lung,/9.5%liver/6.3%adrenal/1.6%kidney/1.6% pancreatic/39.8% LN/15.9% ST. Lung mets had 25% PR/75% SD/0%PD. Treatment resulted in lung lesion cavitation, which could not be interpreted as CR (at best PR). Liver mets had 83.3%SD/16.7%PD. There was no ORR in liver/adrenal/kidney/pancreatic mets. LN mets had 8%CR/8%PR/72%SD/12%PD. ST mets had 90%SD/10%PD. Of 5 pts in cohort 2, 60% had improvement by NaF FDG/PET. mOS: 9.3 mos (95% CI: 3.6–12.5). Of 10 evaluable pts in cohort 3, there were 0%CR/PR/50%SD/50%PD. mPFS: 2.9 mos (95% CI: 1.8–3.7); mOS: 4.6 mos (95% CI: 2.6–8.0).
Cabozantinib has clinical activity in relapsed/refractory pts with mUC. Lung and LN mets had higher ORR. Lung lesion cavitation was frequently noted in responders. Further studies are underway to correlate responses with MET expression, immune subsets, CTCs, and cytokine/mutational profiles.
Clinical trial identification
Legal entity responsible for the study
All authors have declared no conflicts of interest.