P1-17-10: Cabozantinib (XL184) in Patients with Metastatic Breast Cancer: Results from a Phase 2 Randomized Discontinuation Trial.
Authors: Tolaney SM , Nechushtan H , Berger R , Kurzrock R , Ron IG , Schöffski P , Awada A , Yasenchak CA , Burris HA , Ramies DA , Shen X , Winer EP 
Published: June 2012

Abstract
Background: Cabozantinib is an oral, potent inhibitor of MET and VEGFR2. MET overexpression has been observed in metastatic breast cancer (MBC). High levels of VEGF and its receptors are associated with poor prognosis in patients (pts) with breast cancer. Simultaneous targeting of the MET and VEGF signaling pathways with cabozantinib may therefore be a promising treatment strategy. Results of a phase 2 randomized discontinuation trial (RDT) with single-agent cabozantinib have demonstrated clinical activity in a broad range of tumor types. In addition to observed effects on soft tissue lesions, cabozantinib has also been associated with effects on bone metastases as exhibited by partial or complete bone scan resolution, pain relief and/or reduction of narcotic use.
Methods: MBC pts (ER [+], triple [-] or inflammatory subtype) with progressive and measurable disease received single-agent cabozantinib at 100 mg qd PO over a 12 week (wk) lead-in period. Up to 4 prior treatment regimens (hormonal excluded) for MBC were allowed. Tumor response was assessed every 6 wks per mRECIST 1.0. Treatment beyond wk 12 was based on response: pts with partial response (PR) continued with open-label cabozantinib, those with stable disease (SD) were randomized to cabozantinib vs. placebo, and those with progressive disease were discontinued. The primary endpoint was objective response rate (ORR) in the lead-in period, and progression free survival in the randomized period. Post-hoc evaluations of bone scans were conducted.
Results: 20 MBC pts were enrolled with a median age of 55 years (range: 31–71).19 pts had invasive ductal carcinoma (1 pt with inflammatory MBC), and 1 pt had invasive lobular carcinoma. 75% of pts were ER/PR [+]; 15% were HER2/neu [+]. 85% of pts had visceral disease including 65% with liver metastases; 70% had bone disease. The median number of prior regimens was 3; 45% received prior anti-VEGF therapy. Most common related adverse events ≥ Grade 3 were fatigue/asthenia, 20%; and hand-foot syndrome, 20%. Dose reductions and permanent discontinuations for AEs occurred in 35% and 15% of pts, respectively.
Soft tissue effects: At wk 12, ORR per RECIST was 10% and overall disease control rate (PR+SD) was 45%. Notably, tumor shrinkage was observed in 15/16 pts (94%) with ≥1 post-baseline tumor assessment.
Bone effects: 2/3 pts evaluable by bone scan at baseline had partial resolution of lesions and one pt had SD on follow-up bone scans as early as Wk 6. Out of 7 pts receiving narcotics for bone pain, 3 pts reported improved pain and 2 pts had decreased narcotic use, per investigator. The majority of pts analyzed had declines in plasma CTx, an osteoclast marker. Additional enrollment and further bone marker analyses are ongoing.
Conclusions: Cabozantinib exhibits clinical activity in pts with MBC regardless of receptor and prior treatment status as reflected by high rate of tumor regression and effects on bone metastases. Cabozantinib is generally well tolerated and the safety profile is comparable to that seen with other tyrosine kinase inhibitors.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-17-10.