Activity of cabozantinib (XL184) in soft tissue and bone: Results of a phase II randomized discontinuation trial (RDT) in patients (pts) with advanced solid tumors.

Abstract

3010 Background:Cabozantinib (Cabo) is an oral, potent inhibitor of MET and VEGFR2. An RDT evaluated clinical efficacy and safety in 9 tumor types: breast (B), gastric/GEJ (G), non-small cell lung (NS), ovarian (O), pancreatic (PA), castration-resistant prostate (P), small cell lung (S), hepatocellular (H), and melanoma (M). Indications were selected based on the role of MET and VEGFR2 in tumor biology. Methods:All eligible pts had progressive measurable disease ± bone metastasis (mets). Pts received Cabo at 100 mg qd over a 12 wk lead-in stage. Tumor response (mRECIST) assessed q6 wks. Treatment ≥ wk 12 was based on response: pts with PR continued open-label Cabo, pts with SD were randomized to Cabo vs placebo, and pts with PD discontinued. Primary endpoint was ORR in the lead-in stage. Accrual in any cohort could be halted for either high rates of ORR or PD. Results:398/483 enrolled pts were evaluable for the lead-in stage. 154/398 (39%) had bone mets at baseline (68 with bone scan f/u). Median # prior regimens was 2. Most common related AEs grade ≥ 3: fatigue (9%), hand-foot syndrome (8%), and HTN (5%). Dose reductions and permanent discontinuations for AEs occurred in 41% and 12% of pts, respectively. Soft tissue effects: ORR at wk 12: overall = 34/398 (9%); O 12/51 (24%), H 4/29 (14%), P 5/100 (5%), NS 6/60 (10%), B 2/20 (10%), S 1/21 (5%), M 4/76 (5%). 12 additional PRs await confirmation. 226/328 (69%) with ≥1 post-baseline scan had tumor regression. Highest DCR (PR + SD) at wk 12: H (76%), P (71%), and O (58%). Bone effects: 59/68 pts (P, B, and M) with bone mets and ≥1 post-baseline bone scan had partial or complete bone scan resolution, often with symptom improvement seen by wk 6. Osteoclast effects were observed across tumor types: 66/121 (55%) pts ± bone mets had declines of ≥50% in plasma C-telopeptide. Decreased serum tALP seen in P. Median max rise in hemoglobin in anemic pts (Hb < 11 g/dL) = 2.3 g/dL. All max Hb changes w/in first 12 wks. Randomization in cohorts P and O was halted and pts unblinded due to observed efficacy. Conclusions:Cabo is broadly active with cPRs in 8/9 indications, with high DCRs in H, P, and O. Complete or partial resolution of bone scan lesions was observed in 3 tumor types.