Cabozantinib for metastatic breast carcinoma: results of a phase II placebo-controlled randomized discontinuation study

Sara M Tolaney, Hovav Nechushtan, Ilan-Gil Ron, Patrick Schöffski, Ahmad Awada, Chris A Yasenchak, A Douglas Laird, Bridget O'Keeffe, Geoffrey I Shapiro, Eric P Winer, Sara M Tolaney, Hovav Nechushtan, Ilan-Gil Ron, Patrick Schöffski, Ahmad Awada, Chris A Yasenchak, A Douglas Laird, Bridget O'Keeffe, Geoffrey I Shapiro, Eric P Winer

Abstract

Purpose: Cabozantinib (XL184), a multi-targeted oral tyrosine kinase inhibitor with activity against MET, VEGFR2, AXL, and other tyrosine kinases, was assessed in a cohort of metastatic breast cancer (MBC) patients in a phase II randomized discontinuation trial (RDT).

Methods: Patients received 100 mg cabozantinib daily during a 12-week lead-in stage. Those with stable disease per modified Response Evaluation Criteria in Solid Tumors version 1.0 at 12 weeks were randomized to either continue cabozantinib or receive placebo. Primary endpoints were objective response rate (ORR) during the 12-week lead-in stage and progression-free survival (PFS) after randomization. Patients were also followed for overall survival (OS).

Results: Forty-five patients with MBC and a median of three prior lines of chemotherapy for metastatic disease were enrolled. The ORR during the lead-in stage was 13.6 % (95 % confidence interval [CI] 6-25.7 %), and the disease control rate at week 12 was 46.7 % (95 % CI 31.7-61.6 %). Per the initial RDT study design, patients with stable disease at week 12 were randomized to cabozantinib or placebo. Following a Study Oversight Committee recommendation, randomization was suspended. Patients in the lead-in stage continued on open-label cabozantinib. Patients in the randomization stage were subsequently unblinded. The overall median PFS for all MBC patients was 4.3 months. Median OS was 11.4 months (95 % CI 10.5-16.5 months). The most common grade 3/4 adverse events in the lead-in stage were palmar-plantar erythrodysesthesia (13 %) and fatigue (11 %). One death from respiratory failure was reported as drug-related during the lead-in stage.

Conclusions: In heavily pretreated MBC patients, cabozantinib monotherapy demonstrated clinical activity including objective response and disease control.

Trial registration: ClinicalTrials.gov NCT00940225.

Keywords: Cabozantinib; Metastatic breast cancer; Overall survival; Progression-free survival; Tumor response; Vascular endothelial growth factor receptor.

Conflict of interest statement

SMT has received support for clinical research from Exelixis. HN has received support for clinical research from Exelixis. I-GR has no conflicts to report. PS has received institutional research support from Exelixis, and received travel support and honoraria for participation in educational and advisory functions from Exelixis and SOBI. AA has no conflicts to report. CAY has no conflicts to report. ADL was an employee and stockholder of Exelixis. BO was an employee and stockholder of Exelixis. GIS has received support for clinical research from Exelixis. EPW has received support for clinical research from Exelixis.

Figures

Fig. 1
Fig. 1
Schematic of randomized discontinuation trial (RDT) design. ER estrogen receptor, CR complete response, PD progressive disease, PR partial response, SD stable disease
Fig. 2
Fig. 2
CONSORT diagram: disposition of enrolled metastatic breast cancer patients. aTwo deaths were disease progression, and the third death was reported as respiratory compromise. bPatients with stable disease at week 12 continued on open-label cabozantinib after randomization was suspended upon recommendation of the independent study oversight committee
Fig. 3
Fig. 3
a Summary of modified RECIST version 1.0 (mRECIST) response. All responses were confirmed by week 18. Disease control rate is the sum of patients with confirmed partial response or stable disease at week 12. b Best change from baseline in investigator-assessed measurements of soft-tissue lesions using mRECIST was determined for patients who had baseline and at least one post-baseline radiographic scan in the first 12 weeks (n = 39). aConfirmed partial response. RECIST, Response Evaluation Criteria in Solid Tumors
Fig. 4
Fig. 4
a Estimated overall progression-free survival for 45 metastatic breast cancer patients, determined as described by Ratain et al. [21]. b Overall survival (26 death events and 19 patients censored). aSee “Patients and Methods” section for details on the PFS calculations

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