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

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.

An open-label phase 2 trial of entospletinib (GS-9973), a selective spleen tyrosine kinase inhibitor, in chronic lymphocytic leukemia.

Small-molecule inhibitors of kinases involved in B-cell receptor signaling are an important advance in managing lymphoid malignancies. Entospletinib (GS-9973) is an oral, selective inhibitor of spleen tyrosine kinase. This multicenter, phase 2 study enrolled subjects with relapsed or refractory chronic lymphocytic leukemia (CLL; n = 41) or non-Hodgkin lymphoma (n = 145). Participants received 800 mg entospletinib twice daily. We report efficacy outcomes in the CLL cohort (n = 41) and safety outcomes in all cohorts (N = 186). The primary end point was a progression-free survival (PFS) rate at 24 weeks in subjects with CLL. The PFS rate at 24 weeks was 70.1% (95% confidence interval [CI], 51.3%-82.7%); median PFS was 13.8 months (95% CI, 7.7 months to not reached). The objective response rate was 61.0% (95% CI, 44.5%-75.8%), including 3 subjects (7.3%) who achieved nodal response with persistent lymphocytosis. Fifty-four subjects (29.0%) had serious adverse events (SAEs). The most common treatment-emergent SAEs included dyspnea, pneumonia, febrile neutropenia, dehydration, and pyrexia. Common grade 3/4 laboratory abnormalities included neutropenia (14.5%) and reversible alanine aminotransferase/aspartate aminotransferase elevations (13.4%). Entospletinib demonstrates clinical activity in subjects with relapsed or refractory CLL with acceptable toxicity. This trial was registered at www.clinicaltrials.gov as #NCT01799889.