Abstract P6-20-07: Efficacy and safety of CB-839, a small molecule inhibitor of glutaminase, in combination with paclitaxel in patients with advanced triple negative breast cancer (TNBC): Initial findings from a multicenter, open-label phase 2 study
Authors: Vidal G , Kalinsky K , Stringer-Reasor E , Lynce F , Cole J , Valdes-Albini F , Soliman H , Nikolinakos P , Silber A , DeMichele A , Ali H , Graham D , Giguere J , Brufsky A , Liang Y , Holland S , Fiji G , O'Keeffe B , Gogineni K 
Published: May 2019

Abstract
Background: CB-839 is an investigational first-in-class, potent, oral inhibitor of glutaminase (GLS), a mitochondrial enzyme that controls a critical step in tumor cell utilization of glutamine. TNBC is associated with high GLS expression and depends on GLS conversion of glutamine to glutamate for tumor cell survival and proliferation. Higher glutamine utilization has been observed in TNBC tumors from patients (pts) of African ancestry (AA), compared to those of European ancestry. CB-839 has demonstrated preclinical antitumor activity in both in vitro and in vivo models of TNBC and synergizes with paclitaxel (Pac) by reversing GLS-dependent mechanisms that lead to taxane resistance. In a phase 1 study, the Pac+CB-839 combination was well tolerated and demonstrated clinical activity in a cohort of heavily pretreated pts with TNBC (22% overall response rate [ORR]; 59% disease control rate [DCR] at ≥600 mg BID dose [n=37]), including those with taxane-refractory disease or of AA (Kalinsky et al. SABCS 2017). Here we present initial findings from an ongoing phase 2 study of Pac+CB-839 in pts with advanced TNBC (NCT03057600).
Methods: Key eligibility criteria included advanced/metastatic TNBC with ECOG PS 0-1 and either 0 (1L) or ≥2 prior lines (3L+) of therapy for metastatic disease were eligible (N=112 pts max). Prior taxane therapy for the 3L+ cohorts was required. For the 1L cohorts, prior neo/adjuvant therapy (including taxanes) was allowed if time to recurrence was &gt;12 months (mo). Pts were allocated to cohorts by line of therapy (1L or 3L+) and ancestry (AA or non-AA) in order to ensure sufficient enrollment to each of these subgroups. Pts received oral CB-839 (800 mg BID) in combination with intravenous Pac (80 mg/m2 on days 1, 8, 15 of each 28-day cycle). The primary endpoint was ORR. Other endpoints included overall survival, duration of response, clinical benefit rate, biomarker analyses, and safety.
Results: As of the June 15, 2018 data cutoff, 44 pts have been enrolled (median age, 59 yrs; 41% AA; n=22 each in 1L or 3L+). In the 1L cohort, 64% and 36% had ECOG PS of 0 and 1, respectively. In the 3L+ cohort, 36% and 55% had ECOG PS of 0 and 1, respectively (9% unknown). Of 14 evaluable 1L pts, ORR was 43% and DCR (partial response [PR] + stable disease ≥8 weeks [SD]) was 79% (n=6 PR; n=5 SD). Of 16 evaluable 3L+ pts, ORR was 6% and DCR was 25% (n=1 PR; n=3 SD). Most common CB-839- or Pac-related treatment-emergent adverse events (TEAE) occurring in &gt;15% included fatigue (34%), diarrhea (23%), nausea (18%), neuropathy (18%), alopecia (16%), anemia (16%), AST increased (16%), and hypophosphatemia (16%). Treatment-related grade ≥3 TEAEs occurred in 8 (18%) pts; the most common (occurring in &gt;1 pt) were hypophosphatemia and neutrophil count decreased (n=2 each). No events of febrile neutropenia were reported.
Conclusions: Early analyses of this phase 2 study show that Pac+CB-839 has clinical activity and is well tolerated in pts with advanced/metastatic TNBC. Updated data including exploratory biomarker analysis will be presented.
Citation Format: Vidal G, Kalinsky K, Stringer-Reasor E, Lynce F, Cole J, Valdes-Albini F, Soliman H, Nikolinakos P, Silber A, DeMichele A, Ali H, Graham D, Giguere J, Brufsky A, Liang Y, Holland S, Fiji G, O'Keeffe B, Gogineni K. Efficacy and safety of CB-839, a small molecule inhibitor of glutaminase, in combination with paclitaxel in patients with advanced triple negative breast cancer (TNBC): Initial findings from a multicenter, open-label phase 2 study [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-20-07.