Background: CB-839 is a first-in-class oral highly selective inhibitor of glutaminase (GLS), a mitochondrial enzyme that plays a key role in cancer cell metabolism. Triple negative breast cancer (TNBC) has high GLS expression and demonstrates high glutamine utilization and glutamine dependence in clinical and preclinical studies. CB-839 has monotherapy antitumor activity in vitro and in vivo in preclinical models of TNBC, and also demonstrates synergistic anti-cancer activity with the standard of care agent paclitaxel (Pac).
In an ongoing Phase 1 study, CB-839 combined with Pac (Pac-CB) is being evaluated in patients (pts) with metastatic TNBC. We previously reported that Pac-CB was well-tolerated and active in heavily pre-treated TNBC pts, including those previously refractory to taxane treatment for metastatic disease. We report here updated results from this ongoing study.
Methods: Pts with refractory metastatic TNBC (prior taxane therapy allowed) received escalating doses of CB-839 (400-800 mg BID) in combination with full dose Pac of 80 mg/m2 Days 1, 8, 15 every 28 days. After demonstration of safety and tolerability, an expansion cohort was opened at the CB-839 recommended phase 2 dose of 800 mg PO BID.
Results: As of the May 2017 data cut, 45 pts have enrolled across the dose escalation and expansion cohorts (7 pts at 400 mg, 12 at 600 mg, and 26 at 800 mg). 15 pts (33%) have received ≥5 prior lines of systemic therapy for metastatic disease (median 3 prior lines), and 39 pts (87%) have received prior taxane therapy. The Pac-CB regimen has been well tolerated with the most frequent treatment-related Grade ≥3 AEs being neutropenia (24%), anemia (7.6%), fatigue (2.6%), WBC decreased (2.6%), and peripheral neuropathy (2.6%). At CB-839 doses ≥600 mg BID (n=27 RECIST-evaluable), the ORR has been 22% and disease control rate (DCR=CR+PR+SD) 59%; in the subgroup of pts refractory to previous taxane therapy (n=19) the ORR has been 21% (4 pts) and DCR 47% (9 pts). The highest ORR in this study has been seen in pts of African ancestry (AA, n=11 RECIST evaluable) with an ORR of 36% (4 pts) and DCR 55% (6 pts), with all 4 AA responders being refractory to prior taxane treatment for advanced/metastatic disease.
Conclusions: TNBC has elevated glutamine metabolism that requires mitochondrial GLS. In TNBC pts with heavy pretreatment and previous taxane exposure, the combination of CB-839 with Pac has demonstrated clinical activity including a 21% ORR in pts refractory to taxane. Notably, in patients of African ancestry, a population reported to have especially high glutamine utilization in TNBC tumors, the encouraging ORR of 36% suggests a potential genetic association with treatment response. The Pac-CB regimen has been well tolerated in late line TNBC pts, including a Gr 3 neuropathy signal of only 2.6%. A Phase 2 study, CX-839-007, has been initiated to further evaluate the activity and safety of Pac-CB in pts with TNBC, including defined cohorts of pts with 1st line and 3rd line+ metastatic disease in pts of African and non-African ancestry. Responses in relation to genetic background, molecular subtype of TNBC and glutamine biology will be studied.
Citation Format: Kalinsky K, Harding JJ, DeMichele A, Infante JR, Gogineni K, Owonikoko TK, Isakoff S, Iliopoulos O, Patel MR, Munster P, Telli ML, Jenkins Y, Fiji GP, Whiting SH, Meric-Bernstam F. Phase 1 study of CB-839, a first-in-class oral inhibitor of glutaminase, in combination with paclitaxel in patients with advanced triple negative breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr PD3-13.