Abstract PD6-13: Phase 1b/2 study to evaluate eribulin mesylate in combination with pembrolizumab in patients with metastatic triple-negative breast cancer
Authors: Tolaney SM , Kalinsky K , Kaklamani V , Savulsky C , Olivo M , Aktan G , Kaufman PA , Xing D , Almonte A , Misir S , Karantza V , Diab S 
Published: February 2018

Abstract
Background: Eribulin mesylate (ERI), a nontaxane microtubule inhibitor with effects on tumor biology (increased vascular perfusion, reversal of epithelial to mesenchymal transition), is approved as a monotherapy for the treatment of patients (pts) with metastatic breast cancer who received ≥2 prior chemotherapeutic regimens for metastatic disease. In a pooled analysis, ERI significantly prolonged OS compared with capecitabine or treatment of physician's choice in pts with metastatic triple-negative breast cancer (mTNBC; 12.9 vs 8.2 mo, n=428). Pembrolizumab (PEM) is a human programmed death (PD) receptor-1–blocking antibody approved for the treatment of several advanced cancers. In a phase (Ph) 2 study in mTNBC, PEM monotherapy as first-line therapy demonstrated ORR, 23%; median PFS, 2.1 mo [95% CI 2.0-3.9], and in pts pretreated with ≥1 prior chemotherapy demonstrated ORR, 5%; median OS, 8.9 mo [95% CI 7.2-11.2]).
Methods:This open-label Ph 1b/2 trial enrolled pts (aged ≥18 yrs; ECOG PS ≤1) with mTNBC treated with ≤2 prior lines of chemotherapy for metastatic disease. Ph 1b included a safety cohort of ≥6 pts who received intravenous (IV) ERI 1.4 mg/m2 on day (d) 1 and d8 and IV PEM 200 mg on d1 of a 21-d cycle. In Ph 2, pts were enrolled based on prior chemotherapy in the metastatic setting [0 vs 1–2 lines]. Primary endpoints: safety, tolerability (Ph 1b), and ORR (Ph 2); secondary endpoints: PFS, OS, and efficacy in PD-L1+ pts.
Results: We report data from 82 of 104 enrolled pts (data cut-off Nov 1, 2016).The RP2D was ERI 1.4 mg/m2 on d1 and d8 and PEM 200 mg on d1 of a 21-d cycle. Most common treatment-emergent adverse events (TEAEs) were fatigue (73.2%), nausea (51.2%), peripheral sensory neuropathy (46.3%), alopecia (43.9%), and pyrexia (36.6%). Most common Grade (G) 3 or 4 TEAEs related to ERI: neutropenia (29.3%), peripheral neuropathy (8.5%), and asthenia/fatigue (7.3%). G3/4 immune-related TEAEs related to PEM: 19.5% of pts. TEAEs that led to drug withdrawal/dose reduction: 18.3%/28.0% of pts. G5 events: 3 pts (respiratory failure, pleural effusion, and multiple organ failure; none related to study drug). Response was irrespective of PD-L1 status (Table1). Results of the final analysis will be available for presentation.
Overall (n=82)No prior chemotherapy in metastatic setting (n=48)1-2 Prior lines of chemotherapy in metastatic setting (n=34)PD-L1+ (n=35)PD-L1- (n=36)ORR, n (%) [95% CIa]21 (25.6) [16.8, 35.4]12 (25.0) [14.0, 37.8]9 (26.5) [13.3, 41.8]9 (25.7) [12.9, 40.8]9 (25.0) [12.5, 39.8]CBRb, n (%)25 (30.5)13 (27.1)12 (35.3)10 (28.6)12 (33.3)DCRc, n (%)46 (56.1)28 (58.3)18 (52.9)19 (54.3)21 (58.3)Median PFS, mo [95% CI]4.1 [2.3-4.8]4.1 [2.2-4.9]3.9 [2.1-6.3]4.1 [2.1-4.8]4.1 [2.3-6.3]Median OS, mo [95% CI]NE [17.7-NE]17.7 [13.7-NE]NE [13.1-NE]----a Credible interval from Bayesian analysis; b clinical benefit rate = CR+PR+SD; c disease control rate = CR+PR+SD ≥24 weeks. NE, not estimable.
Conclusions: ERI+PEM was well tolerated and demonstrated activity in pts with mTNBC. The combination resulted in improved ORR, with longer PFS, OS, and comparable TEAEs to those observed with either treatment as monotherapy. Further exploration of this combination is warranted.
Citation Format: Tolaney SM, Kalinsky K, Kaklamani V, Savulsky C, Olivo M, Aktan G, Kaufman PA, Xing D, Almonte A, Misir S, Karantza V, Diab S. Phase 1b/2 study to evaluate eribulin mesylate in combination with pembrolizumab in patients with metastatic 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 PD6-13.