Phase Ib study of selinexor and eribulin combination in advanced solid tumors and triple-negative breast cancer.
Authors: Nelson Blessie Elizabeth , Saleem Sadia , Damodaran Senthil , Somaiah Neeta , Piha-Paul Sarina Anne , Moore Julia Ann , Yilmaz Bulent , Karp Daniel D. , Dumbrava Ecaterina Elena , Tsimberidou Apostolia Maria , Hong David S. , Rodon Ahnert Jordi , Booser Daniel J. , Ibrahim Nuhad K. , Conley Anthony Paul , Bhosale Priya , Rojas Hernandez Cristhiam Mauricio , Tripathy Debu , Naing Aung , Meric-Bernstam Funda 
Published: June 2022

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Background: Selinexor (KPT-330) is potent inhibitor of Exportin-1. In vitro, Selinexor was found to be synergistic with eribulin in triple negative breast cancer (TNBC) cell lines and enhanced antitumor activity of eribulin in TNBC patient-derived xenografts (PMID 28810913). Methods: We conducted a phase Ib trial in combination of selinexor and eribulin using 3 + 3 design in dose escalation for patients with advanced solid tumors and in TNBC in dose expansion cohort. Eribulin could be discontinued after combination for 6 cycles at physician discretion. Primary objectives: Safety, Recommended Phase 2 Dose (RP2D). Secondary Objectives: Objective Response Rate (ORR), Duration of Response (DOR), Disease Control Rate (DCR), Overall Survival (OS) and Progression Free Survival (PFS). Results: 31 patients, TNBC (n = 19), sarcoma (n = 8), others (n = 4) enrolled in dose escalation (n = 10) and dose expansion phases (n = 21). Median prior therapies:4 (1–6). Study initiated selinexor at 60mg twice weekly and eribulin 1.4mg/m2 on Day1, Day8 every 3 weeks which led to 1 Dose Limiting Toxicity (DLT) and hence, selinexor 80mg once weekly and eribulin 1mg/m2 was elected as RP2D due to efficacy and tolerability. As of 01/15/2022, of 29 patients (94%) who have discontinued treatment, 24 (77%) were due to progressive disease, 3 (10%) withdrew consent and 2 (6%) due to toxicities (G1 pneumonitis; G3 neutropenia) while 2 (6%) remain on trial. All 31 patients had at least one treatment emergent adverse event (TEAE) while most prevalent TEAEs (all grades) were leukopenia (77%), nausea (71%), anemia and neutropenia (68%) and fatigue (48%). The most common G3/4 TEAE were leukopenia (26%) and neutropenia (29%). 2 DLTs occurred; 1 in first dose level (DL); 1 in second DL dosed at selinexor 80 mg once weekly due to G3 neutropenia. ORR for all was 10% while DCR (SD+PR+CR) > 6 months seen in 3 (15%) TNBC and 2 (20%) sarcoma patients. The median OS and PFS for all were 12.3 (7.3, 27.3) months and 2.3 (1.6, 4.1) months. In dose escalation cohort, ORR was 10% where one patient (3%) with vaginal SCC had confirmed PR (-44%) for 2.1 months. Five patients (62.5%) with sarcoma had stable disease (SD). One patient with high grade sarcoma has SD for 68 months and remains on selinexor after 4 months of eribulin and selinexor. In TNBC dose expansion (n = 19), ORR was 10.5% with 2 confirmed PRs and median duration of response (DOR) of 10.8 months. One patient who has remained on treatment for 18 months, and after receiving 8 months of eribulin and selinexor, remains on selinexor with 100% target regression and an indeterminate brain lesion. Conclusions: Selinexor with eribulin is safe with manageable toxicity profile and modest overall clinical efficacy. Durable responses and disease control were observed with metastatic TNBC. Further study is needed to examine the determinants of response to this combination. Clinical trial information: NCT02419495.