Phase Ib trial of selinexor (SEL) in combination with nivolumab (NIVO) alone or nivolumab plus ipilimumab (NIVO+IPI) in patients (pts) with advanced malignancies: The renal cell carcinoma (RCC) experience.

4551 Background: SEL is a first-in-class nuclear exportin 1 inhibitor, which blocks the transport of several proteins involved in cancer-cell growth from the nucleus to the cytoplasm. A syngeneic RENCA mouse model showed that SEL combined with checkpoint blockade resulted in increased effector and activated T cells, and NKT cells and reductions in myeloid cells and Tregs. We hypothesized that SEL+NIVO and SEL+NIVO+IPI are well tolerated and improve the overall response rate (ORR) observed with anti-PD1/CTLA-4. Methods: NCT02419495 is an open label, single center phase IB study of SEL with multiple standard chemotherapy or immunotherapy regimens in pts with advanced malignancies using 3 + 3 design in dose escalation. For SEL+NIVO+IPI, SEL was 60 mg (N = 4) or 80 mg (N = 6) given P.O. weekly with NIVO 3 mg/kg x 4 cycles then 480 mg Q4W plus IPI 1 mg/kg Q3W for 4 cycles only. For SEL+NIVO, SEL was 40 mg twice a week (N = 8), or 60 mg twice a week (N = 11) given with NIVO 240 mg Q2W or 480 mg Q4W. Primary objective was to establish the safety and tolerability of SEL+NIVO and SEL+NIVO+IPI. Secondary objectives included ORR and progression free survival (PFS). Results: 29 pts with RCC (25 males) were enrolled (table), including 3 pts with nonclear cell RCC (nccRCC), with a median age of 64 years (IQR 56-69). 21 patients (72%) had prior systemic therapies. Most common SEL or NIVO/IPI treatment-related ≥ grade (G) 3 adverse events (AEs) included endocrine disorders (N = 3), hyponatremia (N = 3), leukopenia (N = 3), transaminitis (N = 3), thromboemobolic events (N = 2), asymptomatic lipase increased (N = 2), anemia (N = 1), pneumonitis (N = 1), nephritis (N = 1), colitis (N = 1), fatigue (N = 1). Two pts discontinued therapy due to AEs (G3 pneumonitis from SEL+NIVO+IPI and G3 transaminitis from SEL+NIVO, respectively). At a median follow up of 17.5 months, 5 (17%) pts achieved a PR, and 17 (59%) achieved a stable disease (SD). The median PFS for the entire cohort was 17.5 months (SEL+NIVO+IPI: 7.2 months, SEL+NIVO: 17.5 months). Among the patients with clear cell RCC who received SEL+NIVO+IPI as first line (1L) therapy (N = 4), all (100%) achieved SD as best overall response. Among the patients with ccRCC who received SEL+NIVO as 1L (N = 2), one patient achieved confirmed PR and the other achieved SD. The median overall survival (OS) was 27.8 months (SEL+NIVO+IPI: unreached, SEL+NIVO: 21.3 months). Conclusions: Treatment with SEL in combination with NIVO or NIVO+IPI is well-tolerated and shows modest clinical activity as compared to historic NIVO or NIVO+IPI activity. Clinical trial information: NCT02419495.