Open-label phase 1 study evaluating the tolerability and anti-tumor activity of selinexor and pembrolizumab in colorectal cancer.
Authors: Golan Talia , Shentzer Kutiel Talia , Geva Ravit , Gottfried Maya , Zick Aviad , Dudnik Julia , Netiv Einat , Zhang Yue , Yang Fan , Sharoni Shmuel , Duic J Paul , Meng Changting , Michel Dayana , Shah Jatin J. , Kauffman Michael G. , Shacham Sharon , Zer Alona 
Published: June 2021

e15579 Background: Colorectal cancer (CRC) is the fourth leading cause of cancer-related deaths worldwide and is heterogenous in its molecular features. Checkpoint inhibitors (CPIs) are approved for only about 5% of unresectable or metastatic CRC with MSI-high (MSI-H)/deficient MMR (dMMR); however, they do not benefit the majority of advanced CRC patients. Selinexor is a first-in-class, oral selective inhibitor of nuclear export (SINE) compound with demonstrated activity in cancers with RAS mutations which are found in ̃50% of CRC. This study aims to evaluate the combination of selinexor with pembrolizumab, an anti-PD-L1 CPI, in chemotherapy refractory CRC. Methods: This phase 1/2, open-label study enrolled patients with advanced/metastatic CRC with progression after prior chemotherapy (1-3 lines for KRAS wild-type (wt), 1-2 for KRAS mutant (mut)), initially into a selinexor monotherapy period to evaluate bioavailability/bioequivalence of a new selinexor formulation, followed by a combination therapy where patients were treated with selinexor 80 mg PO QW and pembrolizumab 200 mg IV every 3 weeks. Patients were assessed for anti-tumor activity, safety, and tolerability of the combination therapy. Results: Enrollment in this study has been completed, and 29 patients have received at least 1 dose of combination therapy: median age was 56 years, 19 (65.5%) male, and 15 (51.7%) have RAS mutations. Median number of lines of prior antineoplastic therapies was 2. Median duration of combination treatment is 39 days (range: 1-246 days). Seventeen patients (58.6%) discontinued therapy mostly due to progressive disease, and 18 patients are evaluable for response. Best response was stable disease in 7 patients (6 of them (85.7%) had RAS mut CRC), and progressive disease in 11 patients (8 of them (72.7%) had RAS wt CRC. Median progression free survival (PFS) is 120 days for patients with RAS mut CRC and 41 days for those with RAS wt CRC. Notably, none of the RAS mut had MSI-H/dMMR CRC while one RAS wt with SD had MSI-H/dMMR CRC. The most common treatment-emergent adverse events (total; ≥Grade 3) were nausea (72.4%; 0%), vomiting (41.4%; 0%), decreased appetite (34.5%; 0%), and fatigue (34.5%; 10.3%). Seven patients (24.1%) had at least 1 treatment-emergent serious adverse event. Conclusions: Selinexor in combination with pembrolizumab has demonstrated disease control in patients with chemotherapy refractory advanced/metastatic CRC. Greater anti-tumor activity was observed in patients with RAS mutations despite absence of MSI-H/dMMR. The therapy was well tolerated with no unanticipated adverse events observed. These results warrant further investigation of selinexor in combination with pembrolizumab in CRC, particularly in CRC with RAS mutations. Clinical trial information: NCT04256707.