Selinexor in Combination with R-CHOP for Frontline Treatment of Non-Hodgkin Lymphoma: Results of a Phase 1b Study (2020)

Introduction: The chemoimmunotherapeutic regimen of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) is curative for many patients (pts) with diffuse large B cell lymphoma (DLBCL), but a subset of high-risk pts, including those with transformed and double-hit lymphomas, are less likely to be cured by R-CHOP. Exportin-1 (XPO1), a nuclear export protein, is overexpressed in NHL and correlates with chemotherapy-resistance and poor prognosis. Overexpression of XPO1 results in increased nuclear export of tumor suppressor proteins (TSPs) leading to their functional inactivation, and enhanced expression of Bcl-2 family members and c-Myc. Inhibition of XPO1 leads to TSP activation and oncoprotein reduction. Selinexor, a novel, oral selective inhibitor of XPO1, was approved by the FDA for DLBCL after 2 prior therapies based on an overall response rate (ORR) of 29% including a 13% complete response (CR) rate. Our previous preclinical results in vitro and in vivo showed potent additive or synergistic cytotoxicity of selinexor with chemotherapy in xenograft NHL mouse models. We evaluated the safety and preliminary efficacy of the combination of selinexor with R-CHOP chemotherapy in pts with untreated NHL. Methods: This is an open-label phase 1b study to determine the safety, tolerability, recommended phase 2 dose (RP2D) and maximum tolerated dose (MTD) of selinexor in combination with R-CHOP in pts with NHL. Pts with stage III/IV DLBCL (including transformed DLBCL) who had no prior therapy, and pts with indolent lymphomas who had either no prior therapy or received one prior therapy not containing an anthracycline, were included. A standard 3 + 3 dose escalation design in which pts received 6 cycles of R-CHOP (rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2 IV, vincristine 0.5 mg/kg on day 1, prednisone 100 mg po on days 1-5 in a 21 day cycle) and 60 mg or 80 mg selinexor on days 1, 8, and 15 of each cycle was used. Weekly selinexor maintenance, at the dose employed at the conclusion of R-CHOP, was continued for an additional year. Blood samples were obtained on days 0, 3, 5, 8 and 15 for RNA isolation followed by RT-PCR to evaluate the expression of targets or downstream effectors including XPO1, AABCG2, AKT, Bcl-2, Bax and ERK. Results: A total of 12 pts were enrolled: 10 pts had DLBCL (1 GCB, 5 non-GCB, 4 transformed from indolent NHL); 2 pts had follicular lymphoma. Median age was 55 years. Six pts received selinexor 60 mg weekly + R-CHOP and 6 pts received selinexor 80 mg weekly + R-CHOP. Among the first 3 pts in the 60 mg cohort, there was an episode of grade 3 supraventricular tachycardia and an episode of grade 3 syncope. No further cardiac events occurred amongst these 3 pts, and this cohort was expanded by 3 pts. No further serious cardiac adverse events (AEs) occurred for the entire cohort. Among the first 3 pts in the 80 mg cohort, 1 DLT occurred: grade 3 nausea and vomiting. There were more discontinuations and dose reductions in the 80 mg cohort than in the 60 mg cohort; The majority of AEs were grade 1 or 2 and included nausea (100%), fatigue (67%), skin and nail changes (58%), constipation (42%), dizziness (42%), sinus congestion (42%), and vomiting (42%) with nausea and fatigue lasting ~1-2 days. AEs leading to selinexor discontinuation in 5 pts included fatigue +/- nausea. Dose reductions occurred in 3 pts, all due to fatigue. 8 pts completed all 6 cycles of R-CHOP with Selinexor, and 6 continued maintenance therapy. 2 pts came off study for non-compliance. MTD was not reached, however because of the higher frequency of selinexor discontinuation and dose reductions in the 80 mg cohort, selinexor 60 mg weekly + R-CHOP is the recommended RP2D. Among 10 efficacy evaluable pts (6 at 60 mg and 4 at 80 mg), the ORR was 100%: 9 pts with a CR (including 4 non-GCB pts) and 1 with a PR. Median follow up is 476 days. In line with previous reports, XPO1 mRNA expression was consistiently increased in all pt blood samples at day 3. Conclusions: R-CHOP in combination with weekly selinexor showed encouraging preliminary efficacy with an ORR of 100% and CR of 90%. At the 60 mg selinexor dose level, AEs were manageable and milder (grade 1/2) than those previously reported with selinexor. The results of correlative studies performed were consistent with our preclinical findings. A phase 2 study of this combination is ongoing in frontline DLBCL and Richter's transformation (NCT03147885). Disclosures Seymour: Incyte: Research Funding; Janssen/Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Genentech: Research Funding; Seattle Genetics: Research Funding; Bristol-Myers Squibb: Research Funding. Ramchandren:Seattle Genetics, Sandoz-Novartis, Pharmacyclics, an AbbVie Company, Janssen, Bristol-Myers Squibb: Consultancy; Merck, Seattle Genetics, Janssen, Genentech: Research Funding. Yang:Protagonist: Research Funding; AROG: Research Funding; AstraZeneca: Research Funding; Jannsen: Research Funding. Bhutani:Sanofi: Consultancy, Research Funding. Azmi:Rhizen Phamaceuticals Inc, EISAI: Research Funding; GLC, Guidepoint: Consultancy. Zonder:Intellia, Amgen, Takeda, Janssen, Regeneron, Alnylam, Caelum, Oncopeptides: Consultancy; BMS, Celgene: Research Funding.