82P - NEXUS: A phase I dose escalation study of selinexor plus nivolumab and ipilimumab in Asian patients with advanced/metastatic solid malignancies

Background

Selinexor (SEL) is an oral inhibitor of nuclear export protein Exportin 1 (XPO1) previously shown to upregulate PD-L1 and CTLA-4 expression. We hypothesized that the combination of SEL, nivolumab (NIVO) and ipilimumab (IPI) is safe and may demonstrate activity in Asian patients with treatment refractory solid organ cancers.

Methods

We investigated the safety, tolerability and antitumor activity of escalating doses of SEL in combination with NIVO+IPI. Patients were enrolled in a 3+3 design. NIVO and IPI were dosed at 240mg Q2W and 1mg/kg Q6W respectively. SEL was dosed with a 2 week run-in prior to triplet therapy, at dose levels (DL) 1 and 2 at 40mg weekly and 60mg weekly respectively. Dose-limiting toxicity (DLT) was assessed over the first 6 weeks.

Results

Twelve patients were enrolled; 11 were evaluable for response and 6 were evaluable for DLT (1 had a non-treatment related stroke and 5 had progressive disease [PD] prior to completion of the DLT period). Median age was 64.5 (range 39-78). Median lines of prior therapy was 3 (range 2-6). Dose escalation proceeded through DL1 (n=7, 3 evaluable for DLT) and DL2 (n=5, 3 evaluable for DLT). No DLTs were observed. No patients required dose reduction of SEL. Most frequent treatment related AEs were fatigue (5/12; G≥3=1), nausea (5/12; G≥3=0), anorexia (4/12; G≥3=0), transaminitis (2/12; G≥3=0), hypomagnesemia (2/12; G≥3=0). The recommended phase 2 dose was SEL 60mg weekly with NIVO+IPI. One patient had partial response (PR; progression-free survival [PFS] 61 days), 3 had stable disease (SD; 141, 344, 442 days) and 7 had PD. All patients with SD or PR had previously progressed on immunotherapy. Table: 82P

Conclusions

SEL in combination with NIVO+IPI was well tolerated without any unexpected safety signals. The combination showed promising anti-tumor activity in Asian patients with advanced malignancies who had failed prior immunotherapy, and merits further investigation. Translational studies are underway.

Clinical trial identification

NCT04850755.

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Karyopharm Therapeutics provided funding for the study.

Disclosure

R. Sundar: Financial Interests, Personal, Advisory Board: Bristol Myers Squibb, Merck, Eisai, Bayer, Taiho, Novartis, MSD, GSK, DKSH, Astellas; Financial Interests, Personal, Invited Speaker: MSD, Eli Lilly, BMS, Roche, Taiho, AstraZeneca, DKSH, Ipsen; Financial Interests, Personal, Stocks/Shares: Teladoc; Financial Interests, Institutional, Advisory Board: Paxman Coolers; Financial Interests, Personal and Institutional, Local PI: Taiho, MSD, BMS, Novartis; Non-Financial Interests, Personal, Advisory Role: Paxman Coolers; Non-Financial Interests, Personal, Principal Investigator: MSD, Natera. W.P. Yong: Financial Interests, Personal, Invited Speaker: DKSH Singapore Pte Ltd, AstraZeneca Singapore Pte Ltd, Bristol Myers Squibb (S) Pte Ltd, MSD Pharma (Singapore) Pte Ltd, Novartis (S) Pte Ltd; Financial Interests, Personal, Advisory Board: Ipsen Pharma Singapore Pte Ltd, Amgen; Financial Interests, Institutional, Local PI: Novartis (S) Pte Ltd, Amgen. N.Y.L. Ngoi: Financial Interests, Institutional, Invited Speaker: MSD, AstraZeneca, ASGO, JSGO; Financial Interests, Institutional, Advisory Board: Merck/Pfizer, AstraZeneca. A. Wong: Financial Interests, Personal, Funding: Otsuka Pharmaceuticals; Financial Interests, Personal, Advisory Board: Pfizer, Eisai, AstraZeneca, Eli Lilly-DKSH. R.A. Soo: Financial Interests, Personal, Advisory Board: Amgen, AstraZeneca, Bayer, BMS, Lily, Merck, Novartis, Pfizer, Roche, Taiho, Takeda, Yuhan, Janssen, Merck Serono, Puma Biotech, Thermo Fisher; Financial Interests, Personal, Invited Speaker: Boehringer Ingelheim; Financial Interests, Institutional, Research Grant: AstraZeneca, Boehringer Ingelheim. C.E. Chee: Financial Interests, Institutional, Advisory Board: AstraZeneca, Roche, Merck; Financial Interests, Institutional, Invited Speaker: Amgen; Financial Interests, Institutional, Other, Educational meeting chair: Pierre Fabre. J. Lim: Financial Interests, Personal, Advisory Board: pfizer, Novartis, AstraZeneca, DKSH, MSD, Everest Medicine; Financial Interests, Personal, Invited Speaker: AstraZeneca, MSD; Financial Interests, Institutional, Local PI: Synthon pharmaceuticals, Daiichi, Taiho pharmaceuticals; Financial Interests, Institutional, Funding: CTI biopharma. B. Goh: Financial Interests, Institutional, Invited Speaker: MSD; Financial Interests, Institutional, Advisory Board: Bayer Healthcare; Financial Interests, Personal, Other, Consultancy: Adagene pharmaceutical; Financial Interests, Institutional, Research Grant, Support for investigator initiated trial: MSD; Financial Interests, Institutional, Other, Pharmaceutical support for clinical trial: BMS; Financial Interests, Institutional, Other, Pharmaceutical support for investigator initiated clinical trial: Taiho pharmaceuticals; Financial Interests, Institutional, Coordinating PI: Adagene, Bayer; Financial Interests, Institutional, Local PI: Pfizer; Financial Interests, Institutional, Local PI, Conducting clinical trial: alx; Financial Interests, Institutional, Local PI, Pharmaceutical phase 1 trial: Novartis; Non-Financial Interests, Institutional, Other, Lead clinical trial platform of the Singapore Translational Cancer Consortium: Consortium for Clinical Research and Innovation Singapore; Non-Financial Interests, Personal, Member: ASCO. S.C. Lee: Financial Interests, Personal, Advisory Board, Advisory board, speaker invitations: Pfizer, Novartis, AstraZeneca, Roche, MSD; Financial Interests, Personal, Advisory Board, Advisory Board: Eli Lilly; Financial Interests, Institutional, Research Grant: Pfizer, ACT Genomics, Eisai, Taiho, MSD, Karyopharm, ASLAN Pharmaceuticals; Financial Interests, Institutional, Local PI: Roche, Novartis, Daiichi sankyo, BMS, AstraZeneca; Financial Interests, Personal, Steering Committee Member: AstraZeneca. D.S. Tan: Financial Interests, Personal, Invited Speaker: AstraZeneca, MSD, Merck Serono, Roche, Eisai, GSK, Takeda; Financial Interests, Personal, Advisory Board: AstraZeneca, Bayer, MSD, Eisai, Roche, Genmab, GSK, Boehringer Ingelheim; Financial Interests, Personal, Stocks/Shares: Asian Microbiome Library (AMiLi); Financial Interests, Institutional, Research Grant: Roche, Bayer, Karyopharm Therapeutics, AstraZeneca; Financial Interests, Institutional, Coordinating PI: AstraZeneca, Bergen Bio; Financial Interests, Institutional, Local PI: Zeria Pharmaceutical Co Ltd, Bayer, Byondis B.V.; Non-Financial Interests, Personal, Leadership Role, Ex society president: Gynecologic Cancer Group Singapore; Non-Financial Interests, Personal, Member of Board of Directors: Gynaecologic Cancer Intergroup (GCIG); Non-Financial Interests, Personal, Leadership Role, Ex- Chair: Asia-Pacific Gynecologic Oncology Trials Group (APGOT); Non-Financial Interests, Institutional, Product Samples, Research Study: MSD, Eisai, AstraZeneca, Cyclacel Pharmaceuticals. All other authors have declared no conflicts of interest.