Abstract 82P
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
Evaluable patients with PR/SD | Tumor | Prior immunotherapy | Best response | Change in sum of diameters of target lesions at best response (%) | PFS (days) |
1 | Cervical squamous cell carcinoma | Yes | PR | -33.0 | 61 |
2 | Metastatic carcinoma of unknown primary | Yes | SD | -18.8 | 442 |
3 | Hepatocellular Carcinoma | Yes | SD | +17.6 | 141 |
4 | Hepatocellular Carcinoma | Yes | SD | -4.9 | 344 |
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.
Resources from the same session
144P - Integrated clinical and genomic models using machine-learning methods to predict the efficacy of paclitaxel-based chemotherapy in patients with advanced gastric cancer from K-MASTER project
Presenter: Jwa Hoon Kim
Session: Poster Display
Resources:
Abstract
145P - Tislelizumab (TIS) + chemotherapy (Chemo)/chemoradiotherapy (CRT) as neoadjuvant treatment for resectable esophageal squamous cell carcinoma (R-ESCC)
Presenter: Longqi Chen
Session: Poster Display
Resources:
Abstract
146P - Phase (ph) Ib results of bemarituzumab (BEMA) added to capecitabine/oxaliplatin (CAPOX) or S-1/oxaliplatin (SOX) with or without nivolumab (NIVO) for previously untreated advanced gastric/gastroesophageal junction cancer (G/GEJC): FORTITUDE-103 study
Presenter: Keun-Wook Lee
Session: Poster Display
Resources:
Abstract
147P - Four-year overall survival (OS) update from the phase III HIMALAYA study of tremelimumab plus durvalumab in unresectable hepatocellular carcinoma (uHCC)
Presenter: Stephen Chan
Session: Poster Display
Resources:
Abstract
148P - Safety and efficacy of atezolizumab (Atezo) + bevacizumab (Bev) in Japanese patients (pts) with unresectable hepatocellular carcinoma (uHCC): Preliminary analysis of a prospective, multicenter, observational study (ELIXIR)
Presenter: Teiji Kuzuya
Session: Poster Display
Resources:
Abstract
149P - A prospective observational study of MSI screening in unresectable chemotherapy-naïve advanced gastric cancer/gastroesophageal junction cancer: WJOG13320GPS
Presenter: Yukiya Narita
Session: Poster Display
Resources:
Abstract
150P - Anlotinib plus chemotherapy as first-line therapy for gastrointestinal tumor patients with unresectable liver metastasis: Updated results from a multi-cohort, multi-center phase II trial ALTER-G-001-cohort C
Presenter: Junwei Wu
Session: Poster Display
Resources:
Abstract
151P - Relationship between depth of response and early tumor shrinkage with overall survival in advanced pancreatic cancer
Presenter: EMIKA KUROKI
Session: Poster Display
Resources:
Abstract
152P - Interim analysis of the NAPOLEON-2 study: Safety evaluation of nanoliposomal irinotecan with fluorouracil and folinic acid for unresectable pancreatic cancer patients with prior biliary drainage
Presenter: Futa Koga
Session: Poster Display
Resources:
Abstract
153P - IMbrave150: Exploratory analyses for investigating associations between overall survival (OS) and depth of response (DpR) or duration of response (DoR) in patients (pts) with unresectable hepatocellular carcinoma (HCC)
Presenter: Masatoshi Kudo
Session: Poster Display
Resources:
Abstract