1489MO - A phase Ib/II study of selinexor as single agent and in combination with imatinib in patients with advanced gastrointestinal stromal tumor (GIST): SeliGIST/GEIS-41 trial

Background

Currently approved agents in metastatic GIST focus on targeted suppression of KIT or PDGFRA oncogenic activation. However, their clinical benefit after imatinib (IM) progression is still modest, suggesting the co-operation of KIT/PDGFRA-independent mechanisms in GIST cell survival. Selinexor is an oral, selective inhibitor of XPO1-mediated nuclear export, and preclinical studies evidenced antitumoral activity in GIST as single agent and in combination with IM in both IM-sensitive and IM-resistant models.

Methods

IM-resistant, advanced GIST patients (pts) were treated in two sequential cohorts: Cohort A studied IM 400 mg daily plus weekly selinexor at dose levels (DL) 1 (60 mg), DL2 (80 mg) and DL3 (100 mg) using a standard 3+3 dosing schema to determine the recommended phase II dose (RP2D) of the combination. Cohort B studied selinexor 60 mg twice weekly. Investigator-assessed response was evaluated every 8 weeks using RECIST 1.1.

Results

As of Feb 10, 2022, 30 pts were enrolled, 12 in Cohort A and 18 in Cohort B. Median age 57 (range 36-77), male 70%, mean prior therapies 4 (range 1-7). One dose limiting toxicity (DLT) occurred at DL3 (G3 nausea) in Cohort A. Other non-DLT G3/4 toxicities were fatigue (2/12 pts), anemia, neutropenia and vomiting (1 pt each). Common G1/2 toxicities (>4 pts) were nausea, vomiting and neutropenia. Grade 3/4 toxicities in Cohort B were fatigue (2/18 pts), neutropenia, thrombocytopenia, and GGT elevation (1 pt each). Common G1/2 toxicities (> 6 pts) were nausea, anemia, thrombocytopenia and fatigue. No unexpected toxicities were observed. All pts were evaluable for response. Clinical benefit rate (CBR = CR, PR, SD) ≥ 16 weeks was 42% (95% CI 0.181-0.685) in Cohort A and 28% (95% CI 0.213-0.354) in Cohort B. Two partial responses were observed in Cohort A (17%) vs. none in Cohort B. Median progression free survival was 3.3 months (95% CI 1.7-4.3) in Cohort A and 2.9 months (95% CI 1.8-5.6) in Cohort B.

Conclusions

Both schedules using selinexor as single agent and in combination with IM show manageable toxicity and clinical activity. At RP2D, selinexor + IM show encouraging antitumor activity in IM-resistant GIST (NCT04138381).

Clinical trial identification

NCT04138381.

Editorial acknowledgement

Legal entity responsible for the study

Spanish Sarcoma Research Group (GEIS).

Funding

Karyopharm.

Disclosure

C. Serrano: Financial Interests, Personal, Advisory Board: Deciphera Pharmaceuticals, Blueprint Medicines, Immunicum AB; Financial Interests, Institutional, Invited Speaker: Blueprint Medicines, Bayer AG; Financial Interests, Personal, Invited Speaker: PharmaMar; Financial Interests, Institutional, Research Grant: Deciphera Pharmaceuticals, Pfizer, Bayer AG; Financial Interests, Personal and Institutional, Invited Speaker: AROG Pharmaceuticals, Karyopharm; Non-Financial Interests, , Invited Speaker: Spanish Group for Sarcoma Research (GEIS), Spanish Society of Medical Oncology (SEOM); Other, Travel Grant: PharmaMar, Pfizer, Bayer AG. C.M. Valverde Morales: Financial Interests, Personal, Advisory Board: PharmaMar, Bayer, GSK, Mundipharma, Lilly, Boehringer Ingelheim; Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Institutional, Invited Speaker: Adaptimmune, Karyopharm, Lilly; Non-Financial Interests, Invited Speaker, President 2018-ongoing: GEIS- Spanish Sarcoma Group for Research. J. Cruz Jurado: Financial Interests, Personal, Advisory Board: PharmaMar, Roche, Lilly, Pfizer, Novartis, Gilead, AstraZeneca, Daiichii, Seagen, GSK, Bayer; Financial Interests, Personal, Invited Speaker: PharmaMar, Roche, Lilly, Pfizer, Novartis, Eisai, Gilead, Astra Zeneca, Daiichi, Seagen, Esteve, Roche. J. Martinez Trufero: Financial Interests, Personal, Advisory Board, Advisory Board meeting: PharmaMar, Eisai; Financial Interests, Personal, Invited Speaker: Roche, Eisai, Merck, Medicamenta; Financial Interests, Institutional, Invited Speaker, Clinical trial: RAIN Therapeutics, Blueprint, Lilly, Kariopharm Therapeutics, Syneos Health; Non-Financial Interests, Invited Speaker, Spanish Group of Sarcoma Research: GEIS Group; Non-Financial Interests, Invited Speaker, Spanish Group of Head and Neck cancer Research: TTCC Group. M. Giuppi: Financial Interests, Personal, Full or part-time Employment: PharmaMar. B. Suarez: Financial Interests, Personal, Full or part-time Employment: Merk. All other authors have declared no conflicts of interest.