1721MO - Safety and efficacy of olutasidenib, an IDH1 mutant inhibitor, for the treatment of recurrent/relapsed or locally advanced or metastatic IDH1 mutated chondrosarcoma

Background

Chondrosarcomas (CS) are rare cartilaginous neoplasms with conventional CS (cCS) accounting for 90% of CS. Other variants consist of dedifferentiated, mesenchymal, and clear cell which all have distinct clinicopathologic features. Surgical excision is the mainstay of treatment. Chemotherapy is ineffective in cCS. Mutations in isocitrate dehydrogenase 1/2 (IDH1/2m+) occur in 65% of CS and are thought to contribute to tumorigenesis. Consequently, inhibition of IDH1/2 m+ represents an attractive therapeutic option. We report the safety and efficacy of olutasidenib (OLU), an IDH1m+ inhibitor approved for recurrent/relapsed (R/R) AML, in patients with CS.

Methods

This analysis includes patients with R/R, locally advanced or metastatic CS treated with OLU 150mg BID in a phase Ib/II study evaluating OLU in IDH1m+ advanced solid tumors (NCT03684811).

Results

23 patients were enrolled and 16 had cCS, 5 dedifferentiated and 1 each myxoid or unknown subtypes. Median age at consent was 57 years (yrs) (30-71) with a male preponderance (74%). Median number of prior regimens was 2 (1-5). Tumor grade (Gr) included 1 (4%) Gr1, 7 (30%) Gr2, 7 (30%) Gr3, and 8 (35%) unknown. At screening, 17 (74%) patients had metastatic disease while 2 (9%) had locally advanced disease, and 4 (17%) were unknown. 91% (21) patients experienced a treatment emergent adverse event (TEAE) with 48% (11) with serious. 3 (13%) discontinued OLU due to a TEAE. In 21 response-evaluable patients, 11 (52%) had stable disease (SD), 8 (38%) had progressive disease (PD), and 2 (10%) not evaluable. Overall median PFS (mPFS) was 2.71 months (mos) (95% CI: 1.71, 4.88). Subset analysis of the 16 cCS patients showed 10 (63%) SD and 6 (37%) PD. mPFS in this cohort was 3.55 mos (95% CI: 1.74, 5.10) and among the 10 with SD, mPFS was 4.88 mos (95% CI: 1.81, 10.5) with 6 and 12 mos PFS at 100% and 90%, respectively. Notably, following disease progression, 2 patients continued OLU for >2 yrs due to clinical benefit including resolution of CNS metastatic lesions in one.

Conclusions

OLU was well tolerated and conferred durable disease control in cCS. OLU may represent a treatment option for patients with IDH1m+ cCS who otherwise have no other effective treatment.

Clinical trial identification

NCT03684811.

Editorial acknowledgement

Legal entity responsible for the study

Rigel Pharmaceuticals, Inc.

Funding

Rigel Pharmaceuticals, Inc.

Disclosure

R.L. Jones: Financial Interests, Personal, Advisory Board, I worked as a consultant.: Adaptimmune, Athenex, Bayer, Boehringer Ingelheim, Blueprint, Clinigen, Eisai, Epizyme, Daiichi, Deciphera, Immunedesign, Lilly, Springworks, Tracon, Upto Date, PharmaMar, Astex, Immunicum, Karma Oncology, Merck, Mundipharma, Synox; Financial Interests, Institutional, Research Grant, Research grant for a clinical trial.: MSD. R. Groisberg: Financial Interests, Personal, Full or part-time Employment: Merck. J. Blay: Financial Interests, Institutional, Invited Speaker: MSD, MSD, PharmaMar; Financial Interests, Institutional, Advisory Board: Bayer, GSK, Roche; Financial Interests, Personal, Advisory Board: Deciphera; Financial Interests, Personal, Other, member of the supervisory board. No remunerations in 2021 and 2022.: Innate pharma; Financial Interests, Personal, Member of Board of Directors: Transgene; Financial Interests, Institutional, Funding: MSD, BMS, Deciphera; Financial Interests, Institutional, Research Grant: AstraZeneca, Roche, Bayer, GSK, Novartis, OSE pharma. M. de la Fuente: Financial Interests, Institutional, Other: OncLIve, Oncology Information Group, Targeted Oncology; Financial Interests, Personal, Advisory Board: Forma, Foundation Medicine, Agios, Puma. P. Roxburgh: Financial Interests, Personal, Invited Speaker: GSK, MSD; Financial Interests, Personal, Other, consultancy: Starpharma; Financial Interests, Institutional, Local PI: Starpharma, Eisai, astra Zeneca, Bayer, Atrios, Immunocore, Immutep, Sierra, mersana, iovance, nucana, PsiOxus, Replimune, Forma Therapeutics; Financial Interests, Institutional, Research Grant: Atrios; Financial Interests, Institutional, Coordinating PI: StepPharma; Non-Financial Interests, Institutional, Product Samples: Tesaro/GSK; Non-Financial Interests, Leadership Role, Clinical lead for cancer genomics: Scottish Strategic Network for Genomic Medicine. M.M. Chao, H. Tian: Financial Interests, Personal, Full or part-time Employment: Rigel; Financial Interests, Personal, Stocks or ownership: Rigel. C.P. Massard: Other, Christophe Massard: Consultant/Advisory fees from Amgen, Astellas, AstraZeneca, Bayer Ipsen, Janssen, MSD, Novartis, Pfizer, Roche, Sanofi, Netcancer, PegascyPrincipal/sub-Investigator of Clinical Trials for Abbvie, Aduro, Agios, Amgen, Argen-x, Astex, AstraZeneca, Aveo pharmaceuticals, Bayer, Beigene, Blueprint, BMS, Boeringer Ingelheim, Celgene, Chugai, Clovis, Daiichi Sankyo, Debiopharm, Eisai, Eos, Exelixis, Forma, Gamamabs, Genentech, Gortec, GSK, H3 biomedecine, Incyte, Innate Pharma, Janssen, Kura Oncology, Kyowa, Lilly, Loxo, Lysarc, Lytix Biopharma, Medimmune, Menarini, Merus, MSD, Nanobiotix, Nektar Therapeutics, Novartis, Octimet, Oncoethix, Oncopeptides AB, Orion, Pfizer, PharmaMar, Pierre Fabre, Roche, Sanofi, Servier, Sierra Oncology, Taiho, Takeda, Tesaro, Xencor: Company. B.A. Van Tine: Financial Interests, Personal, Advisory Board, Attended Advisory Board Meeting: Apexigen Inc; Financial Interests, Personal, Advisory Board, Attended an Advisory Board Meeting: Daiichi Sankyo; Financial Interests, Personal, Other, Consulting: Advenchen, Putnam, Salarius Pharm, Boxer Capital LLC, Acuta Capital Partners, LLC, Aadi; Financial Interests, Personal, Invited Speaker, 2023 West Oncology Talk. Travel provided: Total Health conference; Financial Interests, Personal, Advisory Board, Also paid for travel to the meeting: Kronos; Financial Interests, Personal, Other, Travel: Polaris; Financial Interests, Personal, Advisory Board, Sigma-2 Receptor Ligands and Therapeutic uses therefor (006766), Modular Platform for Targeted Therapeutic Delivery (006755), Sigma-2 Receptor Ligand Drug Conjugates as Antitumor Compounds, Methods of synthesis and Uses Thereof (014229): Accuronix Therapeutics; Financial Interests, Personal and Institutional, Research Grant, Research Grant for trial: Polaris; Non-Financial Interests, Other, Non-paid Safety Monitor Board Member: Polaris. All other authors have declared no conflicts of interest.