Efficacy of LNS8801 in melanoma patients with prior immune-related adverse events from immune-checkpoint inhibitors

BackgroundLNS8801 is an agonist of the G-protein coupled estrogen receptor (GPER). LNS8801 treatment increases melanocytic differentiation, reduces c-Myc protein levels, inhibits tumor proliferation, and increases immune recognition of cancer cells. In the first-in-human study, LNS8801 was safe and tolerable, without serious adverse events or dose limiting toxicities (NCT04130516).MethodsPatients with immune checkpoint inhibitor (ICI)-refractory cutaneous melanoma (CM), prior immune-related adverse events (irAEs), and subsequent progression were enrolled. Patients received LNS8801 (125 mg, QD, PO) (NCT04130516). Endpoints included safety and tolerability, pharmacokinetics, pharmacodynamics, and disease control rate (DCR, CR+PR+SD). Presence of a consensus, fully functional, germline GPER sequence was assessed as a predictive biomarker.ResultsAs of 05/01/2024, 9 patients were treated. All patients received prior PD-1 and CTLA-4 directed ICIs and had prior irAEs that warranted ICI discontinuation. 7 of 9 patients had AEs possibly related to study drug (n=5 with grades 1-2 and n=2 with grade 3), with only AST/ALT elevation occurring in >1 patient (G3 and G1). Overall, 8 patients were evaluable, 5 of 8 patients have had stable disease, resulting in a DCR of 63%. Consensus germline GPER (C/C) was present in 5 of 8 sequenced patients. Of patients positive for this biomarker, 4 of 5 had stable disease (DCR 80%), with a preliminary median progression-free survival of 9 months. This includes a patient that is on treatment for over 4 years with resolution of all soft-tissue nontarget lesions and no evidence of active disease in the residual bone-associated target lesion or elsewhere by PET/CT.ConclusionsLNS8801 is safe and tolerable and demonstrates encouraging activity in patients with ICI treatment-refractory CM and prior irAEs. Consensus germline GPER is a promising predictive biomarker for benefit and continues to be associated with improved outcomes in patients treated with LNS8801. These data support further development of LNS8801 as a therapy for patients with CM who can no longer tolerate ICI therapy. Further validation of the consensus biomarker to predict response is warranted.Clinical trial identificationNCT04130516.Legal entity responsible for the studyLinnaeus Therapeutics Inc.FundingLinnaeus Therapeutics Inc.DisclosureT.K. Garyantes: Financial Interests, Personal, Ownership Interest: Linnaeus Therapeutics. C.A. Natale: Financial Interests, Personal, Ownership Interest: Linnaeus Therapeutics ; Financial Interests, Personal, Leadership Role: Linnaeus Therapeutics. S. Patel: Financial Interests, Personal, Advisory Board: TriSalus, Cardinal Health, Castle Biosciences, Delcath, Novartis, BMS, Pfizer, Immatics, MSD; Financial Interests, Personal, Other, Consultant for educational materials: Advance Knowledge in Healthcare; Financial Interests, Personal, Invited Speaker, Non-promotional speaker: BMS, MSD; Financial Interests, Personal, Other, IDMC member: Ideaya; Financial Interests, Personal, Invited Speaker: Clinical Education Alliance, Projects in Knowledge, Melanoma Research Foundation, Answers in CME; Financial Interests, Institutional, Trial Chair: Provectus Biopharmaceuticals; Financial Interests, Institutional, Local PI: Lyvgen, InxMed, Foghorn Therapeutics, Ideaya, Novartis, Seagen, Syntrix Bio; Financial Interests, Institutional, Steering Committee Member: TriSalus Life Sciences; Non-Financial Interests, Member: ASCO, AACR, International Society of Ocular Oncology, Society for Melanoma Research; Non-Financial Interests, Leadership Role: SWOG. J. Rodon: Financial Interests, Personal, Advisory Board: Ellipses Pharma, IONCTURA SA, Aadi Bioscience, Envision Pharma, Molecular Partners, Mekanistic, Amgen; Financial Interests, Personal, Other, Consultancy: Clarion Healthcare, Debiopharm, Cullgen, Pfizer, Macrogenics, Oncology One, Columbus Venture Partners, Sardona Therapeutics, Avoro Capital Advisors, Vall d'Hebron Institute of Oncology/Ministero De Empleo Y Seguridad, Chinese University of Hong Kong, Boxer Capital, LLC, Tang Advisors, LLC, Alnylam Pharmaceuticals, Bridgebio Pharma; Financial Interests, Personal, Other, Consultancy/Advisory Board: Monte Rosa Therapeutics, Merus N.V, Incyte; Financial Interests, Institutional, Other, Clinical Research: Novartis, Spectrum Pharmaceuticals, Symphogen, BioAtla, Pfizer, GenMab, CytomX, Kelun-Biotech, Takeda-Millenium, GSK; Financial Interests, Institutional, Other, Research Funding: Blueprint Medicines, Black Diamond, Merck Sharp & Dohme; Financial Interests, Institutional, Research Grant, Research Funding/Clinical Research: Hummingbird, Yingli; Financial Interests, Institutional, Research Grant, Research Funding: Vall d'Hebron Institute of Oncology/Cancer Core Europe; Financial Interests, Institutional, Research Grant, Clinical Research: Bicycle Therapeutics, Taiho, Roche Pharmaceuticals, Merus, Curis, AadiBioscience, Nuvation, ForeBio, BioMed Valley Discoveries, Loxo Oncology, Cellestia, Deciphera, Ideaya, Amgen, Tango Therapeutics, Mirati, Linnaeus Therapeutics, Bayer, Hutchinson MediPharma; Other, Other, Other: VHIO/Ministero De Empleo Y Seguridad Social; Other, Other, Travel: European Society for Medical Oncology, Loxo Oncology. A.N. Shoushtari: Financial Interests, Personal, Advisory Board: Bristol Myers Squibb, Immunocore, Novartis, Erasca; Financial Interests, Personal, Royalties: UptoDate; Financial Interests, Institutional, Local PI: Bristol Myers Squibb, Immunocore, Pfizer, Novartis, Checkmate Pharmaceuticals, Linnaeus Therapeutics, Foghorn Therapeutics, Prelude Therapeutics, Iovance Biotherapeutics, Obsidian Therapeutics; Financial Interests, Institutional, Coordinating PI: Polaris, Xcovery, Targovax ASA; Non-Financial Interests, Member: ASCO. All other authors have declared no conflicts of interest.