1101P - The effect of LNS8801 in combination with pembrolizumab in patients with treatment-refractory cutaneous melanoma

Background

LNS8801 is an oral G-protein coupled estrogen receptor (GPER) agonist. LNS8801 treatment results in increased melanocytic differentiation, reduced c-Myc protein levels, inhibition of proliferation, and enhancement of immune recognition of cancer cells in the first-in-human study, LNS8801 was safe and tolerable alone and in combination with pembrolizumab in patients with advanced solid tumors (NCT04130516). LNS8801 also demonstrated monotherapy activity in cutaneous melanoma (CM) patients, including a patient that is on treatment for over 3 years with no evidence of active or recurrent disease.

Methods

Patients with treatment-refractory CM received LNS8801 (125 mg, QD, PO) and pembrolizumab (200 mg, Q3W, IV) (NCT04130516). The primary objective was safety and tolerability. Secondary endpoints include pharmacokinetic, pharmacodynamics, objective response rate (ORR) and disease control rate (DCR, CR+PR+SD). Presence of a consensus, fully-functional, germline GPER coding sequence was assessed as a potential predictive biomarker.

Results

As of 4/15/23, 10 CM patients were treated. All patients received prior PD-1 and CTLA-4 directed ICIs, and were treated with a median of 2.5 prior lines of systemic therapies. 8 of 10 patients had AEs possibly related to study drugs (n=4 with grades 1-2 and n=4 with grade 3), with AST/ALT elevation, diarrhea, or fatigue occurring in more than 1 patient. Regarding efficacy, 2 had partial responses (PR), 4 had stable disease (SD), and 1 patient has not been evaluated, resulting in an ORR of 20% and DCR of 60%. Both patients with PRs remained on treatment for greater than 24 weeks. Consensus germline GPER was present in 7 of 10 sequenced patients. Of patients positive for this biomarker, 2 had PR and 3 had SD, resulting in an ORR of 29% and DCR of 71%.

Conclusions

LNS8801 and pembrolizumab is tolerable and has encouraging activity in patients with treatment-refractory CM, including patients who enrolled immediately after confirmed progression on ICIs. Consensus germline GPER is a promising predictive biomarker, and is associated with improved outcomes in patients treated with LNS8801. These data support further development of LNS8801 in combination with pembrolizumab treat advanced CM patients.

Clinical trial identification

NCT04130516.

Editorial acknowledgement

Legal entity responsible for the study

Linnaeus Therapeutics Inc.

Funding

Linnaeus Therapeutics.

Disclosure

J. Rodon: Financial Interests, Personal, Advisory Board: Ellipses Pharma, iOnctura SA; Financial Interests, Personal, Other, Consultancy: Aadi Bioscience, Clarion Healthcare, Debiopharm, Monte Rosa Therapeutics, Cullgen, Pfizer, Merus N.V., Macrogenics, Oncology One, Envision Pharma, 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, Incyte; Financial Interests, Institutional, Other, Clinical Research: Novartis, Spectrum Pharmaceuticals, Symphogen, BioAtla, Pfizer, GenMab, CytomX, Kelun-Biotech, Takeda-Millennium, 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, Aadi Bioscience, Nuvation, Fore Biotherapeutics, BioMed Valley Discoveries, Loxo Oncology, Cellestia, Deciphera, IDEAYA, Amgen, Tango Therapeutics, Mirati, Linnaeus Therapeutics, Bayer, Hutchinson MediPharma; Other: VHIO/Ministero de Empleo y Seguridad Social; Other, Travel: European Society for Medical Oncology. M.F. Chaney: Financial Interests, Personal, Full or part-time Employment: Merck and Co., Inc.; Financial Interests, Personal, Stocks/Shares: Merck and Co., Inc.; Non-Financial Interests, Member: ASCO, AACR. J. Cohen: Financial Interests, Personal, Advisory Role: Regeneron, Sanofi; Financial Interests, Institutional, Research Funding: Linnaeus Therapeutics. T.K. Garyantes: Financial Interests, Personal, Full or part-time Employment: Linnaeus Therapeutics. J. Ishizuka: Financial Interests, Personal, Stocks or ownership: Jounce Therapeutics, Kronos Bio; Financial Interests, Personal, Advisory Role: Danger Bio, Phenomic AI, Rheos Medicines, Tango Therapeutics, Two River Group; Financial Interests, Personal, Research Funding: AstraZeneca; Financial Interests, Institutional, Research Funding: Linnaeus Therapeutics. J.J. Lin: Financial Interests, Personal, Other, Consulting: Turning Point Therapeutics, Nuvalent, Elevation Oncology, C4 Therapeutics, Bayer, Novartis, Mirati Therapeutics, Regeneron, CLaiM Therapeutics; Financial Interests, Personal, Advisory Board, Consulting: Blueprint Medicines, Genentech; Financial Interests, Personal, Other, Honorarium, travel: Pfizer; Financial Interests, Institutional, Local PI: Turning Point Therapeutics, Neon Therapeutics, Relay Therapeutics, Bayer, Elevation Oncology, Roche/Genentech, Novartis, Hengrui Therapeutics, Pfizer, Nuvalent. P. Lorusso: Financial Interests, Personal, Advisory Board: AbbVie, Genmab, Genentech, CytomX, Takeda, Cybrexa, Agenus, IQVIA, TRIGR, Pfizer, ImmunoMet, Black Diamond, Glaxo-Smith Kline, QED Therapeutics, AstraZeneca, EMD Serono, Shattuck, Astellas, Salarius, Silverback, MacroGenics, Kyowa Kirin, Kineta, Zentalis, Molecular Templates, ABL Bio, STCube, Bayer, Seagen, imCheck, Relay Therapeutics, Stemline, Compass BADX, Mekanist, Mersana, Roivant Sciences, BAKX Therapeutics, Scenic Biotech, Qualigen, NeuroTrials; Financial Interests, Personal, Other, Data Safety Monitoring Board: Agios, Five Prime, Halozyme; Financial Interests, Personal, Other, imCORE Alliance: Roche-Genentech; Financial Interests, Personal, Other, Consultant: SOTIO, SK Life; Financial Interests, Personal, Other, Data Safety Monitoring Committee: Tyme; Financial Interests, Personal, Advisory Board, Advisory Board & Consultant: I-Mab; Financial Interests, Personal, Stocks/Shares: BAXK; Financial Interests, Institutional, Local PI: AbbVie, ADC Therapeutics, ALX Oncology, Astellas Pharma, Black Diamond, Astex Pharmaceuticals, AstraZeneca, Bayer, Boehringer Ingelheim, Calico Life Sciences, Corvus Pharmaceuticals, CytomX Therapeutics, Eisai Pharmaceuticals, Eli Lilly, EMD Serono, Five Prime, FLX Bio, F-Star Delta Limited, Genentech, Genmab, Incyte, Linnaeus Therapeutics, MedImmune, Merck Sharp & Dohme, Moderna Therapeutics, NextCure, Pfizer, Ribon Therapeutics, SOTIO, Stemline Therapeutics, Takeda, Tesaro, Jounce; Non-Financial Interests, Other, AACI Clinical Research Innovation Steering Committee - Member: Association of American Cancer Institutes; Non-Financial Interests, Other, Molecular Cancer Therapeutics Editorial Board - Member: American Association for Cancer Research; Non-Financial Interests, Other, AACR Methods in Clinical Cancer Research Workshop - Co-Director: American Association for Cancer Research; Non-Financial Interests, Other, AACR Annual Report Committee - Member: American Association for Cancer Research; Non-Financial Interests, Other, Continuing Medical Education Committee - Member: American Association for Cancer Research; Non-Financial Interests, Other, ASCO Conquer Cancer Young Investigator Award Grand Selection Committee - Member: American Society of Clinical Oncology; Non-Financial Interests, Other, New Drugs in Oncology Seminar Planning Committee - Member: American Society of Clinical Oncology; Non-Financial Interests, Other, New Agents Committee: Translational Research Panel - Chair: Cancer Research Unite Kingdom; Non-Financial Interests, Other, Scientific Advisory Board - Member: Targeted Anti-Cancer Therapies; Non-Financial Interests, Other, Chair - Phase 0 Task Force: American Association of Cancer Research; Non-Financial Interests, Member: American Association for Cancer Research, ASCO; Other, Investigational Drug Steering Committee - Committee Member: National Cancer Institute; Other, Phase I Special Emphasis Panel - Grant Reviewer/Discussion Leader: National Cancer Institute; Other, NeXT Special Emphasis Panel - Grant Reviewer: National Cancer Institute/National Institute of Health; Other, Board of Scientific Counselors, Clinical Sciences & Epidemiology: National Cancer Institute; Other, Young Investigator Meeting, Cancer Therapy Evaluation Program - Professor: National Cancer Institute; Other, Academic Advisory Board SPORE GI Malignancies - Case Western Reserve University: Case Western Reserve University; Other, External Advisory Board - Member: University of Arizona; Other, External Scientific Advisory Board - Member: University of New Mexico; Other, Scientific External Advisory Board - Member: University of California at San Diego. A. Mita: Financial Interests, Personal, Speaker’s Bureau: Genentech. M. Mita: Financial Interests, Institutional, Research Funding: Linnaeus Therapeutics. C. Muller: Financial Interests, Personal, Advisory Role: GSK; Financial Interests, Institutional, Research Funding: Agenus, AstraZeneca, Incyte, Linnaeus Therapeutics, Merck, Roche, TapImmune, VBL Therapeutics. C. Natale: Financial Interests, Personal, Full or part-time Employment: Linnaeus Therapeutics. M. Orloff: Financial Interests, Institutional, Research Funding: Bristol Myers Squibb, Delcath Systems, IDEAYA Biosciences, Immunocore, Linnaeus Therapeutics, Plexxikon. K.P. Papadopoulos: Financial Interests, Personal, Advisory Board: Turning Point Therapeutics, Bicycle, Basilia; Financial Interests, Institutional, Full or part-time Employment: START; Financial Interests, Personal, Ownership Interest: START; Financial Interests, Institutional, Local PI, For conduct of clinical trial: 3D Medicines, AbbVie, ADC Therapeutics, Amgen, AnHeart Therapeutics, Bayer, Daiichi Sankyo, EMD Serono, F-Star, Incyte, Jounce Therapeutics, Lilly, Linnaeus Therapeutics, Merck, Mersana, Mirati Therapeutics, Pfizer, Regeneron Pharmaceuticals, Revolution Medicines, Syros Pharmaceuticals, Tempest Therapeutics, Treadwell Therapeutics. S. Patel: Financial Interests, Personal, Advisory Board: TriSalus, Cardinal Health, Castle Biosciences, Novartis, BMS, Pfizer, Immatics; Financial Interests, Personal, Other, Consultant for educational materials: Advance Knowledge in Healthcare; Financial Interests, Personal, Advisory Board, Advisory Board and Corporate Day speaker (unbranded): Delcath; Financial Interests, Personal, Other, Independent Data Monitoring Committee: Immunocore; Financial Interests, Personal, Other, Consultant: Guidepoint Global; Financial Interests, Institutional, Trial Chair: Provectus Biopharmaceuticals, Bristol Myers Squibb; 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: International Society of Ocular Oncology, ASCO, AACR, Society for Melanoma Research; Non-Financial Interests, Leadership Role: SWOG. A.N. Shoushtari: Financial Interests, Personal, Advisory Board: Bristol Myers Squibb, Immunocore, Novartis; Financial Interests, Personal, Royalties: UpToDate; Financial Interests, Institutional, Local PI: Bristol Myers Squibb, Immunocore, Pfizer, Novartis, Checkmate Pharmaceuticals, Linnaeus Therapeutics, Prelude Therapeutics; Financial Interests, Institutional, Coordinating PI: Polaris, Xcovery, Targovax ASA; Financial Interests, Personal, Local PI: Foghorn Therapeutics; Non-Financial Interests, Member: ASCO.