1295P - EP0031 a next-generation selective RET inhibitor (SRI): Correlation of molecular and clinical responses in patients with RET alteration positive solid tumours naïve to or following prior SRI

Background

EP0031 is under evaluation as a promising next gen SRI (ASCO 2023: 3007). Preliminary data for pts in the US and Europe showed responses in SRI pretreated or naive pts and promising tolerability (ENA 2023: B043). We report an exploratory analysis of corresponding ctDNA data.

Methods

This Phase I study (NCT05443126) included pts with RET-altered solid tumors including NSCLC, MTC and other: ≥ 18 years of age, PS 0 or 1, with/without asymptomatic, stable brain mets. Blood samples for ctDNA analysis (Guardant Infinity) were collected on C1D1 (pre-dose), C1D15 and C2-12 (D1). Methylation molecular response (MR), defined as ≥ 50% decrease in ctDNA, was derived between C1D1 and C2D1.

Results

As of 8 Mar 24, a total of 35 pts (21 F, 14 M, median age 57y), 19 NSCLC (17 SRI pretreated), 10 MTC (6 SRI pretreated) and 6 other tumors (4 SRI pretreated) were enrolled across 4 cohorts: 20 (n=3), 60 (n=10), 90 (n=13) and 120 (n=9) mg QD. SRI pretreated pts received 1-6 prior lines. In 22 clinical response evaluable pts: NSCLC, 4 PRs and 3 SDs in 9 prior SRI pts, and 1 CR, 1 PR in 2 SRI naive pts; MTC, 2 PRs and 1 SD in 3 SRI naïve pts, and 3 SDs in 5 prior SRI pts; other tumors, 1 SD in 3 prior SRI pts. All tumors harbored either a RET fusion, somatic nucleotide variant, large genomic rearrangement or insertion. Of the 22 clinical response evaluable pts, 18 were evaluable for methylation MR, of which 14 were quantifiable. 6 of these pts had a MR: clinically 1 had a CR, 2 had a PR and 1 SD. Early reductions in ctDNA correlated with higher doses of EP0031. Comprehensive data will be presented.

Conclusions

There was encouraging evidence of clinical responses across the pt population, including pts naïve to or who had received prior SRI. Methylation-based ctDNA MR appears to show a strong correlation with the best clinical response. MR appears to be an early indicator of clinical response. Clinical responses observed were largely independent of the genetic heterogeneity of the tumors, including the presence of non-RET alterations. This study is continuing in Phase 2 with evaluation of expansion cohorts in SRI naïve and pre-treated pts.

Clinical trial identification

EP0031-101, NCT05443126.

Editorial acknowledgement

Legal entity responsible for the study

Ellipses Pharma Limited.

Funding

Ellipses Pharma Limited.

Disclosure

E. Garralda: Financial Interests, Personal, Invited Speaker: MSD, Roche, Thermo Fisher, Novartis, Seagen; Financial Interests, Personal, Advisory Board: Roche, Ellipses Pharma, Boehringer Ingelheim, Janssen Global Services, Seattle Genetics, Thermo Fisher, MabDiscovery, Anaveon, Hengrui, F-Star Therapeutics, Sanofi, Incyte, Medscape; Financial Interests, Personal, Full or part-time Employment: NEXT Oncology; Financial Interests, Personal, Stocks/Shares: 1TRIALSP; Financial Interests, Institutional, Funding: Novartis, Roche, Thermo Fisher, AstraZeneca, Taiho; Financial Interests, Institutional, Research Grant: BeiGene, Janssen. L. Clark: Financial Interests, Personal and Institutional, Financially compensated role: Ellipses Pharma. J.S. Wang: Financial Interests, Personal, Advisory Board, Single consultancy engagement, 4/28/22: Kanaph Therapeutics; Financial Interests, Personal, Invited Speaker, Speaker for Speaker's Bureau for Levatinib, stopped in 7/2022: Eisai; Financial Interests, Personal, Advisory Board, on Safety Advisory Board, single engagement 6/22/23: Fusion Pharma; Financial Interests, Institutional, Funding, Clinical Trial PI/Sub-I: Accutar, Adagene, Artios Pharma, Astellas, AstraZeneca, Bayer Healthcare, BeiGene, Bicycle Therapeutics, BioNTech, Blueprint, Boehringer Ingelheim, Celgene/BMS, Cullinan, Cyteir, Daiichi Sankyo, Erasca, Forty Seven, Genentech/Roche, GSK, H3 Biomedicine, Hotspot, IGM Biosciences, Immuno-Gen, ImmunoOnc, Janssen, Jazz Pharma, Klus Pharma, Kymab, LSK BioPartners, MabSpace, Macrogenics, Medikine, Moderna, NGM Bio, Novartis, Nurix, Olema Therapeutics, Pionyr, Prelude Therapeutics, PureTech Health, Pyxis, Qilu Pugent Sound, Relay Therapeutics, Revolution Medicines, Ribon Therapeutics, Sanofi, StingThera, Syndax, Teneobio, TopAlliance, Treadwell Therapeutics, Xencor, Zymeworks, Compass, OnCusp, Tango, Vividion, Allorion, Kura, Georgimmune, Conjupro, Duality Bio, Ellipses, Compugen, Biostar, Centessa, Kineta, C4 Therapeutics. M.H. Taylor: Financial Interests, Personal, Advisory Board: Bristol Myers Squibb, Eisai Inc., Novartis, Merck, Pfizer, Bayer, Sanofi/Genzyme, Regeneron, Loxo oncology, Blueprint Medicines, Immune-onc, Exelixis, Cascade Prodrug. D.R. Spigel: Financial Interests, Institutional, Other, Consulting: AstraZeneca, BeiGene, Bristol Myers Squibb, Evidera, GSK, Ipsen Biopharmaceuticals, Janssen, Jazz Pharmaceuticals, Lilly, Molecular Templates, Monte Rosa Therapeutics, Novartis, Pfizer, Regeneron, Sanofi-Aventis, AbbVie, Novocure, Roche/Genentech; Financial Interests, Institutional, Research Grant, Serve as PI: Amgen, Aeglea Biotherapeutics, Agios, Arrys Therapeutics, Astellas, AstraZeneca, Bayer, BeiGene, BIND Therapeutics, Blueprint Medicine, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Celldex Therapeutics, Clovis, Daiichi Sankyo, Eisai, Lilly, Genentech/Roche, G1 Therapeutics, Gilead Sciences, GSK, GRAIL, Hutchinson MediPharma, ImClone Systems, Ipsen, Janssen, Loxo, MacroGenics, MedImmune, Merck, Nektar, Neon Therapeutics, Novartis, Novocure, Rgenix, Seagen, Taiho Oncology, Tarveda, Tizona Therapeutics, Transgene, UT Southwestern, Verastem, Arcus Biosciences, Molecular Template, Cyteir Therapeutics, BioNTech, Apollomics, Pure Tech Health, Elevation Oncology, Repare Therapeutics, Razor Genomics, Denovo Biopharma, Erasca, Kronos Bio, Zai Laboratory, Faeth Therapeutics, Ascendis Pharma, Lyell Immunopharma, Synthekine, Shenzhen Chipscreen Biosciences, AbbVie, AnHeart Therapeutics, Calithera, Endeavor, FujiFilm Pharmaceuticals, Incyte, Jazz Pharmaceuticals, Millennium Pharmaceuticals, Moderna, Monte Rosa Therapeutics, Peloton Therapeutics, Stemline Therapeutics, Tango Therapeutics, Tesaro. S.V. Liu: Financial Interests, Personal, Advisory Board, Consultant: AstraZeneca, Daiichi Sankyo, Elevation Oncology, Genentech / Roche, Janssen, Jazz Pharmaceuticals, Merck, Novartis, Regeneron, Sanofi; Financial Interests, Personal, Advisory Board: Bristol Myers Squibb, Catalyst, RAPT Therapeutics, Gilead, Guardant Health, Merus, Takeda, Revolution Medicines, Amgen, AbbVie, Boehringer Ingelheim, Mirati, Pfizer; Financial Interests, Institutional, Local PI: Alkermes, Elevation Oncology, Gilead, Merck, Merus, Nuvalent, RAPT, Turning Point Therapeutics, AbbVie, AstraZeneca, Puma; Financial Interests, Institutional, Steering Committee Member: Genentech; Financial Interests, Institutional, Coordinating PI: OSE Immunotherapeutics; Non-Financial Interests, Member: ASCO, IASLC. M.G. Krebs: Financial Interests, Personal, Advisory Board: Bayer, Roche, Janssen, Guardant Health, Zai Lab; Financial Interests, Personal, Invited Speaker: Roche, Janssen; Financial Interests, Institutional, Advisory Board: AstraZeneca, Seattle Genetics; Financial Interests, Institutional, Coordinating PI: AstraZeneca, Carrick, Janssen, Pyramid Biosciences, Ellipses; Financial Interests, Institutional, Local PI: Blueprint, Astex, Bayer, BerGenBio, Immutep, Novartis, Nurix, Nuvalent, Roche, Seattle Genetics, Turning Point Therapeutics, Relay Therapeutics; Financial Interests, Institutional, Research Grant: Roche, Novartis; Other, Travel expenses for congress: Immutep, Janssen; Other, Travel expenses: Roche, Zai Lab. M.D. Forster: Financial Interests, Personal, Advisory Board: Bayer, Merck, MSD, Roche, Takeda, ultrahuman, Transgene, Immunotep, Amgen, BMS, EQRx, GSK, Janssen, Oxford VacMedix, PharmaMar, Regeneron, Syncorp; Financial Interests, Institutional, Research Grant: AstraZeneca, Boehringer Ingelheim, MSD, Merck; Financial Interests, Institutional, Local PI: Roche, Apollomics, Takeda, Ellipsis, Moderna, Exsciencia, ALXOncology, GenMab; Financial Interests, Personal and Institutional, Coordinating PI, Presented data at ESMO-IO 2022: Achilles; Financial Interests, Institutional, Coordinating PI: Oxford VaxMedix, Janssen; Financial Interests, Institutional, Coordinating PI, Presented Data at SITC 2023: Immutep; Non-Financial Interests, Advisory Role, Chair of Scientific Advisory Group: Ruth Strauss Foundation. L.G. Paz-Ares: Financial Interests, Personal, Advisory Board, Speaker fees: Roche, MSD, BMS, AZ, Lilly, PharmaMar, BeiGene, Daiichi Sankyo, Medscape, PER; Financial Interests, Personal, Advisory Board: Merck Serono, Pfizer, Bayer, Amgen, Janssen, GSK, Novartis, Takeda, Sanofi, Mirati, Boehringer; Financial Interests, Personal, Other, Board member: Genomica, Altum sequencing; Financial Interests, Personal, Other, lectures: AICME; Financial Interests, Personal, Other, Lectures: CCO; Financial Interests, Personal, Member of Board of Directors, Board member: Stab Therapeutics; Financial Interests, Personal, Other, spinn off (I have arounfd 8% of stocks): Altum sequencing; Financial Interests, Personal, Ownership Interest, spin-off (10%): Stab Therapeutics; Financial Interests, Institutional, Coordinating PI: Daiichi Sankyo, Astrazeneca, Merck Sharp & Dohme corp, BMS, Janssen-Cilag international NV, NOvartis, Roche, Sanofi, Tesaro, Alkermes, Lilly, Takeda, Pfizer, PharmaMar; Financial Interests, Personal, Coordinating PI: Amgen; Financial Interests, Other, Member: AACR, ASCO, ESMO; Financial Interests, Other, Foundation Board Member: AECC; Financial Interests, Other, President ASEICA (Spanish Association of CancerResearch ): ASEICA; Financial Interests, Other, Foundation president: ONCOSUR; Financial Interests, Other, member: Small Lung Cancer Group; Non-Financial Interests, Other, Board member of this anti-cancer Charity: AECC; Non-Financial Interests, Member, Past-President: ASEICA (Spanish Cancer Research Association); Non-Financial Interests, Leadership Role, President: Oncosur Foundation. G. Fisher, S. Brook, S. Patel, H. Arkenau: Financial Interests, Personal and Institutional, Financially compensated role: Ellipses Pharma. B. Overstreet: Financial Interests, Personal and Institutional, Financially compensated role: Guardant. G. Yalamanchili: Financial Interests, Personal and Institutional, Financially compensated role: Guardant. P. Garrido Lopez: Financial Interests, Personal, Invited Speaker: Amgen, AstraZeneca, Janssen, MSD, Touch Expert, Medscape; Financial Interests, Personal, Advisory Board: AstraZeneca, GSK, Janssen, Lilly, MSD, Novartis, Roche, Takeda, Daiichi Sankyo, Sanofi, Amgen; Financial Interests, Personal, Advisory Board, Spouse: Gebro, Janssen, Nordic; Financial Interests, Personal, Invited Speaker, Spouse: Janssen, Boehringer Ingelheim, Pfizer, Amgen, Nordic; Financial Interests, Personal, Other, Data monitoring committee for INC280I12201 trial in 2020: Novartis; Financial Interests, Personal, Steering Committee Member, CACZ885V2201C_CANOPY-N trial: Novartis; Financial Interests, Personal, Other, Lung Cancer Medical Education TASC Committee 2021: Janssen; Financial Interests, Institutional, Local PI: Novartis, Janssen, AstraZeneca, Pfizer, Blue print, Apollomics, Amgen, Array Biopharma; Financial Interests, Personal, Steering Committee Member, IO102-012/KN-764 trial: IO Biotech; Financial Interests, Personal, Steering Committee Member, JNJ-61186372 (JNJ-372) Clinical Development Program: Janssen; Financial Interests, Institutional, Other, Spouse: Mitsubishi, AbbVie; Financial Interests, Institutional, Other, Spouse, clinical trial team: Janssen, Boehringer Ingelheim; Financial Interests, Personal, Steering Committee Member, JDQ443G12301 trial, Steering Committee member: Novartis; Non-Financial Interests, Leadership Role, Past Council member as Women for Oncology Committee ChairPast Fellowship and Award Committee and Press Committee Faculty for lung and other thoracic tumors: ESMO; Non-Financial Interests, Leadership Role, President of the Spanish Federation of Medical Societies (FACME) 2020-2022Past President 2023-2024: FACME; Non-Financial Interests, Leadership Role, Former President of Spanish Medical Oncology Society: SEOM; Non-Financial Interests, Leadership Role, Member of the Scientific Committee of the Spanish Against Cancer Research Foundation (aecc) and also Board member: AECC; Non-Financial Interests, Leadership Role, IASLC Women in Thoracic Oncology Working Group Member, Educational Committee member, Academy member: IASLC; Non-Financial Interests, Advisory Role, Member of the Spanish National Health Advisory Board: Spanish Minister of Health; Non-Financial Interests, Advisory Role, Assessment for lung cancer screening evaluation: EUnetHTA; Non-Financial Interests, Advisory Role: Spanish National Evaluation network (RedETS), member of the King Hussein Award’s Board of Directors; Non-Financial Interests, Advisory Role, scientific advisory group member for clinical immunological, oncology and lung cancer areas: EMA; Other, My son is working with the pharma company TEVA as an engineer. I do not have any relationship with TEVA: TEVA. All other authors have declared no conflicts of interest.