PO.CTP01.03 · 进行中的临床试验
A phase I/II study to evaluate EP0031 (lunbotinib), a next-generation selective RET inhibitor, as monotherapy and in combination with chemotherapy, in patients with advanced RET -fusion-positive NSCLC
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摘要 Abstract
Background: EP0031 (lunbotinib, A400), a first-in-class, next-generation selective RET inhibitor (SRI), has broad potency against common RET alterations, including resistance mutations, and has greater potency, antitumor activity, and CNS penetration/activity compared with first-generation SRIs (1,2). Clinical data indicates that EP0031 is active in patients who are SRI-naïve or have received prior SRI treatment, including those with brain metastases and/or on-target RET resistance mutations, and has acceptable tolerability (2,3,4). Resistance to first-generation SRIs is heterogeneous, characterized by RET -dependent and -independent pathways (4). SRI + chemotherapy may represent a promising strategy to address underlying disease heterogeneity. There is growing evidence that RET fusion-positive NSCLC is sensitive to pemetrexed-based chemotherapy and preclinical evidence confirms strong synergy between EP0031 and chemotherapy. This is the first study to evaluate this combination approach.
Study Design and Methods: This is an ongoing phase I/II trial. A monotherapy RP2D of 90 mg daily was selected based on dose optimization data (4). Phase II expansion cohorts are recruiting patients with advanced RET fusion-positive NSCLC (NCT05443126) across three cohorts: (1) SRI-naïve patients receiving first-line therapy with EP0031 (N=25); (2) SRI-naïve patients receiving first-line therapy with EP0031 in combination with platinum-pemetrexed (N=25); and (3) Patients previously treated with a first-generation SRI, receiving second-line treatment with EP0031 in combination with platinum-pemetrexed (N=25). Key inclusion criteria include age ≥ 18 years, an Eastern Cooperative Oncology Group performance status ≤ 1, and RET fusion-positive NSCLC measurable by RECIST v1.1, with or without asymptomatic, stable brain metastases. EP0031 is administered orally, continuously once daily. In combination cohorts, the chemotherapy doublet is administered every 21 days at standard doses for four cycles followed by pemetrexed maintenance. Each combination cohort has a 3+3 safety run-in before expansion in 25 patients at the combination RP2D. Endpoints include tumor response per RECIST v1.1, progression-free survival, and overall survival. Other key endpoints include safety (including incidence of dose-limiting toxicities and adverse events) and pharmacokinetic parameters. Circulating tumor DNA is collected to evaluate the emergence of on- and off-target mutations. The study is currently recruiting across the US, Europe, and the UAE.
References 1. Zhou Q, et al. J Clin Oncol 2023:41:16_suppl, abstract 3007 2. Garralda E, et al. J Clin Oncol 2024:42:16_suppl, abstract 8556 3. Garralda E, et al. Ann Oncol 2024; 35: S824, abstract 1295P 4. Alonso G, et al. J Clin Oncol 2025: 43:16_suppl, 8598
利益披露 Disclosure
J. Rubio-Perez, None.
E. Garralda,
Novartis, Roche, AZ, Taiho, BeiGene, Janssen, BI, Seattle Genetics, Thermo Fisher, MabDiscovery, Anaveon, F-Star, Hengrui, Sanofi, Incyte, Medscape, Pfizer, Amgen; MSD, Roche, Thermo Fisher, Novartis ).
, SeaGen, Adaptimmune, Affimed, Amgen, Anaveon, , Bicycletx Ltd, BioInvent, Biontech, B, , Catalym, Cyclacel, Cytovation, Cytomx, Roche, F-Star Beta Limited, Genentech, Genmab, Hifibio, Hutchison, Ic ).
, Icon, Imcheck, Immunocore, Incyte, Servier SL, Medimmune, Merck & Co, Peptomyc, Relay, Replimmune, Ribon, Ryvu, Sotio, Sqz Biotechnologies, Symphogen, Taiho, T-Knife ).
1TRIALSP Stock Option.
B. Besse,
Abbvie, Biontech, Beijing Avistone, BMS, CureVac, Pharmamar, Regeneron, Sanofi, Lilly, Genmab, Roche, Beigene, Janssen, Foghorn, Owkin, AZ, Amgen, MSD, Takeda, Servier, Daiichi Other, Consulting/advisory boards/speaker.
M. Aldea,
Viatris, Sandoz, Amgen, AZ ), Travel.
Y. Elamin,
Lilly, AZ, Turning Pt, Takeda, Sanofi, Spectrum, BMS, Nuvation, J&J, Taiho, ).
P. Garrido,
AbbVie, Amgen, AstraZeneca, Bayer, BeOne, Boehringer Ingelheim, Bristol Myers Squibb International, Daiichi Sankyo, GlaxoSmithKline, Johnson and Johnson, Lilly, MSD, Novartis, PharmaMar, Pierre Fabre ).
S. Khan,
Roche, Serono, Eisai, Genmab, Kineto, Novartis, Merck, Threshold, Gilead, Bayer, Celldex, Abbvie ).
J. Wang,
Abbvie, Abdera Therapeutics, Accent Therapeutics, Accutar Biotech, Acrivon Therapeutics, Adagene, Allorion Therapeutics, Alterome Therapeutics, Apollo, Artios, Astellas Pharma, Avenzo, BeiGene, Bicyc ).
L. Paz Ares,
Roche/Genentech, Lilly, Pfizer, BMS, MSD, AZ, PharmaMar, Novartis, Amgen, Sanofi, Bayer, Takeda, GSK, Janssen, BI, AbbVie, Gilead, BeOne, PharmaMar, Mirati, Regeneron, Astellas, Merck Serono, Daiichi ).
Altum Sequencing, Stab Therapeutics Stock Option.
D. Morgensztern,
Abbvie, Lilly, Merck, Bayer, BMS, Natera, Tubulis, J&J, Genprex, AZ, Roche, Array, Surface, Arcus, BI, Immunity Bio, Astellas, NeoImmune ).
P. Cassier,
OSE, BMS, BI, Brenus, Scenic, Strat, MabQuest, Grey Wolf, Novartis, Pierre Fabre, Merck, Servier ), Travel.
S. Punekar, None.
S. Liu,
Roche, BMS, AZ, Takeda, Regeneron, Guardant, MSD, Jazz, Daiichi, Novartis, Gilead, Merus ).
M. Taylor,
Eisai, BMS, Exelexis, Merck, Pfizer, Moderna ).
L. Joseph, None.
A. Gianoukakis,
Eisai ).
J. Hines, None..
J. Garcia-Corbacho, None..
P. Tomasini, None.
D. Spigel,
Roche, AZ, GSK, Abbvie, Circle, Daiichi, MideX, Gatorade, Gilead, Medpace, Ottimo, Pyxis ).
M. Krebs,
Astellas, Bayer, Guardant Health, Janssen, Roche, Seattle Genetics, Zai Lab, BMS, Eisai, Servier, Novartis, BMS ), Travel.
A. Italiano, None..
M. Al Masri, None.
G. Fisher,
Ellipses Employment, Stock Option.
S. Serrano,
Ellipses Employment, Stock Option.
H. Arkenau,
Ellipses Employment, Stock Option.
A. Drilon,
14ner/Elevation Oncology, Amgen, Abbvie, AnHeart Therapeutics, ArcherDX, AstraZeneca, Beigene, BergenBio, Blueprint Medicines, Bristol Myers Squibb, Boehringer Ingelheim, Chugai Pharmaceutical, EcoR1 ), Honoraria.
Bayer, MonteRosa, Abbvie, EcoR1 Capital, LLC, Amgen, Helsinn, Novartis, Loxo/Lilly, AnHeart Therapeutics, Bristol Myers Squibb, Nuvalent ), Advisory boards.
MonteRosa, Innocare, Boundless Bio, Treeline Bio, Nuvalent, 14ner/Elevation Oncology, Entos, Prelude, Bayer, Applied Pharmaceutical Science, Bristol Myers Squibb, Enlaza, Pfizer, Roche/Genetech, Nova ), Other, Consulting.
mBrace, Treeline Stock.
Applied Pharmaceutical Science, Inc, AXIS, Clinical Care Options, Doc Congress, EPG Health, Harborside Nexus, I3 Health, Imedex, Liberum, Medendi, Medscape, Med Learning, MedTalks, MJH Life Sciences, Other, CME honoraria.
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