A first-in-human phase 1 study of LY3410738, a covalent inhibitor of mutant IDH1 and IDH2, as monotherapy and in combination with cisplatin and gemcitabine in advanced IDH-mutant cholangiocarcinoma

IDH1 and 2 (IDH1/2) are mutated in 10-15% of intrahepatic cholangiocarcinoma (CCA). The reversible IDH1 inhibitor ivosidenib is approved in 2L IDH1-mutant CCA. Cisplatin and gemcitabine (CISGEM) is the standard 1L chemotherapy backbone for advanced CCA. Addition of PD1/PDL1 inhibitors have demonstrated modest improvement in OS (median 12.8 months), highlighting ongoing unmet need. LY3410738 is an oral, potent, selective, dual inhibitor of IDH1/2 mutations (IDH1/2m). LY3410738 binds covalently at a novel binding site, enabling continued potency in preclinical models in the setting of second site IDH resistance mutations. Here, we present the translational in vivo findings and data from the ongoing phase 1 study of LY3410738 as monotherapy and with CISGEM in advanced IDH1/2m CCA (NCT04521686).

In the phase 1 study, dose escalation (3+3 design) evaluated LY3410738 monotherapy in advanced relapsed/refractory (R/R) IDH1/2m CCA and other solid tumors. Dose expansion evaluated LY3410738 in combination with CISGEM in treatment naïve advanced IDH1/2m CCA patients. Objectives included determining the RP2D, safety, PK/PD, and antitumor activity.

In an IDH1m CCA PDX model, single agent LY3410738 (10-30 mpk, QD) demonstrated >60% tumor growth inhibition. In a combination PDX study, LY3410738 (30 mpk, QD) plus CISGEM (3/60 mpk, Q7Dx3, 3/40mpk, Q7Dx3) treatment for 6 weeks followed by 15 weeks of LY3410738 maintenance led to 85% tumor growth inhibition, while CISGEM alone achieved only 47% tumor growth inhibition (p < 0.001). In the phase 1 dose escalation cohorts, as of November 01, 2022, 45 patients with R/R CCA received LY3410738 monotherapy (25 - 600 mg QD or 150 - 300 mg BID) (1). Median number of prior lines of therapy was 2 (range, 1-7). The ORR was 4.5% with 2 PR and 23 SD. mPFS was 3.5 months (95% CI, 1.9-5.1). 6 months PFS rate was 32.5% (95% CI 18.8-47.0). In the dose expansion cohort, 13 patients with treatment naïve advanced CCA received LY3410738 (300 mg BID or 400 mg QD) in combination with CISGEM. The median age was 64 years (range, 51-77). Median time on treatment was 5.95 months (range, 2.3-9.1). No DLTs were observed. TEAE ≥30% regardless of attribution were anemia (54%), platelet count decreased (54%), nausea (46%), decreased appetite (39%), neutrophil count decreased (39%), and constipation (31%). Most frequent grade ≥3 TEAE ≥25% were neutrophil count decreased (39%), platelet count decreased (39%), and anemia (31%). 7 (54%) patients reported LY3410738 related AEs of which nausea and neutrophil count decreased were grade 3. The ORR was 46% with 6 PR/uPR (pending confirmation and ongoing) and 6 SD. mPFS was not reached, and 6 months PFS rate was 83.3% (95% CI, 27.3-97.5). The PK/PD profiles were consistent with LY3410738 monotherapy (1).

In this phase 1 study, LY3410738 in combination with CISGEM demonstrated a favorable safety profile and preliminary efficacy in treatment naïve locally advanced or metastatic IDH1/2m CCA. RP2D evaluation is ongoing. Reference: 1. Rodon J. et al. To be presented at AACR 2023, Apr 14-19.

NCT04521686.

Medical writing support was provided by Loxo Oncology at Lilly.

Loxo Oncology at Lilly.

Loxo Oncology at Lilly.

J. Harding: Honoraria (self): HCC Connect, OncLive; Advisory / Consultancy: Adaptimmune, AstraZeneca, Bristol Myers Squibb, Exelexis, Elevar, Eisai, Genoscience (uncompensated), Hepion, Imvax, Merck (DSMB) Medivir, QED, Tyra, Zymeworks (uncompensated); Research grant / Funding (institution): Bristol Myers Squibb, Boehringer Ingelheim, CytomX, Debiopharm, Eli Lilly, Genoscience, Incyte, Loxo @ Lilly, Novartis, Polaris, Pfizer, Zymeworks, Yiviva. M. Ikeda: Honoraria (self): AbbVie, AstraZeneca, Chugai, Eisai, Eli Lilly Japan, Fujifilm Toyama Chemical , Guardant Health Japan, Incyte Biosciences Japan, MSD, NIHON SERVIER , Novartis, Nippon Kayaku, Ono, Taisho Pharmaceutical, Teijin, Takeda, Taiho, Yakult; Advisory / Consultancy: NIHON SERVIER , Novartis, AstraZeneca, MSD, Chugai; Research grant / Funding (institution): AstraZeneca, Bayer, Bristol-Myers Squibb, Boehringer Ingelheim, Chugai, Chiome Bioscience, Delta-Fly Pharma, Eisai, Eli Lilly Japan, Invitae, MSD, J-Pharma, Merck biopharma, Merus N.V. , Novartis, NIHON SERVIER, Ono, Pfizer, Syneos Health. L. Goyal: Advisory / Consultancy: Alentis Therapeutics AG, Black Diamond, H3Biomedicine, Incyte Corp., QED Therapeutics, Servier, Sirtex Medical Ltd., Taiho Oncology; Research grant / Funding (self): AstraZeneca (DMSC); Research grant / Funding (institution): Adaptimmune, Bayer, Eisai, Merck, Macrogenics, Genentech, Novartis, Incyte, Eli Lilly, Loxo Oncology, Relay Therapeutics, QED Therapeutics Inc, Servier, Taiho Oncology, Bristol Meyers Squibb, Nucana, Alentis, Exelixis; Full / Part-time employment: Massachusetts General Brigham, Mass General Hospital Cancer Center. J. Rodon: Advisory / Consultancy: Ellipses Pharma, IONCTURA, Aadi Bioscience, Clarion Healthcare, Debiopharm, Monte Rosa Therapeutics, Cullgen. Pfizer, Merus N.V., Macorgenics, Oncology One, Envision Pharma, Columbus Venture Partners, Sardona Therapeutics, Avoro Capital Advisors, Vall d'Hebron Institute of Oncology/Ministero De Empleo Y Seguridad Social, Chinese University of Hong, Kong, Boxer Capital, LLC, Tang Advisors, LLC, Incyte; Research grant / Funding (institution): Blueprint Medicines, Black Diamond Therapeutics, Merck Sharp & Dohme, Hummingbird, Yingli, Vall d'Hebron Institute of Oncology/Cancer Core Europe, Novartis, Spectrum Pharmaceuticals, Symphogen, BioAtla, Pfizer, GenMab, CytomX, Kelun-Biotech, Takeda-Millenium, GalxoSmithKline, Taiho, Roche Pharmaceuticals, Bicycle Therapeutics, Merus, Curis, Bayer, AadiBioscience, Nuvation, ForeBio, BioMed Valley Discoveries, Loxo Oncology, Hutchinson MediPharma, Cellestia,Deciphera, Ideaya, Amgen, Tango Therapeutics, Mirati, Linnaeus Therapeutics ; Travel / Accommodation / Expenses: European Society for Medical Oncology. L. Chen: Honoraria (self): PharmaEgine, Taivex, OBI; Advisory / Consultancy: ONO, BMS, Eli Lilly, MSD, Ipsen, TTY, Syncore, Novartis, AstraZeneca, CStone, Astellas, Taivex; Research grant / Funding (institution): Syncore BioPharma, TTY, Polaris, ACT genomics, Pfizer, BMS, Novartis, Merck Serono; Licensing / Royalties: HuniLife, Taiwan; Full / Part-time employment: Kaohsiung Medical University Hospital, Kaohsiung Medical University, Taiwan, National Institute of Cancer Research, National Health Research Institutes, Taiwan; Officer / Board of Directors: ScinoPharm Taiwan, Ltd.. M. Ueno: Research grant / Funding (institution): Eli Lilly, boehringer-ingelheim. S. Kondo: Research grant / Funding (institution): Elli lliy; Travel / Accommodation / Expenses: Eisai. T. Yokota: Honoraria (self): Merck Biopharma, ONO PHARMACEUTICAL CO., LTD., Bristol-Myers Squibb, AstraZeneca, Chugai, MSD, Eisai, Rakuten Medical; Advisory / Consultancy: Merck Biopharma, MSD, Rakuten Medical; Research grant / Funding (self): Japan Agency for Medical Research and Development; Research grant / Funding (institution): AstraZeneca, Pfizer, ONO PHARMACEUTICAL CO., LTD., Novartis, INCB, MSD, Roche, Lilly, Merck Biopharma, Syneos Health, Incyte, GlaxoSmithKline, Ascent, Nanobiotix, Abbvie. R. Shroff: Advisory / Consultancy: AstraZeneca, Clovis, Genentech, Incyte, Merck, QED Therapeutics, Servier , Boehringer Ingelheim, Taiho, Zymeworks Biopharm, CAMI, Servier, SYROS; Research grant / Funding (institution): Bayer, BMS, Bristol-Myers Squibb, Exelixis Pharm., IMV Inc., LOXO, Novocure, NUCANA, Pieris, Rafael Pharm., Seagen, Taiho, QED. T. Satoh: Honoraria (self): Bristol-Myers, Ono Pharmaceutical, Elli-Lilly, Chugai Pharmazeutical, Daiichi-Sankyo; Research grant / Funding (self): Yakult Honsha, Taiho, Chugai Pharmaceutical; Research grant / Funding (institution): Yakult Honsha, Ono Pharmaceutical, Taiho, Chugai Pharmaceutical. A. Hollebecque: Honoraria (Institution): Astra-Zeneca, Roche; Advisory / Consultancy: Abbvie, Amgen, Basilea, BMS, Incyte, Servier, QED therapeutics, Relay Therapeutics, Seagen, Taiho; Research grant / Funding (self): Incyte; Research grant / Funding (institution): AstraZeneca; Travel / Accommodation / Expenses: AstraZeneca. M. Bender: Full / Part-time employment: Eli Lilly and Company. H. Liu: Full / Part-time employment: LOXO Oncology at Lilly. T. Macarulla: Advisory / Consultancy: Ability Pharmaceuticals SL, AstraZeneca, Basilea Pharma, Baxter, BioLineRX Ltd, Celgene, Eisai, Incyte, Ipsen Bioscience Inc, ; Speaker Bureau / Expert testimony: Janssen, Lilly, ; Research grant / Funding (self): MSD, Novocure, QED Therapeutics, Roche Farma, Sanofi-Aventis, Servier, Zymeworks ; Travel / Accommodation / Expenses: Servier, AstraZeneca, Sanofi, Incyte and MSD. All other authors have declared no conflicts of interest.