LY3410738 / Eli Lilly - LARVOL DELTA

Final Results from a First-in-Human Phase 1 Study of the Dual Isocitrate Dehydrogenase (IDH) 1/2 Inhibitor, LY3410738, in Advanced Solid Tumors Harboring IDH1 or IDH2 Mutations. (PubMed, Clin Cancer Res) - P1 | "LY3410738 demonstrated largely cytostatic antitumor activity in IDH1- or IDH2-mutated cholangiocarcinoma and IDH1-mutated gliomas. LY3410738 plus cisplatin-gemcitabine exhibited favorable antitumor activity in patients with treatment-naïve IDH-mutated cholangiocarcinoma, warranting further exploration as a treatment strategy."

First-in-human • Journal • P1 data • Biliary Cancer • Brain Cancer • Cholangiocarcinoma • Glioma • Oncology • Solid Tumor • IDH1 • IDH2

State of the Art of IDH Inhibitors: Emerging Questions and Perspectives. (PubMed, Anticancer Agents Med Chem) - "Selective inhibitors like ivosidenib (AG-120) and enasidenib (AG-221), targeting mutant IDH1 and IDH2 respectively, block 2- HG production and induce differentiation, achieving clinical success - particularly in AML...In response, novel approaches have emerged, such as covalent inhibitors like LY3410738, which irreversibly bind mutant residues, and dual inhibitors like vorasidenib (AG-881), which act on both IDH1 and IDH2 mutations and penetrate the blood-brain barrier for treating solid tumors...We underscore that discovering new antitumor compounds targeting IDH requires a collaborative effort across biomedical fields. These advancements aim to overcome resistance, broaden therapeutic options, and improve the effectiveness of IDH-targeted treatments."

Journal • Acute Myelogenous Leukemia • Biliary Cancer • Brain Cancer • Cholangiocarcinoma • Glioma • Hematological Malignancies • Leukemia • Metabolic Disorders • Oncology • Solid Tumor • IDH1 • IDH2

LOXO-IDH-20002: Study of LY3410738 Administered to Patients With Advanced Solid Tumors With IDH1 or IDH2 Mutations (clinicaltrials.gov) - P1 | N=200 | Active, not recruiting | Sponsor: Eli Lilly and Company | Trial completion date: May 2025 ➔ May 2026

Trial completion date • Biliary Cancer • Brain Cancer • Cholangiocarcinoma • Glioma • Oncology • Sarcoma • Solid Tumor • IDH1 • IDH2

LOXO-IDH-20001: Study of Oral LY3410738 in Patients With Advanced Hematologic Malignancies With IDH1 or IDH2 Mutations (clinicaltrials.gov) - P1 | N=260 | Active, not recruiting | Sponsor: Eli Lilly and Company | Trial completion date: May 2025 ➔ May 2026

Trial completion date • Acute Myelogenous Leukemia • Chronic Myelomonocytic Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Myeloproliferative Neoplasm • Oncology • IDH1 • IDH2

A phase 1b/2, safety lead-in and dose-expansion trial of ivosidenib plus durvalumab and gemcitabine/cisplatin as first-line therapy in patients with locally advanced, unresectable or metastatic cholangiocarcinoma with an IDH1 mutation. (ASCO 2025) - P1/2 | "Finally, encouraging activity has been observed in treatment-naive mIDH1 patients administered with the mIDH1 inhibitor LY3410738 in combination with GEM/CIS...The primary objective is to evaluate the safety and tolerability of the quadruplet combination, and to determine the recommended combination dose (RCD). The expansion phase will enroll approximately 40 patients who will be treated with the RCD, with the primary objective being to assess the clinical activity of the combination, as determined by a primary endpoint of confirmed complete or partial response using RECIST v1.1 criteria."

Clinical • Metastases • P1/2 data • Biliary Cancer • Cholangiocarcinoma • Oncology • Solid Tumor • IDH1

Study of Oral LY3410738 in Patients With Advanced Hematologic Malignancies With IDH1 or IDH2 Mutations (clinicaltrials.gov) - P1 | N=260 | Active, not recruiting | Sponsor: Eli Lilly and Company | Trial completion date: May 2024 ➔ May 2025

Metastases • Trial completion date • Acute Myelogenous Leukemia • Chronic Myelomonocytic Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Myeloproliferative Neoplasm • Oncology • IDH1 • IDH2

Study of LY3410738 Administered to Patients With Advanced Solid Tumors With IDH1 or IDH2 Mutations (clinicaltrials.gov) - P1 | N=200 | Active, not recruiting | Sponsor: Eli Lilly and Company | Trial completion date: May 2024 ➔ May 2025

Metastases • Trial completion date • Biliary Cancer • Brain Cancer • Cholangiocarcinoma • CNS Tumor • Gastrointestinal Cancer • Glioma • Oncology • Sarcoma • Solid Tumor • IDH1 • IDH2

A Study of LY3410738 in Healthy Adult Participants (clinicaltrials.gov) - P1 | N=42 | Completed | Sponsor: Eli Lilly and Company

New P1 trial

A Study Comparing Different Formulations of LY3410738 in Healthy Adult Participants (clinicaltrials.gov) - P1 | N=60 | Completed | Sponsor: Eli Lilly and Company

New P1 trial

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 (ESMO-GI 2023) - P1 | "The reversible IDH1 inhibitor ivosidenib is approved in 2L IDH1-mutant CCA. 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."

Combination therapy • IO biomarker • Metastases • Monotherapy • P1 data • Biliary Cancer • Cholangiocarcinoma • Gastrointestinal Cancer • IDH1 • IDH2

Study of LY3410738 Administered to Patients With Advanced Solid Tumors With IDH1 or IDH2 Mutations (clinicaltrials.gov) - P1 | N=200 | Active, not recruiting | Sponsor: Eli Lilly and Company | Trial completion date: May 2023 ➔ May 2024 | Trial primary completion date: May 2023 ➔ Aug 2023

Metastases • Trial completion date • Trial primary completion date • Biliary Cancer • Brain Cancer • CNS Tumor • Gastrointestinal Cancer • Glioma • Oncology • Sarcoma • Solid Tumor • IDH1 • IDH2

Study of Oral LY3410738 in Patients With Advanced Hematologic Malignancies With IDH1 or IDH2 Mutations (clinicaltrials.gov) - P1 | N=260 | Active, not recruiting | Sponsor: Eli Lilly and Company | Trial primary completion date: May 2024 ➔ Aug 2023

Metastases • Trial primary completion date • Acute Myelogenous Leukemia • Chronic Myelomonocytic Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Myeloproliferative Neoplasm • Oncology • IDH1 • IDH2

A first-in-human phase 1 study of LY3410738, a covalent inhibitor of mutant IDH, in advanced myeloid malignancies (AACR 2023) - P1 | "LY3410738 demonstrated a favorable safety profile with potent and sustained D-2-HG inhibition in pts with IDH1m R132, IDH2m R172, and IDH2m R140 mutations. Preliminary efficacy was also seen in all genotypes, in a dose dependent manner. RP2D evaluation is ongoing.Table: Response in R/R AML IDH Inhibitor Naive (N=68)IDH1 R132IDH2 R172IDH2 R140No prior Venetoclax (n=13)Prior Venetoclax (n=19)Total (N=32)Low Dosesa (n=5)(High Dosesb)Total (N=13)Low Dosesa (n=9)(High Dosesb)Total (N=23)No prior Venetoclax (n=3)Prior Venetoclax (n=5)No prior Venetoclax (n=6)Prior Venetoclax (n=8) CR+CRh, n (%)5 (38%)2 (11%)7 (22%)-3 (100%)2 (40%)5 (38%)-2 (33%)-2 (9%) CR, n (%)3 (23%)2 (11%)5 (16%)-2 (67%)2 (40%)4 (31%)-2 (33%)-2 (9%) CRh, n (%)2 (15%)-2 (6%)-1 (33%)-1 (8%)----CRc (CR+CRh+CRi/CRp), n (%)6 (46%)6 (32%)12 (38%)-3 (100%)3 (60%)6 (46%)-2 (33%)-2 (9%)MFLS, n (%)1 (8%)3 (16%)4 (13%)2 (40%)--2 (15%)1 (11%)--1 (4%)IDH Inhibitor Pre-Treated (N=33)IDH1 R132IDH2 R172IDH2 R140No..."

IO biomarker • Metastases • P1 data • Acute Myelogenous Leukemia • Hematological Malignancies • Oncology • IDH1 • IDH2

Study of Oral LY3410738 in Patients With Advanced Hematologic Malignancies With IDH1 or IDH2 Mutations (clinicaltrials.gov) - P1 | N=260 | Active, not recruiting | Sponsor: Eli Lilly and Company | Recruiting ➔ Active, not recruiting

Enrollment closed • Metastases • Acute Myelogenous Leukemia • Chronic Myelomonocytic Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Myeloproliferative Neoplasm • Oncology • IDH1 • IDH2

Study of LY3410738 Administered to Patients With Advanced Solid Tumors With IDH1 or IDH2 Mutations (clinicaltrials.gov) - P1 | N=200 | Active, not recruiting | Sponsor: Eli Lilly and Company | Recruiting ➔ Active, not recruiting

Enrollment closed • Metastases • Biliary Cancer • Brain Cancer • CNS Tumor • Gastrointestinal Cancer • Glioma • Oncology • Sarcoma • Solid Tumor • IDH1 • IDH2

A first-in-human phase 1 study of LY3410738, a covalent inhibitor of mutant IDH, in advanced IDH-mutant cholangiocarcinoma and other solid tumors (AACR 2023) - P1 | "LY3410738 demonstrated a favorable safety profile with potent and sustained D-2-HG inhibition in pts with IDH1/2m advanced solid tumors. Consistent with the expectations for IDH inhibitor monotherapy in this setting, CCA and glioma pts exhibited prolonged stable disease. RP2D evaluation is ongoing."

Metastases • P1 data • Biliary Cancer • Brain Cancer • Cholangiocarcinoma • CNS Tumor • Gastrointestinal Cancer • Glioma • Oncology • Solid Tumor • IDH1 • IDH2

MD Anderson Research Highlights AACR 2023 Special Edition (MD Anderson Press Release) - "The University of Texas MD Anderson Cancer Center’s Research Highlights showcases the latest breakthroughs in cancer care, research and prevention....Researchers led by Courtney DiNardo, M.D., evaluated the use of LY3410738 in a first-in-human study including 130 patients from around the world. Treatment was well tolerated, with sustained 2-hydroxyglutarate inhibition in IDH1-mutated patients at all dose levels and in IDH2-mutated patients at higher dose levels. Preliminary efficacy was observed in both IDH1- and IDH2-mutant patients, with most responses occurring in those who had never received prior BCL2 inhibitor therapy and had not received prior IDH-targeted therapy. The Phase I trial is ongoing, with current activity focused on adding the treatment to standard frontline AML therapy."

P1 data • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • IDH1 • IDH2

Lilly Announces Details of Presentations at 2023 American Association for Cancer Research (AACR) Annual Meeting (PRNewswire) - "Eli Lilly and Company...announced that data from its oncology portfolio will be presented at the American Association for Cancer Research (AACR) Annual Meeting in Orlando, April 14 - 19, 2023. The presentations include the first clinical data from the Phase 1 studies of LY3537982 (KRAS G12C inhibitor) and LY3410738 (IDH inhibitor) and the Phase 2 study of Verzenio® (abemaciclib; CDK4/6 inhibitor) in metastatic treatment refractory castration-resistant prostate cancer. In addition, preclinical characterization data on Jaypirca's™ (pirtobrutinib; BTK inhibitor) binding mechanism will also be presented."

P1 data • P2 data • Preclinical • Biliary Cancer • Biliary Tract Cancer • Cholangiocarcinoma • Colorectal Cancer • Endometrial Cancer • Gastrointestinal Cancer • Genito-urinary Cancer • Gynecologic Cancers • Hematological Malignancies • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Ovarian Cancer • Pancreatic Cancer • Prostate Cancer • Solid Tumor • Thoracic Cancer • Uterine Cancer

Study of the Effects of Itraconazole and Carbamazepine on LY3410738 in Healthy Participants (clinicaltrials.gov) - P1 | N=27 | Terminated | Sponsor: Eli Lilly and Company | Trial completion date: Jan 2023 ➔ Apr 2022 | Active, not recruiting ➔ Terminated | Trial primary completion date: Jan 2023 ➔ Apr 2022; Data from part 2 no longer deemed necessary for this program.

Trial completion date • Trial primary completion date • Trial termination

Study of the Effects of Itraconazole and Carbamazepine on LY3410738 in Healthy Participants (clinicaltrials.gov) - P1 | N=27 | Active, not recruiting | Sponsor: Eli Lilly and Company | Recruiting ➔ Active, not recruiting

Enrollment closed

Study of LY3410738 Administered to Patients With Advanced Solid Tumors With IDH1 or IDH2 Mutations (clinicaltrials.gov) - P1 | N=200 | Recruiting | Sponsor: Eli Lilly and Company | Trial completion date: Sep 2023 ➔ May 2023

Trial completion date • Biliary Cancer • Brain Cancer • CNS Tumor • Gastrointestinal Cancer • Glioma • Oncology • Sarcoma • Solid Tumor • IDH1 • IDH2

Study of Oral LY3410738 in Patients With Advanced Hematologic Malignancies With IDH1 or IDH2 Mutations (clinicaltrials.gov) - P1 | N=260 | Recruiting | Sponsor: Eli Lilly and Company | Trial completion date: Mar 2023 ➔ May 2024 | Trial primary completion date: Mar 2023 ➔ May 2024

Trial completion date • Trial primary completion date • Acute Myelogenous Leukemia • Chronic Myelomonocytic Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Myeloproliferative Neoplasm • Oncology • IDH1 • IDH2

Secondary IDH1 resistance mutations and oncogenic IDH2 mutations cause acquired resistance to ivosidenib in cholangiocarcinoma. (PubMed, NPJ Precis Oncol) - "The irreversible mutant IDH1 inhibitor LY3410738 binds and blocks (R)-2HG production and cellular transformation by IDH1 R132H/D279N. These resistance mechanisms suggest that IDH1-mutated cholangiocarcinomas remain dependent on (R)-2HG even after prolonged ivosidenib treatment. Sequential mutant IDH inhibitor therapy should be explored as a strategy to overcome acquired resistance to mutant IDH inhibitors."

Journal • Preclinical • Biliary Cancer • Cholangiocarcinoma • Gastrointestinal Cancer • Oncology • Solid Tumor • IDH1 • IDH2

Study of the Effects of Itraconazole and Carbamazepine on LY3410738 in Healthy Participants (clinicaltrials.gov) - P1 | N=27 | Recruiting | Sponsor: Eli Lilly and Company | Trial completion date: May 2022 ➔ Jan 2023 | Trial primary completion date: May 2022 ➔ Jan 2023

Trial completion date • Trial primary completion date

Study of Oral LY3410738 in Patients With Advanced Hematologic Malignancies With IDH1 or IDH2 Mutations (clinicaltrials.gov) - P1 | N=220 | Recruiting | Sponsor: Eli Lilly and Company | Trial completion date: Sep 2023 ➔ Mar 2023

Trial completion date • Acute Myelogenous Leukemia • Chronic Myelomonocytic Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Myeloproliferative Neoplasm • Oncology • IDH1 • IDH2