miptenalimab (BI 754111) / Boehringer Ingelheim - LARVOL DELTA

Targeting LAG3 to alter the tumor immune reactivity of CD8+T cells is a potential therapy for skin cutaneous melanoma. (PubMed, Sci Rep) - "Assay results demonstrated that both the LAG3 inhibitor ZYF0033 and the monoclonal antibody Miptenalimab significantly suppressed tumor proliferation and metastasis, while enhancing immune cell infiltration in murine models...Moreover, reduced LAG3 expression significantly enhanced CD8 + T cell immune infiltration, highlighting the regulatory role of LAG3 in CD8 + T cell function within the tumor microenvironment. These findings provided further evidence that SKCM may be effectively treated by targeting LAG3."

IO biomarker • Journal • Cutaneous Melanoma • Melanoma • Oncology • Solid Tumor • CD8 • LAG3

Platform Trial Evaluating Safety and Efficacy of BI 754091 Anti- PD-1 Based Combination Therapies in PD-(L)1 naïve and PD- (L)1 Pretreated Patient Populations With Advanced/Metastatic Solid Tumours (clinicaltrials.gov) - P2 | N=212 | Completed | Sponsor: Boehringer Ingelheim | Active, not recruiting ➔ Completed | Trial completion date: May 2025 ➔ Dec 2024 | Trial primary completion date: May 2025 ➔ Dec 2024

Trial completion • Trial completion date • Trial primary completion date • Endometrial Cancer • Esophageal Adenocarcinoma • Esophageal Cancer • Gastric Cancer • Lung Cancer • Oncology • Solid Tumor

A minimal physiologically-based pharmacokinetic modeling platform to predict intratumor exposure and receptor occupancy of an anti-LAG-3 monoclonal antibody. (PubMed, CPT Pharmacometrics Syst Pharmacol) - "Here, we present the development and application of a minimal physiologically-based pharmacokinetic (mPBPK) modeling approach to integrate biodistribution data in a quantitative platform to characterize and predict intratumor exposure and receptor occupancy (RO) of BI 754111, an IgG-based anti-lymphocyte-activation gene 3 (LAG-3) monoclonal antibody (mAb)...The developed mPBPK model allowed an adequate description of observed tumor radioactivity concentrations and tumor-to-plasma ratios leading to subsequent adequate prediction of LAG-3 RO at different dose levels. In the future, the developed model could be used as a platform for the prediction and analysis of biodistribution data for other mAbs and may ultimately support dose optimization by identifying dosages resulting in saturated RO."

Journal • PK/PD data • Oncology

Platform Trial Evaluating Safety and Efficacy of BI 754091 Anti- PD-1 Based Combination Therapies in PD-(L)1 naïve and PD- (L)1 Pretreated Patient Populations With Advanced/Metastatic Solid Tumours (clinicaltrials.gov) - P2 | N=212 | Active, not recruiting | Sponsor: Boehringer Ingelheim | Trial completion date: Jun 2024 ➔ May 2025 | Trial primary completion date: Jun 2024 ➔ May 2025

Combination therapy • Metastases • Trial completion date • Trial primary completion date • Endometrial Cancer • Esophageal Adenocarcinoma • Esophageal Cancer • Gastric Cancer • Gastrointestinal Cancer • Lung Cancer • Oncology • Solid Tumor

A Study in Patients With Different Types of Advanced Cancer (Solid Tumors) to Test Different Doses of BI 907828 in Combination With BI 754091 (Ezabenlimab) and BI 754111 or BI 907828 in Combination With BI 754091 (Ezabenlimab) (clinicaltrials.gov) - P1 | N=119 | Active, not recruiting | Sponsor: Boehringer Ingelheim | Recruiting ➔ Active, not recruiting

Combination therapy • Enrollment closed • Metastases • Biliary Tract Cancer • Cholangiocarcinoma • Gastric Cancer • Gastrointestinal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • MDM2 • TP53

A Study in Patients With Different Types of Advanced Cancer (Solid Tumors) to Test Different Doses of BI 907828 in Combination With BI 754091 (Ezabenlimab) and BI 754111 or BI 907828 in Combination With BI 754091 (Ezabenlimab) (clinicaltrials.gov) - P1 | N=140 | Recruiting | Sponsor: Boehringer Ingelheim | Phase classification: P1a/1b ➔ P1

Combination therapy • Metastases • Phase classification • Biliary Tract Cancer • Cholangiocarcinoma • Gastric Cancer • Gastrointestinal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • MDM2 • TP53

Efficacy and safety of brigimadlin (BI 907828), an MDM2–p53 antagonist, in patients (pts) with advanced biliary tract cancer: Data from two phase Ia/Ib dose-escalation/expansion trials. (ASCO-GI 2024) - P1, P1a/1b | "Pts in the combination trial received escalating doses of brigimadlin and 240 mg ezabenlimab on day 1 Q3W (doublet); one pt also received the anti-LAG-3 antibody BI 754111 (which has since been discontinued; triplet). Brigimadlin showed a manageable safety profile and encouraging preliminary efficacy in pts with BTC, with 7 PRs and 7 SDs in 16 pts. A Phase IIa/IIb trial of brigimadlin in patients with MDM2-amplified, TP53 wild-type BTC and other solid tumors is ongoing (Brightline-2). Clinical trial information: NCT03449381 and NCT03964233."

Clinical • Metastases • P1 data • Ampulla of Vater Carcinoma • Biliary Cancer • Biliary Tract Cancer • Cholangiocarcinoma • Gallbladder Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • MDM2

This Study Aims to Find a Safe and Effective Dose of BI 754091. The Study Also Aims to Find Safe and Effective Doses of BI 754091 and BI 754111 in Combination. This Study is Done in Asian Patients With Different Types of Cancer (clinicaltrials.gov) - P1 | N=146 | Completed | Sponsor: Boehringer Ingelheim | Active, not recruiting ➔ Completed

Combination therapy • Metastases • Monotherapy • Trial completion • Esophageal Cancer • Gastric Cancer • Gastrointestinal Cancer • Hepatocellular Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ALK • EGFR

This Study Tests the New Medicine BI 754111 Alone or in Combination With Another New Substance BI 754091 in Patients With Advanced Cancer. The Study Tests Different Doses to Find the Best Dose for Continuous Treatment. (clinicaltrials.gov) - P1 | N=172 | Completed | Sponsor: Boehringer Ingelheim | Active, not recruiting ➔ Completed

Combination therapy • Metastases • Trial completion • Colorectal Cancer • Gastrointestinal Cancer • Immune Modulation • Lung Cancer • Lung Non-Squamous Non-Small Cell Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ALK • EGFR • MSI • TMB

Efficacy and safety of the MDM2–p53 antagonist BI 907828 in patients with advanced biliary tract cancer: Data from two phase Ia/Ib dose-escalation/expansion trials. (ASCO-GI 2023) - P1a/1b, P2a/2b | "Patients in the combination trial received escalating doses of BI 907828 and 240 mg ezabenlimab q3w (doublet); one patient also received the anti-LAG-3 antibody BI 754111 (a drug that has since been discontinued; triplet). The MDM2–p53 antagonist BI 907828 has shown a manageable safety profile and encouraging preliminary efficacy in patients with BTC, with 5 PRs and 2 SD in 8 patients. A phase IIa/IIb trial of BI 907828 (45 mg q3w) in patients with BTC is planned to start recruitment at the end of 2022 (NCT05512377). Clinical trial information: NCT03449381 and NCT03964233."

Clinical • IO biomarker • Metastases • P1 data • Ampulla of Vater Carcinoma • Biliary Cancer • Biliary Tract Cancer • Cholangiocarcinoma • Gallbladder Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • MDM2 • TP53

PHASE IA/IB, DOSE-ESCALATION/EXPANSION STUDY OF THE MURINE DOUBLE MINUTE 2–TUMOR PROTEIN 53 ANTAGONIST BI 907828 IN COMBINATION WITH IMMUNE CHECKPOINT INHIBITORS IN PATIENTS WITH ADVANCED SOLID TUMORS (CTOS 2022) - P1a/1b | "This Phase Ia/Ib study (NCT03964233) is assessing BI 907828, an MDM2–p53 antagonist, combined with immune checkpoint inhibitors in TP53 wild-type cancers. In Phase Ia (dose escalation), patients with advanced/metastatic solid tumors received escalating doses of BI 907828 guided by a Bayesian Logistic Regression Model (starting dose 10 mg orally) plus ezabenlimab 240 mg (anti-PD-1 antibody) and BI 754111 600 mg (anti-LAG-3 antibody) every 21 days (q3w). The doublet combination of BI 907828 plus ezabenlimab showed a manageable safety profile and early signs of anti-tumor activity. Eleven patients remain on treatment; recruitment is ongoing."

Checkpoint inhibition • Combination therapy • P1 data • Preclinical • Anemia • Biliary Cancer • Biliary Tract Cancer • Cholangiocarcinoma • Gastric Adenocarcinoma • Gastric Cancer • Gastrointestinal Cancer • Hematological Disorders • Hepatology • Immune Modulation • Inflammation • Leiomyosarcoma • Liposarcoma • Lung Cancer • Neutropenia • Non Small Cell Lung Cancer • Oncology • Sarcoma • Soft Tissue Sarcoma • Solid Tumor • Synovial Sarcoma • Thrombocytopenia • Undifferentiated Pleomorphic Sarcoma • Urothelial Cancer • MDM2

Characterization of the LAG-3 targeting antibody BI 754111 in monotherapy and in combination with the anti-PD-1 antibody BI 754091 (AACR 2018) - P1; "The combination of anti-PD-1 and anti-LAG-3 resulted in a median TGI of 103% and doubled the number of complete responses (8/10).BI 754111 binds to cynomolgus monkey LAG-3 with comparable affinity as to hLAG-3 thus allowing pharmacokinetic and toxicological assessment in this species. Repeated high doses of BI 754111 were well tolerated without adverse immune-related side effects.The above results describe synergistic effects upon combination of PD-1 and LAG-3 treatment thus supporting the ongoing clinical trial in which BI 754111 is being tested in combination with BI 754091."

Combination therapy • IO Biomarker • Monotherapy • PD(L)-1 Biomarker • Oncology

Zr-immuno-PET using the anti-LAG-3 tracer [Zr]Zr-BI 754111: demonstrating target specific binding in NSCLC and HNSCC. (PubMed, Eur J Nucl Med Mol Imaging) - P1 | "[Zr]Zr-BI-754111 PET imaging shows favorable technical and biological characteristics for developing a potential predictive imaging biomarker for LAG-3-directed therapies."

IO biomarker • Journal • Head and Neck Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma of Head and Neck

Platform Trial Evaluating Safety and Efficacy of BI 754091 Anti- PD-1 Based Combination Therapies in PD-(L)1 naïve and PD- (L)1 Pretreated Patient Populations With Advanced/Metastatic Solid Tumours (clinicaltrials.gov) - P2 | N=212 | Active, not recruiting | Sponsor: Boehringer Ingelheim | Trial completion date: May 2023 ➔ May 2024 | Trial primary completion date: May 2023 ➔ May 2024

Combination therapy • Trial completion date • Trial primary completion date • Esophageal Adenocarcinoma • Esophageal Cancer • Gastric Cancer • Gastrointestinal Cancer • Immune Modulation • Lung Cancer • Oncology • Solid Tumor

This Study Aims to Find a Safe and Effective Dose of BI 754091. The Study Also Aims to Find Safe and Effective Doses of BI 754091 and BI 754111 in Combination. This Study is Done in Asian Patients With Different Types of Cancer (clinicaltrials.gov) - P1 | N=146 | Active, not recruiting | Sponsor: Boehringer Ingelheim | Trial primary completion date: Nov 2022 ➔ Aug 2023

Combination therapy • Monotherapy • Trial primary completion date • Esophageal Cancer • Gastric Cancer • Gastrointestinal Cancer • Hepatocellular Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ALK • EGFR

Phase I study of BI 754111 (anti-LAG-3) plus BI 754091(anti-PD-1) in patients (pts) with advanced solid cancers, followed by expansion in pts with microsatellite stable metastatic colorectal cancer (mCRC), anti-PD-(L)1-pretreated non-small-cell lung cancer (NSCLC) and other solid tumors (ESMO 2018) - P1; "Primary endpoints in the dose escalation are the number of pts with dose-limiting toxicities and the combination MTD. The primary endpoint of the dose expansion portion is the objective response rate."

Clinical • IO biomarker • MSi-H Biomarker • P1 data • PD(L)-1 Biomarker • Tumor Mutational Burden • Microsatellite Instability • Non Small Cell Lung Cancer

A phase Ia/Ib, dose-escalation/expansion study of BI 907828 in combination with BI 754091 (ezabenlimab) and BI 754111 in patients (pts) with advanced solid tumors. (ASCO 2022) - P1a/1b | "The doublet combination of BI 907828 plus ezabenlimab showed a manageable safety profile and early signs of anti-tumor activity. Eleven pts remain on treatment; recruitment is ongoing."

Clinical • Combination therapy • P1 data • Anemia • Biliary Cancer • Biliary Tract Cancer • Cholangiocarcinoma • Gastric Adenocarcinoma • Gastric Cancer • Gastrointestinal Cancer • Hematological Disorders • Hepatology • Immune Modulation • Inflammation • Leiomyosarcoma • Liposarcoma • Lung Cancer • Neutropenia • Non Small Cell Lung Cancer • Oncology • Sarcoma • Soft Tissue Sarcoma • Solid Tumor • Synovial Sarcoma • Thrombocytopenia • Undifferentiated Pleomorphic Sarcoma • Urothelial Cancer • MDM2

This Study Tests the New Medicine BI 754111 Alone or in Combination With Another New Substance BI 754091 in Patients With Advanced Cancer. The Study Tests Different Doses to Find the Best Dose for Continuous Treatment. (clinicaltrials.gov) - P1 | N=172 | Active, not recruiting | Sponsor: Boehringer Ingelheim | Trial completion date: Aug 2022 ➔ Jun 2023 | Trial primary completion date: Aug 2022 ➔ Jun 2023

Combination therapy • Trial completion date • Trial primary completion date • Colorectal Cancer • Gastrointestinal Cancer • Immune Modulation • Lung Cancer • Lung Non-Squamous Non-Small Cell Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ALK • EGFR • MSI • TMB

This Study Aims to Find a Safe and Effective Dose of BI 754091. The Study Also Aims to Find Safe and Effective Doses of BI 754091 and BI 754111 in Combination. This Study is Done in Asian Patients With Different Types of Cancer (clinicaltrials.gov) - P1 | N=146 | Active, not recruiting | Sponsor: Boehringer Ingelheim | Trial completion date: Nov 2022 ➔ Aug 2023

Combination therapy • Monotherapy • Trial completion date • Esophageal Cancer • Gastric Cancer • Gastrointestinal Cancer • Hepatocellular Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ALK • EGFR

Combination of two novel blocking antibodies, anti-PD-1 antibody ezabenlimab (BI 754091) and anti-LAG-3 antibody BI 754111, leads to increased immune cell responses. (PubMed, Oncoimmunology) - P1 | "Upregulation of inhibitory receptors, such as lymphocyte activation gene-3 (LAG-3), may limit the antitumor activity of therapeutic antibodies targeting the programmed cell death protein-1 (PD-1) pathway. Overall, ezabenlimab and BI 754111 bound to their respective targets with high affinity and prevented ligand binding. Combining ezabenlimab with BI 754111 enhanced in vitro activity versus monotherapy, supporting clinical investigation of this combination (NCT03156114; NCT03433898)."

Journal • Oncology • HLA-DRB1 • IFNG • LAG3 • PD-L2

A Study in Patients With Different Types of Advanced Cancer (Solid Tumors) to Test Different Doses of BI 907828 in Combination With BI 754091 (Ezabenlimab) and 754111 or BI 907828 in Combination With BI 754091 (Ezabenlimab) (clinicaltrials.gov) - P1a/1b | N=144 | Recruiting | Sponsor: Boehringer Ingelheim | Trial completion date: Jun 2025 ➔ May 2026 | Trial primary completion date: Oct 2023 ➔ Sep 2024

Combination therapy • Trial completion date • Trial primary completion date • Gastrointestinal Cancer • Hepatocellular Cancer • Immune Modulation • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ALK • BRAF • MDM2 • TP53

Platform Trial Evaluating Safety and Efficacy of BI 754091 Anti- PD-1 Based Combination Therapies in PD-(L)1 naïve and PD- (L)1 Pretreated Patient Populations With Advanced/Metastatic Solid Tumours. (clinicaltrials.gov) - P2 | N=212 | Active, not recruiting | Sponsor: Boehringer Ingelheim | Recruiting ➔ Active, not recruiting

Combination therapy • Enrollment closed • Esophageal Adenocarcinoma • Esophageal Cancer • Gastric Cancer • Gastrointestinal Cancer • Immune Modulation • Lung Cancer • Oncology • Solid Tumor

A Study in Patients With Different Types of Advanced Cancer (Solid Tumors) to Test Different Doses of BI 907828 in Combination With BI 754091 (Ezabenlimab) and 754111 or BI 907828 in Combination With BI 754091 (Ezabenlimab) (clinicaltrials.gov) - P1a/1b; N=144; Recruiting; Sponsor: Boehringer Ingelheim; Trial completion date: May 2024 ➔ Jun 2025; Trial primary completion date: Sep 2022 ➔ Oct 2023

Clinical • Combination therapy • Trial completion date • Trial primary completion date • Gastrointestinal Cancer • Hepatocellular Cancer • Immune Modulation • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ALK • BRAF • MDM2 • TP53

This Study Aims to Find a Safe and Effective Dose of BI 754091. The Study Also Aims to Find Safe and Effective Doses of BI 754091 and BI 754111 in Combination. This Study is Done in Asian Patients With Different Types of Cancer (clinicaltrials.gov) - P1; N=146; Active, not recruiting; Sponsor: Boehringer Ingelheim; Trial primary completion date: May 2021 ➔ Nov 2022

Clinical • Combination therapy • Monotherapy • Trial primary completion date • Esophageal Cancer • Gastric Cancer • Gastrointestinal Cancer • Hepatocellular Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ALK • EGFR

This Study Tests the New Medicine BI 754111 Alone or in Combination With Another New Substance BI 754091 in Patients With Advanced Cancer. The Study Tests Different Doses to Find the Best Dose for Continuous Treatment. (clinicaltrials.gov) - P1; N=172; Active, not recruiting; Sponsor: Boehringer Ingelheim; Trial completion date: Dec 2022 ➔ Sep 2022; Trial primary completion date: Dec 2022 ➔ Aug 2022

Clinical • Combination therapy • Trial completion date • Trial primary completion date • Colorectal Cancer • Gastrointestinal Cancer • Immune Modulation • Lung Cancer • Lung Non-Squamous Non-Small Cell Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ALK • EGFR • MSI • TMB