MedPath

BL-M07D1 Advanced Drug Monograph

Published:May 23, 2025

Generic Name

BL-M07D1

Comprehensive Report on the Investigational Agent BL-M07D1 (Trastuzumab brengitecan)

I. Introduction to BL-M07D1 (Trastuzumab brengitecan)

A. Overview as an Investigational Antibody-Drug Conjugate (ADC)

BL-M07D1 is an investigational antibody-drug conjugate (ADC) engineered for the targeted delivery of a cytotoxic agent to tumor cells, thereby possessing potential antineoplastic activity.[1] ADCs represent a therapeutic class that combines the specificity of monoclonal antibodies with the potent cell-killing ability of chemotherapy drugs, aiming to enhance efficacy while minimizing systemic toxicity.

The International Nonproprietary Name (INN) assigned to BL-M07D1 is Trastuzumab brengitecan.[3] This nomenclature was proposed in the World Health Organization (WHO) INN List 129 in 2023 and subsequently recommended in INN List 91 in 2024, with the assigned INN Number 12677.[3] The adoption of an INN is a crucial milestone in the global development and identification of a pharmaceutical substance, facilitating clear communication among healthcare professionals and researchers worldwide. The "Trastuzumab" component within the INN immediately suggests that the antibody backbone is derived from or related to trastuzumab, an antibody well-known for targeting the Human Epidermal Growth Factor Receptor 2 (HER2).

Other identifiers for this compound include the code names BL M07D1 and BLM07D1.[1] Its Chemical Abstracts Service (CAS) registry number is 2761149-81-7, and it has been assigned the FDA Unique Ingredient Identifier (UNII) 5MHN3G4T8J.[3] Furthermore, BL-M07D1 is classified as a new molecular entity, indicating its novel chemical structure and therapeutic potential.[4]

B. Development and Originator Companies

The development of Trastuzumab brengitecan (BL-M07D1) is being spearheaded by Sichuan Baili Pharmaceutical Co., Ltd., in conjunction with its subsidiary, Systimmune, Inc..[2] Systimmune, Inc. itself is a subsidiary of Sichuan Biokin Pharmaceutical Co Ltd [5], which is also listed as an active organization in the drug's development.[2] This collaborative structure suggests a strategic pooling of resources and expertise, likely encompassing pharmaceutical development, biologics manufacturing, and clinical research capabilities. The drug is reportedly available for licensing opportunities for the treatment of breast cancer and gastric cancer, signaling a potential avenue for broader development or commercialization partnerships to maximize its therapeutic reach.[4]

C. Therapeutic Rationale

BL-M07D1 is being developed with the primary aim of treating various types of cancer, with a particular focus on advanced or metastatic malignancies.[1] The core therapeutic rationale for BL-M07D1 revolves around its ability to selectively target cancer cells that express the HER2 protein. HER2, a member of the epidermal growth factor receptor family, is a well-validated therapeutic target in oncology. It is a receptor tyrosine kinase that, when overexpressed or mutated, plays a significant role in driving tumor cell proliferation, survival, and tumor vascularization.[1] Overexpression of HER2 is a characteristic feature of certain aggressive forms of cancer, most notably a subset of breast cancers and gastric cancers.

While one general source suggested BL-M07D1 targets PD-L1 [6], an overwhelming body of specific technical documentation, including the NCI Drug Dictionary, ADC Review, specialized databases like PatSnap and AdisInsight, materials from the developing company Systimmune, numerous clinical trial registrations, and conference abstracts, consistently and unequivocally identifies BL-M07D1 (Trastuzumab brengitecan) as an anti-HER2 ADC.[1] The INN itself, "Trastuzumab brengitecan," strongly supports this, indicating a trastuzumab (anti-HER2) antibody component. Therefore, the established therapeutic rationale is based on targeting HER2-expressing tumor cells. This approach aims to deliver a potent cytotoxic payload directly to these cells, thereby enhancing anti-tumor efficacy while potentially reducing the systemic side effects often associated with traditional chemotherapy. The development program includes investigations into its utility for cancers that have become resistant to conventional therapies, highlighting a strategy to address unmet medical needs.

II. Molecular Profile and Mechanism of Action

A. Antibody Component: Humanized Anti-HER2 Monoclonal Antibody

The antibody component of Trastuzumab brengitecan (BL-M07D1) is a humanized monoclonal antibody specifically engineered to target the human epidermal growth factor receptor 2 (HER2, also known as EGFR2 or ErbB2).[1] This antibody is based on the well-established anti-HER2 antibody, Trastuzumab.[9] Trastuzumab has a long history of successful clinical use in HER2-positive breast cancer and other HER2-driven malignancies, and its use as the backbone for BL-M07D1 leverages this existing knowledge of target engagement and clinical activity. The antibody is an IgG-based molecule, specifically an IgG1 subtype, which is known for its ability to mediate effector functions.[5] It is produced using recombinant DNA technology in Chinese Hamster Ovary (CHO) cells, a common expression system for therapeutic antibodies.[3] Humanization of the antibody is a critical step to reduce its immunogenicity when administered to patients, thereby minimizing the risk of anti-drug antibody formation and allowing for repeated dosing.

B. Cytotoxic Payload: Ed-04 (Novel Topoisomerase I Inhibitor)

The cytotoxic agent, or payload, conjugated to the anti-HER2 antibody in BL-M07D1 is a novel compound designated Ed-04.[3] Ed-04 is a potent inhibitor of DNA topoisomerase I (TOPO1).[2] Topoisomerase I is an essential nuclear enzyme involved in DNA replication and transcription, relieving torsional stress in DNA by creating transient single-strand breaks. Inhibition of TOPO1 leads to the accumulation of these breaks, ultimately causing DNA damage, cell cycle arrest, and apoptosis in rapidly dividing cancer cells.[26] Ed-04 is specifically described as a derivative of camptothecin, a natural alkaloid known for its topoisomerase I inhibitory activity.[3] The development of novel camptothecin derivatives like Ed-04 often aims to improve upon the pharmacological properties of earlier compounds in this class, such as enhancing potency, increasing solubility, improving the safety profile, or overcoming mechanisms of drug resistance. The selection of a topoisomerase I inhibitor payload aligns BL-M07D1 with other successful ADCs, like trastuzumab deruxtecan (T-DXd), which also utilize this class of cytotoxic agent.

C. Linker Technology and Drug-to-Antibody Ratio (DAR)

The anti-HER2 antibody and the Ed-04 payload in BL-M07D1 are connected by a specialized chemical linker.[3] This linker is designed to be cleavable and is specifically described as a serum-stable, cathepsin-B cleavable linker.[5] Cathepsin B is a lysosomal protease that is often upregulated in tumor cells and the tumor microenvironment. The design of the linker ensures that it remains intact and stable while the ADC circulates in the bloodstream (serum-stable), preventing premature release of the toxic payload, which could lead to off-target toxicity. Upon internalization of the ADC into the target cancer cell and trafficking to lysosomes, the increased cathepsin B activity is intended to cleave the linker, releasing the active Ed-04 payload precisely where it is needed.

Trastuzumab brengitecan is characterized by a high drug-to-antibody ratio (DAR), with an average of approximately 8 molecules of Ed-04 conjugated to each antibody molecule (DAR8) via cysteinyl linkage.[3] This high DAR is a significant feature, as it means that each antibody carries a substantial amount of cytotoxic agent. Compared to ADCs with lower DARs, such as trastuzumab emtansine (T-DM1) which has a DAR of approximately 3.5 [27], a DAR of 8 could potentially deliver a more potent cytotoxic punch to the target cell. This increased payload delivery may be particularly advantageous for treating tumors with heterogeneous or lower levels of HER2 expression, or for overcoming certain drug resistance mechanisms. The combination of a high DAR with a tumor-selective cleavable linker represents a sophisticated strategy in modern ADC design aimed at maximizing the therapeutic index – enhancing on-target efficacy while minimizing systemic toxicity.

D. Detailed Mechanism of Cellular Uptake, Payload Release, and Cytotoxicity

The mechanism of action of Trastuzumab brengitecan (BL-M07D1) is a multi-step process designed for targeted cancer cell killing:

  1. Target Binding: Upon intravenous administration, the anti-HER2 monoclonal antibody component of BL-M07D1 circulates and selectively seeks out HER2 receptors expressed on the surface of tumor cells. It binds to these HER2 receptors with high specificity.[1] This binding itself can exert anti-proliferative effects in HER2-driven solid tumors by interfering with HER2 signaling pathways.[9]
  2. Effector Function Engagement: The IgG1 Fc region of the antibody can engage with Fc receptors on immune effector cells, potentially mediating innate immune responses such as antibody-dependent cell-mediated cytotoxicity (ADCC) against the targeted cancer cells.[9]
  3. Internalization: Following binding to HER2, the BL-M07D1 ADC complex is internalized into the cancer cell through receptor-mediated endocytosis.[1]
  4. Lysosomal Trafficking and Payload Release: Once inside the cell, the ADC is trafficked to lysosomes, which are acidic organelles containing various hydrolytic enzymes.[8] Within the lysosomal environment, the cathepsin-B cleavable linker is enzymatically processed, leading to the liberation of the active cytotoxic payload, Ed-04.[8]
  5. Induction of Cytotoxicity: The released Ed-04, a topoisomerase I inhibitor, then exerts its cytotoxic effect. It interferes with DNA replication and repair processes by stabilizing the cleavable complex between topoisomerase I and DNA, leading to an accumulation of DNA single and double-strand breaks. This induction of genotoxic stress [8] and DNA damage [4] triggers cellular stress responses, activates pathways leading to cell cycle arrest (reportedly at the S phase for Ed-04 [24]), and ultimately results in programmed cancer cell death, primarily through apoptosis.[1]

The overall mechanism is thus a combination of HER2 antagonism (disruption of HER2 signaling) and potent TOP1 inhibition (DNA damage leading to cell death).[2]

E. Bystander Effect

Preclinical investigations have indicated that BL-M07D1 possesses a potent bystander effect.[24] The bystander effect in ADC therapy refers to the ability of the cytotoxic payload, once released from the targeted antigen-positive cancer cell, to diffuse across cell membranes and kill adjacent tumor cells, even if those neighboring cells do not express the target antigen (HER2 in this case) or express it at very low levels. The membrane permeability of the released payload (Ed-04) is a critical determinant of this phenomenon.[27] A strong bystander effect is considered highly advantageous for treating solid tumors, which are often characterized by heterogeneous antigen expression. This allows the ADC to exert a broader anti-tumor effect within the tumor microenvironment, potentially overcoming limitations posed by antigen heterogeneity and improving overall treatment efficacy.

F. Molecular Characteristics

The molecular formula of Trastuzumab brengitecan is reported as C6448​H9930​N1720​O2012​S44​.[3] The estimated average molecular weight of the conjugate is approximately 145175.244 Daltons.[3]

III. Preclinical Evaluation

A. In Vitro and In Vivo Antitumor Activity

Preclinical studies have provided evidence of the antitumor activity of BL-M07D1. The Ed-04 payload technology incorporated into BL-M07D1 is characterized as a potent topoisomerase 1 inhibitor.[5] Systimmune's Chief Medical Officer has remarked on the "encouraging signals of efficacy from the Ed-04 payload".[7] In various in vivo models, BL-M07D1 has demonstrated strong tumor inhibition effects in multiple cell line-derived xenografts (CDX).[24] Mechanistically, the ADC has been shown to drive cell cycle arrest at the S phase and subsequently induce apoptosis in cancer cells.[24]

B. Efficacy in HER2-Positive and HER2-Low Expression Models

A significant aspect of the preclinical evaluation of BL-M07D1 has been its activity across a spectrum of HER2 expression levels, including models resistant to other therapies.

  • HER2-Low Expression Models: In CDX models characterized by low HER2 expression, such as the human epidermal cancer cell line A431 and the human non-small cell lung cancer cell line NCI-H1975, BL-M07D1 reportedly exhibited superior anti-tumor efficacy compared to trastuzumab deruxtecan (DS-8201, Enhertu). Notably, these models are also considered to be insensitive to trastuzumab emtansine (T-DM1).[24] This finding is particularly compelling, as effective treatment for HER2-low tumors represents a substantial unmet medical need, and DS-8201 itself has established efficacy in this setting. Superiority over DS-8201 in these preclinical models suggests BL-M07D1 might possess an even more favorable therapeutic window or enhanced payload delivery and potency in HER2-low contexts.
  • HER2-Positive Models: In a CDX model using the JIMT-1 human breast cancer cell line, which is HER2-positive but known for its resistance to trastuzumab, BL-M07D1 demonstrated better anti-tumor efficacy compared to both T-DM1 and DS-8201.[24] Efficacy in such T-DM1 insensitive models implies that BL-M07D1 may be capable of overcoming resistance mechanisms that limit the activity of T-DM1, which could be related to its different class of payload (topoisomerase I inhibitor versus T-DM1's microtubule inhibitor) or other molecular characteristics.
  • Heterogeneous Models (Bystander Effect): The potent bystander effect of BL-M07D1 was demonstrated in a heterogeneous xenograft model composed of a mixture of HER2-positive (NCI-N87 gastric cancer cells) and HER2-negative (MDA-MB-468 breast cancer cells) tumor cells. In this challenging model, BL-M07D1 exhibited stronger tumor inhibition than T-DM1, an effect consistent with the bystander activity also observed with DS-8201.[24] This capacity is crucial for addressing tumor heterogeneity, a common feature of clinical cancers.

These preclinical results collectively provide a robust rationale for the clinical development of BL-M07D1. The data suggest potential advantages over existing HER2-targeted ADCs, including activity in broader patient populations (HER2-low), the ability to overcome certain resistance mechanisms, and enhanced efficacy due to factors like high DAR and potent bystander effect.

C. Development Platform

BL-M07D1 is a product of Systimmune's proprietary ADC development platforms, referred to as the HIRE-ADC platform [5] and potentially the SHRI platform.[5] The acronym "HIRE" reportedly stands for Heterogeneity overcoming - Immunogenic death inducing - Resistance antagonizing - Enhanced Specificity.[9] This nomenclature suggests a deliberate and multifaceted design strategy aimed at addressing key challenges encountered in ADC therapy, such as intra-tumoral heterogeneity of antigen expression, the development of drug resistance, and the need for improved tumor specificity to widen the therapeutic window.

IV. Clinical Development Program

A. Overview of Clinical Trials

Trastuzumab brengitecan (BL-M07D1) is currently in late-stage clinical development, with multiple studies progressing, the most advanced of which are in Phase 3.[2] The comprehensive clinical program encompasses a range of trial phases, including Phase 1, Phase 1b/II, Phase 2, combined Phase 2/3, and pivotal Phase 3 studies. These trials are investigating BL-M07D1 across a diverse array of cancer types and treatment settings.[2] The primary route of administration for BL-M07D1 in these clinical studies is intravenous (IV) infusion or IV drip.[4]

B. Key Clinical Trials Information

The breadth of the clinical development program for BL-M07D1 is substantial, reflecting a significant investment in evaluating its potential across multiple oncological indications. A summary of key clinical trials is presented in Table 1.

Table 1: Key Clinical Trials of BL-M07D1 (Trastuzumab brengitecan)

NCT/CTR IDPhaseOfficial Title/Brief Summary & Target Indication(s)Key Eligibility (Brief)Dosing Regimen(s) (if specified)Status (as of latest report)SponsorStart Date (Actual/Est.)Est. Primary Completion
NCT05461768 (BL-M07D1-101 / BL-M07D1-ST-101 / NCT06293898)Phase 1/IbFirst-in-Human study: Safety, tolerability, MTD, RP2D, PK, efficacy in locally advanced/metastatic HER2-expressing (positive/low) breast cancer (BC) and other solid tumors (gastric, colorectal, NSCLC)HER2-expressing advanced solid tumors, ≥1 prior therapy (NCT05461768), ≥2 prior therapies (NCT06293898)D-ESC: 1.0mg/kg D1D8 Q3W or 2.6-7.4 mg/kg D1Q3W. D-EXP: 3.8, 4.4, 5.0, 5.6 mg/kg D1Q3WOngoing, Recruiting (NCT06293898 started Feb 2024)Systimmune Inc., Sichuan Baili PharmaceuticalNCT05461768: June 2022 (Actual) / NCT06293898: Feb 2024 (Actual)NCT05461768: Not specified / NCT06293898: Not specified
NCT06031584 (BL-M07D1-202)Phase Ib/IISafety, tolerability, PK, efficacy in locally advanced/metastatic HER2-positive/low-expressing urinary and gastrointestinal solid tumorsUnresectable, locally advanced/metastatic HER2+/low urinary/GI tumors, failed/unsuitable for standard therapyNot specifiedRecruiting (42 est. participants)Sichuan Baili PharmaceuticalJan 2024 (Actual)Mar 2026
NCT06316531 (BL-M07D1-301) / CTR20240858Phase 3Randomized, open-label: BL-M07D1 vs. T-DM1 in unresectable locally advanced/metastatic HER2+ BC, failed prior taxanes & trastuzumabHER2+ BC, failed taxanes & trastuzumabNot specifiedRecruiting (268 est. participants)Sichuan Baili Pharmaceutical Co., Ltd.May 2024 (Actual)Jul 2024 (Primary); Later for full study
NCT06830889 (BL-M07D1-302)Phase 3Randomized, controlled: BL-M07D1 vs. T-DM1 in adjuvant treatment of HER2+ BC with residual invasive cancer after neoadjuvant therapyHER2+ BC, residual invasive disease post-neoadjuvant tx, radical mastectomyNot specifiedNot yet recruiting (1450 est. participants)Sichuan Baili PharmaceuticalMay 2025 (Est.)Not specified
NCT06957886 (BL-M07D1-304)Phase 3Randomized, open-label: BL-M07D1 vs. investigator's choice chemo in unresectable, locally recurrent/metastatic HER2-low BCHER2-low recurrent/metastatic BCNot specifiedNot yet recruiting (564 est. participants)Sichuan Baili PharmaceuticalMay 2025 (Est.)Not specified
NCT06891833Phase 2/3Randomized, controlled: BL-M07D1 + Pertuzumab ± taxane vs. taxane + Trastuzumab + Pertuzumab in neoadjuvant therapy for HER2+ BCHER2+ BC (neoadjuvant)Not specifiedNot yet recruitingSichuan Baili PharmaceuticalApr 2025 (Est.)Not specified
CTR20242193Phase 2BL-M07D1 combination therapy for unresectable locally advanced/metastatic HER2+ gastric or GEJ adenocarcinomaHER2+ Gastric/GEJ adenocarcinomaCombination therapyRecruitingSichuan Baili PharmaceuticalNot specifiedNot specified
NCT06113515 (EudraCT 2023-507243-39-00)Phase Ib/IISafety, tolerability, PK, efficacy in HER2-mutated, locally advanced/metastatic NSCLCHER2-mutated locally advanced/metastatic NSCLCIV infusionRecruitingSystimmune Inc.Not specified (EudraCT) / Dec 2023 (Est. for NCT06114511, similar indication)Not specified
NCT06131450Phase 1/2Gynecological malignanciesHER2-expressing gynecological cancersNot specifiedDue to start Dec 2023Not specifiedDec 2023 (Est.)Not specified
NCT06423885Phase 2HER2-positive Gastric or GEJ Adenocarcinoma (combination therapy)HER2+ gastric/GEJ adeno, age 18-75, ECOG 0-1Combination therapyDue to start June 2024Sichuan Baili PharmaceuticalJun 2024 (Est.)Oct 2024 (Est. Primary)

Sources for Table 1:.2

Note: Status and dates are based on the latest information available in the provided materials and may have changed. "Not specified" indicates data was not found in the provided material.

C. Focus on Key Indications

The clinical development of BL-M07D1 is strategically focused on several key oncological indications where HER2 expression or mutation plays a role:

  • HER2-Positive Breast Cancer: This is a cornerstone of the development program, with multiple trials evaluating BL-M07D1 in various settings: as adjuvant therapy for early-stage disease (NCT06830889) [2], in the neoadjuvant setting (NCT06891833) [2], and for patients with metastatic or locally advanced disease (NCT05461768, NCT06316531).[3] This broad investigation underscores the intent to establish BL-M07D1 across the continuum of HER2-positive breast cancer care.
  • HER2-Low Breast Cancer: Recognizing the significant unmet need and the emerging therapeutic landscape for HER2-low breast cancer, a dedicated Phase 3 trial (NCT06957886) is planned.[2] Additionally, patients with HER2-low breast cancer were included in the initial Phase 1 study (NCT05461768).[17] The rapid advancement to Phase 3 for this specific indication, following promising early clinical signals and supportive preclinical data showing efficacy in HER2-low models [24], highlights a key strategic direction. The success of trastuzumab deruxtecan in HER2-low breast cancer [25] has validated this as a critical area for ADC development, and BL-M07D1 is positioned to potentially offer another important treatment option.
  • Gastric and Gastroesophageal Junction (GEJ) Adenocarcinoma: Several trials are targeting HER2-positive gastric and GEJ cancers, including a Phase 2 combination therapy study (CTR20242193) [2], a Phase 1/II study (NCT06031584) [10], Phase 1 evaluation within broader solid tumor trials (NCT05461768) [12], and a specific Phase 2 trial (NCT06423885).[19]
  • Non-Small Cell Lung Cancer (NSCLC): BL-M07D1 is being investigated in NSCLC, particularly in patients with HER2 mutations (Phase Ib/II study NCT06113515) [11], as well as in broader HER2-expressing NSCLC cohorts within early-phase studies (NCT05461768, NCT06114511).[12]
  • Gynecological Cancers: The development program includes Phase I/II studies for various HER2-expressing gynecological malignancies such as endometrial, cervical, and ovarian cancers.[4] A specific Phase 1/2 trial (NCT06131450) for gynecological cancers was planned to start in December 2023.[19] The phase transition success rate (PTSR) for Phase II drugs in gynecological cancer progressing to Phase III is noted to be around 27%, indicating the challenges in this area.[5]
  • Other Solid Tumors: BL-M07D1 is also being evaluated in a range of other HER2-expressing solid tumors, including urinary tract cancer, urothelial carcinoma, biliary tract carcinoma, and broader gastrointestinal tumors, primarily in early-phase exploratory studies (NCT06031584, NCT05461768).[5]

V. Clinical Efficacy Data

A. Detailed Results from Phase 1/Ib Study (NCT05461768 / BL-M07D1-101 – SABCS 2023 Poster PO2-04-03)

The first-in-human Phase 1/Ib study (NCT05461768, also referred to as BL-M07D1-101) has provided the most detailed efficacy data to date for Trastuzumab brengitecan, particularly in breast cancer. Results were presented at the San Antonio Breast Cancer Symposium (SABCS) in 2023, with a data cut-off of September 30, 2023, involving 130 enrolled patients, of whom 88 breast cancer patients were evaluable for efficacy.[17] Earlier data cuts from this study (e.g., June 25, 2023, with 75 total patients) have also been reported.[12]

Key efficacy findings are summarized in Table 2.

Table 2: Efficacy Results from NCT05461768 in Breast Cancer (SABCS 2023 Data, N=88 Evaluable BC Patients)

Patient CohortNumber of Evaluable Patients (N)ORR (n/N, % [95% CI])cORR (n/N, % [95% CI])DCR (n/N, % [95% CI])Median PFSMedian DOR
Overall Breast Cancer (BC)8859/88, 67.0% [56.2-76.7]42/88, 47.7% [37.0-58.6]83/88, 94.3% [87.2-98.1]Not ReachedNot Reached
HER2-Positive BC5040/50, 80.0% [66.3-90.0]*>60% 2150/50, 100%Not ReachedNot Reached
HER2-Positive BC with Prior HER2-ADC1814/18, 77.8% [52.4-93.6]9/18, 50.0% [26.0-74.0]18/18, 100%Not ReachedNot Reached
HER2-Low BC3819/38, 50.0% [33.4-66.6]**28.9% 2133/38, 86.8% [71.9-95.6]Not ReachedNot Reached

Sources for Table 2:.17 ORR = Objective Response Rate; cORR = confirmed Objective Response Rate; DCR = Disease Control Rate; PFS = Progression-Free Survival; DOR = Duration of Response. Cut-off date Sept 30, 2023, unless specified by 21 which references updated analysis for SABCS 2023/2024 presentations.

*21 reports ORR 80%, cORR >60%, DCR 100% in 50 HER2+ mBC patients.

**21 reports ORR 50%, cORR 28.9%, DCR 86% in 38 heavily pretreated HER2-low mBC patients.

The data demonstrate substantial antitumor activity. In the overall cohort of 88 evaluable breast cancer patients, an ORR of 67.0% and a DCR of 94.3% are clinically meaningful. For patients with HER2-positive breast cancer, the ORR was particularly high at 80.0%, with a DCR of 100%, indicating that all patients in this subgroup experienced at least stable disease.

Critically, BL-M07D1 showed significant efficacy in patients who had previously been treated with other HER2-targeted ADCs. Among 18 such heavily pre-treated HER2-positive breast cancer patients, the ORR was 77.8%, and the DCR was 100%.[17] This level of activity in an ADC-resistant population is highly encouraging and suggests that BL-M07D1 may overcome some mechanisms of resistance to prior ADC therapies. This could be attributed to its distinct payload (Ed-04, a topoisomerase I inhibitor) compared to microtubule inhibitors used in some other ADCs, its high drug-to-antibody ratio, or other unique properties of the HIRE-ADC platform. The majority of these patients (8 out of 9 in an earlier cohort analysis) had received prior HER2-ADCs with microtubule inhibitors.[12]

In the HER2-low breast cancer cohort (38 evaluable patients), BL-M07D1 also demonstrated promising activity, with an ORR of 50.0% and a DCR of 86.8%.[17] This level of response in HER2-low disease, a population with historically limited targeted options until the advent of agents like trastuzumab deruxtecan, further supports the drug's potential in this expanding therapeutic area.

As of the data cut-off, median PFS and median DOR had not been reached for these cohorts, suggesting durable responses in at least a subset of patients. The study enrolled patients who were generally heavily pretreated, with 54% of the total 130 patients having received three or more prior lines of therapy.[17]

Regarding other solid tumors, the SABCS 2023 poster focused primarily on breast cancer. Earlier abstracts from the same study (NCT05461768, data cut-off June 25, 2023) mentioned enrollment of patients with gastric cancer (6 patients), colorectal cancer (4 patients), and non-small cell lung cancer (3 patients) out of a total of 75 patients treated at that time.[12] While specific efficacy figures for these non-breast cancer cohorts were not detailed in these abstracts, the overall conclusion was that BL-M07D1 demonstrated "encouraging efficacy in heavily pretreated HER2 expressing cancers, especially in HER2+ BC."

B. Emerging Data from Other Trials

While detailed efficacy results from the ongoing Phase 2 and Phase 3 trials are not yet available in the provided information, their initiation across various indications and settings (adjuvant, neoadjuvant, metastatic HER2-positive and HER2-low breast cancer, gastric cancer, NSCLC, gynecological cancers) implies that further efficacy data are being actively generated and will be crucial for defining the clinical utility of BL-M07D1.

VI. Safety and Tolerability Profile

A. Comprehensive Overview of Treatment-Related Adverse Events (TRAEs) from NCT05461768

The safety and tolerability of Trastuzumab brengitecan (BL-M07D1) have been primarily characterized through the Phase 1/Ib study (NCT05461768). Data presented at SABCS 2023 (N=130 patients, cut-off Sept 30, 2023) indicated that the most common Grade ≥3 treatment-related adverse events (TRAEs) were predominantly hematologic [17]:

  • Neutropenia: 42%
  • Leukopenia: 28%
  • Anemia: 23%
  • Thrombocytopenia: 17%

An earlier abstract from the same study (N=75 patients, cut-off June 25, 2023) provided a more detailed list of common TRAEs (occurring in >10% of patients, all grades and Grade ≥3) [12], which are summarized in Table 3.

Table 3: Summary of Key Treatment-Related Adverse Events (TRAEs) from NCT05461768 (N=75, data cut-off June 25, 2023)

Adverse EventAll Grades (%)Grade ≥3 (%)
Leukopenia7924
Neutropenia6939
Anemia6311
Nausea470
Thrombocytopenia379
Vomiting371
Decreased appetite270
Lymphopenia248
Alopecia230
Asthenia190
Gamma-glutamyl transferase increased170
Interstitial Lung Disease (ILD)0 (in this cohort of 75)0 (in this cohort of 75)

Sources for Table 3:.[12]

The safety profile indicates that hematological toxicities are the most frequent significant adverse events, a pattern commonly observed with ADCs carrying potent cytotoxic payloads. Most of the non-hematologic AEs reported in the earlier cohort were of low grade (Grade 1 or 2).

B. Dose-Limiting Toxicities (DLTs) and Maximum Tolerated Dose (MTD)

In the dose-escalation phase of the NCT05461768 study, one dose-limiting toxicity (DLT) was observed. This occurred at the 6.2 mg/kg D1Q3W (Day 1 every 3 weeks) dose level and consisted of Grade 3 febrile neutropenia and Grade 4 thrombocytopenia that lasted for more than 7 days in one patient.[12]

Despite this DLT, the maximum tolerated dose (MTD) had not been formally reached as of the June 25, 2023, data cut-off [12], nor as of the September 30, 2023, update mentioned in a later press release.[21] The study proceeded with dose-expansion (D-EXP) cohorts at several D1Q3W regimens, including 3.8 mg/kg, 4.4 mg/kg, 5.0 mg/kg, and 5.6 mg/kg [12], suggesting these doses were considered for further evaluation based on the emerging safety and efficacy profile.

C. Interstitial Lung Disease (ILD)

Interstitial Lung Disease (ILD) is an adverse event of special interest for many ADCs, particularly those targeting HER2 and/or utilizing topoisomerase I inhibitor payloads, due to the known risk associated with agents like trastuzumab deruxtecan.[25]

In the NCT05461768 study, the SABCS 2023 poster (N=130 patients, data cut-off Sept 30, 2023) reported one case of Grade 2 ILD.[17] In the earlier data presentation from the same study (N=75 patients, data cut-off June 25, 2023), no ILD events had been observed.[12]

The occurrence of only one Grade 2 ILD event in 130 patients is, at this stage, a relatively low incidence. For comparison, trastuzumab deruxtecan has been associated with ILD rates of around 10-15% in some pivotal trials, with a portion of those being Grade 3 or higher, and some fatalities.[25] If BL-M07D1 continues to demonstrate a significantly more favorable ILD profile in larger, ongoing, and future clinical trials with longer follow-up, this could represent a major clinical advantage and a key differentiating factor from other HER2-targeted ADCs with similar payloads. However, given the serious nature of ILD and the relatively limited number of patients exposed to BL-M07D1 thus far, continued vigilant monitoring and characterization of pulmonary toxicity will be essential throughout its clinical development.

D. Other Safety Information

As of the SABCS 2023 poster presentation (data cut-off Sept 30, 2023), no drug-related deaths had been observed in the NCT05461768 study.[17] The overall safety profile of BL-M07D1 was generally described as demonstrating adequate safety and tolerability in heavily pretreated patients with HER2-expressing cancers.[12]

VII. Pharmacokinetics (PK)

A. Summary of Available Pharmacokinetic Data

The pharmacokinetic (PK) profile of Trastuzumab brengitecan (BL-M07D1) is a key component of its ongoing clinical evaluation. Several early-phase clinical trials have listed PK assessment as a primary or secondary objective. The first-in-human Phase 1 study (NCT05461768) was designed to evaluate the PK profile alongside safety, tolerability, and initial efficacy.[12] Abstracts related to this study have indicated that "Updated efficacy and pharmacokinetic (PK) results will be presented at the meeting," though specific PK parameters were not detailed in these initial communications.[12]

Furthermore, the Investigational New Drug (IND) clearance granted by the U.S. FDA for a multicenter Phase 1 study (BL-M07D1-ST-101, NCT06293898) explicitly includes the evaluation of BL-M07D1's pharmacokinetic profile in subjects with metastatic or unresectable HER2-expressing cancers in the United States.[21] Other ongoing studies, such as the Phase Ib/II trial NCT06031584 in patients with HER2-positive/low-expressing urinary and gastrointestinal solid tumors [10], and the Phase Ib/II trial NCT06113515 in patients with HER2-mutated non-small cell lung cancer [11], also aim to characterize the pharmacokinetics of BL-M07D1.

Despite these planned evaluations, specific quantitative PK parameters for BL-M07D1—such as maximum concentration (Cmax​), area under the curve (AUC), elimination half-life (t1/2​), or clearance (CL) for the intact ADC, total antibody, or the released Ed-04 payload—are not provided in the currently available research materials.

The comprehensive understanding of BL-M07D1's pharmacokinetics is critical for its development. Data on absorption, distribution, metabolism, and excretion (ADME) will inform dose selection and scheduling for later-phase trials and eventual clinical use. Key considerations for ADC pharmacokinetics include the stability of the linker in circulation, the rate and extent of payload release in tumor versus normal tissues, and the clearance mechanisms of both the antibody component and the cytotoxic payload. The high drug-to-antibody ratio (DAR ~8) of BL-M07D1 might also influence its PK properties compared to ADCs with lower DARs, potentially affecting aspects like plasma clearance or tissue distribution. Establishing a clear PK/PD (pharmacokinetic/pharmacodynamic) relationship, linking drug exposure to both efficacy and toxicity, will be essential for optimizing the therapeutic window of BL-M07D1 and ensuring its safe and effective application.

VIII. Regulatory Status and Intellectual Property

A. FDA Investigational New Drug (IND) Clearances

A significant regulatory milestone for Trastuzumab brengitecan (BL-M07D1) was achieved on November 28, 2023, when the U.S. Food and Drug Administration (FDA) authorized Systimmune, Inc. to proceed with its planned clinical study under an Investigational New Drug (IND) application.[21] This clearance paved the way for the initiation of a multicenter Phase 1 study (identified as BL-M07D1-ST-101, and registered under NCT06293898) in the United States. This study is designed to evaluate the safety, tolerability, pharmacokinetic profile, and initial efficacy of BL-M07D1 in subjects with metastatic or unresectable HER2-expressing cancers.[21] Systimmune has also indicated that it is actively advancing Phase I clinical trials in the United States for BL-M07D1 for the treatment of solid tumors more broadly.[32] The FDA's IND clearance is a critical step that allows for the expansion of the drug's clinical development program into the U.S., facilitating broader patient access and data generation under U.S. regulatory oversight.

B. Other Regulatory Designations

The provided research materials do not explicitly mention any specific expedited regulatory designations for BL-M07D1, such as Breakthrough Therapy, Fast Track, or Priority Review, from major regulatory agencies like the FDA, European Medicines Agency (EMA), or China's National Medical Products Administration (NMPA).[18] While other compounds from Sichuan Baili Pharmaceutical or Systimmune, such as BL-B01D1, have received Breakthrough Therapy Designations in China [32], and other HER2 ADCs from different companies have received such designations internationally [38], no such announcements pertaining directly to BL-M07D1 were found in the supplied information.

The absence of reported expedited pathway designations to date does not preclude future applications or grants as more mature clinical data become available. Such designations are typically awarded based on the potential of a drug to offer substantial improvement over available therapies for serious or life-threatening conditions, supported by compelling early clinical evidence. While the initial efficacy and safety data for BL-M07D1 appear promising, particularly in heavily pretreated HER2-positive and HER2-low breast cancer, the data package may still be maturing for consideration for these accelerated pathways.

C. Overview of Patent Landscape

The intellectual property surrounding BL-M07D1 is crucial for its development and commercialization. Patsnap Synapse indicates the association of "100 Patents (Medical)" with BL-M07D1, although access to the specific details of these patents requires a login to their platform.[2]

One relevant patent application identified is WO-2019034176-A1, filed by Sichuan Baili Pharmaceutical Co Ltd, titled "Camptothecin-antibody Conjugate".[42] This patent application pertains to antibody-drug conjugates where an antitumor compound derived from camptothecin is conjugated to an antibody via a specific linker structure. Given that BL-M07D1 comprises a trastuzumab-based antibody linked to Ed-04 (a novel camptothecin-derivative topoisomerase I inhibitor) via a cleavable linker [3], this patent family is likely to be highly relevant to protecting the BL-M07D1 composition of matter or its method of use. General claims in related patents often describe generic ADC structures involving antibodies, linkers, and cytotoxic drugs.[43]

The novelty of the Ed-04 payload itself, as a distinct topoisomerase I inhibitor, would also be a key area for patent protection by Systimmune and Sichuan Baili Pharmaceutical. Securing robust patent coverage for the specific antibody, the Ed-04 payload, the linker technology, the overall ADC construct, and its therapeutic applications is essential to safeguard the innovation and support the significant investment required for pharmaceutical development. While the provided snippets confirm the existence of relevant patent activity, a detailed analysis of the claims and geographical coverage of the patent estate for Trastuzumab brengitecan and its unique Ed-04 payload is beyond the scope of the supplied information.

IX. Comparative Landscape and Future Perspectives

A. Positioning of BL-M07D1 Relative to Other HER2-Targeted ADCs

Trastuzumab brengitecan (BL-M07D1) is emerging in a dynamic and competitive field of HER2-targeted antibody-drug conjugates. The therapeutic landscape for HER2-expressing cancers has been significantly shaped by two key approved ADCs:

  • Trastuzumab emtansine (T-DM1, Kadcyla®): This ADC combines the trastuzumab antibody with the cytotoxic agent DM1 (a maytansine derivative and microtubule inhibitor) via a non-cleavable linker, with a drug-to-antibody ratio (DAR) of approximately 3.5.[25]
  • Trastuzumab deruxtecan (T-DXd, Enhertu®): This ADC also utilizes a trastuzumab antibody but is linked to DXd (a potent topoisomerase I inhibitor, an exatecan derivative) via a cleavable tetrapeptide-based linker, featuring a higher DAR of approximately 8.[25]

BL-M07D1 shares some structural similarities with T-DXd, notably the trastuzumab-based antibody, a topoisomerase I inhibitor payload, and a high DAR of ~8. However, it distinguishes itself with its novel camptothecin-derivative payload, Ed-04, and a specific cathepsin-B cleavable linker chemistry.[3]

Preclinically, BL-M07D1 has demonstrated a promising profile. It reportedly showed superior efficacy compared to T-DM1 and, in some models, even T-DXd. Specifically, in HER2-positive models like JIMT-1 (known for T-DM1 resistance), BL-M07D1 outperformed both comparators. In HER2-low expression models, BL-M07D1 was reported to be more effective than T-DXd.[24]

Clinically, the early Phase 1 data for BL-M07D1 are encouraging. The ORR of 80% in HER2-positive breast cancer and 50% in HER2-low breast cancer (from NCT05461768) [17] are competitive with outcomes reported for T-DXd in similar, albeit distinct, patient populations and trials (e.g., T-DXd achieved an ORR of approximately 60% in heavily pretreated HER2-positive breast cancer in DESTINY-Breast01, and an ORR of around 52% in HER2-low breast cancer in DESTINY-Breast04). The activity of BL-M07D1 in patients previously treated with other HER2 ADCs (ORR 77.8%) is particularly noteworthy.[17]

A crucial point of differentiation may lie in the safety profile, especially concerning Interstitial Lung Disease (ILD). T-DXd carries a known risk of ILD, which can be serious.[25] BL-M07D1 has, to date, reported a low incidence of ILD (one Grade 2 event in 130 patients from the SABCS 2023 update).[17] If this more favorable ILD profile is maintained in larger and longer-term studies, it could offer a significant clinical advantage for BL-M07D1.

B. Potential Advantages and Unmet Needs Addressed

Based on the available data, Trastuzumab brengitecan may address several unmet needs in the treatment of HER2-expressing cancers:

  • Efficacy in HER2-Low Disease: The strong preclinical rationale and emerging clinical activity in HER2-low breast cancer position BL-M07D1 as a potentially important therapeutic option in this growing patient segment, where targeted therapies have only recently become available.
  • Activity After Prior ADC Therapy: The promising efficacy observed in patients whose disease has progressed after treatment with other HER2-targeted ADCs suggests that BL-M07D1 could provide a valuable treatment sequence option, potentially overcoming acquired resistance to earlier agents.
  • Potentially Improved Safety Profile: While further data are needed, the current low incidence of ILD is a positive signal. A confirmed better safety profile, particularly regarding severe toxicities like ILD, would be a significant benefit for patients.
  • Effective Bystander Killing: The potent bystander effect demonstrated preclinically could translate to improved efficacy in tumors with heterogeneous HER2 expression, a common clinical challenge.
  • Novel Payload and Linker System: The unique Ed-04 payload (a camptothecin derivative) and the specific cathepsin-B cleavable linker might offer a different spectrum of activity and resistance profile compared to existing ADCs.

C. Future Research Directions and Potential Impact on Cancer Therapy

The future development of BL-M07D1 will be guided by the outcomes of its ongoing and planned clinical trials. Key directions include:

  • Completion of Pivotal Trials: Results from the ongoing Phase 3 trials (e.g., NCT06316531 in metastatic HER2+ BC vs. T-DM1; NCT06830889 in adjuvant HER2+ BC vs. T-DM1; NCT06957886 in HER2-low BC vs. chemotherapy) will be critical in establishing its efficacy and safety in larger, randomized settings and defining its place relative to standard-of-care treatments.
  • Expansion into Other Tumor Types: Continued exploration in other HER2-expressing or HER2-mutated solid tumors, such as gastric/GEJ cancer, NSCLC, gynecological cancers, and urinary/GI tumors, is essential to understand the full spectrum of its activity.
  • Combination Therapies: Future studies may investigate BL-M07D1 in combination with other anticancer agents, including chemotherapy, immunotherapy (e.g., checkpoint inhibitors), or other targeted therapies, to potentially enhance efficacy or overcome resistance.
  • Biomarker Development: Identifying predictive biomarkers beyond HER2 expression levels (e.g., specific HER2 mutations, levels of lysosomal enzymes like cathepsin B, or factors influencing payload sensitivity) could help optimize patient selection and personalize treatment strategies.
  • Head-to-Head Comparisons: Direct comparative trials against T-DXd in various settings would provide the clearest evidence of relative efficacy and safety, although such trials are complex and resource-intensive.

BL-M07D1 is entering a competitive HER2 ADC landscape that includes not only T-DM1 and T-DXd but also other investigational agents like disitamab vedotin, ARX788, trastuzumab duocarmazine, and zanidatamab zovodotin, each with distinct molecular features and development programs.[25] The success of earlier ADCs has fueled intense research to develop next-generation agents with improved therapeutic indices. Each new ADC, including BL-M07D1, aims to carve out a niche by demonstrating superiority or advantages in specific patient populations, offering a better safety profile, or providing efficacy where existing treatments have failed. The field is progressively moving towards more nuanced, personalized approaches to HER2-targeted therapy. BL-M07D1's potential contributions will depend on its ability to clearly demonstrate clinical benefits and address existing limitations in this evolving therapeutic arena.

X. Conclusion

A. Summary of Key Findings

Trastuzumab brengitecan (BL-M07D1) is an investigational antibody-drug conjugate that targets HER2-expressing tumor cells. It comprises a humanized trastuzumab-based monoclonal antibody linked to Ed-04, a novel and potent topoisomerase I inhibitor payload (a camptothecin derivative), via a cathepsin-B cleavable linker, with a high drug-to-antibody ratio of approximately 8.

Preclinical studies have demonstrated robust antitumor activity across various HER2 expression levels, including HER2-low and HER2-positive models, with evidence of superiority over existing ADCs like T-DM1 and T-DXd in certain contexts. A significant bystander effect has also been observed, suggesting potential efficacy in heterogeneous tumors.

Early-phase clinical trial data (NCT05461768) have shown promising efficacy, particularly in heavily pretreated breast cancer patients. In HER2-positive breast cancer, an objective response rate of 80% and a disease control rate of 100% were reported. Notably, substantial activity (ORR 77.8%) was also seen in HER2-positive patients who had previously received other HER2-ADCs. In HER2-low breast cancer, an ORR of 50% was achieved. The safety profile observed to date has been generally manageable, with hematologic toxicities being the most common Grade ≥3 treatment-related adverse events. Importantly, the incidence of interstitial lung disease has been low in the data reported so far (one Grade 2 event in 130 patients), which, if maintained, could be a key differentiating factor. The maximum tolerated dose had not been reached in the Phase 1 study as of the latest comprehensive updates. Pharmacokinetic evaluations are ongoing in multiple trials.

B. Overall Therapeutic Potential of BL-M07D1

Trastuzumab brengitecan (BL-M07D1) holds considerable therapeutic potential as a novel agent for patients with HER2-driven malignancies. Its distinct molecular design, incorporating a novel payload and a high DAR, appears to translate into significant antitumor activity, even in challenging, heavily pretreated patient populations and those with acquired resistance to other HER2-targeted therapies. The promising efficacy signals in both HER2-positive and, critically, HER2-low breast cancer suggest a broad applicability within this common malignancy.

The ongoing and planned late-stage clinical trials, including Phase 3 studies in adjuvant, neoadjuvant, and metastatic breast cancer settings, as well as explorations in gastric cancer, NSCLC, and gynecological tumors, will be pivotal in fully defining its efficacy, safety, and ultimate role in the oncology treatment armamentarium. If BL-M07D1 can confirm its early promise, particularly by demonstrating a favorable risk-benefit profile that includes a lower incidence of severe toxicities like ILD compared to some existing agents, it could become a valuable new treatment option. Its development as part of Systimmune's HIRE-ADC platform underscores a commitment to innovative ADC design aimed at overcoming current therapeutic challenges. Ultimately, Trastuzumab brengitecan represents a promising candidate poised to potentially improve outcomes for patients with a range of HER2-expressing cancers.

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Published at: May 23, 2025

This report is continuously updated as new research emerges.

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