trastuzumab vedotin (MRG002) / Lepu Biopharma - LARVOL DELTA

Safety, tolerability, pharmacokinetics, and antitumor activity of SHR-A1811 in HER2-expressing/mutated advanced solid tumors: A global phase 1, multi-center, first-in-human study (AACR 2023) - "Background: SHR-A1811 is an ADC comprised of a humanized anti-HER2 monoclonal antibody (trastuzumab), a cleavable linker, and a DNA topoisomerase I inhibitor payload. SHR-A1811 was well-tolerated and showed promising antitumor activity in heavily pretreated advanced solid tumors.Table 1. Subgroup analyses of ORRNo. of prior treatment lines in metastatic setting in all pts (N=250)HER2 positive BC (N=108)HER2-low BC (N=77)Other tumor types (N=65)≤381.8% (45/55)58.7% (27/46)36.7% (18/49)>381.1% (43/53)51.6% (16/31)31.3% (5/16)Prior anti-HER2 therapies in pts with BC (N=185)*HER2 positive BC (N=108)HER2-low BC (N=77)All BC (N=185)Any82.2% (88/107, 73.7-89.0)68.8% (11/16, 41.3-89.0)80.5% (99/123, 72.4-87.1)Trastuzumab81.9% (86/105, 73.2-88.7)75.0% (9/12, 42.8-94.5)81.2% (95/117, 72.9-87.8)Pertuzumab83.0% (39/47, 69.2-92.4)100% (5/5, 47.8-100)84.6% (44/52, 71.9-93.1)Pyrotinib86.9% (53/61, 75.8-94.1)71.4% (5/7, 29.0-96.3)85.3% (58/68, 74.6-92.7)Lapatinib80.0% (28/35,..."

Clinical • Metastases • P1 data • PK/PD data • Biliary Cancer • Biliary Tract Cancer • Breast Cancer • Colorectal Cancer • Endometrial Cancer • Gastric Cancer • Gastrointestinal Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Urothelial Cancer • HER-2

An Open-Label, Multicenter, Dose-Escalation and Expansion Clinical Study to Evaluate the Tolerability, Pharmacokinetics and Preliminary Efficacy of MRG002 Combined with HX008 in Patients with HER2-Expressing Locally Advanced or Metastatic Urothelial Carcinoma (ChiCTR) - P1/2 | N=42 | Completed | Sponsor: Peking University Cancer Hospital and Institute; Peking University Cancer Hospital and Institute

New P1/2 trial • Oncology • Solid Tumor • Urothelial Cancer • HER-2 • PD-L1

Modular Assembly of Bioconjugates Enabled by a Pyridine-Based Chemoselective Sequential Conjugation Platform. (PubMed, Angew Chem Int Ed Engl) - "The platform supports late-stage peptide diversification and stapling, protein functionalization, and streamlined construction of a HER2-targeting ADC (MRG002) analog with a tunable drug-to-antibody ratio. The resulting ADC shows slightly enhanced cytotoxicity in HER2-positive cells, comparable activity in antigen-negative controls, and markedly improved payload retention in human serum."

Journal • HER-2

Bone marrow from acute myeloid leukemia (AML) and multiple myeloma (MM) patients can be used to evaluate target expression and on-target efficacy for novel antibody drug conjugates (ADCs) (AACR 2026) - "Gemtuzumab ozogamicin (Mylotarg), Belantamab Mofodotin (Blenrep) and Trastuzumab vedotin were evaluated for toxicity to hematopoietic progenitor cells using the colony forming cell assay (CFC) in diseased (on-target efficacy) and normal bone marrow (NBM) (off-target toxicity). Blenrap in MM patient bone marrow had IC50 values which ranged from 4.4 to 46 µg/mL with an average IC50 value of 21 µg/mL, compared to evaluation in NBM which resulted in IC50 values > 30 µg/mL (highest tested concentration) and rarely had any impact on colony growth. These data suggest that the CFC assays with primary normal and diseased bone marrow cells may provide insight as to relative potency of an ADC on a disease-specific target as well as potential off-target toxicity to normal hematopoietic progenitors."

ADC • Clinical • IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Multiple Myeloma • Oncology • CD33 • HER-2

Efficacy and safety of MRG002 monotherapy in treating patients with locally advanced or metastatic breast cancer with low HER2 expression: A multi-center, non-randomized, open-label phase II clinical trial. (PubMed, Eur J Cancer) - "MRG002 demonstrated a manageable safety profile and promising anti-tumor activity in patients with locally advanced or metastatic breast cancer with low HER2 expression."

Journal • Monotherapy • P2 data • Breast Cancer • HER2 Breast Cancer • Interstitial Lung Disease • Oncology • Pain • Pulmonary Disease • Respiratory Diseases • Solid Tumor • HER-2

Pucotenlimab Combined with MRG002 for HER2-positive Cancer of Unknown Primary (clinicaltrials.gov) - P2 | N=50 | Not yet recruiting | Sponsor: Zhiguo Luo, MD, PhD

New P2 trial • Oncology

Efficacy and Safety of MRG002 in Prior TKI-Treated HER2 Positive Breast Cancer Patients: A Single Arm, Open Label, Multicenter, Phase II Study (SABCS 2024) - P2 | "All patients had received HER2-mAb and anti-HER2-TKI drug treatment (Pyrotinib 94 cases, 92.2%). MRG002 showed a potential efficacy in trastuzumab and anti-HER2-TKI treatment failed HER2-positive liver metastasis breast cancer patients with a good tolerance and safety profile. The emergence of MRG002 presented a promising treatment option for patients."

Clinical • P2 data • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • HER-2

Antibody-drug conjugates in patients with advanced/metastatic HER2-low-expressing breast cancer: a systematic review and meta-analysis. (PubMed, Ther Adv Med Oncol) - "Studies evaluating ADCs (trastuzumab deruxtecan (T-DXd), sacituzumab govitecan (SG), MRG002, and RC48-ADC) in patients with HER2-low a/mBC were included. Future studies should focus on bringing ADCs into earlier lines of therapy in this population. This study was registered in PROSPERO (CRD42024452962)."

Journal • Metastases • Retrospective data • Review • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • HER-2

MRG002-101: A Study of MRG002 in Patients with HER2-Positive Advanced Solid Tumors and Locally Advanced or Metastatic Gastric/Gastroesophageal Junction (GEJ) Cancer (clinicaltrials.gov) - P1/2 | N=129 | Active, not recruiting | Sponsor: Shanghai Miracogen Inc. | Recruiting ➔ Active, not recruiting | Trial completion date: Aug 2023 ➔ Dec 2024

Enrollment closed • Metastases • Trial completion date • Esophageal Cancer • Gastric Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • HER-2

MRG002-HER2 ADC combined with pucotenlimab (a PD-1 inhibitor), in patients with locally advanced or metastatic urothelial carcinoma (UC): Preliminary results of a phase I/II study (ESMO 2024) - "This phase I/II study was to evaluate the safety and activity of combination therapy in mUC patients who failed 1st line chemotherapy or not suitable for cisplatin as 1L therapy. IIn dose-escalation stage (Phase I), Eligible patients were assigned to MRG002 at cohort of 1.8mg/kg or 2.2mg/kg Q3W, combined with HX008 3mg/kg (cap with 200mg) Q3W. Compared with other combination of IO+ADCs, MRG002+HX008 results less incidence of grade 3/4 toxicities, and can bring durable progression-free survival benefit. Further evaluation of safety and efficacy is ongoing."

Clinical • IO biomarker • Metastases • P1/2 data • Oncology • Solid Tumor • Urothelial Cancer • HER-2

Antibodies to watch in 2024. (PubMed, MAbs) - "In this installment, we discuss key details for 16 antibody therapeutics granted a first approval in 2023, as of November 17 (lecanemab (Leqembi), rozanolixizumab (RYSTIGGO), pozelimab (VEOPOZ), mirikizumab (Omvoh), talquetamab (Talvey), elranatamab (Elrexfio), epcoritamab (EPKINLY), glofitamab (COLUMVI), retifanlimab (Zynyz), concizumab (Alhemo), lebrikizumab (EBGLYSS), tafolecimab (SINTBILO), narlumosbart (Jinlitai), zuberitamab (Enrexib), adebrelimab (Arelili), and divozilimab (Ivlizi))...These nearly 50 product candidates include numerous innovative bispecific antibodies, such as odronextamab, ivonescimab, linvoseltamab, zenocutuzumab, and erfonrilimab, and antibody-drug conjugates, such as trastuzumab botidotin, patritumab deruxtecan, datopotamab deruxtecan, and MRG002, as well as a mixture of two immunocytokines (bifikafusp alfa and onfekafusp alfa)...Our analyses indicate that these molecules have approval success rates in the range of 14-32%, with higher rates..."

Journal • Infectious Disease • Novel Coronavirus Disease • Oncology • Respiratory Diseases

Lepu Biotech’s ADC pipeline has made significant progress [Google translation] (iis.aastocks.com) - "MRG002 has completed the enrollment of patients in the Phase II pivotal clinical trial of BC liver metastasis with high HER2 expression in China, and has observed good data, which is expected to be presented at CSCO in 2024....The company is conducting a phase II trial of the combination of MRG002 and pucotenlimab in the treatment of patients with HER2-expressing solid tumors, and has observed good results in UC patients. Preliminary data are expected to be presented at the 2024 ESMO Conference."

P2 data • Breast Cancer • Gastrointestinal Cancer • HER2 Breast Cancer • Oncology • Solid Tumor • Urothelial Cancer

MRG 002 for her2 positive advanced paget’s disease: a phase II trial. (ChiCTR) - P1 | N=18 | Not yet recruiting | Sponsor: FUDAN UNIVERSITY SHANGHAI CANCER CENTER; fudan university shanghai cancer center

New P1 trial • Rare Diseases • HER-2

Preliminary safety and efficacy of TQB2930, a HER2-targeted bispecific antibody in patients with advanced breast cancer: Results from a phase 1b study. (ASCO 2024) - P1/2 | "Moreover, 5 pts achieved PR at 30mg/kg (ORR 41.7%), including one with prior exposure to trastuzumab, pyrotinib, tucatinib, ARX788, and the other one prior to trastuzumab, pertuzumab, lapatinib, MRG002. TQB2930 is well tolerated and has demonstrated promising single-agent anti-tumor activity in HER2-positive breast cancer who have failed standard anti-HER2 therapies, including multiple lines of prior HER2 targeted agents. These early signs of activity support the further exploration of combination therapy of TQB2930 and the study is ongoing."

Clinical • Metastases • P1 data • Anemia • Breast Cancer • Hematological Disorders • HER2 Breast Cancer • HER2 Positive Breast Cancer • Leukopenia • Neutropenia • Oncology • Solid Tumor • CD4 • HER-2

Antibody-drug conjugates (ADC) in patients with advanced/metastatic HER2-low expressing breast cancer: A systematic review and meta-analysis. (ASCO 2024) - "Other ADCs have also shown encouraging results, including sacituzumab govitecan (SG), MRG002, and RC48-ADC. Our systematic review and meta-analysis supports the efficacy of ADCs in HER2-low a/mBC patients over TPC. Future studies should focus on bringing ADCs into earlier lines of therapy in this population. Anti-tumor activity of ADCs presented as overall % (95% CI)."

Metastases • Retrospective data • Review • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • HER-2

A single-arm, multicenter, phase 2 clinical study of recombinant humanized anti-HER2 monoclonal antibody-MMAE conjugate (MRG002) in HER2-positive unresectable locally advanced or metastatic urothelial carcinoma. (PubMed, Eur J Cancer) - "Preliminary results of MRG002 demonstrated a clinically meaningful response in pretreated HER-2 positive unresectable locally advanced or metastatic UC patients. MRG002 at 2.2 mg/kg was well tolerated with a manageable toxicity."

Journal • Metastases • P2 data • Alopecia • Hematological Disorders • Immunology • Neutropenia • Oncology • Solid Tumor • Urothelial Cancer

A Single-Arm, Multicenter, Phase 2 Clinical Study of Recombinant Humanized Anti-HER2 Monoclonal Antibody-MMAE Conjugate (MRG002) in HER2-Positive Unresectable Locally Advanced or Metastatic Urothelial Carcinoma (Eur J Cancer) - P2 | N=58 | NCT04839510 | Sponsor: Shanghai Miracogen Inc. | "As of February 24, 2023, a total of 43 patients were enrolled. The median age was 60. 9 patients were dosed at 2.6mg/kg and 34 patients were dosed at 2.2mg/kg. At baseline, most patients (29/43) received ≥ 2 lines of treatment and 35 (81.4%) patients had prior ICI therapy. FISH test was performed in 41 patients and 9 (22.0%) were positive. By the cut-off date, 41 patients were evaluable and the ORR was 53% (95%CI：38.9%-67.5%), with 6.9% CR, and the DCR was 83.7% (95%CI：70.0%-91.9%). The median PFS and OS for the 43 patients were 7.0 months (95%CI：5.4-NE) and 14.9 months (95%CI：11.9-NE), respectively. The ORR was 77.8% in 9 patients with positive HER2 FISH results."

P2 data • Urothelial Cancer

ADC vs HP dual-antibody for HER2-positive advanced breast cancer after failed to TKI. (ASCO 2023) - "Among these patients,73 cases were in the new generation ADC group (including DS8201 30 cases, MRG002 24 cases, ARX788 10 cases and RC48 9 cases), 71 cases were in T-DM1 group and 69 cases were in HP group (combination chemotherapy including taxane, vinorelbine, gemcitabine and capecitabine). In our study, the new generation ADC significantly improved PFS and ORR compared with that for T-DM1 with manageable toxicity, so it can be considered an optimized subsequent treatment for HER2 positive advanced breast cancer after TKI failure. In addition, there was no significant difference in PFS and CBR between HP and the new generation ADC, thus HP dual-antibody regimen is also an optional treatment for patients who never used pertuzumab."

Metastases • Breast Cancer • Hematological Disorders • HER2 Breast Cancer • HER2 Positive Breast Cancer • Interstitial Lung Disease • Neutropenia • Oncology • Pulmonary Disease • Respiratory Diseases • Solid Tumor • Thrombocytopenia

A Study of MRG002 Versus Investigator's Choice of Chemotherapy in the Treatment of Patients With HER2-positive Unresectable Advanced or Metastatic Urothelial Cancer (clinicaltrials.gov) - P3 | N=290 | Recruiting | Sponsor: Shanghai Miracogen Inc. | Not yet recruiting ➔ Recruiting

Enrollment open • Metastases • Genito-urinary Cancer • Oncology • Solid Tumor • Urothelial Cancer • HER-2

A Study of MRG002 in the Treatment of Patients With HER2-positive Unresectable Locally Advanced or Metastatic Breast Cancer (clinicaltrials.gov) - P2/3 | N=350 | Recruiting | Sponsor: Shanghai Miracogen Inc. | Phase classification: P3 ➔ P2/3

Metastases • Phase classification • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor

Lepu Biological Announces 2022 Annual Results (ACN Newswire) - "MRG002: The registration study is progressing smoothly, and the enrollment has been completed. Advanced breast cancer with high expression of HER2: Enrollment in the registration phase II clinical trial has been completed, and the NDA application is expected to be submitted in 2023."

Enrollment closed • NDA • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor

A multiple center, open-label, single-arm, phase II clinical trial of MRG002, an HER2-targeted antibody-drug conjugate, in patients with HER2-low expressing advanced or metastatic breast cancer. (ASCO 2022) - P2 | "Background: MRG002 is a novel HER2-targeted ADC, composed of a sugar-modified trastuzumab, MMAE payload and a cleavable vc-linker. MRG002 shows promising efficacyand well tolerated in patients with HER2-low breast cancer. Further evaluation is underway."

Clinical • P2 data • Alopecia • Breast Cancer • Constipation • Diabetes • Gastroenterology • Gastrointestinal Disorder • HER2 Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • HER-2

A Study of MRG002 Versus Investigator's Choice of Chemotherapy in the Treatment of Patients With HER2-positive Unresectable Advanced or Metastatic Urothelial Cancer (clinicaltrials.gov) - P3 | N=290 | Not yet recruiting | Sponsor: Shanghai Miracogen Inc.

Metastases • New P3 trial • Genito-urinary Cancer • Oncology • Solid Tumor • Urothelial Cancer • HER-2

A Study of MRG002 in the Treatment of Patients With HER2-positive Unresectable Locally Advanced or Metastatic Breast Cancer. (clinicaltrials.gov) - P3 | N=290 | Recruiting | Sponsor: Shanghai Miracogen Inc. | Phase classification: P2 ➔ P3 | N=60 ➔ 290

Enrollment change • Metastases • Phase classification • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor

Efficacy and toxicity of HER2-targeted antibody-drug conjugates (ADCs) in the treatment of metastatic urothelial cancer (mUC): A systematic review (ESMO Asia 2022) - "The search method included the terms bladder carcinoma or urothelial carcinoma; disitamab vedotin; HER2-targeted therapy; antibody-drug conjugate...Results Ultimately, 6 phase 1 or 2 clinical trials with 236 pts were selected and 3 drugs were identified: Disatamab vedotin (DV), Trastuzumab Deruxtecan (TDXd), and MRG002...Preliminary results of DV combined with toripalimab as 1L in cis-ineligible pts or 2L treatment showed a RR of 76.7% and DCR of 96.7%...A phase 1b is testing TDXd combined with nivolumab, the ORR was 36.7%, with a median duration of response of 13.1 months...DV received FDA breakthrough therapy designation in 2020 for 2L treatment of HER2+ mUC. Confirmatory trials and better biomarker-based patient selection are needed."

Clinical • Review • Alopecia • Bladder Cancer • Genito-urinary Cancer • Hematological Disorders • Inflammation • Oncology • Pneumonia • Solid Tumor • Urothelial Cancer