vobramitamab duocarmazine (MGC018) / MacroGenics, Byondis - LARVOL DELTA

Vobramitamab duocarmazine, an anti-B7-H3 antibody-drug conjugate, in patients with advanced solid tumors: Final results of a phase 1 cohort expansion. (PubMed, Cancer) - P1/2, P2 | "Vobramitamab duocarmazine demonstrated modest antitumor activity across tumor types, with the most pronounced activity in mCRPC. Treatment was limited by toxicity, particularly pleural effusions and fatigue, which restricted dosing duration. Study treatment was discontinued to refocus on mCRPC in a randomized phase 2 study (TAMARACK/NCT05551117), which was later discontinued after assessment of the vobramitamab duocarmazine safety and efficacy profile."

Journal • P1 data • Castration-Resistant Prostate Cancer • Fatigue • Genito-urinary Cancer • Head and Neck Cancer • Hematological Disorders • Melanoma • Neutropenia • Oncology • Prostate Cancer • Respiratory Diseases • Solid Tumor • CD276

Genotoxic antibody-drug conjugates combined with BCL-XL inhibitors enhance therapeutic efficacy in metastatic castration-resistant prostate cancer. (PubMed, J Clin Invest) - "Lastly, enhanced in vivo antitumor activity of vobramitamab duocarmazine by systemic A-1331852 was shown. Collectively, our findings provide rationale for the development of ADC therapies combining genotoxic payloads with BCL-XL inhibitors for mCRPC."

Journal • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Hematological Disorders • Oncology • Prostate Cancer • Solid Tumor • BCL2L1 • CD276 • STEAP1

Tamarack: A Study of Two Dose Levels of Vobramitamab Duocarmazine in Participants With Metastatic Castration Resistant Prostate Cancer (clinicaltrials.gov) - P2 | N=100 | Recruiting | Sponsor: MacroGenics | Phase classification: P2/3 ➔ P2 | N=420 ➔ 100

Enrollment change • Metastases • Phase classification • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

MGC018-SCLC: MGC018 in Patients With Relapsed or Refractory Extensive-Stage Small-Cell Lung Cancer (clinicaltrials.gov) - P2 | N=9 | Active, not recruiting | Sponsor: Georgetown University | Trial completion date: May 2026 ➔ Apr 2027

Trial completion date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor • EGFR

Tamarack: MGC018 Versus Androgen Receptor Axis-targeted Therapy in Participants With Metastatic Castration Resistant Prostate Cancer (clinicaltrials.gov) - P2/3 | N=420 | Recruiting | Sponsor: MacroGenics | Initiation date: Nov 2022 ➔ Feb 2023

Metastases • Trial initiation date • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

A Newly Designed Antibody-drug Conjugate Targeting B7-H3 Demonstrates Enhanced Therapeutic Efficacy Across a Spectrum of Cancers. (PubMed, Pharm Res) - "This study positions BR112 as a promising therapeutic candidate with enhanced efficacy and a stable pharmacokinetic profile for the treatment of B7-H3-expressing solid tumors."

Journal • Oncology • Solid Tumor

A Moderate-Affinity Antibody-Drug Conjugate Targeting B7-H3 Exerts Potent Antitumor Efficacy. (PubMed, Pharmaceuticals (Basel)) - "Among these treatments, antibody-drug conjugates (ADCs) have shown potent activity, and several clinical trials, including DS7300a and MGC018, are currently ongoing. This design combined moderate affinity and acceptable pharmacokinetics, resulting in potent antitumor efficacy in vivo. Our study suggests that affinity optimization could be a useful consideration for enhancing ADC efficacy, positioning CD276-8 ADC as a promising therapeutic for B7-H3-expressing solid tumors."

Journal • Oncology • Solid Tumor • TOP1

The B7-H3 targeting antibody-drug conjugate (ADC) vobramitamab duocarmazine (vobra duo) is potently effective against a broad panel of pediatric solid tumor xenograft models: A study from the Pediatric Preclinical In Vivo Testing (PIVOT) Consortium (AACR 2025) - P1/2 | "Vobra duo is potently efficacious across a broad panel of pediatric solid tumor xenograft models supporting clinical development of this agent and other agents targeting B7-H3 for children with cancer."

ADC • Preclinical • Castration-Resistant Prostate Cancer • Ewing Sarcoma • Genito-urinary Cancer • Hematological Malignancies • Hepatoblastoma • Neuroblastoma • Oncology • Osteosarcoma • Prostate Cancer • Rhabdoid Tumor • Rhabdomyosarcoma • Sarcoma • Solid Tumor • Wilms Tumor

Preclinical development of MGC026, a glycan-linked, exatecan-based antibody-drug conjugate (ADC) targeting B7-H3 for solid cancer (AACR 2024) - "A duocarmycin-based B7-H3-targeted DNA-alkylating ADC, vobramitamab duocarmazine (vobra duo), has shown encouraging clinical activity in the treatment of metastatic castration-resistant prostate cancer. MGC026 exhibited a favorable preclinical profile, with potent in vivo activity toward B7-H3-expressing tumor xenografts representing a range of cancer indications. MGC026 was tolerated in cynomolgus monkeys, a relevant toxicology model, at exposure levels exceeding those required for antitumor activity. These data support clinical development of MGC026 for the treatment of B7-H3-expressing solid cancers."

ADC • Preclinical • Genito-urinary Cancer • Head and Neck Cancer • Melanoma • Oncology • Prostate Cancer • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck

PRECLINICAL ACTIVITY OF THE B7-H3- TARGETING ANTIBODY-DRUG CONJUGATE (ADC) VOBRAMITAMAB DUOCARMAZINE (VOBRA DUO) IN PEDIATRIC SOLID TUMORS. (PubMed, Clin Cancer Res) - P1/2 | "These findings demonstrate broad preclinical efficacy of vobra-duo in pediatric solid tumors and support further clinical investigation of B7-H3-targeted therapies in children."

Journal • Preclinical • Castration-Resistant Prostate Cancer • Ewing Sarcoma • Genito-urinary Cancer • Hepatoblastoma • Nephrology • Neuroblastoma • Oncology • Osteosarcoma • Pediatrics • Prostate Cancer • Rhabdoid Tumor • Rhabdomyosarcoma • Sarcoma • Solid Tumor • Wilms Tumor

Preclinical characterization of the anti-tumor activity of the investigational anti-B7-H3 antibody-drug conjugate (ADC), vobramitamab duocarmazine (vobra duo), in pediatric sarcomas (pSC) (AACR 2025) - "Vobra duo shows anti-tumor activity toward in vitro and in vivo models of pSC. Further in depth pre-clinical assessment to support potential clinical application is warranted."

ADC • Preclinical • Neuroblastoma • Oncology • Osteosarcoma • Rhabdomyosarcoma • Sarcoma • Solid Tumor • ANXA5 • CASP3 • CD276 • LAMP1 • MAP1LC3A

Tamarack: A Study of Vobramitamab Duocarmazine in Participants With Metastatic Castration Resistant Prostate Cancer and Other Solid Tumors (clinicaltrials.gov) - P2 | N=192 | Terminated | Sponsor: MacroGenics | Completed ➔ Terminated; Business reasons

Trial termination • Anal Carcinoma • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Head and Neck Cancer • Laryngeal Cancer • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Oral Cancer • Prostate Adenocarcinoma • Prostate Cancer • Small Cell Lung Cancer • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • PD-L1

The investigational anti-B7-H3 antibody-drug conjugate vobramitamab duocarmazine exerts anti-tumor activity in vitro and in vivo in pediatric sarcoma preclinical models. (PubMed, Cell Death Dis) - "Repeated vobra duo doses ameliorated this outcome, reverting rhabdomyosarcorma to rhabdomyoma tumor, by increasing Desmin and Myogenin/Myf-4 differentiation markers expression, and reducing both Ki-67 and CD133. In conclusion, the in vitro and in vivo anti-tumor effects towards pSC highlight the need to extend the investigation to patient-derived preclinical models, to pave the way for clinical translation."

Journal • Preclinical • Neuroblastoma • Oncology • Osteosarcoma • Pediatrics • Rhabdomyosarcoma • Sarcoma • Solid Tumor • CASP3 • CD133 • CD276 • EIF4EBP1 • Myogenin

Optimal dosing of vobramitamab duocarmazine, a CD276 (B7-H3) antibody-drug conjugate, leads to durable eradication of Acute Myeloid Leukemia in preclinical xenograft models (ASH 2025) - "Therapeutic targeting of CD276 using an optimized dosing schema of the antibody-drugconjugate, vobra duo, resulted in remarkable anti-leukemia efficacy and durable responses in a clinicallyrelavent high-risk patient derived xenograft model of AML. The established safety profile of vobra duocombined with the robust preclinical evaluations in AML reported here provides rationale for rapidtranslation of this targeted therapy for high-risk AML patients in dire need of novel targeted therapeuticapproaches."

IO biomarker • Preclinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Solid Tumor • AFDN • CD276 • KMT2A

CD276 (B7-H3) Is an Immunotherapeutic Target in Acute Myeloid Leukemia with Preclinical Efficacy of Vobramitamab Duocarmazine, an Investigational CD276 Antibody-Drug Conjugate (ASH 2023) - "Vobra duo showed robust in vitro cytolytic activity against CD276 positive AML cells highlighting the need for ongoing preclinical evaluations of CD276 targeted therapies in AML. Given the established safety profile for vobra duo this provides a clear path for rapid translation to clinical use for high risk AML patients."

IO biomarker • Preclinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Pediatrics • Solid Tumor • CBFA2T3 • CD276 • CREBBP • GLIS2 • KAT6A • KMT2A

CP-MGC018-02: A Study of MGC018 in Combination With MGD019 in Participants With Advanced Solid Tumors (clinicaltrials.gov) - P1 | N=31 | Completed | Sponsor: MacroGenics | Active, not recruiting ➔ Completed

Checkpoint inhibition • Trial completion • Castration-Resistant Prostate Cancer • Epithelial Ovarian Cancer • Genito-urinary Cancer • Hepatocellular Cancer • Liver Cancer • Melanoma • Oncology • Ovarian Cancer • Pancreatic Cancer • Prostate Cancer • Renal Cell Carcinoma • Solid Tumor

A Phase II Study of Vobramitamab Duocarmazine in Patients With Relapsed or Refractory Extensive-Stage Small-Cell Lung Cancer (IASLC-WCLC 2025) - P2 | "Patients received a median of 1 prior line of therapy (range 1-2); all patients received frontline platinum-etoposide chemotherapy with anti-PD-L1 immunotherapy. Conclusions : In this phase II study of vobramitamab duocarmazine in patients with relapsed/refractory ES-SCLC, limited efficacy was observed, with no objective responses leading to early termination of trial. For optimization of B7-H3 ADCs for SCLC, further work is needed to understand the ideal cytotoxic payload, dosing strategy, and biomarkers of response and resistance."

Clinical • IO biomarker • P2 data • Anemia • Anorexia • Conjunctivitis • Fatigue • Infectious Disease • Lung Cancer • Mucositis • Neutropenia • Ocular Infections • Ocular Inflammation • Oncology • Ophthalmology • Pneumonia • Respiratory Diseases • Small Cell Lung Cancer • Solid Tumor • Stomatitis • Thrombocytopenia

Genotoxic antibody-drug conjugates combined with Bcl-xL inhibitors enhance therapeutic efficacy in metastatic castration-resistant prostate cancer. (PubMed, bioRxiv) - "Lastly, we found enhanced in vivo antitumor activity in mCRPC by combining the clinically relevant agents B7-H3-seco-DUBA (vobramitamab duocarmazine) and A-1331852. Collectively, our findings provide rationale for the development of ADC therapies combining genotoxic payloads with Bcl-xL inhibitors for mCRPC. B7-H3, PSMA, and STEAP1 targeted ADC therapies combining genotoxic payloads with Bcl-xL inhibitors induce p53-dependant apoptotic cell death in mCRPC, providing a clinically viable strategy for the treatment of advanced prostate cancer."

Journal • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Hematological Disorders • Oncology • Prostate Cancer • Solid Tumor • BCL2L1 • CD276 • STEAP1

Recent advances in antibody-drug conjugates for metastatic castration-resistant prostate cancer. (PubMed, Zhejiang Da Xue Xue Bao Yi Xue Ban) - P3 | "Among prostate-specific membrane antigen (PSMA)-targeted ADCs, ARX517 demonstrates superior safety and more significant prostate-specific antigen (PSA) reductions compared to earlier agents such as MLN2704, PSMA-ADC, and MEDI3726. ADCs targeting B7-H3, such as MGC018 and DB-1311, have also shown antitumor activity. ADCs targeting other antigens, including six-transmembrane epithelial antigen of the prostate (STEAP)1 (DSTP3086S), trophoblast cell surface antigen (TROP)2 (sacituzumab govitecan), and solute carrier (SLC) 44A4 (ASG-5ME), have shown preliminary antitumor activity in early trials but face challenges with insufficient efficacy or toxicity. Tisotumab vedotin (targeting tissue factor) has shown no significant therapeutic response in mCRPC. Meanwhile, disitamab vedotin (HER2-targeted), ABBV-969 (dual PSMA/STEAP1-targeted), and DXC008 (dual PSMA/STEAP1-targeted) are currently under evaluation. Notably, the B7-H3-targeted ADC ifinatamab deruxtecan has initiated..."

Journal • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • HER-2 • SLC44A4 • SLC4A4 • STEAP1

Vobramitamab Duocarmazine Does Not Achieve Responses in R/R ES-SCLC (Cancer Network) - "In all 9 patients treated with vobramitamab duocarmazine, no objective responses were reported; 1 patient had stable disease through all 8 cycles of treatment. Two patients had progressive disease, and 7 patients had stable disease. Furthermore, the median progression-free survival (PFS) was 2.0 months (95% CI, 1.8-not available [NA]), and the median overall survival (OS) was 4.3 months (95% CI, 3.4-NA)."

P2 data • Small Cell Lung Cancer

CP-MGC018-02: A Study of MGC018 in Combination With MGD019 in Participants With Advanced Solid Tumors (clinicaltrials.gov) - P1 | N=32 | Active, not recruiting | Sponsor: MacroGenics | N=278 ➔ 32

Checkpoint inhibition • Enrollment change • Castration-Resistant Prostate Cancer • Epithelial Ovarian Cancer • Genito-urinary Cancer • Hepatocellular Cancer • Liver Cancer • Melanoma • Oncology • Ovarian Cancer • Pancreatic Cancer • Prostate Cancer • Renal Cell Carcinoma • Solid Tumor

MGC018-SCLC: MGC018 in Patients With Relapsed or Refractory Extensive-Stage Small-Cell Lung Cancer (clinicaltrials.gov) - P2 | N=9 | Active, not recruiting | Sponsor: Georgetown University | N=17 ➔ 9 | Recruiting ➔ Active, not recruiting

Enrollment change • Enrollment closed • Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor

CP-MGC018-02: A Study of MGC018 in Combination With MGD019 in Participants With Advanced Solid Tumors (clinicaltrials.gov) - P1 | N=278 | Active, not recruiting | Sponsor: MacroGenics | Trial completion date: Jun 2025 ➔ Oct 2025 | Trial primary completion date: Apr 2025 ➔ Jul 2025

Checkpoint inhibition • Trial completion date • Trial primary completion date • Castration-Resistant Prostate Cancer • Epithelial Ovarian Cancer • Genito-urinary Cancer • Hepatocellular Cancer • Liver Cancer • Melanoma • Oncology • Ovarian Cancer • Pancreatic Cancer • Prostate Cancer • Renal Cell Carcinoma • Solid Tumor

Update on Vobramitamab Duocarmazine (GlobeNewswire) - P2 | N=192 | TAMARACK (NCT05551117) | Sponsor: MacroGenics | "Results for the concluded TAMARACK Phase 2 study included, based on a February 21, 2025 data cut-off, mature median radiographic progression-free survival (rPFS) of 9.5 months for the 2.0 mg/kg cohort (95% CI, 8.5-11.2) and 10.0 months for the 2.7 mg/kg cohort (95% CI, 7.4-11.4) in patients with mCRPC. Safety data from the study remained consistent with prior data disclosures. Based on its assessment of the vobra duo safety and efficacy profile and an internal resource and portfolio review, MacroGenics has decided not to pursue further internal development of vobra duo and will instead explore potential alternatives for partnering this program."

P2 data • Pipeline update • Castration-Resistant Prostate Cancer

Tamarack: A Study of Vobramitamab Duocarmazine in Participants With Metastatic Castration Resistant Prostate Cancer and Other Solid Tumors (clinicaltrials.gov) - P2 | N=192 | Completed | Sponsor: MacroGenics | Active, not recruiting ➔ Completed

Trial completion • Anal Carcinoma • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Head and Neck Cancer • Laryngeal Cancer • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Oral Cancer • Prostate Adenocarcinoma • Prostate Cancer • Small Cell Lung Cancer • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck