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Oncology News Central (ONC)Five Deaths in Prostate Cancer Trial Send MacroGenics’ Stock Plummeting

Five patient deaths in the TAMARACK trial for vobramitamab duocarmazine in metastatic castration-resistant prostate cancer have raised concerns about the safety of antibody-drug conjugates targeting the B7-H3 antigen, while highlighting the potential for broader implications in oncology treatment protocols.

MacroGenics reported five patient deaths during the Phase II TAMARACK trial of their investigational antibody-drug conjugate (ADC) vobramitamab duocarmazine (vobra duo), aimed at treating metastatic castration-resistant prostate cancer (mCRPC). These adverse events, including myocardial infarction, cardiac arrest, pneumonitis, and pleural effusion, prompted a significant drop in the company’s stock value. Despite these setbacks, the trial continues, with some investigators expressing confidence in managing the treatment’s toxicities. MacroGenics plans to proceed with a Phase III study contingent on further data.

Key Points:

  • Trial Overview:
    • Phase II TAMARACK trial evaluates vobramitamab duocarmazine (vobra duo) for metastatic castration-resistant prostate cancer (mCRPC).
    • Vobra duo targets the B7-H3 antigen, carrying the alkylating agent seco-duocarmycin hydroxybenzamide azaindole.
  • Fatal Adverse Events:
    • Five deaths reported: two grade 5 toxicities (acute myocardial infarction, cardiac arrest) deemed unrelated to the treatment.
    • Other deaths involved pneumonitis (inflammation of lung tissues) and pleural effusion (fluid build-up in the pleural cavity).
  • Ongoing Investigation:
    • MacroGenics is investigating the causes of pneumonitis and pleural effusion-related deaths.
    • The TAMARACK trial is ongoing with incomplete follow-up.
  • CEO’s Statement:
    • CEO Scott Koenig expressed that the side effects are “extremely manageable.”
    • Investigators are reportedly “very comfortable” with managing these toxicities and encouraged by safety and activity data.
  • Trial Data:
    • Lower dose (2.0 mg/kg) vobra duo: 24.4% overall response rate (ORR), 91.1% disease control rate.
    • Higher dose (2.7 mg/kg) vobra duo: 43.8% ORR, 87.5% disease control rate.
  • Future Plans:
    • Potential Phase III study in mCRPC planned for 2025, depending on final TAMARACK analysis and progression-free survival data.
  • Historical Context:
    • MacroGenics previously reported two fatal grade 5 toxicities in a Phase I study of vobra duo.
    • Seven patient deaths in 2022 linked to enoblituzumab, another B7-H3 targeting antibody, led to discontinuation of a Phase II study in head and neck cancer.

Recent research indicates that there is a certain signal link between eight specific ADCs and cardiovascular issues.

More on ADCs

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