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.

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