MacroGenics, Inc. (NASDAQ: MGNX) presented updated efficacy and safety results from the TAMARACK Phase 2 study of vobramitamab duocarmazine (vobra duo) at the European Society for Medical Oncology (ESMO) Congress in Barcelona, Spain. Vobra duo, an antibody-drug conjugate (ADC) targeting B7-H3, is being evaluated for patients with metastatic castration-resistant prostate cancer (mCRPC). The data suggest that vobra duo is an active drug in mCRPC, potentially offering a new treatment option for this challenging disease.
The primary goal of the TAMARACK study was to improve upon the treatment duration observed in a prior Phase 1 study by reducing the starting dose of vobra duo and increasing the dosing interval. This approach aimed to enhance safety and tolerability, extend treatment duration, and improve radiographic progression-free survival (rPFS).
TAMARACK Study Design and Patient Population
The TAMARACK trial enrolled 181 participants, with 176 receiving at least one dose of vobra duo at either 2.0 mg/kg every four weeks (q4W) (n=90) or 2.7 mg/kg q4W (n=86). The study population had a median age of 70 years, with approximately 49% having an ECOG performance status of 1 or 2. Sixteen percent of participants had visceral disease at baseline, and approximately 54% had received prior taxane therapy. The treatment arms were well-balanced across key baseline characteristics.
Efficacy Results
The updated data, with a cut-off date of July 9, 2024, demonstrated encouraging antitumor activity. In the intent-to-treat (ITT) population, the 6-month rPFS rate was 69% for the 2.0 mg/kg arm (95% CI, 57-79) and 70% for the 2.7 mg/kg arm (95% CI, 58-79). These rates were consistent across both taxane-naïve and taxane-pre-treated participants.
Median rPFS was approximately 8.5 months for the 2.0 mg/kg cohort (95% CI, 7.2-11.2) and 7.5 months for the 2.7 mg/kg cohort (95% CI, 7.2-10.6). However, MacroGenics noted that these results are immature and likely to change as additional events accrue. Mature median rPFS data is expected no later than early 2025.
Objective response rates (ORR) were also assessed. In the 2.0 mg/kg arm, the confirmed ORR was 20.0% (n=9/45), while the unconfirmed ORR was 26.7% (n=12/45). In the 2.7 mg/kg arm, the confirmed ORR was 40.6% (n=13/32), and the unconfirmed ORR was 46.9% (n=15/32). Confirmed ORR was comparable between taxane-naïve (26.7%) and taxane-pre-treated (17.5%) participants.
Safety and Tolerability
Regarding safety, in the 2.0 mg/kg cohort, 65.6% of participants experienced a Grade ≥3 treatment-emergent adverse event (TEAE), with a discontinuation rate of 25.6% and a dose reduction rate of 50.0% due to TEAEs. In the 2.7 mg/kg cohort, 62.8% experienced a Grade ≥3 TEAE, with a discontinuation rate of 38.4% and a dose reduction rate of 54.7% due to TEAEs.
The most common all-grade TEAEs (≥20% incidence) included asthenia, peripheral edema, decreased appetite, nausea, pleural effusion, diarrhea, fatigue, constipation, anemia, palmar-plantar erythrodysesthesia (PPE), neutropenia, and stomatitis. The majority of TEAEs were Grade 1/2 events.
Notably, rates of pleural effusion, pericardial effusion, and PPE were lower in both the 2.0 mg/kg and 2.7 mg/kg cohorts compared to the Phase 1 mCRPC dose expansion cohort, despite an increased median number of vobra duo doses administered in TAMARACK.
There were eight fatal treatment-related AEs, as assessed by the treating physician. These included pneumonitis, cardiac failure, stress cardiomyopathy, ventricular fibrillation, pleural effusion, and gastrointestinal hemorrhage.
Future Directions
"We believe that these latest results from TAMARACK continue to demonstrate that vobra duo is an active drug in prostate cancer," said Scott Koenig, M.D., Ph.D., President and CEO of MacroGenics. "Ultimately, our path forward for the molecule will depend on the final safety and efficacy data, including mature median rPFS, which we expect to have in hand no later than early 2025. We expect to make decisions about potential future development in the context of a competitive treatment landscape assessment, resource allocation across our clinical portfolio and potential partnering opportunities for vobra duo."
