ESMO 2024: TAMARACK: Randomized Phase 2 Trial of the B7-H3 Targeting Antibody Drug Conjugate Vobramitamab

(UroToday.com) The 2024 European Society for Medical Oncology (ESMO) Annual Congress held in Barcelona, Spain between September 13^th and 16^th, 2024 was host to a genitourinary cancers poster session. Dr. Johann De Bono presented TAMARACK, a randomized phase II trial of the B7-H3 targeting antibody-drug conjugate, vobramitamab.

Vobra duo (MGC018) is an investigational B7 homolog 3 (B7-H3; CD276)-targeting antibody-drug conjugate (ADC) with a duocarmycin-based DNA-alkylating payload. B7-H3 is highly expressed in multiple solid tumors, including primary and metastatic mCRPC, with limited expression in normal tissue.^1-3

Phase 1 testing of vobra duo (CP-MGC018-01/NCT03729596) demonstrated acceptable short-term safety at doses up to 4 mg/kg IV every 3 weeks in study participants with solid tumors.⁴ In the interim analysis of an expansion cohort of study participants with mCRPC who received vobra duo at 3 mg/kg every 3 weeks on study CP-MGC018-01, adverse events resulted in discontinuation, dose reduction, or interruption of the drug in 10%, 30%, and 55% of study participants, respectively, and the median number of doses received was 3.5 (range: 1–8).⁵
The TAMARACK study was designed to test the hypothesis that lowering the starting dose of vobra duo while increasing the dosing interval may improve tolerability (by delaying the onset, incidence, and severity of adverse events), extend treatment duration (by reducing the need for dose modifications), and maintain or enhance the efficacy of vobra duo in study participants with mCRPC. 

TAMARACK is a randomized, open-label, global, phase II dose-selection study assessing the efficacy, safety, and tolerability of vobra duo at two dose levels (2.0 mg/kg and 2.7 mg/kg IV every 4 weeks) in mCRPC study participants.

The study population included men with mCRPC previously treated with one prior androgen receptor pathway inhibitor (abiraterone, enzalutamide, or apalutamide) for prostate cancer in either the metastatic or nonmetastatic, castration-sensitive or castration-resistant setting. Study participants were to receive Vobra Duo until progressive disease per Prostate Cancer Working Group 3 (PCWG3) criteria, adverse events requiring discontinuation, physician decision, withdrawal of consent, or maximum allowed treatment duration (26 cycles or 2 years) was reached. On July 23, 2024, after the data cutoff date for this presentation, Vobra Duo was discontinued in all remaining study participants on treatment (n=32) after review of the totality of data, including efficacy and emerging adverse events associated with prolonged exposure and considering potential risk/benefit to participants. Most (n=27) of these remaining study participants had already received ≥8 cycles of vobra duo. All study participants continue to be monitored for adverse events, progressive disease, and survival.

The primary endpoint was a radiographic progression-free survival rate at 6 months, as assessed by investigators using PCWG3 criteria. Key secondary endpoints included:

• Safety
• PSA50 response
• Objective response rate (ORR)
• Duration of response (DOR)

The study's key eligibility criteria are summarized below:

The efficacy assessment was as follows:

Between June 2023 and November 2023, 181 study participants were enrolled and randomized to either vobra duo at 2 mg/kg every 4 weeks (n=91) or 2.7 mg/kg every 4 weeks (n=90).

The baseline patient characteristics are summarized below. The median patient age was 70 years, and 49% had an ECOG performance status of 1–2. 17% of study participants had visceral disease at baseline, with liver or lung disease in 14% of study participants. 45% of study participants had measurable disease at baseline. 54% of patients had received a prior taxane.


In the TAMARACK study, among RECIST response evaluable study participants with measurable disease at baseline, the confirmed ORR was:

• 2.0 mg/kg arm: 20% (9/45)
• 2.7 mg/kg arm: 41% (13/32)
• CP-MGC018-01 (3.0 mg./kg): 8.3%

Tumor responses did not appear to correlate with baseline B7-H3 expression, based on archival tissue samples of mixed age.
Among PSA response evaluable study participants, the confirmed PSA50 responses were as follows:

• 2.0 mg/kg arm: 45%
• 2.7 mg/kg arm: 39%
• CP-MGC018-01: 44%

PSA responses did not appear to correlate with baseline B7-H3 expression based on archival tissue samples of mixed age.
In the TAMARACK study, the protocol-specified primary endpoint, landmark 6-month rPFS rate, in the intent-to-treat population was 69% for the 2.0 mg/kg arm and 70% for the 2.7 mg/kg arm. Although immature, with only 65 (35.9%) rPFS events as of the data cutoff date, median rPFS is currently 8.5 months in the 2.0 mg/kg arm and 7.5 months in the 2.7 mg/kg arm. In CP-MGC018-01, median rPFS in the mCRPC expansion cohort was 5.5 months.

An overall summary of treatment-emergent adverse events in the TAMARACK and the CP-MGC018-01 studies is presented below:
Fewer treatment-emergent pleural effusion, pericardial effusion, and palmar-plantar erythrodysesthesia (PPE) syndrome events occurred in the 2.0 mg/kg, arm versus the 2.7 mg/kg arm, and generally, most of these adverse events were of grade 1–2.

Treatment-emergent pleural effusion, pericardial effusion, and PPE syndrome occurred in 36.4%, 15.3%, and 23.3%, respectively, of the participants on TAMARACK and 48.8%, 17.1%, and 46.3%, respectively, of the participants on the earlier phase 1 study despite the longer median duration of study treatment on TAMARACK.

Dr. De Bono concluded as follows:

• Vobra duo yields antitumor activity in mCRPC, as demonstrated by ORR, PSA response rate, and 6-month rPFS rate.
• Treatment with 2.7 mg/kg every 4 weeks yielded a higher ORR than 2.0 mg/kg Q4W
  • PSA responses were similar between the two arms
• Six-month landmark rPFS rates for 2.7 mg/kg and 2.0 mg/kg every 4 weeks are comparable.
• Neutropenia, anemia, thrombocytopenia, pleural effusion, and PPE syndrome events decreased with the reduction of the starting dose and dosing frequency.
• Adverse events associated with prolonged exposure to vobra duo, including edema, pleural effusions, and pericardial effusions, the latter two of which were less frequent with a 2.0 mg/kg starting dose, could possibly be mitigated by a longer dosing interval (e.g., every 6 weeks) or by use of a loading dose strategy.
• As of the data cutoff date, median rPFS is considered immature and subject to potential change, given that only 35.9% of participants have had rPFS events. Maturation of PFS is awaited.

Presented by: Professor Johann De Bono, MD, MSc, PhD, FRCP, Regius Professor of Cancer Research and a Professor in Experimental Cancer Medicine at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, London, UK

Written by: Rashid Sayyid, MD, MSc – Robotic Urologic Oncology Fellow at The University of Southern California, @rksayyid on Twitter during the 2024 European Society of Medical Oncology (ESMO) Annual Meeting, Barcelona, Spain, Fri, Sept 13 – Tues, Sept 17, 2024. 

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