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TROP2 Targeted Therapy: Module

CME

TROP-2–Targeted Therapy: Redefining the Therapeutic Landscape in HER2-Negative Breast Cancer

Physicians: Maximum of 0.75 AMA PRA Category 1 Credit™

Released: February 22, 2024

Expiration: February 21, 2025

CME/CE Information

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Implications of Resistance Mechanisms for ADC Sequencing

Currently, sacituzumab govitecan is the first and only FDA-approved TROP-2‒directed ADC in the HER2-negative breast cancer setting. As with all cancer therapeutics, it is clear that the efficacy and/or activity of sacituzumab govitecan will become undermined by the development of resistance to this agent. Resistance to sacituzumab govitecan may develop via genomic alterations that affect either TROP-2 or TOPO-I.17 Sacituzumab govitecan is designed to act by inducing cell killing via the TROP-2‒dependent delivery of its cytotoxic payload (SN-38) through binding to TOPO-I at the DNA interface, and this interaction triggers double-strand DNA breakage and tumor cell death. A possible mutation in TOPO-I causing a change in sequence specificity may result in the failure of SN-38 binding and prevent the intended tumor cell kill. Also, a mutation in TROP-2 may abrogate sacituzumab govitecan binding to the humanized antibody and prevent SN-38 delivery. These potential scenarios give rise to the question of how to optimally sequence ADCs for our patients with HER2-negative advanced breast cancer.

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Retrospective Studies of Sequencing Sacituzumab Govitecan vs T-DXd in HER2-Low Advanced Breast Cancer: Efficacy

Besides sacituzumab govitecan, T-DXd is the other ADC with FDA approval for patients with HER2-negative or HER2-low metastatic breast cancer.2,18 T-DXd is approved by the FDA for patients with unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ISH-) breast cancer who have received a prior chemotherapy in the metastatic setting or developed disease recurrence within 6 months of completing adjuvant chemotherapy.18 It has a drug-to-antibody ratio of approximately 8:1 and comprises a monoclonal antibody, trastuzumab, linked via a cleavable peptide linker to a cytotoxic TOPO-I inhibitor (DXd) payload (an exatecan derivative).19,20 Following the binding of T-DXd to HER2 on tumor cells, the cleavage of the linker results in the release of DXd, which in turn causes targeted DNA damage and cell death.

An analysis of 3 different institutional datasets showed glimpses of how sequencing sacituzumab govitecan and T-DXd may affect efficacy.21-23 In general, it seems clear that the median PFS achieved with the second ADC is shorter than that achieved with the use of the first ADC. This is especially true in patients with HR-positive/HER2-negative disease. However, the caveat with these studies is that they are retrospective and include a very small number of patients. In these studies, ADCs were either immediately sequenced after progression on one or after other treatments were administered before the second ADC was used. The number of prior therapies before and between the use of these 2 ADCs is unclear. Although various factors may have contributed to the results obtained, it is important to further explore ADC sequencing in larger studies. Fortunately, efforts are underway to investigate how to optimally sequence ADCs in this space.

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TBCRC Registry of Sequential ADC Use in HR-Positive TNBC or HER2-Low Advanced Breast Cancer

There is an effort by the Translational Breast Cancer Research Consortium (TBCRC) for a multicohort trial of the sequential use of T-DXd and sacituzumab govitecan for patients with multiple advanced breast cancer subtypes, including HR-positive/HER2-negative or HER2-low breast cancer and TNBC. Scenarios of sequences that may be studied include T-DXd followed by sacituzumab govitecan, sacituzumab govitecan followed by T-DXd, or either of these ADCs followed by an intervening chemotherapy. It will be interesting to see what the outcomes from the use of these sequencing approaches will be.

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TRADE-DXd (TBCRC 064): Planned Trial of T-DXd or Dato-DXd for ADC-Refractory Advanced Breast Cancer

TRADE-DXd (TBCRC 064) is a planned trial of the sequential use of T-DXd and Dato-DXd for patients with confirmed inoperable advanced breast cancer.24 Patients with a history of HER2-low breast cancer will be eligible to participate in the study. No previous exposure to a TOPO-I inhibitor‒based therapy is allowed. Crossover from T-DXd to Dato-DXd and vice versa will be allowed upon disease progression on the first ADC received. Tumor assessments will be performed, and blood samples will be collected and analyzed at multiple timepoints. The primary endpoint is ORR, and the secondary endpoints include PFS and OS. This trial has the potential to improve our understanding of the optimal sequencing of sacituzumab govitecan and Dato-DXd and reveal the mechanisms of resistance when ADCs with the same cytotoxic TOPO-I inhibitor payload (exatecan derivative; DXd) but different monoclonal antibody targets and drug-to-antibody ratios are used.

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