ADC-Immunotherapy Combinations Reshape TNBC Treatment as Debate Continues on ADC Classification

The ASCENT-04 trial demonstrated improved progression-free survival with sacituzumab govitecan (SG) combined with pembrolizumab compared with standard chemotherapy plus pembrolizumab in the PD-L1-positive metastatic triple-negative breast cancer (TNBC) population. Importantly, the combination did not result in increased overall toxicity, which was particularly reassuring given the overlapping risk of diarrhea associated with both immunotherapy and SG.

These findings have led many clinicians to adopt SG plus pembrolizumab as a preferred first-line regimen for most PD-L1-positive patients, with chemotherapy-based approaches reserved for select lower-risk or oligometastatic cases. The discussion also highlights the increasingly competitive ADC landscape, with ongoing studies evaluating alternative ADC-immunotherapy combinations, including Dato-DXd plus immune checkpoint inhibitors.

Beyond the PD-L1-positive setting, several trials are investigating whether ADCs may enhance immunotherapy benefit in PD-L1-negative disease, where current options are limited. Studies such as Saci-IO TNBC and TROPION-Breast11 are evaluating ADC plus checkpoint inhibition compared with ADC alone or chemotherapy. A key theme is the recognition that PD-L1 is an imperfect biomarker in TNBC, with inconsistent correlation to immunotherapy response.

In preclinical development, researchers identified chondroitin sulfate proteoglycan 4 (CSPG4) expression in neoadjuvant treatment-resistant TNBC to guide ADC development. Three anti-CSPG4 IgG1 antibodies with distinct variable regions (225.28S, 763.74, and 9.2.27) were engineered and compared. 225.28S IgG1 demonstrated the most efficient internalisation and potent cancer cell cytotoxicity when conjugated to the tubulin inhibitor MMAE.

To determine the optimal isotype, researchers generated 225.28S IgG4 and directly compared it with 225.28S IgG1. The IgG1 isotype showed superior internalisation and killing activity as an MMAE-conjugated ADC. Conjugation of 225.28S IgG1 to the topoisomerase inhibitor DXd produced an ADC with a drug-to-antibody ratio (DAR) of 8. This ADC was capable of robust internalisation into cancer cells and tumour cell cytotoxicity in vitro, and significant growth restriction of two CSPG4-expressing TNBC patient-derived xenografts (PDX) implanted orthotopically in mouse mammary fat pads.

Emerging data about the use of antibody-drug conjugates in breast cancer highlight the importance of target quantification, unresolved sequencing questions, and the evolving balance between targeted and cytotoxic effects. Key breast cancer opinion leaders outlined the limitations of immunohistochemistry assays that are currently FDA approved for pathologist use in interpreting HER2 expression levels, noting that these assays are not optimized to accurately discriminate between HER2-low and HER2-ultralow cases.

Additionally, they debated whether ADCs should be considered similar to targeted therapy due to the fact that target expression levels and mutations mediate ADC efficacy and mechanisms of resistance, or whether this class of agents is more akin to an advanced form of chemotherapy, owing to these drugs' inability to spare normal cells and antitumor activity that is not well correlated with target expression levels.

There's evidence showing that ADCs get cleaved externally, so they function as a lower or different type of dosing of the chemotherapeutic payload. There's also plenty of evidence demonstrating that the target makes a difference, that bringing the payload to the target makes the drug much more effective. When there's a controversy like this, both parties are correct, and both probably have some merit.

No one really knows how to sequence ADCs ultimately. When you get to higher-line metastatic settings, there are a lot of different opinions on what should be first. Some people think you should give ADCs in sequence, and some people think you should put chemotherapy between the two ADCs. There isn't much evidence for any of those methods at this point.

The phase 2 TRADE-DXd trial (NCT06533826) is investigating the efficacy and safety of sequencing T-DXd followed by Dato-DXd, or vice versa, in patients with HER2-negative locally advanced unresectable or metastatic breast cancer. Patients in group 1 will be randomly assigned to receive either T-DXd or Dato-DXd; if they progress on the study drug they are initially assigned, they will cross over to group 2 and receive the other study drug. Overall response rate in groups 1 and 2 serves as the primary end point. Key secondary end points include progression-free survival, overall survival, clinical benefit rate, time to progression, time to response, duration of response, safety, and change in HER2 expression level from baseline.

Overall, ADC-immunotherapy combinations are reshaping first-line TNBC management, with ongoing trials expected to further refine patient selection and treatment strategies.