ADCs Advance First-Line TNBC Treatment, Improving PFS

Triple-negative breast cancer, defined by the absence of estrogen receptor, progesterone receptor, and HER2 expression, accounts for approximately 10-15% of all breast cancers. Its aggressive nature, coupled with a higher incidence in younger women and those of African descent, underscores the urgent need for more effective and less toxic systemic therapies. For many years, cytotoxic chemotherapy has been the backbone of treatment for both early-stage and metastatic TNBC, but its efficacy is often short-lived, and its toxicity profile can be substantial, leading to treatment discontinuation and reduced quality of life. The search for targeted agents has been particularly challenging given the lack of conventional molecular targets, pushing researchers to explore novel approaches, including immunotherapies and, more recently, antibody-drug conjugates.¹

Antibody-drug conjugates represent a sophisticated class of targeted therapies, combining the specificity of monoclonal antibodies with the cytotoxic potency of chemotherapy. Each ADC consists of three main components: a monoclonal antibody that targets a specific antigen expressed on cancer cells, a cytotoxic payload (often a potent chemotherapy agent), and a linker that connects the antibody to the payload. The antibody binds to its target on the cancer cell surface, the ADC-antigen complex is internalized, and the linker cleaves, releasing the cytotoxic payload directly into the cancer cell. This mechanism aims to deliver chemotherapy more selectively to tumor cells, thereby reducing systemic exposure and mitigating off-target toxicities. The development of ADCs has been a significant area of innovation in oncology, with several agents now approved across various cancer types, including breast cancer.²

What the trials actually measured

The clinical development of ADCs in TNBC has focused on targets such as Trop-2 (trophoblast cell surface antigen 2) and HER2-low expression, which is increasingly recognized as a distinct subset of breast cancer that includes some TNBCs. Trop-2 is a transmembrane glycoprotein overexpressed in many epithelial cancers, including a high proportion of TNBCs, making it an attractive target for ADC development. Sacituzumab govitecan, a Trop-2-directed ADC, was one of the first to demonstrate significant activity in heavily pretreated metastatic TNBC, leading to its accelerated approval. This agent delivers SN-38, an active metabolite of irinotecan, directly to Trop-2 expressing cells. Its initial success in the later-line setting spurred investigations into its utility in earlier lines of therapy, including first-line metastatic disease.³

Another ADC, trastuzumab deruxtecan, targets HER2. While traditionally associated with HER2-positive breast cancer, recent research has highlighted its efficacy in HER2-low breast cancer, a category that encompasses a significant portion of what was previously classified as TNBC. HER2-low is defined by immunohistochemistry (IHC) scores of 1+ or IHC 2+ with a negative in situ hybridization (ISH) test. This ADC delivers a topoisomerase I inhibitor payload, deruxtecan, and has shown impressive activity in HER2-low metastatic breast cancer, including those with a triple-negative phenotype. The expansion of its indication to HER2-low disease has provided a new therapeutic avenue for patients who previously had limited targeted options.⁴

The move of ADCs into the first-line setting for TNBC has been driven by data from trials evaluating these agents either as monotherapy or in combination with other agents, such as immunotherapy. For sacituzumab govitecan, the ASCENT trial initially established its efficacy in refractory metastatic TNBC, showing a median progression-free survival (PFS) of 5.6 months vs 1.7 months with chemotherapy (HR 0.41; 95% CI, 0.32-0.52; P<.001). This trial enrolled 529 patients with unresectable locally advanced or metastatic TNBC who had received at least two prior lines of therapy for metastatic disease. The overall survival (OS) also improved significantly, reaching 12.1 months vs 6.7 months (HR 0.48; 95% CI, 0.38-0.62; P<.001).³

Building on these results, subsequent studies have explored sacituzumab govitecan in earlier lines. While specific first-line TNBC trials for sacituzumab govitecan as a standalone agent are still maturing, its role in combination with immune checkpoint inhibitors is under active investigation. Early phase trials suggest that combining ADCs with immunotherapy may offer synergistic benefits, potentially overcoming resistance mechanisms and enhancing anti-tumor immunity. The rationale is that ADCs induce immunogenic cell death, releasing tumor antigens and activating immune cells, which can then be further amplified by checkpoint blockade.⁵

For trastuzumab deruxtecan, the DESTINY-Breast04 trial was pivotal. This Phase III study enrolled 557 patients with unresectable or metastatic HER2-low breast cancer, including both hormone receptor-positive and triple-negative subtypes, who had received one or two prior lines of chemotherapy for metastatic disease. Patients were randomized 2:1 to receive trastuzumab deruxtecan or physician's choice of chemotherapy. The trial demonstrated a significant improvement in PFS for the overall cohort, with a median PFS of 9.9 months for trastuzumab deruxtecan vs 5.1 months for chemotherapy (HR 0.50; 95% CI, 0.40-0.63; P<.001). The OS also improved, reaching 23.4 months vs 16.8 months (HR 0.64; 95% CI, 0.49-0.84; P=.001).⁴

Within DESTINY-Breast04, a subgroup analysis of the 63 patients with HER2-low TNBC showed a median PFS of 8.5 months with trastuzumab deruxtecan compared to 2.9 months with chemotherapy (HR 0.46; 95% CI, 0.25-0.83). This data, while from a smaller subgroup, strongly supports the use of trastuzumab deruxtecan in HER2-low TNBC, pushing it into earlier lines of therapy for this specific patient population. The overall response rate (ORR) in the HER2-low TNBC cohort was 50% for trastuzumab deruxtecan vs 16.7% for chemotherapy. These numbers are compelling, offering a new standard of care for a previously underserved patient group.⁴

The safety profiles of these ADCs are distinct from conventional chemotherapy but require careful management. Sacituzumab govitecan is associated with myelosuppression, particularly neutropenia (grade 3 or 4 in 49% of patients), and gastrointestinal toxicities such as diarrhea (grade 3 or 4 in 11% of patients). Fatigue and nausea are also common. Trastuzumab deruxtecan carries a risk of interstitial lung disease (ILD) or pneumonitis, which can be severe and even fatal. In DESTINY-Breast04, ILD occurred in 12.1% of patients, with grade 3 or 4 events in 0.8% and five deaths (0.8%). Clinicians must monitor patients closely for respiratory symptoms and initiate prompt management, including corticosteroid therapy, if ILD is suspected.^3,4

The open-label design of many of these trials is an obvious caveat. While blinding is challenging for agents with distinct toxicity profiles, it introduces potential for bias in subjective endpoints. Still, the magnitude of benefit observed in PFS and OS endpoints, which are less susceptible to subjective bias, provides confidence in the reported efficacy. The trials were also generally well-conducted with robust statistical methodologies. The patient populations were representative of those seen in clinical practice, including patients with varying numbers of prior lines of therapy and different metastatic sites.^3,4

One limitation is that the current data for first-line TNBC with ADCs largely comes from subgroup analyses or ongoing trials. While DESTINY-Breast04 provided strong evidence for HER2-low TNBC, a dedicated, large-scale Phase III trial specifically in the first-line setting for all-comer TNBC, or even Trop-2 high TNBC, is still needed to fully define the optimal sequencing and combination strategies. The heterogeneity of TNBC itself also poses a challenge; not all TNBCs are alike, and biomarker-driven selection beyond HER2-low or Trop-2 expression may further refine patient selection for these expensive therapies.⁶

The financial toxicity of these novel agents is another consideration. ADCs represent a significant cost burden to healthcare systems, and demonstrating clear, sustained clinical benefit in the first-line setting is crucial for justifying their widespread adoption. Long-term follow-up data on overall survival and quality of life will be essential to fully understand the value proposition of these therapies. Furthermore, the optimal duration of treatment and strategies for managing cumulative toxicities in a first-line setting, where patients may live longer, are still being elucidated.⁷

The field is now moving towards combining ADCs with other active agents, particularly immune checkpoint inhibitors, in the first-line setting. Early data from studies like the Saci-IO TNBC trial (NCT04464103) and others exploring combinations of trastuzumab deruxtecan with immunotherapy are eagerly anticipated. These combinations aim to leverage different mechanisms of action to achieve deeper and more durable responses, potentially transforming the treatment paradigm for TNBC. The goal is not just to extend survival but to improve the quality of life for patients by offering more effective and tolerable treatment options upfront.⁸