Precise targeting cytotoxicity of antibody-drug conjugate combined with immunotherapy as first-line regimen for metastatic triple-negative breast cancer in ASCENT-04

The ASCENT-04 trial is the first global phase III study to demonstrate that the combination of trophoblast cell surface antigen 2 (TROP2) antibody-drug conjugate (ADC) and immunotherapy is superior to traditional chemotherapy combined with immunotherapy in the first-line treatment of advanced triple-negative breast cancer (TNBC). The results were reported at the American Society of Clinical Oncology (ASCO) meeting in June 2025 (1). This marks another breakthrough in the treatment of TNBC, breaking the long-standing dominance of first-line chemotherapy in the advanced setting. Patients now have more and better treatment options, and this is expected to change clinical practice in the future.

TNBC is characterized by the absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). It accounts for approximately 15–20% of all breast cancers. TNBC is highly heterogeneous and aggressive. Historically, it was believed to lack clear therapeutic targets, resulting in poorer outcomes and survival compared to other subtypes. However, another advantage of TNBC treatment is gradually emerging. TNBC has the distinct characteristic of being an “immune-hot tumor”, which is characterized by higher expression levels of programmed death-ligand 1 (PD-L1), tumor-infiltrating lymphocytes (TILs), and tumor mutation burden (TMB). These features constitute the molecular basis for the sensitivity of TNBC to immunotherapy (2-4). Another key type of drug that has improved the efficacy of TNBC treatment is the application of the new generation ADC (5,6). For a long time, traditional chemotherapy has been the cornerstone of TNBC therapy. The new generation ADCs, with their improved drug structure, have achieved a progression from the non-specific cytotoxicity of traditional chemotherapy to the precise targeting and highly effective cytotoxicity of ADCs (7).

Although the combination of traditional chemotherapy and immunotherapy is currently the standard first-line treatment for advanced TNBC, further breakthroughs are still needed

Immunotherapy has significantly improved the efficacy in the treatment of TNBC, and the combination of immune checkpoint inhibitors and chemotherapy has become the standard first-line regimen for advanced PD-L1 positive TNBC (8-10). The phase III KEYNOTE-355 study elucidated the significant efficacy of first-line standard chemotherapy combined with the programmed death-1 (PD-1) inhibitor pembrolizumab. In the population with PD-L1 combined positive score (CPS) ≥10, there was a significant improvement in median progression-free survival (PFS) and overall survival (OS). However, patients with rapid progression [disease-free interval (DFI) of 6–12 months] derived less benefit from this first-line treatment regimen (11). The phase III IMpassion130 study showed that first-line treatment with chemotherapy combined with the PD-L1 inhibitor atezolizumab resulted in significant PFS benefits in both the intent-to-treat (ITT) population and the PD-L1 immune cell (IC) >1% population. However, this benefit did not translate into the OS improvement in the ITT population (12).

In the first-line treatment of advanced TNBC, new drugs and regimens are constantly being explored. BNCT327 (PM8002) and AK112 (ivonescimab), bispecific antibody that simultaneously targets PD-1 and vascular endothelial growth factor-A (VEGF-A), enabling dual blocking of PD-1-mediated immunosuppression and VEGF-A-driven tumor angiogenesis, leading to improved functional activities and potent anti-tumor efficacy in immune “cold” tumors (such as TNBC) in preclinical models and phase I or II trials. BNT327 (PM8002) has shown significant potential in the first-line treatment of metastatic TNBC (mTNBC), and has also demonstrated great efficacy in in PD-L1 negative (PD-L1 CPS <1) population, promising a new treatment option for patients with poor response to regular immunotherapy (13). AK112 (ivonescimab) showed promising antitumor activity in first-line treatment of advanced non-small cell lung cancer (NSCLC) patients without or with epidermal growth factor receptor (EGFR)-functional mutation who failed previous EGFR-tyrosine kinase inhibitor (TKI) therapy (14). The research of AK112 (ivonescimab) in mTNBC and other solid tumors is ongoing (15). Another direction of progress is around the new generation ADCs and the combination with other mechanisms and agents.

The new generation ADCs possess structural advantages, surpassing traditional chemotherapy to achieve precise targeting and efficient cytotoxicity in advanced TNBC

Compared with traditional chemotherapy, the new generation ADCs have precise targeting characteristics, realizing the anti-tumor ideal of the “magic bullet”. Under the guidance of the antibody, ADCs can accurately reach the tumor site to exert cytotoxic effects. The drug-to-antibody ratio (DAR) has been optimized, and the bystander effect also significantly kills adjacent tumor cells with low antigen expression. Therefore, they surpass the efficacy of traditional chemotherapy, achieving more precise targeting and efficient cytotoxicity (16). TROP2 is a transmembrane glycoprotein that is expressed on the surface of various malignant tumor cells, with a particularly high expression rate of over 90% in TNBC, making it an important target for the new generation ADCs (17). Sacituzumab govitecan (SG) is an ADC targeting TROP2. The antibody is linked to the high activity payload SN-38 (active metabolites of topoisomerase I inhibitor irinotecan) via a cleavable CL2A linker, with a DAR as high as 7.6:1. The CL2A linker is potential of hydrogen (pH)-sensitive and can release the payload in the acidic environment of the tumor microenvironment or within tumor cells, creating the “dual bystander effect” (18). The ASCENT phase III study demonstrated that SG significantly prolonged PFS and OS in mTNBC compared to chemotherapy, thereby improving patient survival (19).

The replacement of traditional chemotherapy by SG, in combination with immunotherapy, represents an important research progress in advanced TNBC (20). The unique molecular mechanism of SG in enhancing immune effects is the basis for the synergistic effect of the two types of drugs: (I) in the preclinical exploration, the double-strand DNA breaks induced by the payload SN-38 of SG activate the cGAS-STING pathway, thereby stimulating type I interferon (IFN) secretion and enhancing cancer chemoimmunotherapy (21); (II) SN-38 upregulates the expression of major histocompatibility complex (MHC) class I molecules and PD-L1 on tumor cells and increases the expression of tumor-infiltrating ICs, thereby enhancing the effector functions of cytotoxic T cells and ultimately strengthening the anti-tumor immune response (22). The initial exploration of SG in combination with immunotherapy as first-line treatment for PD-L1 positive (IC ≥1%) mTNBC was conducted in the MORPHEUS-panBC phase Ib/II trial. Results reported at the 2024 European Society for Medical Oncology (ESMO) Breast Cancer Annual Congress showed that the combination of SG and atezolizumab significantly improved efficacy compared to the combination of paclitaxel and atezolizumab, with an objective response rate (ORR) of 76.7% vs. 66.7%, and PFS of 12.2 vs. 5.9 months [hazard ratio (HR) =0.27] (23). These findings have become strong evidence and a solid foundation for further research on the combination of SG and immunotherapy.

ASCENT-04 trial—Trop2-ADC (sacituzumab govitecan) combined with immunotherapy has achieved a breakthrough in the first-line treatment of mTNBC

Study design

The ASCENT-04 trial population consists of patients with locally advanced unresectable or mTNBC who are untreated in the advanced setting, PD-L1 positive (CPS ≥10), and have a DFI of ≥6 months. Patients were randomly assigned in a 1:1 ratio to receive either SG (10 mg/kg on d1, d8 of each 21-day cycle) in combination with pembrolizumab (200 mg on d1 of each 21-day cycle), or chemotherapy (options included paclitaxel 90 mg/m² or nab-paclitaxel 100 mg/m² on d1, d8, d15 of each 28-day cycle, or gemcitabine 1,000 mg/m² plus carboplatin area under the curve (AUC) =2 on d1, d8 of each 21-day cycle) in combination with pembrolizumab (200 mg on d1 of each 21-day cycle). All treatments were continued until disease progression or intolerable toxicity. Patients in the chemotherapy group were permitted to cross over to second-line monotherapy with SG after disease progression as assessed by blinded independent central review (BICR). The primary endpoint was PFS assessed by BICR. Secondary endpoints included OS, ORR, and duration of response (DoR) as assessed by BICR, safety, and quality of life (QoL). There were three stratification factors: de novo vs. DFI 6–12 months vs. DFI >12 months; United States/Canada/Western Europe vs. other regions; and if prior exposure to PD-(L)1 inhibitor therapy (Figure 1).

Figure 1 Study design profile of ASCENT-04 (1). AUC, area under the curve; BICR, blinded independent central review; CPS, combined positive score; DoR, duration of response; IV, intravenous; mTNBC, metastatic triple-negative breast cancer; ORR, objective response rate; OS, overall survival; PD-L1, programmed death-ligand 1; PFS, progression-free survival; QoL, quality of life; SG, sacituzumab govitecan; TNBC, triple-negative breast cancer.

Results and clinical value

The ASCENT-04 trial enrolled a total of 443 patients (221 in the SG + immunotherapy group and 222 in the chemotherapy + immunotherapy group). Among them, 34% were de novo, 18% had a DFI of 6–12 months, and 48% had a DFI of >12 months. Nearly 50% had previously failed taxane (and received the GP regimen in this trial). Only 4.5% (20 cases) had prior exposure to PD-(L)1 inhibitors. As of the data cutoff date on March 3, 2025, 43% vs. 23% of patients in the two groups were still receiving treatment.

Compared with chemotherapy plus immunotherapy, SG plus immunotherapy significantly improved the median PFS in PD-L1 positive (CPS ≥10) mTNBC {11.2 months [95% confidence interval (CI): 9.3–16.7 months] vs. 7.8 months (95% CI: 7.3–9.3 months), HR =0.65 (95% CI: 0.51–0.84), P<0.001}. This met the primary endpoint, demonstrating a statistically and clinically meaningful improvement in PFS, and is longer than the PFS of other first-line immunotherapy-containing phase 3 trials for mTNBC (Figure 2). Moreover, the PFS curves of the two groups showed early separation, with the benefit increasing over time. Looking back at the enrolled population, nearly 20% experienced rapid progression, and nearly 50% showed failure to prior taxane. Achieving a PFS of 11.2 months with SG plus immunotherapy indicates significant efficacy. The key secondary endpoint OS data is not yet mature and has an early trend of improvement. The ORR of the SG plus immunotherapy group was higher (60% vs. 53%), especially the complete response (CR) rate was higher (13% vs. 8%), and the DoR was significantly prolonged (16.5 vs. 9.2 months), indicating faster and more sustained anti-tumor activity of SG plus immunotherapy.

Figure 2 PFS of first-line immunotherapy-containing phase 3 trials for mTNBC (1,8,11,12). CPS, combined positive score; HR, hazard ratio; IC, immune cell; mPFS, median progression-free survival; mTNBC, metastatic triple-negative breast cancer; PFS, progression-free survival; SG, sacituzumab govitecan.

The subgroup analysis of PFS showed a consistent trend of benefit with SG plus immunotherapy. Only the subgroup of patients who had previously received PD-(L)1 inhibitors appeared to favor chemotherapy plus immunotherapy. However, this subgroup included only 20 patients (4.5%), which is too small a sample size to draw a definitive conclusion. It is worth noting that the therapeutic advantage of SG plus immunotherapy was most significant in the subgroup with DFI >12 months (16.6 vs. 8.7 months, HR =0.52), while the difference between SG plus immunotherapy and chemotherapy plus immunotherapy was the smallest in the de novo subgroup (8.1 vs. 7.7 months, HR =0.89). In addition, the advantage of SG plus immunotherapy was greater in the taxane failure subgroup (11.3 vs. 7.4 months, HR =0.52) compared to the taxane sensitivity subgroup (11.1 vs. 9.2 months, HR =0.82).

The safety profile of SG plus immunotherapy is consistent with the known safety of each drug. No new safety signals were identified with the combination therapy. Compared with SG alone, there was no additive toxicity, and no increase in immune-related adverse events (AEs) was observed (24). The most common AEs in the SG plus immunotherapy group were diarrhea, nausea, and neutropenia. The incidence of grade ≥3 AEs was 71% in the SG + immunotherapy group vs. 70% in the chemotherapy + immunotherapy group, and treatment discontinuation due to AEs was 12% vs. 31%, respectively.

The ASCENT-04 trial successfully challenged the long-standing dominance of chemotherapy in the first-line treatment of advanced TNBC, providing patients with more and better treatment options in the future. It fully demonstrates the enormous therapeutic potential of the synergistic effect of ADC’s precise targeting, cytotoxicity, and immunotherapy in the first-line treatment of mTNBC, bringing breakthroughs to both immunotherapy and ADC treatment, and has important clinical value and significance.

Thinking and prospect: round table discussion

Selection of the optimal beneficial population for Trop2-ADC plus immunotherapy

Trop2-ADC plus immunotherapy cannot completely replace chemotherapy plus immunotherapy; the key is to identify the optimal beneficial population of this regimen. Currently, subgroup analyses indicate that patients with metastatic disease benefit more, while the de novo population benefits less (HR =0.89). In addition, SG plus immunotherapy shows a greater advantage for patients who have failed prior taxane compared to those who are taxane sensitive. Therefore, based on the currently published data, patients with metastatic disease after (neo)adjuvant therapy and those who have failed prior taxane therapy are the beneficial populations for SG plus immunotherapy. Further exploration of the optimal beneficial populations will require the release of more research data and the development of more trials to focus on this subject.

Definition of the population benefiting from Trop2-ADC plus immunotherapy

The population of the ASCENT-04 trial was patients with advanced TNBC who had a PD-L1 CPS ≥10, so is the boundary of the population benefiting from SG plus immunotherapy limited to those with CPS ≥10? Do patients with CPS 1–9 benefit? If research can confirm the benefit in patients with CPS ≥1, it will expand the applicability population for this regimen. The Chinese original PD-1 inhibitor, toripalimab, is indicated for advanced TNBC with PD-L1 CPS ≥1. Therefore, the upcoming ASCENT-C04 trial in Chinese patients will further expand the PD-L1 positivity threshold to CPS ≥1, to further explore the definition of the population benefiting from Trop2-ADC plus immunotherapy.

Maintenance therapy following effective Trop2-ADC plus immunotherapy

After achieving effectiveness with Trop2-ADC plus immunotherapy, is it still necessary to continue long-term combination therapy? How should maintenance therapy be performed? However, there is no evidence to clarify whether discontinuing ADC and continuing with immunotherapy maintenance will still provide benefits, and there is also no evidence to suggest the appropriate timing for discontinuing ADC. Especially for some patients, SG-related toxicity occurs early or severely, which cannot be tolerated; how to reasonably arrange subsequent maintenance therapy still needs to be explored in further research.

The impact of early-stage immunotherapy on first-line Trop2-ADC plus immunotherapy

How should we interpret and apply the results of the ASCENT-04 trial in the context of increasing application of immunotherapy in the neoadjuvant stage of TNBC? The ASCENT-04 study included a low proportion of patients who had previously received PD-(L)1 inhibitors, only 4.5% (20 cases), so it was not possible to obtain clear results for this subgroup population. Under the current treatment situation, it is also time to think about the issue of rechallenge with immunotherapy in the field of breast cancer. For patients who have benefited from neoadjuvant immunotherapy, if treated again with immunotherapy in combination with SG after recurrence or metastasis, it may still be a good treatment opportunity. On the other hand, if patients with poor efficacy of neoadjuvant chemotherapy plus immunotherapy switch to ADC combined with immunotherapy rechallenge as the first-line treatment in an advanced setting, it is worth exploring whether they can overcome resistance. The upcoming ASCENT-C04 trial targeting the Chinese patient population will include more patients who have previously received immunotherapy, actively exploring the impact of early-stage immunotherapy on first-line treatment with Trop2-ADC plus immunotherapy.

The safety profile of Trop2-ADC plus immunotherapy needs attention

It was reported that the safety profile of SG plus immunotherapy was consistent with the known safety signals of each drug in ASCENT-04 trial; meanwhile, no increase in immune-related AEs was observed. Despite all this, the incidences of grade ≥3 AEs were 71% and treatment-related serious AEs (SAEs) were 28% in SG plus immunotherapy treatment, which are relatively high. Special attention should be paid to gastrointestinal AEs. The incidence of gastrointestinal AEs (diarrhea, nausea, and vomiting) was significantly higher in the SG plus immunotherapy group than in the chemotherapy plus immunotherapy group; more safety data need to be accumulated in the future to support this first-line treatment regimen.

Conclusions

The treatment of TNBC has evolved from “no drug available” in the past to “synergistic combination” today. The combination regimen of ADC plus immunotherapy in ASCENT-04 trial, which lights up a new hope for further prolonging the survival of patients with TNBC. As the OS data matures in the future, the first-line treatment strategy of “powerful combination of ADC and immunotherapy” will change clinical practice and reshape the treatment landscape of TNBC. The future ASCENT-C04 trial, to be conducted in Chinese patients, is highly anticipated. It is closer to the current treatment status and, through its more complete design, innovatively explores key unresolved issues.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was a standard submission to the journal. The article has undergone external peer review.

Peer Review File: Available at https://tbcr.amegroups.com/article/view/10.21037/tbcr-25-32/prf

Funding: This work was supported by National Science and Technology Major Projects (No. 2024ZD0519800).

Conflicts of interest: All authors have completed the ICMJE uniform disclosure form (available at https://tbcr.amegroups.com/article/view/10.21037/tbcr-25-32/coif). Y.Y. serves as an unpaid editorial board members of Translational Breast Cancer Research from March 2024 to February 2026. The other authors have no conflicts to declare.

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