Editor's Note: In first-line treatment of metastatic triple-negative breast cancer (mTNBC), should immunotherapy be combined with chemotherapy or an antibody–drug conjugate (ADC)? As the ADC era advances, this debate is intensifying. At the 2026 CSCO Annual Meeting, Oncology Frontier invited Professor Wenyan Chen of Nanchang People's Hospital and Professor Tengfei Chao of Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, to debate the issue in light of the ASCENT-03, TROPION-Breast02 (TB-02), and ASCENT-04 studies, among others. Professor Wenyan Chen advocated for immunotherapy plus chemotherapy, emphasizing robust evidence, manageable safety, and greater affordability. Professor Tengfei Chao supported immunotherapy plus an ADC, arguing that this approach could address unmet treatment needs in patients with PD-L1 combined positive score (CPS) ≥10 and those with early relapse, while offering promising mechanistic synergy. This article presents the key arguments from both experts.Presenting the Arguments and Examining the Evidence
Professor Wenyan Chen: In First-Line Treatment of Advanced TNBC, Immunotherapy Should Be Combined with Chemotherapy
Breast cancer treatment has entered the ADC era. In this context, we increasingly view ADCs as an upgraded form of chemotherapy. But does this mean that, in every clinical setting, we should follow the prevailing trend and automatically choose an ADC whenever immunotherapy is added? I believe this is the central question behind today’s debate.
There is a growing view that ADCs are reshaping the first-line treatment landscape for advanced TNBC. I remain cautious about this assertion. When I received this debate topic, I began considering a fundamental question: Do all patients with advanced TNBC really need this kind of “treatment escalation”? I reviewed the relevant clinical studies with this question in mind, and several concerns emerged.
First, setting immunotherapy aside, are ADCs necessarily more effective than chemotherapy in the first-line treatment of advanced TNBC?
When comparing two landmark studies in advanced TNBC—the ASCENT-03 and TB-02 trials—I noticed that both included patient populations that were not particularly favorable to the chemotherapy control arms.
In ASCENT-03, 21% of patients in the sacituzumab govitecan (SG) group and 20% in the chemotherapy group had a disease-free interval (DFI) of 6–12 months. In TB-02, there was no minimum DFI requirement for enrollment. The datopotamab deruxtecan (Dato-DXd) group included 15% of patients with a DFI of 0–6 months, compared with 16% in the chemotherapy group. These patients may have been receiving adjuvant treatment or experienced recurrent metastatic disease shortly after surgery.
Furthermore, some patients enrolled in these trials had previously received chemotherapy and may already have had limited sensitivity to it. When chemotherapy is used again in these patients, its efficacy may be reduced because they are likely to represent a population less responsive to chemotherapy. Comparing chemotherapy with an ADC in such a population could therefore disadvantage the chemotherapy arm. This led me to focus on the objective response rate (ORR).
In ASCENT-03, the ORR was 46% in the chemotherapy group and 48% in the SG group (HR 1.1). ORR is an important efficacy endpoint, yet these results do not demonstrate a clear advantage for the ADC over chemotherapy.
In TB-02, the difference between the two groups was much more pronounced: the ORR was only 29.3% in the chemotherapy group, compared with 62.5% in the Dato-DXd group. However, when we examine the chemotherapy regimens used in the two studies, an important distinction emerges. TB-02 used single-agent chemotherapy in the control arm, whereas 50% of patients in the ASCENT-03 chemotherapy arm received gemcitabine plus carboplatin. Combination chemotherapy would generally be expected to produce a higher ORR than single-agent chemotherapy. Taking this difference into account, I believe the apparent benefit of ADCs in TB-02 may be less substantial than the ORR figures initially suggest.
Second, when immunotherapy is added, are ADC-based combinations more effective than chemotherapy-based combinations?
After reviewing ASCENT-04, I still favor immunotherapy combined with chemotherapy. Both treatment groups included nearly 20% of patients with a DFI of 6–12 months. The ORR was 60% with SG plus pembrolizumab and 53% with chemotherapy plus pembrolizumab (HR 1.3). These results do not demonstrate a clear advantage in ORR for ADC plus immunotherapy over chemotherapy plus immunotherapy.
Taken together, these two questions point toward my conclusion. In addition, one of the greatest concerns clinicians have about immunotherapy is the management of immune-related adverse events. When managing immunotherapy-related toxicity is already challenging, combining immunotherapy with an ADC that we may be less familiar with can lead to overlapping toxicities, such as interstitial lung disease, immune-mediated pneumonitis, and immune-related ocular toxicity. Clinicians may be less experienced in managing these overlapping adverse events than in managing the toxicities associated with immunotherapy plus chemotherapy, potentially making it more difficult to ensure patient safety.
For these reasons, I believe immunotherapy plus chemotherapy remains an advantageous option at present. Chemotherapy also has an economic advantage, potentially allowing patients to achieve meaningful treatment benefits at a lower cost.
Although ASCENT-04 is an important study, its findings are not sufficient to revolutionize the treatment landscape for mTNBC or replace the established role of chemotherapy combined with immunotherapy. The evidence supporting immunotherapy plus chemotherapy in the first-line setting is already robust. While a single study cannot establish a definitive conclusion, ASCENT-04 remains particularly important in advancing the field.
Of course, I hope that future ADCs will offer better options for combination with immunotherapy—maintaining safety while achieving higher ORRs—to help address the current challenges in treating advanced TNBC.
Professor Tengfei Chao: In First-Line Treatment of Advanced TNBC, Immunotherapy Should Be Combined with an ADC
The ADC era offers considerable promise for combining immunotherapy with ADCs. First, we should ask why, despite the substantial body of evidence supporting immunotherapy plus chemotherapy, we should challenge the established role of chemotherapy. The reason is that immunotherapy plus chemotherapy has certain limitations.
First, the KEYNOTE-355 trial investigated the efficacy and safety of pembrolizumab plus chemotherapy as first-line treatment for mTNBC and demonstrated a significant survival benefit with pembrolizumab in patients with PD-L1 CPS ≥10. However, patients with PD-L1 CPS ≥10 may account for only approximately one-third of the mTNBC population, limiting the number of patients eligible to benefit.
Second, even among patients with CPS ≥10, median progression-free survival (mPFS) with pembrolizumab plus chemotherapy was 9.7 months, which remains far from meeting all patients’ treatment needs.
Third, as Professor Wenyan Chen has emphasized, patients who experience early relapse may respond less favorably to chemotherapy when it is administered again. For this population, we need to identify better treatment options that can improve survival.
Given these three unmet needs, I believe ADCs combined with immunotherapy could help improve the current treatment landscape.
Most importantly, ADCs and conventional chemotherapy differ in their mechanisms of action. ADCs can selectively target tumor cells. For example, more than 80% of patients with TNBC express Trop-2, providing a potential target for Trop-2-directed ADCs to deliver cytotoxic agents to tumor cells. ADC-mediated tumor killing can induce immunogenic cell death and improve the tumor immune microenvironment. This process differs from the cytotoxic effects of conventional chemotherapy and may better support the antitumor activity of PD-1 or PD-L1 immune checkpoint inhibitors. In addition, some ADCs exert a bystander effect, enabling them to kill heterogeneous tumor cells with low Trop-2 expression and potentially achieve better tumor control.
Although the combination of an ADC and immunotherapy is mechanistically promising, the clinical evidence remains limited. ASCENT-04 nevertheless delivered encouraging results, with an mPFS of 11.2 months versus 7.8 months (HR 0.85). I acknowledge that this remains a single study and that further evidence is needed.
The combination also performed favorably in terms of treatment discontinuation due to treatment-related adverse events. The discontinuation rate was 31% in the chemotherapy group, compared with only 12% in the SG plus pembrolizumab group. In my view, a regimen that offers efficacy while also allowing patients to remain on treatment is likely to become an important preferred option in the future.
However, we must clearly define the boundaries of treatment. This does not mean that all chemotherapy-plus-immunotherapy regimens should automatically be replaced with ADC-plus-immunotherapy combinations. ADC treatment also presents specific challenges, and treatment selection must remain individualized. We should not routinely recommend ADC plus immunotherapy in the following situations: first, in patients with contraindications or pre-existing conditions that raise safety concerns, such as interstitial lung disease or underlying pulmonary disorders; and second, in patients facing financial difficulties that limit access to treatment.
For patients without relevant contraindications, ADC plus immunotherapy may become a preferred treatment direction in the future. We also look forward to the release of data from the TB-05 study and the results of investigations of domestically developed ADCs combined with immunotherapy in patients with PD-L1-negative disease. These findings may help expand the population of patients with TNBC who can benefit from ADC-based immunotherapy combinations while further improving PFS and overall survival (OS).
Professor Wenyan Chen
Professor Tengfei Chao
