Editor’s Note: In the rescue treatment of advanced triple-negative breast cancer (TNBC), should immunotherapy be combined with chemotherapy or with antibody–drug conjugates (ADCs)? At the 2025 Summer Breast Cancer Forum · Northern Salon, Professors Xuening Ji of Zhongshan Hospital, Dalian University, and Yuhua Song of the Affiliated Hospital of Qingdao University debated this question in the “Debate” session. Here, in Oncology Frontier’s “In-Depth” column, they further share their views based on evidence.Key Arguments and Rationale
Professor Xuening Ji: Chemotherapy as the Preferred Partner
I believe chemotherapy remains the optimal partner for immunotherapy in the rescue treatment of advanced TNBC. These patients face poor prognoses, with early visceral metastases and limited effective treatment options. While we are exploring precision medicine strategies—such as the “Fudan four-subtype” model or other classification systems—chemotherapy continues to be a cornerstone of treatment.
Since 2013, when immunotherapy was ranked among Science’s top ten breakthroughs, multiple studies such as KEYNOTE-355 and TORCHLIGHT have demonstrated that in PD-L1–positive patients (CPS ≥10 or ≥1), immunotherapy combined with chemotherapy agents like nab-paclitaxel achieves meaningful improvements in PFS and even OS, supported by solid evidence.
Mechanistically, chemotherapy plus immunotherapy is rational for three reasons:
- Chemotherapy induces immunogenic cell death, enhancing immune activity against tumors.
- It remodels the tumor immune microenvironment, including reducing regulatory T cells (Tregs), improving CD8+ tumor-infiltrating lymphocytes (TILs), and refreshing immune cell pools.
- It has synergistic effects with immunotherapy, such as upregulating antigen expression and enhancing antigen presentation.
The ASCENT-04 study, presented at ASCO 2024, showed PFS superiority for immunotherapy + ADC over immunotherapy + chemotherapy, but this was in PD-L1 CPS ≥10 patients. In real-world practice, patients with CPS ≥1 may still benefit from immunotherapy + chemotherapy. Ongoing studies such as ASCENT-C04, led by Professor Zefei Jiang, will provide further insight and may expand the eligible population. Cost is also a key consideration: immunotherapy + ADC regimens are currently much more expensive. We must provide treatments that are both effective and affordable, balancing efficacy with toxicity and clinical goals with financial burden. For these reasons, I believe immunotherapy combined with chemotherapy remains the preferred choice at present.
Professor Yuhua Song: ADCs as the Future ChoiceWhile immunotherapy + chemotherapy is currently the first-line standard for advanced TNBC and is less costly, immunotherapy + ADC combinations clearly represent the future direction. With more innovative ADCs gaining approval and entering national reimbursement negotiations, they will inevitably provide greater benefit for patients. Agents such as sacituzumab govitecan (SG), disitamab vedotin, and the soon-to-be-approved datopotamab deruxtecan (Dato-DXd) have all shown superior efficacy to chemotherapy in both frontline and later-line settings, with fewer toxicities. Although economic barriers remain, every oncologist hopes to pair immunotherapy with the best possible partner.
The ASCENT-04 study demonstrated a PFS advantage for immunotherapy + SG, and even allowed crossover to ADCs in the control arm after immunotherapy + chemotherapy failure. Despite this, the experimental arm still showed a trend toward OS benefit. If, despite 80% of the control group receiving ADCs in later lines, the study still achieves an OS benefit, this would strongly argue for “using the best drug first.” If only PFS improves without OS, then a sequential approach—first immunotherapy + chemotherapy, followed by ADC at progression—remains a valid option.
Looking beyond ASCENT-04, other studies reinforce the case for immunotherapy + ADC. The phase II BEGONIA trial, testing Dato-DXd plus durvalumab, achieved an impressive mPFS of 13.8 months and an ORR close to 80%, without limiting enrollment to PD-L1–positive patients. The phase II trial of SG plus atezolizumab doubled mPFS and median duration of response compared with atezolizumab + nab-paclitaxel. For HER2-low patients, early phase II data on trastuzumab deruxtecan (T-DXd) + durvalumab showed an mPFS of 12.6 months. Compared with KEYNOTE-355, where mPFS was 9.7 months for immunotherapy + chemotherapy, the immunotherapy + ADC results are striking, with no clear additive toxicities. With increasing approvals of ADCs for first-line TNBC, immunotherapy + ADC combinations will ultimately be widely adopted.
Professor Xuening Ji
MD, Professor, Chief Physician, Master’s Supervisor, Deputy Director, Department of Oncology IZhongshan Hospital, Dalian University
Professor Yuhua Song
MD, Professor, Chief Physician, Master’s Supervisor Deputy Director, Breast Center; Director, Breast Oncology Department Affiliated Hospital of Qingdao University
