The ASCENT-04 study is a global, multicenter, randomized, open-label phase III clinical trial designed to evaluate the efficacy and safety of the TROP2-targeted antibody-drug conjugate (ADC) sacituzumab govitecan (SG) combined with the PD-1 inhibitor pembrolizumab (Keytruda, K drug) compared to chemotherapy combined with K drug in first-line treatment of PD-L1 positive (CPS≥10) metastatic triple-negative breast cancer (mTNBC). The groundbreaking results of this study represent a paradigm shift in the treatment of TNBC.
1. Core Study Design and Population
– Inclusion Criteria: A total of 443 patients with locally advanced unresectable or metastatic TNBC who had not previously received systemic treatment for advanced disease were included, requiring PD-L1 CPS≥10 (detected using the 22C3 assay) and a disease-free interval (DFI) of ≥6 months.
– Treatment Regimen:
– Experimental Group: SG (10 mg/kg on days 1 and 8) + K drug (200 mg on day 1), every 21 days for a cycle, continued until disease progression or intolerable toxicity.
– Control Group: Chemotherapy (gemcitabine + carboplatin, paclitaxel, or albumin-bound paclitaxel) + K drug, regimen chosen by the physician.
– Primary Endpoint: Progression-free survival (PFS) assessed by independent blinded central review (BICR); secondary endpoints include overall survival (OS), objective response rate (ORR), duration of response (DOR), and safety.
2. Key Efficacy Results
1. Significant Improvement in PFS:
– Experimental Group: The median PFS was 11.2 months, extending 3.4 months compared to the control group’s 7.8 months, with a 35% reduction in the risk of disease progression or death (HR=0.65, 95% CI: 0.51–0.84, P=0.0009).
– Subgroup Analysis: Patients with metastatic breast cancer (especially treatment-naive populations) and those who previously failed taxane treatment benefited more significantly, indicating that this regimen has advantages for chemotherapy-resistant populations.
2. Depth and Durability of Response:
– ORR: The experimental group had an ORR of 60%, compared to 53% in the control group; complete response (CR) rates were 13% vs 8%, respectively.
– DOR: The median duration of response in the experimental group reached 16.5 months, significantly longer than the control group’s 9.2 months, demonstrating long-term stability of efficacy.
3. Early Positive Trend in OS:
– As of the data cutoff (median follow-up of 14 months), OS data had not matured (maturity rate 26%), but the experimental group showed an improving trend (HR=0.89), with further follow-up expected to validate this.
3. Safety Profile
– Overall Tolerability is Good: The treatment-related adverse event (TEAE) discontinuation rate in the experimental group was 12%, significantly lower than the control group’s 31%.
– Major Adverse Reactions:
– Hematologic Toxicity: Neutropenia (43%) was the most common grade 3 or higher TEAE, which can be prevented or managed with granulocyte colony-stimulating factor (G-CSF).
– Non-Hematologic Toxicity: Diarrhea (10%) was the main grade 3 or higher non-hematologic toxicity, most of which can be controlled with antidiarrheal medications.
– No New Safety Signals: No rare but serious adverse reactions such as interstitial lung disease or ocular toxicity were observed, and the safety profile was consistent with the known toxicities of SG and K drug monotherapy.
4. Clinical Significance and Guideline Impact
1. Establishing a New First-Line Standard:
– ASCENT-04 is the first global phase III study to confirm that ADC combined with immunotherapy is superior to chemotherapy combined with immunotherapy in first-line treatment of TNBC, providing a better option for mTNBC patients with PD-L1 CPS≥10.
– Compared to existing standard regimens (such as atezolizumab + albumin-bound paclitaxel), the SG + K drug regimen shows significant advantages in PFS, DOR, and safety, likely to rewrite recommendations in guidelines such as NCCN and ESMO.
2. Expansion of Precision Therapy:
– Subgroup analysis suggests that treatment-naive metastatic patients, taxane-resistant populations, and patients with high PD-L1 expression (CPS≥10) are the core beneficiaries of SG + K drug, providing a basis for clinical stratified treatment.
– The durable response (DOR 16.5 months) of this regimen offers patients a longer treatment-free interval, potentially improving quality of life and delaying the need for subsequent treatments.
5. Challenges and Competition
1. Importance of Long-Term Follow-Up:
– Although early trends in OS are positive, longer-term data is needed to confirm survival benefits, especially in direct comparisons with other emerging therapies (such as PD-1/VEGF dual antibodies).
2. Competition from Similar Drugs:
– Domestic PD-1/VEGF dual antibodies (such as PM8002, AK112) have shown strong efficacy in TNBC (e.g., PM8002’s 12-month OS rate of 80.8%), which may create differentiated competition in the future.
– HER2 ADCs (such as DS-8201) have made breakthroughs in HER2 low-expressing TNBC (ORR 50%), providing new options for some patients.
3. Progress of Local Research in China:
– China is conducting the ASCENT-C04 study to explore the efficacy of SG combined with toripalimab compared to chemotherapy combined with immunotherapy, expected to provide more precise treatment options for Chinese patients.
The ASCENT-04 study has established SG combined with K drug as the new first-line standard for PD-L1 CPS≥10 mTNBC patients by significantly extending PFS, achieving durable responses, and maintaining controllable safety. The success of this regimen not only promotes the synergistic application of ADC and immunotherapy but also opens new pathways for personalized treatment of TNBC. Despite facing competition from other therapies, SG + K drug, backed by robust phase III data, has become the benchmark regimen for current first-line treatment of TNBC.
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