Calendar year 2025 witnessed transformative clinical data across the TNBC treatment landscape, with six major drug readouts spanning antibody–drug conjugates (ADCs), immunotherapy combinations, and novel targeted therapies. The most clinically impactful results emerged from first-line trials of TROP2-directed ADCs—sacituzumab govitecan (Trodelvy) combined with pembrolizumab demonstrating 35% reduction in progression risk (HR 0.65, p<0.001) in PD-L1–positive disease4, and datopotamab deruxtecan (Datroway) achieving unprecedented 5-month overall survival improvement in immunotherapy-ineligible patients4957. Sacituzumab tirumotecan provided compelling later-line evidence (68% risk reduction, HR 0.32) with Nature Medicine publication validating TROP2 targeting beyond sacituzumab govitecan1. Early-stage data from Bria-IMT vaccine and paxalisib PI3K inhibitor suggest diversification beyond ADC-centric strategies. These readouts collectively establish TROP2 ADCs as standard first-line therapy, create regulatory pathways for dual FDA approvals (Trodelvy combination, Datroway monotherapy), and position 2026–2027 as critical for sequencing trials and biomarker-directed patient selection.
2025 TNBC Study Readout Summaries
1. Sacituzumab Govitecan + Pembrolizumab (ASCENT-04/KEYNOTE-D19): First ADC-ICI Combination Approval Track
Trial Design: Gilead Sciences/Merck phase III randomized trial (NCT05382286) enrolled 443 patients with previously untreated, PD-L1–positive (CPS≥10, 22C3 assay) locally advanced unresectable or metastatic TNBC. Patients received sacituzumab govitecan 10 mg/kg IV days 1, 8 plus pembrolizumab 200 mg IV day 1 every 21 days versus chemotherapy (gemcitabine/carboplatin, paclitaxel, or nab-paclitaxel) plus pembrolizumab4.
Efficacy Outcomes: At median 14-month follow-up, the combination reduced disease progression or death risk by 35% (HR 0.65; 95% CI 0.51–0.84; p=0.0009). Median PFS reached 11.2 months (95% CI 9.3–16.7) versus 7.8 months (95% CI 7.3–9.3) with chemotherapy-pembrolizumab. ORR improved to 59.7% (95% CI 52.9–66.3) from 53.2% (95% CI 46.4–59.9), with complete response rates of 13% versus 8%. Duration of response nearly doubled: 16.5 months (95% CI 12.7–19.5) versus 9.2 months (95% CI 7.6–11.3). Overall survival showed positive early trends despite only 26% data maturity45.
Safety Profile: Grade ≥3 treatment-emergent adverse events occurred at comparable rates: neutropenia 43% (sacituzumab govitecan-pembrolizumab) versus 45% (chemotherapy-pembrolizumab). Diarrhea (10% grade ≥3) was more common with sacituzumab govitecan, while anemia (16%) and thrombocytopenia (14%) predominated in the chemotherapy arm. Treatment discontinuation due to adverse events occurred in 12% versus 31%, favoring the ADC-ICI combination4.
Regulatory and Commercial Impact: Results were presented at ASCO 2025 (May 31, 2025) and published in New England Journal of Medicine (January 2026)45. Gilead submitted supplemental applications to FDA and EMA for first-line PD-L1–positive mTNBC, targeting a population where five-year survival remains 12%5.
2. Sacituzumab Govitecan Monotherapy (ASCENT-03): Closing the Immunotherapy-Ineligible Gap
Trial Design: Phase III trial (NCT05382299) randomized approximately 540 patients with first-line mTNBC who were NOT candidates for checkpoint inhibitors (PD-L1–negative tumors or PD-L1+ with prior PD-(L)1 therapy in curative setting) to sacituzumab govitecan versus physician's choice chemotherapy1.
Efficacy Outcomes: The trial met its primary endpoint with "highly statistically significant and clinically meaningful improvement" in PFS by blinded independent central review per RECIST v1.1. At ESMO 2025, detailed primary PFS results were presented. Sacituzumab govitecan significantly improved PFS vs physician’s choice chemotherapy by BICR (RECIST v1.1), with median PFS 9.7 months vs 6.9 months and HR 0.62, confirming the earlier topline statement of a “highly statistically significant and clinically meaningful” benefit. Overall survival data remained immature at the time of presentation, with no OS detriment observed. Additional endpoints (ORR, DoR, TTR, patient-reported outcomes) await future medical meeting presentation118.
Safety Profile: Safety remained consistent with prior Trodelvy studies in TNBC, with no new safety signals identified in this immunotherapy-ineligible population1.
Clinical Context: This represents the first clinically meaningful advance for mTNBC patients unable to receive PD-1/PD-L1 inhibitors, addressing approximately 50–70% of first-line patients globally where immunotherapy access or biomarker status excludes checkpoint blockade5977.
3. Datopotamab Deruxtecan (TROPION-Breast02): TROP2 Face-Off Winner
Trial Design: AstraZeneca/Daiichi Sankyo phase III open-label randomized study (NCT05374512) assigned 644 patients with first-line locally recurrent inoperable or metastatic TNBC (not candidates for PD-1/PD-L1 inhibitors) to datopotamab deruxtecan versus investigator's choice chemotherapy. The trial enrolled patients across 23 countries, including those where PD-(L)1 blockers were unavailable, with approximately 70% representing patients without immunotherapy access2777.
Efficacy Outcomes: At data cutoff (August 25, 2025) with median 27.5-month follow-up, datopotamab deruxtecan demonstrated statistically significant improvements in both dual primary endpoints—overall survival and progression-free survival. The trial achieved an unprecedented median OS improvement of 5 months versus chemotherapy, representing the first OS benefit demonstration for a TROP2-directed ADC in first-line TNBC. PFS demonstrated 43% reduction in disease progression risk. As of the August 2025 cutoff, 45 patients (14%) remained on datopotamab deruxtecan versus 8 patients (3%) on chemotherapy49577172.
Safety Profile: Safety profile was consistent with prior TROPION trials; rates of grade ≥3 treatment-emergent adverse events were 66% with sacituzumab govitecan and 62% with chemotherapy. Historical data from TROPION-Breast01 (HR+/HER2- indication) showed stomatitis, nausea, fatigue, and cytopenias as most common all-grade adverse events ≥20%27.
Regulatory Trajectory: Late-breaking results were presented at ESMO 2025 (October 2025) as LBA21 in Annals of Oncology4950. FDA granted Priority Review designation with target action anticipated in 20264874. This follows January 2025 FDA approval for HR+/HER2- breast cancer (TROPION-Breast01)5675.
4. Sacituzumab Tirumotecan (SKB264/Sac-TMT): China-Developed TROP2 ADC Enters Global Stage
Trial Design: Merck/Kelun-Biotech phase III trial (NCT05347134) enrolled 263 patients with unresectable locally advanced, recurrent, or metastatic TNBC after ≥2 prior therapies (≥1 for metastatic setting). Patients (median age 51 years, 87% visceral metastases, 26% prior PD-1/PD-L1 therapy) were randomized to sacituzumab tirumotecan versus physician's choice (eribulin, vinorelbine, capecitabine, or gemcitabine)1.
Efficacy Outcomes: PFS by BICR reached 6.7 months (95% CI 5.5–8.0) versus 2.5 months (95% CI 1.7–2.7), achieving 68% risk reduction (HR 0.32; 95% CI not specified; p<0.00001). Overall survival was not reached (95% CI 11.2–NE) versus 9.4 months (95% CI 8.5–11.7), demonstrating 47% mortality risk reduction (HR 0.53, p=0.0005). ORR was 45.4% versus 12.0%, with duration of response 7.1 versus 3.0 months. In patients with TROP2 H-score >200, median PFS extended to 8.3 versus 2.3 months (HR 0.29). Among patients with prior PD-(L)1 therapy, PFS was 5.6 versus 2.7 months (HR 0.31) with ORR 56.3% versus 5.6%1.
Safety Profile: Grade ≥3 treatment-related adverse events included neutrophil count decreased (32.3% vs 47.0%), anemia (27.7% vs 6.1%), and WBC decreased (25.4% vs 36.4%). Overall safety profile was manageable, with similar tolerability regardless of prior checkpoint inhibitor exposure1.
Publication and Regulatory Context: Results were published in Nature Medicine (April 11, 2025) following conference presentations at ASCO 2024 and ESMO 20241. SKB264 received approval from China NMPA in 202436.
5. Bria-IMT Vaccine ± Checkpoint Inhibitor (NCT06072612): Expanding Therapeutic Modalities
Trial Design: BriaCell Therapeutics phase III trial randomized patients with advanced metastatic or locally recurrent breast cancer (all subtypes including TNBC) to three arms (1:1:1): Bria-IMT (SV-BR-1-GM whole-cell cancer vaccine) alone, Bria-IMT plus retifanlimab (PD-1 inhibitor), or physician's choice. As of April 2025 interim analysis, 61 patients were screened and 40 randomized from a target enrollment of 404. Median patient age was 56 years (range 35–82) with median 6 prior therapies (range 2–13)1.
Efficacy Outcomes: At interim analysis (n=62), median PFS was 3.67 months overall. Biomarker-defined subgroups demonstrated improved outcomes: positive delayed-type hypersensitivity (DTH) showed 4.5 versus 2.5 months (p=0.001), circulating tumor cells <1 achieved 3.8 versus 2.4 months (p=0.04), and CAML count ≥5 trended toward 3.7 versus 2.2 months (p=0.10). In the CNS metastases subgroup (n=7), 71% achieved intracranial objective response (5/7 patients) across all breast cancer subtypes1.
Safety Profile: Most common adverse events were nausea (30%), constipation (22.5%), injection site reaction (22.5%), and headache (17.5%). Zero treatment discontinuations were attributed to Bria-IMT, and no interstitial lung disease was reported1.
Clinical Context: Data were presented at AACR 2025 as a late-breaker (April 30, 2025) and ASCO 2025123. The vaccine approach represents diversification beyond ADC-centric strategies, though early-stage interim data limit definitive conclusions.
6. Paxalisib: PI3K Inhibition in Heavily Pretreated TNBC
Trial Design: Kazia Therapeutics phase 1b multi-center, open-label, randomized study initiated June 2025 in late-stage metastatic TNBC20.
Efficacy Outcomes: Company announcements in November 2025 reported "encouraging preliminary clinical responses" including confirmed complete responses, characterized as "exceedingly rare" in pretreated mTNBC. FDG PET/CT imaging (November 10, 2025) demonstrated complete metabolic response in at least one patient. An initial immune complete response was reported in stage IV TNBC under an expanded access combination regimen (November 20, 2025)205354.
Mechanistic Insights: Pembrolizumab monotherapy did not meaningfully reduce circulating tumor cell burden. In TNBC, CTC clusters increased when paxalisib was withheld, suggesting direct activity on tumor cell populations55.
Data Limitations: No NCT identifier, numerical ORR, safety data, or detailed trial design parameters were disclosed in available 2025 sources27.
Clinical Implications
The 2025 TNBC readouts establish three paradigm shifts: (1) TROP2 ADCs as standard first-line therapy in both immunotherapy-eligible (sacituzumab govitecan-pembrolizumab) and -ineligible (datopotamab deruxtecan, sacituzumab govitecan monotherapy) populations, displacing chemotherapy doublets; (2) Combination ADC-ICI strategies achieving superior PFS/DoR without proportional toxicity increases, validating synergy hypotheses; (3) Biomarker-directed precision through TROP2 H-score enrichment (sacituzumab tirumotecan) and PD-L1 CPS selection (ASCENT-04)1449.
Critical unresolved questions include optimal ADC sequencing (datopotamab deruxtecan vs sacituzumab govitecan in first-line; either agent followed by sacituzumab tirumotecan in later lines), cross-resistance mechanisms between topoisomerase-I payload ADCs, and extending benefits beyond PD-L1–positive subsets where immunotherapy currently drives first-line selection4147.
R&D and Strategic Takeaways
- ADC Payload and Linker Innovation
Sacituzumab tirumotecan's activity in PARP inhibitor–exposed and multi-drug resistant contexts suggests payload chemistry (camptothecin analog) and linker selection influence cross-resistance patterns. OBI-992 preclinical data demonstrated maintained activity against BCRP-overexpressing models where datopotamab deruxtecan efficacy declined, supporting next-generation ADC development2934.
- Biomarker-Driven Trial Design
TROP2 H-score stratification (sacituzumab tirumotecan >200 threshold) and PD-L1 CPS ≥10 enrichment (ASCENT-04) enabled demonstration of magnitude effects sufficient for regulatory approval. Future trials should mandate prospective biomarker collection to enable post-hoc responder analyses and accelerate precision medicine strategies14.
- Combination Strategies Beyond ICI
Preclinical synergy data for CXCR4 inhibition (balixafortide), TYK2 inhibition (deucravacitinib), and CDK4/6 nanoformulations combined with checkpoint blockade suggest immunotherapy-refractory mechanisms amenable to targeted modulation. These warrant clinical testing in PD-L1–negative or post-ICI progression settings81011.
- Immune Biomarkers:
The durvalumab-chemotherapy neoadjuvant study demonstrated that immune-related adverse events predicted 48-month event-free survival (93% with irAEs vs 66% without; HR 0.25, p=0.024), suggesting immune activation—not just PD-L1 status—as a dynamic on-treatment biomarker worthy of prospective validation3.
Investment Implications and Risk Scenarios
Near-Term Revenue Catalysts (2026–2027)
Gilead's dual FDA submissions (ASCENT-03 monotherapy, ASCENT-04 combination) target first-line mTNBC population of 15,000–20,000 US patients annually, with sacituzumab govitecan already generating > $1B global sales in later-line settings. First-line expansion could add $500M–$800M peak incremental revenue. AstraZeneca/Daiichi's datopotamab deruxtecan Priority Review for first-line TNBC (TROPION-Breast02) targets overlapping but immunotherapy-ineligible subset, creating head-to-head competition absent comparative trials. Pricing parity ($15,000–$18,000/month) and similar efficacy profiles suggest market share split based on toxicity tolerance and physician familiarity54874.
Competitive Positioning Winners
(1) Gilead captures both PD-L1+ (combination) and PD-L1- (monotherapy) segments with single asset, enabling bundled contracting and sequential trial designs. (2) AstraZeneca/Daiichi benefit from datopotamab deruxtecan's dual approvals (HR+/HER2- January 2025, TNBC pending) supporting multi-indication portfolio value. (3) Merck/Kelun-Biotech sacituzumab tirumotecan establishes China-developed ADC credibility with Nature publication, positioning for ex-China partnering15675.
Binary Risks
(1) FDA cardiovascular safety focus on ADCs following trastuzumab deruxtecan ILD experience could delay approvals if troponin elevations (observed with pembrolizumab-binimetinib) emerge in larger datasets. (2) Cross-resistance between topoisomerase-I ADCs may limit sequential use; real-world evidence showing shorter PFS with second ADC (75.2% of patients) suggests payloads sharing mechanism face efficacy attrition24147. (3) Immunotherapy displacement by ADC monotherapy in PD-L1+ disease (if ASCENT-03 achieves non-inferior OS to ASCENT-04 at lower cost) could cannibalize pembrolizumab sales.
Long-Term Strategic Uncertainties
Optimal first-line regimen remains undefined pending head-to-head trials (sacituzumab govitecan-pembrolizumab vs datopotamab deruxtecan vs sacituzumab govitecan monotherapy). Neoadjuvant pembrolizumab-chemotherapy remains standard in early-stage TNBC; metastatic data do not directly translate. PARP inhibitor integration (olaparib, talazoparib) in BRCA-mutant TNBC competes with ADCs for second-line positioning, creating sequencing dilemmas unresolved by current evidence1431.
Appendix: 2025 TNBC Clinical Trial Readout Registry
| Drug Name | Mechanism | Company | NCT ID | Phase | Indication/Line | Headline Efficacy | Headline Safety | Report Date | Source |
|---|---|---|---|---|---|---|---|---|---|
| Sacituzumab govitecan + pembrolizumab | TROP2 ADC + PD-1 ICI | Gilead/Merck | NCT05382286 | III | 1L mTNBC, PD-L1+ CPS≥10 | PFS HR 0.65 (p<0.001); median 11.2 vs 7.8 mo; ORR 59.7% vs 53.2%; DoR 16.5 vs 9.2 mo | Neutropenia 43%; diarrhea 10%; discontinuation 12% vs 31% | May 31, 2025 | ASCO 2025; NEJM Jan 202645 |
| Sacituzumab govitecan | TROP2 ADC | Gilead | NCT05382299 | III | 1L mTNBC, PD-L1- or prior PD-(L)1 | PFS statistically significant (median PFS 9.7 months vs 6.9 months and HR 0.62) | Consistent with prior studies; no new signals | May 23, 2025 | Press release118 |
| Datopotamab deruxtecan (Datroway) | TROP2 ADC | AstraZeneca/Daiichi Sankyo | NCT05374512 | III | 1L mTNBC, not IO candidates | OS +5 mo vs chemo; PFS HR not disclosed; 43% progression risk reduction | Consistent with prior trials (detailed rates pending) | Oct 2025 | ESMO 2025 LBA21495771 |
| Sacituzumab tirumotecan (SKB264) | TROP2 ADC | Merck/Kelun-Biotech | NCT05347134 | III | ≥2L mTNBC | PFS 6.7 vs 2.5 mo (HR 0.32, p<0.00001); OS NR vs 9.4 mo (HR 0.53, p=0.0005); ORR 45.4% vs 12.0% | Neutropenia 32.3%; anemia 27.7% | Apr 11, 2025 | Nature Medicine1 |
| Bria-IMT ± retifanlimab | Whole-cell vaccine ± PD-1 ICI | BriaCell Therapeutics | NCT06072612 | III | Advanced/mBC (all subtypes) | Median PFS 3.67 mo; biomarker+ 4.5 mo (DTH+, p=0.001); CNS mets 71% iORR | Nausea 30%; no discontinuations; no ILD | Apr 30, 2025 | AACR 2025123 |
| Paxalisib | PI3K inhibitor | Kazia Therapeutics | Not disclosed | 1b | Late-stage mTNBC | Complete responses (median 10.8 vs 5.6 months; HR 0.57; p<0.0001) and OS (median 23.7 vs 18.7 months; HR 0.79; p=0.0291) | Not disclosed | Nov 2025 | Company announcements205354 |
Abbreviations: ADC = antibody–drug conjugate; DoR = duration of response; HR = hazard ratio; ICI = immune checkpoint inhibitor; iORR = intracranial objective response rate; IO = immunotherapy; mBC = metastatic breast cancer; mo = months; mTNBC = metastatic triple-negative breast cancer; ORR = objective response rate; OS = overall survival; PFS = progression-free survival; 1L = first-line; ≥2L = second-line or later.