Triple-Negative Breast Cancer Clinical Trial Landscape

The TNBC trial landscape in 2026

Triple-negative breast cancer (TNBC) — defined by the absence of estrogen receptor, progesterone receptor, and HER2 expression — accounts for 15–20% of all breast cancer diagnoses but has historically carried the worst prognosis. For decades, chemotherapy was the only option; there was no targetable receptor. That changed between 2019 and 2023 with three major approvals: sacituzumab govitecan (Trodelvy) targeting TROP2, pembrolizumab (Keytruda) for PD-L1-positive disease, and PARP inhibitors for BRCA-mutated patients. But each approval opened new competitive races rather than closing them.

In 2026, the defining story in TNBC is the antibody-drug conjugate wars. Merck has committed three Phase 3 trials to sacituzumab tirumotecan (MK-2870), its next-generation TROP2 ADC designed to improve on Trodelvy's therapeutic index. AstraZeneca's TROPION-Breast03 tests dato-DXd (another TROP2 ADC) in the adjuvant setting. Bristol Myers Squibb is running IZABRIGHT-Breast01 testing izalontamab brengitecan, a HER3-directed ADC for patients who can't receive immunotherapy. Meanwhile, Akeso's bispecific PD-1/VEGF antibody AK112 is in a Phase 3 that could expand the immunotherapy-eligible TNBC population beyond the current PD-L1-selected indication. TNBC in 2026 is not one competitive race — it is four simultaneous ones.

The ADC arms race: Merck's three-Phase-3 TROP2 program

Sacituzumab govitecan (Trodelvy, Gilead) established TROP2-directed ADCs as a standard of care in relapsed/refractory TNBC. Its April 2021 FDA approval for unresectable locally advanced or metastatic TNBC after two or more prior therapies was followed by an expanded indication into earlier lines. Trodelvy's commercial success — $1.7B in sales in 2024 — triggered an immediate industry response: multiple companies developed competing TROP2 ADCs with different payloads, linkers, or drug-to-antibody ratios, each claiming an improved therapeutic index.

Merck's sacituzumab tirumotecan (Sac-TMT, MK-2870) is the most advanced challenger. Like Trodelvy, it targets TROP2, but pairs the antibody with a belotecan-based topoisomerase I inhibitor payload engineered for more stable linker chemistry and potentially reduced off-target toxicity — the primary limitation of Trodelvy, which causes grade 3/4 neutropenia in ~50% of patients. Merck has launched three simultaneous Phase 3 programs:

TroFuse-011: Sac-TMT monotherapy and combination with pembrolizumab in TNBC (NCT06841354) — started Mar 2025

NCT06841354 (TroFuse-011, started March 2025) is Merck's broadest TNBC Phase 3 — it evaluates Sac-TMT as monotherapy and in combination with pembrolizumab across multiple TNBC settings and lines of therapy. By testing both the ADC alone and paired with Merck's blockbuster PD-1 inhibitor, this trial is positioned to capture the full range of TNBC patients regardless of PD-L1 status: monotherapy for PD-L1-negative patients (where pembrolizumab adds little), combination for PD-L1-positive patients. The design reflects Merck's intent to position Sac-TMT as the TNBC backbone across lines, potentially displacing Trodelvy in earlier settings.

MK-2870-012: Sac-TMT plus pembrolizumab in TNBC non-pCR after neoadjuvant therapy (NCT06393374) — started Jun 2024

NCT06393374 (MK-2870-012, started June 2024) targets a specific high-risk TNBC population: patients who received neoadjuvant pembrolizumab plus chemotherapy but did not achieve pathological complete response (non-pCR). Non-pCR after NAT is a major unmet need — currently, capecitabine (based on CREATE-X) is the only approved post-NAT option, and olaparib for BRCA-mutated patients. This trial pits Sac-TMT plus pembrolizumab against physician's choice of therapy in the non-pCR setting, directly competing with AstraZeneca's TROPION-Breast03 in the same patient population. The head-to-head competition between two TROP2 ADCs (MK-2870 vs. Dato-DXd) for the same non-pCR indication will determine which agent becomes the new standard of care post-NAT.

MK-2870-032: Sac-TMT in breast cancer broadly (NCT06966700) — started Jun 2025

NCT06966700 (MK-2870-032, started June 2025) evaluates Sac-TMT in a broader breast cancer population including TNBC and HR low-positive/HER2-negative disease. This expansion reflects Merck's strategy to extend TROP2 ADC coverage beyond TNBC into adjacent subtypes — similar to how sacituzumab govitecan received expanded indications after its initial TNBC approval. The trial is early-stage in enrollment but signals Merck's longer-term ambition for the Sac-TMT franchise.

AstraZeneca: dato-DXd in the adjuvant setting (TROPION-Breast03)

Datopotamab deruxtecan (Dato-DXd) is AstraZeneca and Daiichi Sankyo's TROP2-targeted ADC with a DXd (exatecan derivative) payload — the same DXd payload used in trastuzumab deruxtecan (Enhertu) and other ADCs in AstraZeneca's oncology pipeline. Dato-DXd achieved positive Phase 3 results in HR+/HER2-low breast cancer (TROPION-Breast01) and demonstrated activity in TNBC in Phase 2. TROPION-Breast03 extends the program into the curative-intent adjuvant/post-NAT setting.

TROPION-Breast03: Dato-DXd ± durvalumab vs. chemotherapy in early TNBC non-pCR (NCT05629585) — active, not recruiting

NCT05629585 (TROPION-Breast03, started November 2022) is AstraZeneca's Phase 3 comparing Dato-DXd with or without durvalumab (AstraZeneca's PD-L1 inhibitor) against investigator's choice of therapy in Stage I-III TNBC patients with residual disease after neoadjuvant therapy. The inclusion of a durvalumab arm tests whether adding PD-L1 inhibition to the TROP2 ADC enhances efficacy in the post-NAT setting — a hypothesis motivated by evidence that the non-pCR tumor microenvironment may be more immunosuppressive. The trial is now active but no longer recruiting, meaning enrollment is complete and primary endpoint follow-up is underway. TROPION-Breast03 and MK-2870-012 are direct competitors in the same patient population; their relative readout timing will determine which TROP2 ADC gets first regulatory review in post-NAT TNBC.

Bristol Myers Squibb: izalontamab brengitecan and the HER3 ADC approach (IZABRIGHT-Breast01)

While Merck and AstraZeneca compete with TROP2-directed ADCs, Bristol Myers Squibb is pursuing a distinct target: HER3 (ErbB3). HER3 is a receptor tyrosine kinase overexpressed in approximately 70–80% of TNBC tumors and has limited kinase activity on its own, but forms heterodimers with HER2 and other ErbB family members to drive PI3K/AKT signaling. HER3 has historically been a difficult target for antibody-based therapy because simple HER3 antibody blockade showed modest clinical activity — but ADC delivery of a cytotoxic payload to HER3-expressing cells bypasses this limitation.

IZABRIGHT-Breast01: izalontamab brengitecan vs. chemotherapy in 1L metastatic TNBC (NCT06926868) — started Sep 2025

NCT06926868 (IZABRIGHT-Breast01, started September 2025) evaluates izalontamab brengitecan — BMS's HER3-directed antibody conjugated to a topoisomerase I inhibitor payload — versus chemotherapy in previously untreated metastatic TNBC patients who are ineligible for anti-PD-(L)1 drugs. This population is specifically patients who cannot receive pembrolizumab — whether due to PD-L1-negative status, contraindications, or prior treatment — representing approximately half the first-line metastatic TNBC population. The HER3 target provides mechanistic differentiation from TROP2 ADCs: for patients who progress through sacituzumab govitecan or Sac-TMT, a HER3 ADC offers a distinct mechanism with potential activity regardless of TROP2 expression status.

Immunotherapy: beyond pembrolizumab — Akeso's AK112 bispecific Phase 3

Pembrolizumab plus chemotherapy became the first-line standard of care for PD-L1-positive metastatic TNBC after the KEYNOTE-522 Phase 3 trial (November 2021 FDA approval). But KEYNOTE-522's benefit was restricted to PD-L1 combined positive score (CPS) ≥10 patients — approximately 40% of metastatic TNBC. The majority of TNBC patients — those with lower or absent PD-L1 expression — still receive chemotherapy alone without immunotherapy benefit. Akeso's bispecific antibody AK112 (ivonescimab) is designed to address this gap by simultaneously blocking PD-1 and VEGF.

AK112 Phase 3: bispecific PD-1/VEGF vs. placebo in 1L metastatic TNBC (NCT06767527) — started Feb 2025

NCT06767527 (started February 2025) compares AK112 plus nab-paclitaxel against placebo plus nab-paclitaxel in first-line inoperable locally advanced or metastatic TNBC, without PD-L1 selection criteria. The dual PD-1/VEGF mechanism is the key hypothesis: VEGF drives immunosuppressive changes in the tumor microenvironment (immature vasculature, hypoxia, exclusion of effector T cells), and combining VEGF blockade with PD-1 inhibition may normalize the immune environment in tumors that respond poorly to PD-1 alone. AK112 has already shown positive Phase 3 data in non-small cell lung cancer (HARMONi-2 trial), giving Akeso a validated mechanism to extend into TNBC. If AK112 shows activity regardless of PD-L1 status, it could expand the proportion of first-line metastatic TNBC patients who benefit from immunotherapy beyond the current 40% ceiling.

Roche tobemstomig Phase 2: PD-1/TIM-3 bispecific vs. pembrolizumab in 1L PD-L1+ TNBC (NCT05852691) — active

NCT05852691 (started July 2023) is Hoffmann-La Roche's Phase 2 comparing tobemstomig — a bispecific PD-1/TIM-3 inhibitor — plus nab-paclitaxel against pembrolizumab plus nab-paclitaxel in previously untreated, PD-L1-positive, metastatic TNBC. TIM-3 (T-cell immunoglobulin and mucin domain-3) is an immune checkpoint that is co-expressed with PD-1 on exhausted T cells, and blocking both simultaneously may restore anti-tumor immunity more effectively than PD-1 blockade alone. This is a direct head-to-head with the current standard of care; a positive result would position tobemstomig as a pembrolizumab replacement in PD-L1-positive first-line TNBC. The trial is active but no longer enrolling.

Early-stage TNBC: the post-NAT battleground

The highest-unmet-need setting in TNBC in 2026 is early-stage disease — specifically patients who do not achieve pathological complete response (pCR) following neoadjuvant chemoimmunotherapy. These non-pCR patients face 3-year event-free survival rates of approximately 50%, compared to over 90% for pCR patients. Currently, the only approved post-NAT therapy is capecitabine (based on CREATE-X, which studied patients who did not receive neoadjuvant immunotherapy). The pipeline of trials competing in this setting is now the most crowded in TNBC:

• TROPION-Breast03 (AZ, NCT05629585) — Dato-DXd ± durvalumab vs. chemotherapy; enrollment complete, in follow-up
• MK-2870-012 (Merck, NCT06393374) — Sac-TMT + pembro vs. TPC; recruiting since June 2024
• NCT07486687 (NCI Netherlands) — Adjuvant pembrolizumab in TNBC residual disease post-NAT pembro; starting April 2026

The NCI Netherlands trial (NCT07486687) asks a specific clinical question: for patients who received neoadjuvant pembrolizumab plus chemotherapy and had residual disease, does continuing adjuvant pembrolizumab improve outcomes? This is the re-challenge hypothesis — and its answer will affect how oncologists interpret the ADC trial results, since pembrolizumab re-challenge could be a concurrent standard of care if proven effective.

Actively recruiting and active TNBC trials (2026)

Competitive dynamics: the race to own post-Trodelvy TNBC

The market logic driving TNBC investment in 2026 is simple: sacituzumab govitecan (Trodelvy) proved that a TROP2 ADC can be approved in TNBC and generates significant revenue. The race is now to build an ADC franchise that displaces Trodelvy with better tolerability, earlier lines of therapy, or a unique target combination. Merck, AstraZeneca, and BMS have each committed to this thesis with substantial Phase 3 investment.

Merck's three simultaneous Phase 3 trials represent the most aggressive TROP2 ADC campaign in oncology. The strategy is to seed multiple settings simultaneously — post-NAT residual disease (MK-2870-012), broad TNBC monotherapy and combination (TroFuse-011), and broad breast cancer (MK-2870-032) — and read out data across all settings before a competitor establishes itself. This hedges against the risk that any single trial fails while maximizing the probability of at least one FDA registration pathway.

AstraZeneca's TROPION-Breast03, having finished enrollment, is the closest to readout. The trial's two-arm design — Dato-DXd alone vs. Dato-DXd plus durvalumab — also tests the ADC-immunotherapy combination hypothesis in TNBC. If the combination arm shows superiority over ADC alone, it creates a competitive moat that Merck's Sac-TMT program would need to match. If the combination arm adds toxicity without efficacy, it simplifies the approval path for ADC monotherapy in the post-NAT setting.

BMS's izalontamab brengitecan occupies a distinct niche: the PD-L1-ineligible first-line patient. If approved, it would be the first non-chemo, non-TROP2 option for this population, addressing the roughly 60% of first-line metastatic TNBC patients who cannot receive pembrolizumab. The commercial prize for this indication is large, and HER3 targeting provides mechanistic differentiation that avoids direct TROP2 ADC competition — at least until TROP2 ADCs expand into first-line through their own trials.

Why monitor TNBC trials?

TNBC is one of the highest-velocity clinical trial environments in oncology. Key developments to track:

• TROPION-Breast03 readout: AstraZeneca's post-NAT Dato-DXd trial has completed enrollment — primary endpoint data are expected within the next 12–18 months. This is likely the first Phase 3 TROP2 ADC readout in the non-pCR adjuvant TNBC setting.
• Merck Sac-TMT enrollment pace: Three simultaneous Phase 3 trials means enrollment competition between MK-2870-011, -012, and -032. Enrollment velocity in MK-2870-012 (the non-pCR trial competing directly with TROPION-Breast03) signals Merck's confidence in beating AstraZeneca to data.
• AK112 first-line results: Akeso's AK112 already showed positive Phase 3 data in NSCLC. TNBC is its next major expansion. Interim safety data or enrollment milestones are early signals of the trial's trajectory.
• BMS IZABRIGHT enrollment: Izalontamab brengitecan started September 2025 — a newly recruiting Phase 3. Rapid or slow enrollment will signal HER3 ADC enthusiasm among oncology trial sites.
• Post-ADC sequencing: Fudan University's ADC rechallenge platform trial (NCT06649331) directly asks what works after TROP2 ADC progression — a question that becomes commercially urgent as Trodelvy becomes standard first-line therapy.

Related clinical trial monitors

TNBC shares ADC and immunotherapy mechanisms with other solid tumor programs. Related monitors on DataLookout:

• Breast cancer clinical trials — broader breast cancer pipeline including HR+/HER2+, HER2-low, and metastatic programs
• Cervical cancer clinical trials — overlapping immunotherapy (pembrolizumab, tisotumab vedotin ADC) and PD-L1 selection strategies
• Endometrial cancer clinical trials — HER2-directed ADC (trastuzumab deruxtecan) and immunotherapy combinations; ADC pipeline overlap
• Bladder cancer clinical trials — TROP2 ADC (sacituzumab govitecan approved in urothelial), PD-L1 immunotherapy; direct mechanism overlap
• NSCLC clinical trials — Akeso AK112 positive Phase 3 in NSCLC informs TNBC trial design; PD-L1/VEGF bispecific mechanism

Frequently asked questions