HER3-DXd shows promise in treating brain metastases: Inside the TUXEDO-3 trial results from ASCO 2025

In a landmark moment for CNS-oncology therapeutics, HER3-DXd (patritumab deruxtecan) has emerged as a potential breakthrough treatment for patients suffering from brain metastases and leptomeningeal disease linked to breast and lung cancers. The updated data from the Phase II TUXEDO-3 clinical trial, presented at the American Society of Clinical Oncology (ASCO) Annual Meeting 2025 and simultaneously published in Nature Medicine, has generated significant momentum among medical researchers and biotechnology analysts alike.

Funded by Daiichi Sankyo and Merck & Co., Inc. (known as MSD outside North America), and supported by oncology research firm MEDSIR, this trial marks a major step in validating antibody-drug conjugates (ADCs) for CNS-involved metastatic cancers—a field historically underserved due to the complexity of crossing the blood-brain barrier. With the global ADC market projected to exceed $25 billion by 2030, HER3-DXd could represent a pivotal commercial and clinical asset in this sector.

Why Is HER3-DXd a Focus for Investors and Oncologists in 2025?

The TUXEDO-3 trial investigates HER3-DXd in patients with metastatic breast cancer (mBC) and advanced non-small cell lung cancer (aNSCLC), specifically those with active brain metastases and leptomeningeal disease. These complications are notoriously hard to treat with systemic therapy due to the blood-brain and blood–CSF barriers, and they typically signal poor prognosis with minimal survival advantage using existing treatment options.

HER3-DXd is a next-generation ADC combining a fully human monoclonal antibody targeting HER3 (a known contributor to therapy resistance) with a cytotoxic payload derived from exatecan (DXd). The conjugate is connected by a cleavable tetrapeptide linker designed to release its cytotoxic effect directly into HER3-expressing tumor cells. Analysts tracking ADC innovation have noted that HER3, while less oncogenic than HER2, plays a key role in downstream signaling and drug resistance—making it a promising new target in oncology R&D.

What Did the TUXEDO-3 Trial Reveal About Intracranial Response Rates?

The Phase II TUXEDO-3 trial met its primary endpoints, posting meaningful intracranial objective response rates (ORR) across patient subgroups. Among patients with metastatic breast cancer and active brain metastases, the trial recorded a 23.8% ORR. For the aNSCLC cohort, the ORR stood at 30%. These results are clinically significant, particularly given that patients with brain metastases typically show minimal response to systemic therapies.

In addition, in the leptomeningeal disease cohort—considered one of the most lethal CNS complications in solid tumors—65% of patients remained alive three months after initiating HER3-DXd treatment. Historically, the three-month survival rate in leptomeningeal disease rarely crosses 40%, pointing to a potential shift in the treatment paradigm.

These data have placed HER3-DXd on the radar for potential priority review pathways, especially in markets such as the United States and Japan, where unmet needs in CNS-involved cancers are a growing concern for regulators and providers.

How Does HER3-DXd Perform in Tumors With and Without Known Driver Mutations?

An important insight from the TUXEDO-3 trial was HER3-DXd’s activity across various molecular subtypes and genetic profiles. Responses were observed in breast cancer subtypes including HER2-positive, luminal, and triple-negative breast cancer (TNBC), even among patients who had previously failed on other ADCs. This underscores the possibility that HER3-DXd may overcome resistance mechanisms inherent to first-generation targeted therapies.

Similarly, in the aNSCLC cohort, responses were seen not just in EGFR- or KRAS-mutated tumors but also in patients with no known driver mutations. For biotech investors, this signals broader commercial applicability and opens the door to label expansions beyond narrowly defined biomarker-positive subgroups.

What Are Analysts Saying?

Although HER3-DXd is still classified as an investigational asset, sentiment around its commercial viability has grown more optimistic. At ASCO 2025, analysts from biotech-focused research firms such as Evaluate Vantage and SVB Securities noted that HER3-DXd could be a “category-defining” therapy in the ADC-CNS interface, a niche that has been largely ignored by larger pharmaceutical portfolios due to delivery challenges.

Early investor sentiment around Daiichi Sankyo’s broader ADC platform—already validated by the commercial success of Enhertu (trastuzumab deruxtecan)—has been strengthened by the HER3-DXd data. Some analysts suggest that the HER3-DXd program could eventually unlock a new CNS-specific revenue stream exceeding $2–3 billion annually by the early 2030s, assuming favorable Phase III data and global market uptake.

Market watchers also noted that Merck & Co., Inc., through its strategic collaboration, may leverage HER3-DXd to further diversify its oncology pipeline, especially as it seeks next-generation assets beyond Keytruda as it nears LOE (loss of exclusivity) in 2028.

Where Does This Fit in the Broader Trend of ADC-Driven Oncology?

The oncology industry has witnessed a sharp uptick in investment into ADC platforms in the last three years, with 2024 alone seeing over $10 billion in licensing and acquisition deals tied to ADC programs. HER3-DXd now joins a new class of CNS-active ADCs, such as those under development by Seagen, AstraZeneca, and Gilead Sciences.

Historically, solid tumor CNS involvement has been considered the final therapeutic frontier, due to challenges in achieving pharmacologically active concentrations within the brain. HER3-DXd, with its early-phase efficacy in the CNS, may set a precedent for future programs—raising expectations for blood-brain barrier penetrance as a default development benchmark rather than a secondary consideration.

What Else Is MEDSIR Presenting at ASCO 2025?

Beyond TUXEDO-3, MEDSIR is presenting two additional trials at ASCO 2025: the ADELA study and the WIN-B study. ADELA, a Phase III trial in collaboration with The Menarini Group and Stemline Therapeutics, explores the combination of elacestrant and everolimus in patients with advanced ER+/HER2- breast cancer and ESR1 mutations. The study is enrolling across Europe, North America, and South America, and is being closely watched for its impact on endocrine resistance.

The WIN-B study, meanwhile, is testing a novel WEE1 inhibitor (Debio 0123) in combination with Gilead’s sacituzumab govitecan (Trodelvy®). This study could reshape expectations for synthetic lethality-based combination therapies in TNBC and HR+/HER2- cancers.

Together, these presentations reinforce MEDSIR’s positioning as a leading independent clinical research organization (CRO) in oncology, with a proven ability to run multi-continent, investigator-initiated trials aligned with both scientific rigor and commercial interest.

What Comes Next for HER3-DXd and the TUXEDO Program?

With TUXEDO-3 achieving its primary endpoints and attracting scientific validation from both ASCO and Nature Medicine, the logical next step is a randomized Phase III study to confirm HER3-DXd’s clinical benefit over standard-of-care treatments such as radiotherapy, intrathecal chemotherapy, or systemic TKIs. A potential path forward could involve accelerated approval for select indications in leptomeningeal disease or brain metastases in HER3-positive mBC or aNSCLC patients.

Regulatory filings may be considered in major markets by late 2026, depending on ongoing development and data maturity. Strategic partnerships with diagnostics companies to co-develop HER3 testing kits are also likely, given the increasing regulatory emphasis on companion diagnostics in oncology approvals.

From an institutional sentiment perspective, early buy-side feedback indicates strong interest in HER3-DXd’s pipeline progression, especially among long-horizon biotech investors focused on differentiated assets in neuro-oncology.

HER3-DXd’s emergence from the TUXEDO-3 trial as a viable treatment option for difficult-to-treat brain metastases and leptomeningeal disease represents a decisive moment in the convergence of precision oncology and CNS therapeutics. As ADC platforms continue to evolve and CNS-targeting technologies advance, HER3-DXd may prove to be not just a drug, but a blueprint for the future of brain metastasis management.