Oncology's Next Battlefield: Why HER3 Is Reshaping Cancer Therapy

DUBLIN, Ireland – November 27, 2025 – The release of a new competitive intelligence report on HER3-targeted immunotherapies signals a pivotal shift in oncology. What was once considered a secondary, almost inert protein is now at the center of a multi-billion-dollar race to develop the next generation of cancer drugs. This burgeoning market is not just about adding another tool to the oncologist's belt; it represents a strategic assault on one of cancer's most formidable defenses: therapeutic resistance.

For years, the Human Epidermal Growth Factor Receptor 3 (HER3) was overshadowed by its more famous siblings, EGFR and HER2, primary targets for blockbuster drugs. The reason for this was simple: HER3 has a deficient kinase domain, meaning it cannot independently trigger the signaling cascades that drive cell growth. However, deeper investigation has revealed its true, more insidious role. HER3 acts as a master collaborator, forming potent partnerships (heterodimers) with other receptors to potently activate the PI3K/Akt pathway—a central highway for cancer cell proliferation, survival, and spread. This makes it a critical node in the complex wiring of a tumor, and its widespread presence is alarming.

HER3 is overexpressed in a startlingly broad range of tumors, including over 50% of melanoma, lung, gastric, and ovarian cancers, and a significant portion of breast and prostate cancers. More importantly, its expression is often amplified precisely when a tumor is under attack, serving as an escape route from therapies targeting EGFR and HER2, as well as from hormonal treatments and even chemotherapy. This ability to drive acquired resistance has transformed HER3 from a biological curiosity into a high-value strategic target for the pharmaceutical industry.

A New Arsenal: ADCs and Bispecifics Lead the Charge

The renewed focus on HER3 is being powered by a technological evolution in drug design, moving far beyond the first-generation monoclonal antibodies that showed limited success. The current pipeline is dominated by sophisticated modalities engineered for precision and potency, primarily antibody-drug conjugates (ADCs) and bispecific antibodies.

ADCs function like guided missiles, using an antibody to find HER3-expressing cancer cells and deliver a highly toxic payload directly to the tumor, minimizing collateral damage to healthy tissue. Leading this charge is Daiichi Sankyo’s patritumab deruxtecan (HER3-DXd). This ADC has demonstrated significant promise in heavily pre-treated patient populations. In the HERTHENA-Lung02 trial, it improved progression-free survival for patients with advanced EGFR-mutated non-small cell lung cancer (NSCLC) who had already failed other treatments. Its success earned it a Breakthrough Therapy Designation from the FDA, underscoring its potential to address a critical unmet need. Similarly, compelling response rates in metastatic breast cancer trials highlight its broad applicability. The field is not a one-horse race; other novel ADCs like DB-1310 are also advancing, having received Fast Track designation for NSCLC.

Beyond ADCs, bispecific antibodies represent another innovative front. These molecules are engineered to bind to two different targets simultaneously, creating a multi-pronged attack. First-in-class assets like BL-B01D1, an EGFR-HER3 bispecific ADC, are showing promising activity in solid tumors by inhibiting the signaling from both receptors at once. This dual-targeting strategy is designed to short-circuit the compensatory mechanisms that often lead to resistance. Further on the horizon, radioligand therapies (RLTs)—which attach a radioactive isotope to a HER3-targeting molecule to deliver localized radiation—are showing significant potential in preclinical studies, promising another powerful tool to combat drug-resistant cancers.

Navigating the High-Stakes Development Landscape

The journey from lab to clinic for these advanced therapies is fraught with challenges that test the limits of scientific and manufacturing capabilities. The market for targeted cancer therapies, projected to exceed $150 billion within the next decade, is fiercely competitive. For a HER3-targeted drug to succeed, it must not only prove its efficacy but also navigate a complex landscape of biological, logistical, and commercial hurdles.

A primary challenge is patient selection. The biological role of HER3 can vary significantly between tumor types and even between individual patients. The development of a standardized, reliable companion diagnostic to identify patients with active HER3 signaling is paramount for maximizing clinical benefit and securing regulatory approval. Without a clear biomarker strategy, even a potent drug can fail in broad clinical trials.

Furthermore, the manufacturing of these complex molecules is a significant undertaking. The production of ADCs requires a delicate, multi-step process to conjugate a potent cytotoxin to an antibody, demanding specialized facilities and stringent quality control. For RLTs, the challenges are even greater, involving the just-in-time logistics of handling short-lived radioactive isotopes, which requires a specialized supply chain and trained personnel that are currently in short supply. These manufacturing and logistical complexities translate directly into high development costs and, ultimately, high treatment prices, raising future questions about market access and reimbursement.

Redefining Treatment Paradigms for Patients

Beyond the market dynamics and scientific hurdles, the true significance of the HER3 pipeline lies in its potential to transform patient outcomes. For individuals with metastatic cancers that have exhausted standard treatment options, these therapies offer a new line of defense. The clinical activity of drugs like patritumab deruxtecan in patients with resistant NSCLC and breast cancer provides a tangible source of hope where few options previously existed.

The ultimate role of HER3-targeted therapies may be as part of powerful combination regimens. By blocking a key resistance pathway, these drugs could be used alongside existing EGFR or HER2 inhibitors to make them more effective and durable, or combined with immunotherapy to enhance the immune system's attack on the tumor. This strategy aims not just to treat cancer, but to preempt its adaptive maneuvers, potentially establishing a new standard of care.

As the pipeline matures and key clinical trial readouts approach, the industry is watching closely. The success of these next-generation immunotherapies will not only validate HER3 as a crucial oncology target but will also provide a powerful new framework for developing smarter, more resilient cancer treatments designed to stay one step ahead of the disease.