ENHERTU® Plus Pertuzumab Moves Closer to EU Approval as First-Line Therapy for HER2-Positive Metastatic Breast Cancer
In a significant milestone for oncology innovation, the European Medicines Agency (EMA) has officially validated the Type II Variation marketing authorization application for ENHERTU® (trastuzumab deruxtecan) in combination with pertuzumab as a first-line treatment for adult patients with unresectable or metastatic HER2-positive breast cancer. This validation marks the formal initiation of the EMA’s scientific review process by its Committee for Medicinal Products for Human Use (CHMP), bringing hope to thousands of patients across Europe who face one of the most aggressive forms of breast cancer.
The application is grounded in compelling data from the landmark DESTINY-Breast09 phase 3 clinical trial—a global, multicenter study that demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) when ENHERTU was combined with pertuzumab, compared to the current standard of care: taxane plus trastuzumab and pertuzumab (THP). These findings were unveiled during a special late-breaking oral session at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting and subsequently published in The New England Journal of Medicine, underscoring their scientific rigor and clinical relevance.
“This validation in the EU is an important step in moving us closer to offering ENHERTU in combination with pertuzumab as a potential new first-line treatment option for patients with HER2-positive metastatic breast cancer,” said Dr. Ken Takeshita, Global Head of Research and Development at Daiichi Sankyo. “Following the recent approval in the U.S. for this indication, we look forward to working closely with the EMA to bring ENHERTU to eligible patients in the EU who may benefit from improved outcomes in a setting where the standard of care has not changed in more than a decade.”
A Paradigm Shift in First-Line Treatment
For over 12 years, the THP regimen—comprising a taxane chemotherapy agent, trastuzumab, and pertuzumab—has been the cornerstone of first-line therapy for HER2-positive metastatic breast cancer. While this combination represented a major advance when introduced, many patients still experience disease progression within two years, and nearly one-third do not survive long enough to receive second-line treatment. The urgent need for more effective, durable therapies has driven intense research into next-generation anti-HER2 strategies.
ENHERTU, a HER2-directed antibody-drug conjugate (ADC) developed using Daiichi Sankyo’s proprietary DXd technology, offers a novel mechanism of action. It combines a humanized anti-HER2 monoclonal antibody with a potent topoisomerase I inhibitor payload (DXd) via a cleavable tetrapeptide-based linker. This design enables precise delivery of cytotoxic agents directly to HER2-expressing tumor cells while minimizing damage to healthy tissue—a hallmark of ADC precision medicine.
In DESTINY-Breast09, ENHERTU (5.4 mg/kg) administered with pertuzumab significantly outperformed THP in delaying disease progression. The trial enrolled 1,157 patients across five continents—including sites in Africa, Asia, Europe, North America, and South America—ensuring broad demographic and clinical diversity. Participants were randomized 1:1:1 into three arms: ENHERTU monotherapy plus placebo; ENHERTU plus pertuzumab; or standard THP. Randomization was stratified by key prognostic factors, including prior treatment history (de novo metastatic vs. recurrence from early-stage disease), hormone receptor status, and PIK3CA mutation status.
The primary endpoint—PFS assessed by blinded independent central review—was met in both ENHERTU-containing arms, though the combination arm showed the most robust benefit. Secondary endpoints, including overall survival, objective response rate, duration of response, and safety, are still being evaluated, but early signals suggest a favorable risk-benefit profile. Notably, the monotherapy arm remains blinded and will continue until final PFS analysis, preserving the integrity of the trial’s comparative design.
The Burden of HER2-Positive Metastatic Breast Cancer
Breast cancer remains the second most commonly diagnosed cancer worldwide and a leading cause of cancer-related mortality. In 2022 alone, over two million new cases were reported globally, resulting in more than 665,000 deaths. In Europe, approximately 557,000 women are diagnosed with breast cancer each year, with over 144,000 succumbing to the disease annually.
While early-stage breast cancer often carries a favorable prognosis—with five-year survival rates exceeding 90%—the outlook dramatically worsens once the disease becomes metastatic. Only about 30% of patients with metastatic breast cancer survive beyond five years after diagnosis. Among these, 15–20% have tumors that overexpress or amplify the HER2 protein, a receptor tyrosine kinase that drives uncontrolled cell proliferation and tumor aggressiveness.
Although HER2-targeted therapies like trastuzumab and pertuzumab revolutionized care in the early 2000s, resistance and relapse remain common. Most patients on first-line THP experience disease progression within 18–24 months, highlighting the limitations of current regimens. Moreover, access to subsequent lines of therapy is often constrained by rapid clinical deterioration, leaving a critical gap in therapeutic options.
ENHERTU: A Transformative ADC with Expanding Indications
Originally approved based on the DESTINY-Breast03 trial for previously treated HER2-positive metastatic breast cancer, ENHERTU has rapidly reshaped the treatment landscape. Its success led to approvals in over 90 countries for second-line and later settings. Subsequent trials—DESTINY-Breast04 and DESTINY-Breast06—extended its utility to HER2-low and even HER2-ultralow breast cancers, redefining how clinicians classify and treat breast cancer subtypes.
Now, with DESTINY-Breast09, ENHERTU is poised to move into the first-line setting. The U.S. Food and Drug Administration (FDA) has already granted approval for ENHERTU plus pertuzumab in this indication, making the EMA’s ongoing review pivotal for European patients. If approved, this regimen could become the new standard of care, displacing THP after more than a decade of dominance.
Beyond breast cancer, ENHERTU has demonstrated efficacy in multiple HER2-driven malignancies. It is approved in over 70 countries for HER2-mutant non-small cell lung cancer (NSCLC), in more than 80 for HER2-positive gastric or gastroesophageal junction adenocarcinoma, and in select regions for other HER2-positive solid tumors. These approvals reflect the versatility of the DXd platform and the growing recognition of HER2 as a pan-tumor target.
The Power of Collaboration and Innovation
ENHERTU is the product of a strategic global collaboration between Daiichi Sankyo and AstraZeneca, forged in 2019. Under this partnership, both companies jointly develop and commercialize ENHERTU outside Japan, where Daiichi Sankyo retains exclusive rights. Daiichi Sankyo leads manufacturing and supply, leveraging its deep expertise in ADC science.
This alliance exemplifies how cross-industry partnerships can accelerate drug development and expand patient access. AstraZeneca’s global infrastructure complements Daiichi Sankyo’s pioneering ADC technology, enabling rapid translation of clinical insights into real-world impact.
Daiichi Sankyo’s ADC portfolio now includes eight investigational agents, six of which utilize the DXd platform. Beyond ENHERTU, candidates like patritumab deruxtecan (HER3-DXd), ifinatamab deruxtecan, and raludotatug deruxtecan are advancing in trials for lung, colorectal, and other cancers, often in collaboration with Merck & Co. Additional platforms, such as pyrrolobenzodiazepine (PBD)-based and STING agonist payloads, further diversify the pipeline.
Implications for Patients and Healthcare Systems
If the EMA grants marketing authorization, ENHERTU plus pertuzumab could offer European patients not only longer progression-free survival but also improved quality of life—potentially with fewer side effects than traditional chemotherapy-heavy regimens. While ADCs carry unique risks, such as interstitial lung disease (ILD), rigorous monitoring protocols and updated prescribing guidelines have enhanced their safe use.
From a health economics perspective, a more effective first-line therapy could reduce the need for subsequent treatments, hospitalizations, and palliative care, potentially lowering long-term costs despite higher upfront drug expenses. Payers and policymakers will weigh these factors as they consider reimbursement decisions.
More broadly, the success of ENHERTU underscores a paradigm shift in oncology: from broad cytotoxic approaches to precision-targeted therapies that exploit molecular vulnerabilities. As biomarker testing becomes more routine, treatments like ENHERTU will increasingly be matched to patients most likely to benefit—ushering in an era of truly personalized cancer care.
The EMA’s validation of the ENHERTU plus pertuzumab application represents more than a regulatory step—it symbolizes hope for patients facing a historically difficult-to-treat cancer. With robust phase 3 data, global regulatory momentum, and a strong scientific foundation, this combination therapy stands on the brink of redefining first-line standards in HER2-positive metastatic breast cancer across Europe. As the CHMP review progresses, the oncology community watches with anticipation, knowing that for many patients, time is not just a metric—it’s a lifeline.
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