Enhertu® Receives CHMP Recommendation for EU Approval in HER2-Positive Metastatic Solid Tumors
Enhertu has received a positive recommendation for approval in the European Union from the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency for the treatment of adult patients with unresectable or metastatic HER2-positive solid tumors who have previously received treatment and have no satisfactory treatment options remaining.
The recommendation marks a potentially important advancement in precision oncology and could significantly expand access to HER2-targeted treatment beyond traditionally treated cancer types such as breast and gastric cancer.
Enhertu is a HER2-directed DXd antibody-drug conjugate jointly developed and commercialized by Daiichi Sankyo and AstraZeneca. The therapy was originally discovered by Daiichi Sankyo and has emerged as one of the leading antibody-drug conjugates in oncology due to its broad clinical activity across multiple HER2-expressing cancers.
The CHMP recommendation specifically covers adult patients with HER2-positive tumors classified as immunohistochemistry (IHC) 3+ whose cancers are unresectable or metastatic and who have exhausted other satisfactory treatment options.
The positive opinion is based on results from three Phase 2 clinical trials — DESTINY-PanTumor02, DESTINY-Lung01, and DESTINY-CRC02 — which collectively demonstrated meaningful anti-tumor responses across a range of HER2-positive cancers.
The recommendation will now move to the European Commission, which holds the authority to grant final marketing authorization for medicines across the European Union as well as Iceland, Liechtenstein, and Norway.
The CHMP opinion reflects growing recognition of HER2 as a clinically relevant biomarker across multiple tumor types, not just breast and gastric cancers. Researchers increasingly believe that HER2-targeted therapies may provide important treatment opportunities for patients with several difficult-to-treat cancers that overexpress the HER2 protein.
In the DESTINY-PanTumor02 study, Enhertu demonstrated strong clinical activity among patients with a wide range of HER2-positive solid tumors. The trial included previously treated patients with cancers such as biliary tract, bladder, cervical, endometrial, ovarian, and pancreatic tumors, among others.
Among 111 patients with centrally or locally assessed HER2-positive tumors, Enhertu achieved a confirmed objective response rate of 51.4%. The median duration of response reached 14.2 months, indicating durable disease control for many participants despite prior treatment exposure.
Researchers described the findings as clinically meaningful given the limited therapeutic options available for heavily pretreated metastatic cancer patients.
The DESTINY-Lung01 trial focused on patients with HER2-positive non-small cell lung cancer (NSCLC), another area where targeted treatment options have historically been limited.
In that study, Enhertu demonstrated a confirmed objective response rate of 52.9% among previously treated patients with centrally confirmed HER2-positive NSCLC. The median duration of response was 6.9 months.
Although the study involved a relatively small patient population, investigators noted that the results further support the role of HER2-directed therapy in lung cancer treatment.
Meanwhile, the DESTINY-CRC02 trial evaluated Enhertu in patients with HER2-positive colorectal cancer. Among 64 previously treated patients with centrally confirmed HER2-positive colorectal tumors, the therapy achieved a confirmed objective response rate of 46.9%.
The median duration of response in the colorectal cancer study was 5.5 months, further demonstrating activity in a cancer setting where targeted treatment options remain limited after progression on standard therapies.
Collectively, the results from the three studies suggest that Enhertu may offer broad clinical benefit across multiple HER2-expressing cancers regardless of tumor origin.
“This positive CHMP opinion acknowledges the clinical value of Enhertu as the potential first HER2-directed medicine and antibody-drug conjugate available for patients with HER2-positive metastatic solid tumors in the EU,” said John Tsai.
Dr. Tsai noted that Enhertu has shown meaningful responses for patients with advanced cancers that overexpress HER2 and emphasized the importance of expanding treatment options for patients with limited alternatives.
He added that Daiichi Sankyo looks forward to continuing its collaboration with the European Medicines Agency to potentially bring the therapy to eligible patients throughout Europe.
Susan Galbraith also highlighted the broader significance of the recommendation for precision oncology.
She explained that HER2-targeted therapies have already transformed treatment outcomes for certain cancer types, particularly breast and gastric cancers. However, many other tumors also overexpress HER2 while lacking approved targeted treatment options.
According to Galbraith, the CHMP’s positive opinion represents an important step toward making a new targeted therapy available to a broader group of patients living with HER2-positive cancers in the European Union.
In addition to demonstrating clinical efficacy, the studies also provided important safety data regarding Enhertu treatment across multiple tumor types.
The safety profile observed in the trials was generally consistent with previous Enhertu studies, and no new safety concerns were identified.
In DESTINY-PanTumor02, the most common grade 3 or higher drug-related adverse events included neutropenia and anemia, each occurring in 10.9% of patients.
Interstitial lung disease (ILD) or pneumonitis, which has been identified as an important safety consideration for Enhertu, occurred in 10.5% of patients in the study. Most cases were low grade, although researchers reported one grade 3 event and three grade 5 events.
In DESTINY-Lung01, the most common severe treatment-emergent adverse events included disease progression, fatigue, pneumonia, and dyspnea. ILD or pneumonitis occurred in 5% of patients. Most events were low grade, although one grade 5 event was reported, along with an additional drug-related fatal pneumonitis event identified after the data cutoff.
In DESTINY-CRC02, the most common grade 3 or worse adverse events included decreased neutrophil count, anemia, nausea, and decreased white blood cell count.
ILD or pneumonitis occurred in 8% of patients in the colorectal cancer study, though all cases were low grade and no grade 3, grade 4, or grade 5 events were observed.
The positive CHMP recommendation represents another major regulatory milestone for Enhertu as the therapy continues expanding into additional cancer settings worldwide.
If approved by the European Commission, Enhertu could become one of the first HER2-directed therapies broadly available across multiple HER2-positive solid tumors in Europe, potentially opening new treatment possibilities for patients with advanced cancers who currently face limited options after prior therapy failure.
About DESTINY-PanTumor02
DESTINY-PanTumor02 is a global, multicenter, multi-cohort, open-label, phase 2 trial evaluating the efficacy and safety of Enhertu (5.4 mg/kg) for the treatment of previously treated HER2 expressing tumors, including biliary tract, bladder, cervical, endometrial, ovarian, pancreatic cancer or other tumors.
The primary endpoint of DESTINY-PanTumor02 is confirmed ORR as assessed by investigator. Secondary endpoints include DOR, disease control rate (DCR), progression-free survival (PFS), overall survival (OS), safety, tolerability and pharmacokinetics. Results from DESTINY-PanTumor02 were published in the Journal of Clinical Oncology.
DESTINY-PanTumor02 enrolled 267 patients, including 111 HER2 positive (IHC 3+) adult patients at multiple sites in Asia, Europe, North America, South America and Oceania. For more information about the trial, visit ClinicalTrials.gov.
About DESTINY-Lung01
DESTINY-Lung01 is a global, open-label, two-cohort, phase 2 trial evaluating the efficacy and safety of Enhertu (5.4 mg/kg or 6.4 mg/kg) in patients with HER2 mutant (Cohort 2, n=91) or HER2 overexpressing (defined as IHC 3+ or IHC 2+) (Cohort 1 and 1a, n=90) unresectable or metastatic NSCLC who had progressed after one or more systemic therapies.
The primary endpoint of DESTINY-Lung01 is confirmed ORR by independent central review. Key secondary endpoints include DOR, DCR, PFS, OS and safety. Results from the HER2 mutant cohort were published in The New England Journal of Medicine and results from the HER2 overexpressing cohort were published in The Lancet Oncology.
DESTINY-Lung01 enrolled 181 patients, including 17 HER2 positive (IHC 3+) adult patients at multiple sites in Asia, Europe and North America. For more information about the trial, visit ClinicalTrials.gov.
About DESTINY-CRC02
DESTINY-CRC02is a global, randomized, two arm, parallel, multicenter, phase 2 trial evaluating the efficacy and safety of two doses (5.4 mg/kg or 6.4 mg/kg) of Enhertu in patients with locally advanced, unresectable or metastatic HER2 positive colorectal cancer of BRAF wild-type, RAS wild-type or RAS mutant tumor types previously treated with standard therapy. The trial was conducted in two stages. In the first stage, patients (n=80) were randomized 1:1 to receive either 5.4 mg/kg or 6.4 mg/kg of Enhertu. In the second stage, additional patients (n=42) were enrolled in the 5.4 mg/kg arm.
The primary endpoint in DESTINY-CRC02 is confirmed ORR as assessed by blinded independent central review. Secondary endpoints include DOR, DCR, investigator-assessed confirmed ORR, clinical benefit ratio, PFS, OS and safety. Results from DESTINY-CRC02 were published inThe Lancet Oncology.
DESTINY-CRC02 enrolled 122 patients, including 64 HER2 positive (IHC 3+) adult patients at multiple sites in Asia, Europe, North America and Oceania. For more information about the trial, visit ClinicalTrials.gov.
About HER2 Expression in Solid Tumors
HER2 is a tyrosine kinase receptor growth-promoting protein expressed on the surface of various tissue cells throughout the body and is involved in normal cell growth.1 HER2 protein overexpression may occur as a result of HER2 gene amplificationand is often associated with aggressive disease and poor prognosis in some cancers.2
HER2 directed therapies have been used to treat HER2 overexpression in breast, gastric andsalivary glandcancers in the EU.1,3,4,5 Although HER2 is overexpressed in additional solid tumor types including biliary tract, lung, bladder, cervical, colorectal, endometrial, ovarian and pancreatic cancers, HER2 testing is not routinely performed in these additional tumor types and there are currently no HER2 directed treatments approved in the EU to treat a broad range of solid tumors.2,6,7
About Enhertu
Enhertu (trastuzumab deruxtecan; fam-trastuzumab deruxtecan-nxki in the U.S. only) is a HER2 directed ADC. Designed using Daiichi Sankyo’s proprietary DXd ADC Technology, Enhertu is the lead ADC in the oncology portfolio of Daiichi Sankyo and the most advanced program in AstraZeneca’s ADC scientific platform. Enhertu consists of a HER2 monoclonal antibody attached to a number of topoisomerase I inhibitor payloads (an exatecan derivative, DXd) via tetrapeptide-based cleavable linkers.
Enhertu (5.4 mg/kg) is approved in the U.S. for the treatment of adult patients with HER2 positive breast cancer who have residual invasive disease following neoadjuvant trastuzumab (with or without pertuzumab) and taxane-based treatment based on the DESTINY-Breast05 trial.
Enhertu (5.4 mg/kg) followed by THP is approved in China and the U.S. as a neoadjuvant treatment for adult patients with HER2 positive (IHC 3+ or ISH+) stage 2 or stage 3 breast cancer based on the results from the DESTINY-Breast11 trial. Continued approval in China for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.
Enhertu (5.4 mg/kg) in combination with pertuzumab is approved in Israel, Saudi Arabia, Switzerland, the United Arab Emirates and the U.S. as a first-line treatment for adult patients with unresectable or metastatic HER2 positive (IHC 3+ or ISH+) breast cancer, as determined by an FDA-approved test, based on the results from the DESTINY-Breast09 trial.
Enhertu (5.4 mg/kg) is approved in more than 95 countries/regions worldwide for the treatment of adult patients with unresectable or metastatic HER2 positive (IHC 3+ or ISH+) breast cancer who have received a prior anti-HER2-based regimen, either in the metastatic setting or in the neoadjuvant or adjuvant setting, and have developed disease recurrence during or within six months of completing therapy based on the results from the DESTINY-Breast03 trial.
Enhertu (5.4 mg/kg) is approved in more than 95 countries/regions worldwide for the treatment of adult patients with unresectable or metastatic HER2 low (IHC 1+ or IHC 2+/ISH-) breast cancer who have received a prior systemic therapy in the metastatic setting or developed disease recurrence during or within six months of completing adjuvant chemotherapy based on the results from the DESTINY-Breast04 trial.
Enhertu (5.4 mg/kg) is approved in more than 70 countries/regions worldwide for the treatment of adult patients with unresectable or metastatic hormone receptor (HR) positive, HER2 low (IHC 1+ or IHC 2+/ ISH-) or HER2 ultralow (IHC 0 with membrane staining) breast cancer, as determined by a locally or regionally approved test, that have progressed on one or more endocrine therapies in the metastatic setting based on the results from the DESTINY-Breast06trial.
Enhertu (5.4 mg/kg) is approved in more than 75 countries/regions worldwide for the treatment of adult patients with unresectable or metastatic NSCLC whose tumors have activating HER2 (ERBB2) mutations, as detected by a locally or regionally approved test, and who have received a prior systemic therapy based on the results from the DESTINY-Lung02 and/or DESTINY-Lung05 trials. Continued approval in China and the U.S. for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.
Enhertu (6.4 mg/kg) is approved in more than 90 countries/regions worldwide for the treatment of adult patients with locally advanced or metastatic HER2 positive (IHC 3+ or IHC 2+/ISH+) gastric or gastroesophageal junction (GEJ) adenocarcinoma who have received a prior trastuzumab-based regimen based on the results from the DESTINY-Gastric01, DESTINY-Gastric02 and/orDESTINY-Gastric04trials.
Enhertu (5.4 mg/kg) is approved in more than 15 countries/regions worldwide for the treatment of adult patients with unresectable or metastatic HER2 positive (IHC 3+) solid tumors who have received prior systemic treatment and have no satisfactory alternative treatment options based on efficacy results from the DESTINY-PanTumor02, DESTINY-Lung01, DESTINY-CRC02 and/or HERALD trials. Continued approval in the U.S. for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.
About the Enhertu Clinical Development Program
A comprehensive global clinical development program is underway evaluating the efficacy and safety of Enhertu as a monotherapy or in combination or sequentially with other cancer medicines across multiple HER2 targetable cancers.
About the Daiichi Sankyo and AstraZeneca Collaboration
Daiichi Sankyo and AstraZeneca entered into a global collaboration to jointly develop and commercialize Enhertu in March 2019 and Datroway® in July 2020, except in Japan where Daiichi Sankyo maintains exclusive rights for each ADC. Daiichi Sankyo is responsible for the manufacturing and supply of Enhertu and Datroway.
About the ADC Portfolio of Daiichi Sankyo
The Daiichi Sankyo ADC portfolio consists of eight ADCs in clinical development crafted from ADC technology discovered in-house by Daiichi Sankyo.
The DXd ADC Technology platform of Daiichi Sankyo consists of seven ADCs in clinical development where each ADC is comprised of a monoclonal antibody attached to a number of topoisomerase I inhibitor payloads (an exatecan derivative, DXd) via tetrapeptide-based cleavable linkers. The DXd ADCs include Enhertu and Datroway, which are being jointly developed and commercialized globally with AstraZeneca, and ifinatamab deruxtecan (I-DXd), raludotatug deruxtecan (R-DXd) and patritumab deruxtecan (HER3-DXd), which are being jointly developed and commercialized globally with Merck & Co., Inc, Rahway, NJ, USA. DS-3939 and DS3790 are being developed by Daiichi Sankyo.
An additional ADC being developed by Daiichi Sankyo is DS3610, which consists of an antibody attached to a novel payload that acts as an agonist of STING.
Ifinatamab deruxtecan, raludotatug deruxtecan, patritumab deruxtecan, DS-3939, DS3610 and DS3790 are investigational medicines that have not been approved for any indication in any country. Safety and efficacy have not been established.
About Daiichi Sankyo
Daiichi Sankyo (TSE: 4568) is a global healthcare company committed to becoming a trusted healthcare innovator, transforming the lives of people through its strength in science and technology. The company discovers and develops new standards of care to address diverse medical needs to fulfill its purpose of contributing to the enrichment of quality of life around the world. With a strategic focus on oncology, Daiichi Sankyo is advancing an industry-leading antibody drug conjugate portfolio along with identifying new breakthrough generating technologies to deliver practice-changing medicines to patients, healthcare professionals and society.
