Pertuzumab

AstraZeneca and Daiichi Sankyo’s ENHERTU plus pertuzumab showed a median progression-free survival greater than three years First trial in more than a decade to demonstrate an improvement in outcomes in the 1st-line setting for a broad population of patients with HER2-positive metastatic breast cancer WILMINGTON, DE, USA J June 02, 2025 I Positive results from the DESTINY-Breast09 Phase III trial showed ENHERTU ® (fam-trastuzumab deruxtecan-nxki) plus pertuzumab demonstrated a highly statistically significant and clinically meaningful improvement in progression-free survival (PFS) compared to a taxane, trastuzumab and pertuzumab (THP) as a 1st-line treatment for patients with HER2-positive metastatic breast cancer. Results will be presented today during a special late-breaking oral session at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, IL (abstract #LBA1008). In a prespecified interim analysis, ENHERTU plus pertuzumab reduced the risk of disease progression or death by 44% versus THP (based on a hazard ratio [HR] of 0.56; 95% confidence interval [CI] 0.44-0.71; p<0.00001). Median PFS was 40.7 months with ENHERTUplus pertuzumab compared to 26.9 months for THP, as assessed by blinded independent central review (BICR). The PFS benefit for ENHERTU plus pertuzumab versus THP was consistent across subgroups, including for the prespecified stratification factors of de novo or recurrent disease, hormone receptor status and PIK3CA mutation status. Investigator-assessed PFS demonstrated a median PFS of 40.7 months for ENHERTU plus pertuzumab compared to 20.7 months for THP (HR 0.49; 95% CI 0.39-0.61; nominal p-value <0.00001). Confirmed objective response rate (ORR) with ENHERTU plus pertuzumab was 85.1% versus 78.6% with THP. There were 58 complete responses (CRs) with ENHERTU plus pertuzumab compared to 33 with THP. Median duration of response (DOR) for ENHERTU plus pertuzumab exceeded three years (39.2 months) versus 26.4 months with THP. Overall survival (OS) was not mature at the time of the interim analysis (16% maturity at data cut-off); however, interim OS data showed an early trend favoring the ENHERTU combination compared to THP (HR 0.84; 95% CI 0.59-1.19). Sara Tolaney, MD, MPH, Chief of the Division of Breast Oncology, Dana-Farber Cancer Institute and principal investigator in the trial, said: “Patients with HER2-positive metastatic breast cancer often experience disease progression around two years after initiating standard-of-care first-line treatment. With a median progression-free survival of more than three years, the DESTINY-Breast09 results show trastuzumab deruxtecan combined with pertuzumab has the potential to become a new first-line standard of care for these patients.” Susan Galbraith, Executive Vice President, Oncology Haematology R&D, AstraZeneca, said: “Bringing ENHERTU earlier in the treatment of HER2-positive metastatic breast cancer may represent an important advancement for patients. The DESTINY-Breast09 trial showed the combination of ENHERTUand pertuzumab in the first-line setting substantially increased the amount of time before a patient’s cancer progressed compared to standard of care and nearly doubled the number of patients showing no signs of disease on imaging. Establishing a strong therapeutic response as soon as metastatic disease is diagnosed is critical given that about one in three patients do not receive further treatment after progressing in the first-line setting.” Ken Takeshita, Global Head, R&D, Daiichi Sankyo, said: “ENHERTU continues to transform the treatment of metastatic breast cancer with the first new data in more than a decade to demonstrate improved outcomes for a broad population of patients with HER2-positive disease compared to THP in the first-line setting. DESTINY-Breast09 shows that initiating treatment with ENHERTU in combination with pertuzumab at the time of metastatic diagnosis can delay disease progression.” Summary of DESTINY-Breast09 interim analysis results Median duration of follow-up was nearly 2.5 years (29.2 months). As of the data cut-off, 302 (39.6%) patients remained on treatment, 174 in the ENHERTUplus pertuzumab arm and 128 in the THP arm. The safety profile of ENHERTU in combination with pertuzumab in DESTINY-Breast09 was consistent with the known profiles of each individual therapy with no new safety concerns identified. Interstitial lung disease (ILD)/pneumonitis occurred in 12.1% of patients treated with ENHERTU in combination with pertuzumab, as determined by an independent adjudication committee. The majority of ILD events were low Grade (Grade 1 [n=17; 4.5%] or Grade 2 [n=27; 7.1%]). There were no Grade 3 or Grade 4 ILD events. There were two Grade 5 (0.5%) ILD events in the ENHERTU plus pertuzumab arm. An additional investigational arm of the trial assessing ENHERTUmonotherapy versus THP remains blinded to patients and investigators and will continue to the final PFS analysis. ENHERTU is a specifically engineered HER2-directed DXd antibody drug conjugate (ADC) discovered by Daiichi Sankyo and being jointly developed and commercialized by Daiichi Sankyo and AstraZeneca. ENHERTU is already approved in more than 80 countries as 2nd-line treatment for patients with HER2-positive breast cancer based on the results from the DESTINY-Breast03trial. Indications and Important Safety Information Indications ENHERTU is a HER2-directed antibody and topoisomerase inhibitor conjugate indicated for the treatment of adult patients with: Please see accompanying full Prescribing Information , including Boxed WARNINGS, and Medication Guide . Notes HER2-positive metastatic breast cancer Breast cancer is the second most common cancer and one of the leading causes of cancer-related deaths worldwide. 1 More than two million breast cancer cases were diagnosed in 2022, with more than 665,000 deaths globally. 1 While survival rates are high for those diagnosed with early breast cancer, only about 30% of patients diagnosed with or who progress to metastatic disease are expected to live five years following diagnosis. 2 HER2 is a tyrosine kinase receptor growth-promoting protein expressed on the surface of many types of tumors including breast cancer. 3 HER2 protein overexpression may occur as a result of HER2 gene amplification. 4 HER2-positive metastatic breast cancer is an aggressive disease driven by overexpression or amplification of HER2 that affects 15% to 20% of patients with metastatic breast cancer. 5,6 Approximately 23,000 patientsare treated each year in the 1st-line HER2-positive setting across G7 countries alone. 7 While HER2-targeted therapies have improved outcomes, prognosis remains poor with most patients experiencing disease progression within two years of 1st-line treatment with THP, which has been the standard of care for more than a decade. 4,8-10 Further, approximately one in three patients do not go on to receive treatment following 1st-line therapy due to disease progression or death. 11,12 DESTINY-Breast09 DESTINY-Breast09 is a global, multicenter, randomized, open-label, Phase III trial evaluating the efficacy and safety of ENHERTU(5.4 mg/kg) either alone or in combination with pertuzumab versus standard of care THP (a taxane [docetaxel or paclitaxel], trastuzumab and pertuzumab) as a 1st-line treatment in patients with HER2-positive metastatic breast cancer. Patients were randomized 1:1:1 to receive either ENHERTU monotherapy with a pertuzumab matching placebo; ENHERTU in combination with pertuzumab; or THP. Randomization was stratified by prior treatment ( de novo metastatic disease versus progression from early-stage disease), hormone receptor status and PIK3CA mutation status. The primary endpoint of DESTINY-Breast09 is PFS as assessed by BICR in both the ENHERTU monotherapy and ENHERTU combination arms. Secondary endpoints include OS, ORR, DOR, investigator-assessed PFS and PFS2 and safety. DESTINY-Breast09 enrolled 1,157 patients across multiple sites in Africa, Asia, Europe, North America and South America. For more information about the trial, visit ClinicalTrials.gov . ENHERTU ENHERTU 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 (5.4mg/kg) is approved in more than 80 countries worldwide for the treatment of adult patients with unresectable or metastatic HER2-positive (immunohistochemistry [IHC 3+ or in-situ hybridization [ISH]+) breast cancer who have received a (or one or more) 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 (5.4mg/kg) is approved in more than 80 countries 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 (5.4mg/kg) is approved in more than 30 countries 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-Breast06 trial. ENHERTU (5.4mg/kg) is approved in more than 60 countries worldwide for the treatment of adult patients with unresectable or metastatic non-small cell lung cancer (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 US for this indication is contingent upon verification and description of clinical benefit in a confirmatory trial. ENHERTU (6.4mg/kg) is approved in more than 70 countries worldwide for the treatment of adult patients with locally advanced or metastatic HER2-positive (IHC 3+ or 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/or DESTINY-Gastric06 trials. Continued approval in China for this indication will depend on whether a randomized controlled confirmatory clinical trial can demonstrate clinical benefit in this population. ENHERTU (5.4mg/kg) is approved in the US and other countries 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 the results from the DESTINY-PanTumor02 , DESTINY-Lung01 and DESTINY-CRC02 trials. Continued approval for this indication in the US is contingent upon verification and description of clinical benefit in a confirmatory trial. ENHERTU clinical development program A comprehensive global clinical development program is underway evaluating the efficacy and safety of ENHERTU as monotherapy, in combination or sequentially with other anti-cancer therapies across multiple HER2-targetable cancers. Daiichi Sankyo collaboration AstraZeneca and Daiichi Sankyo entered into a global collaboration to jointly develop and commercialize ENHERTU in March 2019 and datopotamab deruxtecan-dlnk 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 datopotamab deruxtecan-dlnk. AstraZeneca in breast cancer Driven by a growing understanding of breast cancer biology, AstraZeneca is challenging, and redefining, the current clinical paradigm for how breast cancer is classified and treated to deliver even more effective treatments to patients in need – with the bold ambition to one day eliminate breast cancer as a cause of death. AstraZeneca has a comprehensive portfolio of approved and promising compounds in development that leverage different mechanisms of action to address the biologically diverse breast cancer tumor environment. With ENHERTU, AstraZeneca and Daiichi Sankyo are aiming to improve outcomes in previously treated HER2-positive, HER2-low and HER2-ultralow metastatic breast cancer, and are exploring its potential in earlier lines of treatment and in new breast cancer settings. In HR-positive breast cancer, AstraZeneca continues to improve outcomes with foundational medicines fulvestrant and goserelin and aims to reshape the HR-positive space with first-in-class AKT inhibitor, capivasertib, the TROP-2-directed ADC, datopotamab deruxtecan-dlnk and next-generation oral SERD and potential new medicine camizestrant. PARP inhibitor olaparib is a targeted treatment option that has been studied in early and metastatic breast cancer patients with an inherited BRCA mutation. AstraZeneca with Merck & Co., Inc. (MSD outside the US and Canada) continue to research olaparib in these settings and to explore its potential in earlier disease. AstraZeneca is also exploring the potential of saruparib, a potent and selective inhibitor of PARP1, in combination with camizestrant in BRCA -mutated, HR-positive, HER2-negative advanced breast cancer. To bring much-needed treatment options to patients with triple-negative breast cancer, an aggressive form of breast cancer, AstraZeneca is collaborating with Daiichi Sankyo to evaluate the potential of datopotamab deruxtecan-dlnk alone and in combination with immunotherapy durvalumab. AstraZeneca in oncology AstraZeneca is leading a revolution in oncology with the ambition to provide cures for cancer in every form, following the science to understand cancer and all its complexities to discover, develop and deliver life-changing medicines to patients. The Company’s focus is on some of the most challenging cancers. It is through persistent innovation that AstraZeneca has built one of the most diverse portfolios and pipelines in the industry, with the potential to catalyze changes in the practice of medicine and transform the patient experience. AstraZeneca has the vision to redefine cancer care and, one day, eliminate cancer as a cause of death. AstraZeneca AstraZeneca is a global, science-led biopharmaceutical company that focuses on the discovery, development, and commercialisation of prescription medicines in Oncology, Rare Diseases, and BioPharmaceuticals, including Cardiovascular, Renal & Metabolism, and Respiratory & Immunology. Based in Cambridge, UK, AstraZeneca’s innovative medicines are sold in more than 125 countries and used by millions of patients worldwide. Please visit astrazeneca-us.com and follow the Company on social media @AstraZeneca . References SOURCE: AstraZeneca

The Enhertu-Perjeta combination gave patients an extra 13.8 months without progression compared with the traditional THP regimen in first-line HER2-positive breast cancer. More than five years after an initial FDA approval as a third-line treatment for HER2-positive breast cancer, AstraZeneca and Daiichi Sankyo’s antibody-drug conjugate Enhertu looks poised to reach newly diagnosed patients, with efficacy data that live up to the pair’s previous “highly statistically significant” description.A combination of Enhertu and Roche’s Perjeta represents a new first-line standard treatment option for HER2-positive breast cancer, Rebecca Dent, M.D., deputy CEO (clinical) at National Cancer Center Singapore, said in a release provided by the American Society of Clinical Oncology (ASCO).Dent made that comment after the Enhertu-Perjeta combo significantly lowered the risk of progression or death by 44% compared with the traditional THP regimen in that disease setting in the phase 3 Destiny-Breast09 trial, according to data being presented today at this year's ASCO conference. THP is a combination of chemotherapy, Roche's Herceptin and Perjeta.As AZ and Daiichi previously characterized, the improvement was highly statistically significant, with a p-value below 0.00001.The Enhertu-Perjeta pair gave patients an extra 13.8 months without progression. The median progression-free survival time reached 40.7 months for the experimental therapy.Enhertu’s tumor progression benefit showed early, starting at around six months, with the difference between Enhertu-Perjeta and THP continuing to widen afterward. At two years, about 70% of patients in the Enhertu-Perjeta arm had not experienced tumor progression versus 52% in the THP group. However, a chart visualizing disease progression events over time showed the gap between the two arms appeared to be closing toward the end, “suggesting some instability of the curve at that time,” lead study author Sara Tolaney, M.D., from the Dana-Farber Cancer Institute, said during a press briefing ahead of the official data presentation.The current data set came at an interim analysis after a median follow-up of 28 months.“Given that 46% of patients continue to remain on steady treatment with [Enhertu] and [Perjeta], it is likely that the median will evolve with further follow up,” Tolaney said. Enhertu’s improvement in efficacy didn’t appear to come at the cost of safety. Grade 3 or above treatment-emergent adverse events happened in 63.5% and 62.3% of patients in the Enhertu-containing group and control, respectively. The rates of serious events were 27% and 25.1%, respectively.However, as expected, Enhertu’s use increased the rate of interstitial lung disease (ILD), a side effect of interest for ADCs developed with Daiichi’s DXd platform. Adjudicated drug-related ILD or pneumonitis occurred in 46 (12.1%) of patients who got Enhertu and Perjeta versus four patients (1%) who received THP. Most cases in the Enhertu-Perjeta arm were grade 1 or 2, but they included two (0.5%) deaths, whereas all events in the THP arm were grade 1 or 2.The ILD events are “very much in line with” existing knowledge of Enhertu, and doctors have become “quite used to managing” the side effect, Tolaney said.Overall survival data were highly immature with only 16% of cases accrued, but researchers observed a positive trend in favor of the novel combination with a preliminary death risk reduction of 16%, according to Tolaney.AstraZeneca has not disclosed its regulatory progress with Enhertu in first-line breast cancer. The company will make an announcement when the FDA has accepted its application for approval, AZ’s oncology R&D head, Susan Galbraith, Ph.D., said during a press briefing.Since its original FDA nod in late 2019 for HER2-positive breast cancer patients who have tried two or more prior anti-HER2 regimens in the metastatic setting, Enhertu has gradually moved up in the treatment sequence with a second-line nod in 2022. The drug’s median progression-free survival length went up from 16.4 months in Destiny-Breast01 in the third line to 28.8 months in Destiny-Breast03, and now to 40.7 months in the first line.“I think people are really starting to see that if you use this drug as early as you possibly can, you're going to get the biggest benefit,” Ken Keller, head of Daiichi’s global oncology business, said in an interview with Fierce Pharma.Following the positive Destiny-Breast09 readout, AZ and Daiichi a few weeks ago said the Destiny-Breast11 study for a presurgical Enhertu-THP regimen has met its pathological complete response goal in high-risk, HER2-positive early-stage breast cancer. The Destiny-Breast05 trial for Enhertu in the postsurgical setting is expected to read out later this year.Destiny-Breast09 has another arm of Enhertu monotherapy. The comparison between single-agent Enhertu and control did not meet the progression-free survival endpoint at this interim analysis. The arm remained blinded and continued to be followed toward its final analysis, according to Tolaney.Even without a monotherapy win, Keller expects quick adoption of the Enhertu-Perjeta combo in the first-line setting as soon as it’s approved. To him, the unknown is how long doctors will be using Enhertu.A phase 3 study coded Patina recently found that the addition of Pfizer’s CDK4/6 inhibitor Ibrance to standard first-line maintenance therapy—Herceptin with or without Perjeta and endocrine therapy—may significantly improve the progression-free survival outcome of patients with HR-positive, HER2-positive breast cancer.“The biggest question will be, what happens when people start on Enhertu and do they treat to progression, or do they start playing around based on the maintenance with Patina?" Keller said. "And that’s what we’ll have to tease out as things go on.” Gastric cancer win Enhertu has also been branching out to other HER2 tumor types. In another phase 3 data set released at ASCO 2025, Enhertu reduced the risk of death by 30% compared with a combination of Eli Lilly’s Cyramza and the chemotherapy paclitaxel in patients with previously treated HER2-positive gastric cancer or gastroesophageal junction adenocarcinoma.In this second-line setting, Enhertu extended patients’ median survival time by 3.3 months to 14.7 months.Besides a life extension benefit, Enhertu also reduced the risk of disease progression by 26%.As ASCO expert Pamela Kunz, M.D., Ph.D., director of the Center for Gastrointestinal Cancers at Smilow Cancer Hospital and Yale Cancer Center, said during a press briefing ahead of the official presentation, findings from the Destiny-Gastric04 study are “practice-validating” in the U.S. because Enhertu is also included in medical guidelines and used by doctors in second-line HER2-positive stomach cancer.“However, it will play a more pivotal role globally,” she said. “It will be practice-changing in many countries outside of the U.S. and will really position [Enhertu] as a preferred second-line treatment.”The positive note aside, Kunz spotlighted the 13.9% adjudicated drug-related interstitial lung disease/pneumonitis rate for Enhertu, suggesting it’s important to consider when selecting which patients to put on the ADC regimen.Daiichi in February launched a phase 3 trial coded Destiny-Gastric05 to assess Enhertu in first-line HER2-positive gastric cancer. Almost simultaneously, AstraZeneca started the Artemide-Gastric01 trial evaluating its PD-1/TIGIT bispecific antibody rilvegostomig either with Herceptin and chemo or with Enhertu and chemo also in the first-line setting.