Fam-trastuzumab deruxtecan-NXKI

AstraZeneca and Daiichi Sankyo's Enhertu (trastuzumab deruxtecan) has delivered a clear progression-free survival (PFS) advantage against Merck & Co.'s checkpoint inhibitor Keytruda (pembrolizumab) plus chemotherapy in first-line HER2-mutant non–small-cell lung cancer (NSCLC), but the initial overall survival (OS) readout seems to point in the opposite direction.Enhertu was granted accelerated approval in 2022 for second-line use based on Phase II data from the DESTINY-Lung02 trial, where it demonstrated a confirmed objective response rate (ORR) of 57.7%.Last month, AstraZeneca revealed the HER2-directed antibody-drug conjugate (ADC) had now succeeded in the first-line setting as well, beating standard of care — Keytruda plus platinum-pemetrexed doublet chemotherapy — on the primary endpoint of PFS in the Phase III DESTINY-Lung04 trial. The randomised study enrolled 454 patients with unresectable, locally advanced or metastatic, non-squamous NSCLC harbouring a HER2 exon 19 or 20 mutation.According to detailed findings shared Monday at the World Conference on Lung Cancer (WCLC), median PFS was 14.3 months with Enhertu monotherapy versus 8.3 months with Keytruda plus chemotherapy, translating into a 37% reduction in the risk of disease progression or death (p<0.0001).Imbalances in subsequent treatmentHowever, the initial interim OS picture was less favourable. Median OS was 29.3 months with Enhertu versus 33.1 months for the Keytruda arm, corresponding to a numerical increase in the risk of death with the ADC (HR 1.15). The OS data were only about 47% mature at the June 9 data cut-off, and no formal hypothesis testing was done."While there was no observed benefit in OS, varied and imbalanced subsequent therapy patterns between arms may limit the interpretation of this result," AstraZeneca said.According to the company, 48% of patients initially assigned to Keytruda plus chemotherapy subsequently received a HER2-directed therapy, compared to 23.3% of those assigned to Enhertu. Also, only 23.8% of patients in the Enhertu arm received subsequent immunotherapy plus chemotherapy.A second interim analysis and final analysis for OS are planned.Lung toxicityEnhertu's safety profile could be another consideration as AstraZeneca and Daiichi look to move the drug toward the first-line setting in lung cancer. Interstitial lung disease (ILD) or pneumonitis occurred in 20.8% of Enhertu-treated patients, including five grade 3 (2.2%), one grade 4 (0.4%) and four fatal grade 5 (1.8%) events. By contrast, the rate was 2.3% with Keytruda plus chemotherapy.Enhertu's label already includes a boxed warning about ILD and pneumonitis, including severe, life threatening and fatal cases that have been reported with the drug.Those lung-specific safety concerns are particularly relevant for patients with lung cancer, according to one expert who spoke to FirstWord after last month's topline readout. "The bar [for safety] is definitely higher in lung cancer. But if the benefit is significant, that would obviously change things a bit," said Vamsi Velcheti, chair of haematology and oncology at Mayo Clinic Comprehensive Cancer Center (see – KOL Views Q&A: AZ, Daiichi's Enhertu faces high bar to rival TKIs like BI's Hernexeos in HER2+ NSCLC).Grade 3 or higher treatment-related adverse events in DESTINY-Lung04 were similar between groups at 34.1% and 33.6%, respectively, though treatment exposure was longer — a median of 5.2 months — with Enhertu.Meanwhile, there were other signs of activity for Enhertu, including an ORR of 70% versus 44.5% for Keytruda plus chemotherapy, and median durations of response of 13.4 months versus 9.7 months, respectively. PFS2 also appeared to favour Enhertu, with a median 22.7 months versus 17.3 months for the comparator arm (HR 0.80), although the difference wasn't statistically conclusive.

Updated exploratory results from the ADAURA Phase III trial showed AstraZeneca’s Tagrisso (osimertinib) demonstrated a sustained, clinically meaningful overall survival (OS) benefit at eight years compared to placebo in the adjuvant treatment of patients with early-stage (IB, II and IIIA) epidermal growth factor receptor-mutated (EGFRm) non-small cell lung cancer (NSCLC) after complete tumour resection with curative intent. These results were presented today during the Presidential Symposium at the IASLC 2026 World Conference on Lung Cancer (#WCLC26) hosted by the International Association for the Study of Lung Cancer in Seoul, Republic of Korea (Abstract PL03.01). These data were also simultaneously published in the Journal of Thoracic Oncology. At eight years of follow-up, results showed that Tagrisso continued to show an OS benefit, reducing the risk of death compared to placebo by 47% in the primary population (Stages II-IIIA) (based on a hazard ratio [HR] of 0.53; 95% confidence interval [CI] 0.38-0.75). In the overall trial population (Stages IB-IIIA), Tagrisso reduced the risk of death compared to placebo by 48% (HR 0.52; 95% CI 0.39-0.71). An estimated 74% of patients treated with Tagrisso were alive at eight years versus 58% of those treated with placebo in the primary population. In the overall trial population, an estimated 79% of patients treated with Tagrisso were alive at eight years versus 64% of those treated with placebo. Consistent with the planned final analysis, OS benefit with Tagrisso versus placebo was observed across all predefined subgroups. Roy S. Herbst, MD, PhD, Director at Dartmouth Cancer Center, and principal investigator in the ADAURA Phase III trial, said: “These ADAURA findings show patients continue to experience meaningful, long-term benefit following early intervention with adjuvant osimertinib, with a 16 per cent point improvement in overall survival at eight years versus placebo. This is especially impressive given high rates of crossover to osimertinib following disease recurrence. This durable overall survival benefit reinforces the importance of prioritising EGFR testing at diagnosis so as many patients as possible can benefit from this transformative therapy.” Susan Galbraith, Executive Vice President, Oncology Haematology R&D, AstraZeneca, said: “ADAURA continues to set new benchmarks in early-stage EGFR-mutated lung cancer, with nearly 80 per cent of patients treated with adjuvant Tagrisso alive at eight years. These results underscore the importance of treating early and reinforce Tagrisso as the adjuvant standard of care and backbone therapy across stages of the disease.” Final safety data for ADAURA were collected at the planned final OS analysis, at which time the safety and tolerability of Tagrisso were consistent with its established profile with no new safety concerns. Complementing the ADAURA clinical trial findings, real-world evidence presented at WCLC26 from a retrospective cohort study of US patients with early-stage (I-IIIA) EGFRm NSCLC (Abstract P1.142) showed that early discontinuation of Tagrisso before completion of the three-year treatment course more than doubled the risk of disease recurrence or death. These results reinforce the importance of maintaining the full treatment duration established in ADAURA and underscore the need for clinician-patient communication to support treatment persistence. In the advanced disease setting, additional data presented at WCLC26 from the FLAURA2 Phase III trial reinforced the benefits of backbone therapy Tagrisso in combination with platinum-pemetrexed chemotherapy in patients with 1st-line advanced EGFRm NSCLC. Results from a novel safety analysis (Abstract PT2.03.03) showed that with long-term follow-up (median 42.6 months), the safety and tolerability of Tagrisso plus platinum–pemetrexed remained consistent with the established safety profiles of these medicines, with clear reductions in new adverse event onset following the initial induction period. Additionally, an exploratory analysis (Abstract P2.237) showed that progression-free survival and OS HRs numerically favoured Tagrisso plus platinum–pemetrexed versus Tagrisso monotherapy regardless of baseline TP53 co-mutation status. Notes NSCLC Lung cancer is the leading cause of cancer death globally, accounting for almost one in five (19%) cancer deaths.1-2 Lung cancer is broadly split into NSCLC and small cell lung cancer, with 80-85% of patients diagnosed with NSCLC.3 Approximately 75% of NSCLC patients are diagnosed with advanced disease while approximately 25-30% present with resectable disease at diagnosis.4-5 Early-stage lung cancer diagnoses are often only made when the cancer is found on imaging for an unrelated condition.6 For patients with resectable tumours, the majority eventually develop recurrence despite complete tumour resection and adjuvant chemotherapy.7 Further, 73% of patients with Stage IB and 56-65% of patients with Stage II disease will survive for five years. This decreases to 41% for patients with Stage IIIA.8 Approximately 10-15% of NSCLC patients in the US and Europe, and 30-40% of patients in Asia have EGFRm NSCLC.9-11 These patients are particularly sensitive to treatment with an EGFR-tyrosine kinase inhibitor (EGFR-TKI) which block the cell-signalling pathways that drive the growth of tumour cells.12 ADAURA ADAURA was a randomised, double-blind, placebo-controlled, global Phase III trial in the adjuvant treatment of 682 patients with Stage IB, II, IIIA EGFRm NSCLC following complete tumour resection and, at physicians’ and patients’ discretion, adjuvant chemotherapy. Patients were treated with Tagrisso 80mg once-daily oral tablets or placebo for three years or until disease recurrence. The trial was enrolled in more than 200 centres across more than 20 countries, including the US, Europe, South America, Asia and the Middle East. The primary endpoint was disease-free survival (DFS) in Stage II and IIIA patients and key secondary endpoints included DFS in Stage IB, II and IIIA patients, and OS in both the primary and overall populations. The exploratory analysis presented at WCLC26 was conducted in all randomised patients including complete or partial extended long-term survival data from approximately 77% of those patients who were still alive at the final planned OS analysis DCO. This included trial participants with additional survival data up until the 4 May 2026 DCO or from accessible medical records/information from last contact date. 127 patients did not have additional survival data and remained censored, with survival time unchanged from the planned final OS analysis until 4 May 2026. Tagrisso Tagrisso (osimertinib) is a third-generation, irreversible EGFR-TKI with proven clinical activity in NSCLC, including the treatment of central nervous system metastases. Tagrisso (40mg and 80mg QD oral tablets) has been used to treat more than one million patients across its indications worldwide and AstraZeneca continues to explore Tagrisso as a treatment for patients across multiple stages of EGFRm NSCLC. Tagrisso is approved as monotherapy in more than 120 countries including the US, EU, China and Japan. Approved indications include for 1st-line treatment of patients with locally advanced or metastatic EGFRm NSCLC, locally advanced or metastatic EGFR T790M mutation-positive NSCLC, adjuvant treatment of early-stage EGFRm NSCLC and locally advanced, unresectable NSCLC following platinum-based chemoradiation therapy. Tagrisso is also approved in combination with chemotherapy in more than 80 countries, including the US, EU, China and Japan, for 1st-line treatment of patients with locally advanced or metastatic EGFRm NSCLC. There is an extensive body of evidence supporting the use of Tagrisso in EGFRm NSCLC, and it is the only targeted therapy shown to improve patient outcomes across all stages of the disease. In late-stage disease, Tagrisso demonstrated improved outcomes as monotherapy in the FLAURA Phase III trial and in combination with chemotherapy in the FLAURA2 Phase III trial. Tagrisso is also being investigated in this setting in combination with Orpathys (savolitinib) in the SAFFRON Phase III trial and in combination with Datroway (datopotamab deruxtecan) in the TROPION-Lung14 and TROPION-Lung15 Phase III trials. In addition to ADAURA, Tagrisso also showed improved outcomes in early-stage disease in the NeoADAURA Phase III trial and in locally advanced stages in the LAURA Phase III trial. As part of AstraZeneca’s ongoing commitment to treating patients as early as possible in lung cancer, Tagrisso is also being investigated in the early-stage adjuvant resectable setting in the ADAURA2 Phase III trial. AstraZeneca in lung cancer AstraZeneca is working to bring patients with lung cancer closer to cure through the detection and treatment of early-stage disease, while also pushing the boundaries of science to improve outcomes in the resistant and advanced settings. By defining new therapeutic targets and investigating innovative approaches, the Company aims to match medicines to the patients who can benefit most. The Company’s comprehensive portfolio includes leading lung cancer medicines and the next wave of innovations, including Tagrisso and Iressa (gefitinib); Zegfrovy (sunvozertinib); Imfinzi (durvalumab) and Imjudo (tremelimumab); Enhertu (trastuzumab deruxtecan) and Datroway in collaboration with Daiichi Sankyo; Orpathys in collaboration with HUTCHMED; as well as a pipeline of potential new medicines and combinations across diverse mechanisms of action. AstraZeneca is a founding member of the Lung Ambition Alliance, a global coalition working to accelerate innovation and deliver meaningful improvements for people with lung cancer, including and beyond treatment. 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 catalyse 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 (LSE/STO/NYSE: AZN) is a global, science-led biopharmaceutical company that focuses on the discovery, development, and commercialisation of prescription medicines in Oncology, Rare Disease, 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.com and follow the Company on social media @AstraZeneca. Contacts For details on how to contact the Investor Relations Team, please click here. For Media contacts, click here. References Oncology Corporate and financial