New study results reinforce Tagrisso as the backbone therapy for EGFR-mutated lung cancer across stages and settings
- In LAURA Phase III trial, Tagrisso continues to demonstrate improved overall survival trend in unresectable, Stage III setting
- SAVANNAH and ORCHARD Phase II trials show the addition of Orpathys or Datroway to Tagrisso upon disease progression demonstrates strong clinical activity
New study results presented at the European Lung Cancer Congress (ELCC) 2025, 26 to 29 March, demonstrate the role of AstraZeneca’s Tagrisso (osimertinib), as monotherapy and as the backbone for novel combinations, across stages and settings of epidermal growth factor receptor-mutated (EGFRm) non-small cell lung cancer (NSCLC). Highlights include:
- LAURA Phase III trial of Tagrisso in unresectable, Stage III EGFRm NSCLC after chemoradiotherapy (CRT) (LBA4).
- SAVANNAH Phase II trial of Tagrisso plus Orpathys (savolitinib) in advanced EGFRm NSCLC with high levels of MET overexpression and/or amplification following disease progression on 1st-line Tagrisso (#2O).
- ORCHARD Phase II platform trial of Tagrisso plus Datroway (datopotamab deruxtecan) in advanced EGFRm NSCLC following disease progression on 1st-line Tagrisso (#1O).
- FLAURA2 Phase III trial of Tagrisso plus chemotherapy as 1st-line treatment for advanced EGFRm NSCLC (#53P).
Myung-Ju Ahn, MD, PhD, Professor of Hemato-Oncology at the Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea, said: “A critical goal in treating every patient with lung cancer is to not only extend a patient's life but also maintain quality of life while on treatment. The continued overall survival trend seen here at ELCC in the unresectable Stage III setting and the promising data for combinations that can address progression in the advanced setting, together reinforce osimertinib as an effective, safe and convenient treatment for patients with EGFR-mutated lung cancer across stages and lines of treatment.”
Susan Galbraith, Executive Vice President, Oncology Haematology R&D, AstraZeneca, said: “Having now treated more than one million patients around the world, Tagrisso has repeatedly transformed expectations for patients with EGFR-mutated lung cancer by not only extending survival but also showing it is possible to maintain quality of life during cancer treatment. The breadth of data at ELCC reinforce Tagrisso as the backbone therapy for patients with this disease and show that adding Orpathys or Datroway at the time of disease progression can help prolong patients’ responses to treatment.”
Professor Virginia Harrison, EGFR Positive UK, said: “For people undergoing treatment for lung cancer, maintaining quality of life is so important, but it can be challenging. The development of simple and effective treatment regimens that minimise negative side effects can make a huge difference. We are excited to see this progress for patients with EGFR-mutated lung cancer, where there is still significant unmet need.”
Tagrisso continued to demonstrate encouraging overall survival (OS) trend in unresectable, Stage III setting in LAURA trial
Updated results from the LAURA Phase III trial showed an improved trend towards OS benefit with Tagrisso compared to placebo in patients with unresectable, Stage III EGFRm NSCLC (hazard ratio [HR] 0.67; 95% confidence interval [CI] 0.40, 1.14, maturity 31%). Median OS was 58.8 months (95% CI 54.1, not calculable [NC]) in patients treated with Tagrisso versus 54.1 months with placebo (95% CI 42.1, NC), despite 78% of patients on placebo receiving subsequent treatment with Tagrisso upon progression. The trial will continue to assess OS as a key secondary endpoint at the final analysis.
Tagrisso previously demonstrated a statistically significant and highly clinically meaningful improvement in progression-free survival (PFS). These results were published in The New England Journal of Medicine and formed the basis for regulatory approvals around the world including in the US, EU and China.
Safety results and discontinuation rates due to adverse events (AEs) were as expected and no new safety concerns were identified.
Tagrisso plus Orpathys showed durable response rates in lung cancer patients with high levels of MET overexpression and/or amplification whose disease progressed on 1st-line Tagrisso in SAVANNAH trial
Results from the SAVANNAH Phase II trial showed Tagrisso plus Orpathys (300mg twice-daily [BID]) demonstrated a clinically meaningful and durable objective response rate (ORR) in patients with EGFRm NSCLC with high levels of MET overexpression and/or amplification whose disease progressed on treatment with 1st-line Tagrisso. Among patients screened for enrollment in SAVANNAH, an estimated 62% had tumors with MET overexpression and/or amplification, and approximately 34% met the defined high MET level cut-off.
Tagrisso plus Orpathys demonstrated a confirmed ORR of 56% (95% CI 45-67%), with a median duration of response (DoR) of 7.1 months (95% CI 5.6-9.6). Median PFS (mPFS) was 7.4 months (95% CI 5.5-7.6).
Safety results and discontinuation rates due to AEs were consistent with the established profiles of each medicine and no new safety concerns were reported. In all patients treated with Tagrisso plus Orpathys (300mg BID), Grade 3 or higher AEs occurred in 57% of patients.
Orpathys is an oral, potent and highly selective MET tyrosine kinase inhibitor (TKI) being jointly developed and commercialised by AstraZeneca and HUTCHMED. In 2023, Tagrisso plus Orpathys received Fast Track designation from the Food and Drug Administration (FDA) in this setting.
Tagrisso plus Datroway showed encouraging response rates in patients whose disease progressed on 1st-line Tagrisso in ORCHARD trial
First results from the Tagrisso plus Datroway module of the ORCHARD Phase II platform trial showed the combination demonstrated promising efficacy and manageable safety in patients with advanced EGFRm NSCLC whose disease progressed on treatment with Tagrisso.
The module enrolled an all-comer population of patients with EGFRm NSCLC and evaluated two doses of Datroway (4 or 6mg/kg) which, in combination with Tagrisso, showed similar ORRs of 43% (80% CI 31-55%) and 36% (80% CI 25-49%), respectively. PFS and DoR results favoured the 6mg/kg dose with a mPFS of 11.7 months (95% CI 8.3, NC) and 64% of patients continuing to respond at 9 months versus a mPFS of 9.5 months (95% CI 7.2-9.8) and 15% of patients continuing to respond at 9 months on the 4mg/kg dose.
The safety profile of Tagrisso plus Datroway was consistent with the known safety profiles of each medicine and no new safety concerns were identified at either dose level. Grade 3 or higher treatment-related AEs occurred in 34% and 56% of patients receiving the 4mg/kg or 6mg/kg doses, respectively.
Datroway is a specifically engineered TROP2-directed antibody drug conjugate (ADC) discovered by Daiichi Sankyo and being jointly developed and commercialised by AstraZeneca and Daiichi Sankyo. The Companies are evaluating Datroway alone and with Tagrisso as treatment for patients with advanced or metastatic EGFRm NSCLC in the TROPION-Lung14 and TROPION-Lung15 Phase III trials.
New results for Tagrisso plus chemotherapy in the 1st-line setting reinforce strong PFS benefit in FLAURA2 Phase III trial
An exploratory post-hoc analysis of the FLAURA2 Phase III trial assessed PFS by length of exposure to pemetrexed maintenance treatment in patients with locally advanced (Stage IIIB-IIIC) or metastatic (Stage IV) EGFRm NSCLC. Patients were treated with Tagrisso with the addition of chemotherapy (pemetrexed plus cisplatin) followed by maintenance treatment with Tagrisso and chemotherapy (pemetrexed) or Tagrisso alone. Results showed an mPFS of more than two years regardless of length of pemetrexed maintenance exposure, with a trend associating longer PFS with longer pemetrexed treatment.
The safety profile of Tagrisso plus chemotherapy was consistent with the established profiles of the individual medicines. Grade 3 or higher chemotherapy-related AEs were reported in 16% of patients who received maintenance treatment for 3 to less than 9 months, and 10% for patients who received maintenance for 9 or more months. Chemotherapy discontinuation rates due to AEs were 18% and 10%, respectively.
Tagrisso plus chemotherapy previously demonstrated a statistically significant and clinically meaningful improvement in PFS. These results were published in The New England Journal of Medicine and formed the basis for regulatory approvals around the world including in the US, EU, Japan and China. Previously presented OS data from the second interim analysis showed a favourable trend with the Tagrisso plus chemotherapy arm (HR 0.75; 95% CI 0.57-0.97, maturity 41%), with consistent results across all prespecified subgroups. The trial will continue to assess OS as a key secondary endpoint.
Notes
NSCLC
Lung cancer is the leading cause of cancer death among men and women, accounting for about one-fifth of all cancer deaths.1 Lung cancer is broadly split into small cell lung cancer or NSCLC, the latter accounting for about 80% of cases.2 Approximately 10 to 15% of patients with NSCLC in the US and Europe and 30 to 40% of patients in Asia have an EGFR mutation.3-5
While EGFR-TKIs have significantly improved outcomes in the 1st-line setting, mechanisms of resistance and disease progression are extremely common, and a significant unmet need exists in later-line settings for effective and well-tolerated treatment options.6-9
LAURA
LAURA is a randomised, double-blind, placebo-controlled, multi-centre, global Phase III trial in patients with unresectable, Stage III EGFRm NSCLC whose disease has not progressed following definitive platinum-based CRT. Patients were treated with Tagrisso 80mg once-daily (QD) oral tablets until disease progression, unacceptable toxicity or other discontinuation criteria were met. Upon progression, patients in the placebo arm were offered treatment with Tagrisso.
The trial enrolled 216 patients in more than 145 centres across more than 15 countries, including in the US, Europe, South America and Asia.
SAVANNAH
SAVANNAH is an ongoing randomised, global Phase II trial studying the efficacy of Orpathys added to Tagrisso in patients with EGFRm, locally advanced or metastatic NSCLC with MET overexpression and/or amplification whose disease progressed following treatment with Tagrisso. Based on the original single-arm trial design, patients were treated with Orpathys 300 or 600mg QD or 300mg BID, in combination with oral Tagrisso 80mg QD. In 2022, a comparison of Orpathys 300mg BID and Tagrisso 80mg QD to Orpathys 300mg BID and placebo was added to the trial to evaluate contribution of components.
The trial has enrolled 369 patients to date in more than 80 centres globally, including in the US, Canada, Europe, South America and Asia. The primary endpoint is ORR and key secondary endpoints include PFS and DoR.
In August 2022, positive interim ORR results from the SAVANNAH trial were presented at the International Association for the Study of Lung Cancer 2022 World Conference on Lung Cancer (WCLC).
The global SAFFRON Phase III trial will further assess the Tagrisso plus Orpathys combination versus platinum-based doublet chemotherapy in patients with EGFRm, MET-overexpressed and/or amplified, locally advanced or metastatic NSCLC following treatment with Tagrisso. Patients are being prospectively selected using the high MET level cut-off identified in SAVANNAH.
ORCHARD
ORCHARD (Osimertinib Resistance CoHorts, Addressing 1L Relapse Drivers) is an open-label, multi-centre Phase II platform trial evaluating numerous Tagrisso-based combinations as a treatment for patients with advanced EGFRm NSCLC whose disease has progressed on 1st-line Tagrisso. The trial has 10 modules examining the efficacy, safety and tolerability of these targeted and non-targeted combination options, including Tagrisso 80mg QD plus Datroway given intravenously at 4 or 6mg/kg on day one of every three-week cycle.
The trial has enrolled 247 patients to date in more than 40 centres globally, including in the US, Europe and Asia. The primary endpoint is ORR. Key secondary endpoints include PFS and DoR.
FLAURA2
FLAURA2 is a randomised, open-label, multi-centre, global Phase III trial in the 1st-line treatment of patients with locally advanced (Stage IIIB-IIIC) or metastatic (Stage IV) EGFRm NSCLC. Patients were treated with Tagrisso 80mg QD oral tablets with the addition of chemotherapy (pemetrexed (500mg/m2) plus cisplatin (75mg/m2) or carboplatin (AUC5) every three weeks for four cycles, followed by Tagrisso with pemetrexed maintenance every three weeks.
The trial enrolled 557 patients in more than 150 centres across more than 20 countries, including in the US, Europe, South America and Asia. The primary endpoint is PFS. The trial is ongoing and will continue to assess the secondary endpoint of OS.
Tagrisso
Tagrisso (osimertinib) is a third-generation, irreversible EGFR-TKI with proven clinical activity in NSCLC, including against central nervous system metastases. Tagrisso (40mg and 80mg QD oral tablets) has been used to treat patients across its indications worldwide and AstraZeneca continues to explore Tagrisso as a treatment for patients across multiple stages of EGFRm NSCLC.
There is an extensive body of evidence supporting the use of Tagrisso in EGFRm NSCLC. Tagrisso is the only targeted therapy to improve patient outcomes in early-stage disease in the NeoADAURA and ADAURA Phase III trials, locally advanced stages in the LAURA Phase III trial and late-stage disease in the FLAURA and FLAURA2 Phase III trials.
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.
Orpathys
Orpathys (savolitinib) is an oral, potent, and highly selective MET TKI that has demonstrated clinical activity in advanced solid tumours. MET is a tyrosine kinase receptor that has an essential role in normal cell development. Orpathys blocks atypical activation of the MET receptor tyrosine kinase pathway that occurs because of mutations (such as exon 14 skipping alterations or other point mutations), gene amplification or protein overexpression. MET overexpression and/or amplification can lead to tumour growth and the metastatic progression of cancer cells, and is a known mechanism of acquired resistance to EGFR TKIs. The prevalence of MET depends on the sample type, detection method and assay cut-off used.
Orpathys is approved in China for the treatment of adult patients with locally advanced or metastatic NSCLC with MET exon 14 skipping alterations.
It is currently under clinical development for multiple tumour types, including lung, kidney and gastric cancers as a single treatment and in combination with other medicines.
Datroway
Datroway (datopotamab deruxtecan-dlnk in the US; datopotamab deruxtecan in rest of world) is a TROP2-directed ADC. Designed using Daiichi Sankyo’s proprietary DXd ADC Technology, Datroway is one of six DXd ADCs in the oncology pipeline of Daiichi Sankyo, and one of the most advanced programmes in AstraZeneca’s ADC scientific platform. Datroway is comprised of a humanised anti-TROP2 IgG1 monoclonal antibody, developed in collaboration with Sapporo Medical University, attached to a number of topoisomerase I inhibitor payloads (an exatecan derivative, DXd) via tetrapeptide-based cleavable linkers.
Datroway (6mg/kg) is approved in the US, Japan and Russia for the treatment of adult patients with unresectable or metastatic HR-positive, HER2-negative (IHC 0, IHC 1+ or IHC 2+/ISH-) breast cancer who have received prior endocrine-based therapy and chemotherapy for unresectable or metastatic disease based on the results from the TROPION-Breast01 Phase III trial.
In the US, a Biologics License Application for Datroway is under Priority Review for the treatment of adult patients with locally advanced or metastatic EGFRm NSCLC who have received prior systemic therapies, including an EGFR-directed therapy. Datroway was also granted Breakthrough Therapy Designation by the FDA for this patient population.
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); 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/Nasdaq: AZN) 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.com and follow the Company on social media @AstraZeneca.
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References
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