Datopotamab deruxtecan showed median overall survival of 14.6 months in patients with advanced nonsquamous non-small cell lung cancer in TROPION-Lung01 Phase III trial

TROPION-Lung01, evaluating AstraZeneca and Daiichi Sankyo’s datopotamab deruxtecan versus chemotherapy, previously met the dual primary endpoint of progression-free survival in the overall trial population. Presidential Symposium for NeoCOAST-2 demonstrates potential for datopotamab deruxtecan plus Imfinzi and chemotherapy in neoadjuvant early-stage non-small cell lung cancer.

Detailed results from the TROPION-Lung01 Phase III trial showed a clinically meaningful trend toward improving overall survival (OS) with datopotamab deruxtecan (Dato-DXd) compared to docetaxel, the current standard of care chemotherapy, in adult patients with locally advanced or metastatic nonsquamous non-small cell lung cancer (NSCLC) treated with at least one prior line of therapy.

These results will be presented today during an oral presentation (OA08.03) at the IASLC 2024 World Conference on Lung Cancer (WCLC) hosted by the International Association for the Study of Lung Cancer.

Datopotamab deruxtecan is a specifically engineered TROP2-directed DXd antibody drug conjugate discovered by Daiichi Sankyo and being jointly developed by AstraZeneca and Daiichi Sankyo.

In the overall trial population, OS results numerically favoured datopotamab deruxtecan compared to docetaxel (12.9 versus 11.8 months) but did not reach statistical significance (hazard ratio [HR] 0.94; 95% confidence interval [CI] 0.78-1.14; p=0.530). In the prespecified subgroup of patients with nonsquamous NSCLC, datopotamab deruxtecan showed a 2.3-month improvement in OS compared to docetaxel (14.6 versus 12.3 months; HR 0.84; 95% CI 0.68-1.05). In patients with nonsquamous NSCLC, OS improvement was observed regardless of the presence of actionable genomic alterations. In patients with squamous NSCLC, consistent with the previous analysis, datopotamab deruxtecan did not show an OS improvement.

Jacob Sands, MD, Dana-Farber Cancer Institute, Medical Oncology and investigator in the trial, said: “Despite many efforts to surpass docetaxel with novel approaches in previously treated advanced or metastatic non-small cell lung cancer, patients only survive for about one year. For datopotamab deruxtecan to show a statistically significant improvement in progression-free survival along with improved response rate, duration of response and an overall survival improvement numerically consistent with progression-free survival is clinically meaningful for patients with nonsquamous lung cancer.”

Susan Galbraith, Executive Vice President, Oncology R&D, AstraZeneca, said: “TROPION-Lung01 showed a clinically meaningful trend towards improving the survival of patients with advanced or metastatic nonsquamous non-small cell lung cancer, building on the previously reported progression-free survival data. Together with the data we have presented for the potential TROP2-QCS biomarker and from NeoCOAST-2 in early-stage disease, these results underscore our confidence in the important role datopotamab deruxtecan can play across segments and settings of non-small cell lung cancer.”

Ken Takeshita, MD, Global Head, R&D, Daiichi Sankyo, said: “For patients with nonsquamous non-small cell lung cancer, disease progression is common, making this patient population difficult to treat. The data from TROPION-Lung01 demonstrate the potential of datopotamab deruxtecan in this setting and support our comprehensive development programme where we are also evaluating this TROP2-directed antibody drug conjugate as part of combination strategies in earlier treatment settings of non-small cell lung cancer.” 

The safety profile of datopotamab deruxtecan in TROPION-Lung01 was consistent with the previous analysis including lower rates of dose reduction (20%, 30%) and discontinuation (8%, 12%) due to adverse events compared to docetaxel. The median treatment duration for datopotamab deruxtecan was 4.2 months versus 2.8 months for docetaxel. Grade 3 or higher treatment-related adverse events (TRAEs) occurred in 26% and 42% of patients in the datopotamab deruxtecan and docetaxel arms, respectively. The most common Grade 3 or higher TRAEs were neutropenia (1%, 23%), leukopenia (0%, 13%), stomatitis (7%, 1%), anemia (4%, 4%), interstitial lung disease (ILD) (4%, 1 %) and asthenia (3%, 2%). No new ILD events of any grade were adjudicated as drug-related since the previous analysis.  

In TROPION-Lung01, patient enrollment by tumour histology was balanced across treatment arms and consistent with real-world incidence with approximately 75% of enrolled patients having nonsquamous NSCLC.^1,2 In both arms, 17% of patients had tumours expressing actionable genomic alterations, such as epidermal growth factor receptor (EGFR) mutations.

This final analysis of OS builds on the positive progression-free survival (PFS) results presented at the 2023 European Society for Medical Oncology Congress, which showed datopotamab deruxtecan demonstrated a statistically significant improvement in PFS in the overall trial population and a clinically meaningful PFS benefit in patients with nonsquamous NSCLC. The OS data have been shared with health authorities currently reviewing applications for this indication.

Summary of TROPION-Lung01 survival results
 

CI, confidence interval; HR, hazard ratio; OS, overall survival

ⁱMedian follow-up was 23.1 months for both the datopotamab deruxtecan and docetaxel arms

Datopotamab deruxtecan plus Imfinzi and chemotherapy showed promising response rates in patients with early-stage resectable NSCLC

Results from the NeoCOAST-2 Phase II platform trial evaluating Imfinzi (durvalumab) in multiple novel combinations, before and after surgery, in patients with early-stage (Stage IIA-IIIB) resectable NSCLC were featured in a WCLC Presidential Symposium (PL02.07). Preliminary results from the trial arm testing neoadjuvant Imfinzi plus datopotamab deruxtecan and carboplatin demonstrated a pathological complete response (pCR) rate of 34.1% (95% CI 20.5-49.9) and a major pathological response (mPR) rate of 65.9% (95% CI 50.1-79.5). This was numerically higher than the response rates shown by other combination regimens tested, however, the trial was not powered to make direct statistical comparisons between arms.

The safety profile of Imfinzi plus datopotamab deruxtecan and carboplatin was consistent with the known safety profiles of these agents. Surgical rates across arms were comparable and in line with those shown in recent Phase III trials. AstraZeneca and Daiichi Sankyo are evaluating datopotamab deruxtecan in combination with Imfinzi in multiple ongoing trials.  

Also featured in a WCLC Presidential Symposium were results from an exploratory analysis of TROPION-Lung01 which showed TROP2 as measured by AstraZeneca’s proprietary computational pathology platform, quantitative continuous scoring (QCS), was predictive of clinical outcomes in patients with advanced or metastatic NSCLC treated with datopotamab deruxtecan.

Notes

Advanced non-small cell lung cancer
Nearly 2.5 million lung cancer cases were diagnosed globally in 2022.¹ NSCLC is the most common type of lung cancer, accounting for about 80% of cases.² Approximately 75% and 25% of NSCLC tumours are of nonsquamous or squamous histology, respectively.³ While immunotherapy and targeted therapies have improved outcomes in the 1st-line metastatic setting, most patients eventually experience disease progression and receive chemotherapy.^4-6 For decades, chemotherapy has been the last treatment available for patients with advanced NSCLC, despite limited effectiveness and known side effects.^4-6

TROP2 is a protein broadly expressed in the majority of NSCLC tumours.⁷ There is currently no TROP2-directed ADC approved for the treatment of lung cancer.^8,9

TROPION-Lung01
TROPION-Lung01 is a global, randomised, multicentre, open-label Phase III trial evaluating the efficacy and safety of datopotamab deruxtecan (6.0mg/kg) versus docetaxel (75mg/m2) in adult patients with locally advanced or metastatic NSCLC with and without actionable genomic alterations who require systemic therapy following prior treatment. Patients with actionable genomic alterations were previously treated with platinum-based chemotherapy and an approved targeted therapy. Patients without known actionable genomic alterations were previously treated, concurrently or sequentially, with platinum-based chemotherapy and a PD-1 or PD-L1 inhibitor.

The dual primary endpoints of TROPION-Lung01 are PFS as assessed by blinded independent central review (BICR) and OS. Key secondary endpoints include investigator-assessed PFS, objective response rate (ORR), duration of response, time to response, disease control rate as assessed by both BICR and investigator, and safety.

TROPION-Lung01 enrolled approximately 600 patients in Asia, Europe, North America, Oceania and South America. For more information visit ClinicalTrials.gov.

NeoCOAST-2
NeoCOAST-2 is a global, randomised, multicentre, open-label, multi-arm Phase II platform trial evaluating the efficacy and safety of Imfinzi in multiple novel combinations, before and after surgery, in patients with resectable, early-stage (Stage II-IIIB) NSCLC.

The dual primary endpoints of NeoCOAST-2 are antitumour activity of neoadjuvant treatment assessed by pCR and the safety and tolerability of neoadjuvant and adjuvant treatment. Key secondary endpoints include event-free survival, disease-free survival and ORR as assessed by both RECIST version 1.1 and investigator, OS, tumour resection and mPR as defined by central blinded independent pathologist review.

NeoCOAST-2 will enrol approximately 490 patients in Asia, Europe and North America. For more information visit ClinicalTrials.gov.

Datopotamab deruxtecan (Dato-DXd)
Datopotamab deruxtecan (Dato-DXd) is an investigational TROP2-directed ADC. Designed using Daiichi Sankyo’s proprietary DXd ADC Technology, datopotamab deruxtecan 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. Datopotamab deruxtecan 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.

A comprehensive global clinical development programme is underway with more than 20 trials evaluating the efficacy and safety of datopotamab deruxtecan across multiple cancers, including NSCLC, triple-negative breast cancer and HR-positive, HER2-negative breast cancer. The programme includes seven Phase III trials in lung cancer and five Phase III trials in breast cancer evaluating datopotamab deruxtecan as a monotherapy and in combination with other anticancer treatments in various settings.

Daiichi Sankyo collaboration
AstraZeneca and Daiichi Sankyo entered into a global collaboration to jointly develop and commercialise Enhertu in March 2019 and datopotamab deruxtecan 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.

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 (osimertinib) and Iressa (gefitinib); Imfinzi (durvalumab) and Imjudo (tremelimumab); Enhertu (trastuzumab deruxtecan) and datopotamab deruxtecan in collaboration with Daiichi Sankyo; Orpathys (savolitinib) 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. 

Contacts
For details on how to contact the Investor Relations Team, please click here. For Media contacts, click here.

References

1. World Health Organization. Global Cancer Observatory: Lung. Available at:  https://gco.iarc.who.int/media/globocan/factsheets/cancers/15-trachea-bronchus-and-lung-fact-sheet.pdf. Accessed September 2024.
2. Cancer.net. Lung Cancer – Non-Small Cell: Statistics. Available at: https://www.cancer.net/cancer-types/lung-cancer-non-small-cell/statistics#:~:text=NSCLC%20is%20the%20most%20common,be%20diagnosed%20with%20lung%20cancer. Accessed September 2024.
3. National Cancer Institute. SEER Cancer Statistics Factsheets: Lung and Bronchus Cancer. Available at: https://seer.cancer.gov/archive/csr/1975_2017/results_merged/sect_15_lung_bronchus.pdf. Accessed September 2024.
4. Chen R, et al. Emerging therapeutic agents for advanced non-small cell lung cancer. J Hematol Oncol. 2020;13(1):58.
5. Majeed U, et al. Targeted therapy in advanced non-small cell lung cancer: current advances and future trends. J Hematol Oncol. 2021;14(1):108.
6. Pircher, A, et al. Docetaxel in the Treatment of Non-small Cell Lung Cancer (NSCLC) – An Observational Study Focusing on Symptom Improvement. Anticancer Research. 2013;33(9):3831-3836.
7. Mito R, et al. Clinical impact of TROP2 in non‐small lung cancers and its correlation with abnormal p53 nuclear accumulation. Pathol Int. 2020;70(5):287-294.
8. Rodríguez-Abreau D, et al. Pemetrexed plus platinum with or without pembrolizumab in patients with previously untreated metastatic nonsquamous NSCLC: protocol-specified final analysis from KEYNOTE-189. Ann Onc. 2021 Jul;32(7): 881-895.
9. American Cancer Society. Targeted Drug Therapy for Non-Small Cell Lung Cancer. Available at: https://www.cancer.org/cancer/types/lung-cancer/treating-non-small-cell/targeted-therapies.html. Accessed September 2024.