Novel Computational Pathology-Based TROP2 Biomarker for Datopotamab Deruxtecan Was Predictive of Clinical Outcomes in Patients With Non-Small Cell Lung Cancer in TROPION-Lung01 Phase III Trial

Follow Drugslib on

September 8, 2024 -- Results from an exploratory analysis of the TROPION-Lung01 Phase III trial 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 non-small cell lung cancer (NSCLC) who were treated with datopotamab deruxtecan (Dato-DXd). In patients with TROP2-QCS biomarker positive tumours, datopotamab deruxtecan demonstrated a meaningfully greater magnitude of efficacy versus docetaxel than in the overall trial population.

These results will be featured in a Presidential Symposium (PL02.11) at the IASLC 2024 World Conference on Lung Cancer (WCLC) hosted by the International Association for the Study of Lung Cancer.

TROP2 is a protein broadly expressed in NSCLC on the surface of and inside tumour cells.1,2 When assessed using conventional immunohistochemistry (IHC)-based pathology, TROP2 expression has not been predictive of patient responses to TROP2-directed antibody drug conjugates (ADC).3,4 QCS is a fully supervised computational pathology platform, developed by AstraZeneca, that analyses digitised images of patient tissue samples and precisely quantifies targets, like TROP2, on and inside a tumour cell.

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

In this analysis, QCS was used to analyse tissue samples collected from patients in TROPION-Lung01. This produced a normalised membrane ratio for each tumour cell in each sample. Patients’ tumours were considered TROP2-QCS biomarker positive if the majority (≥75%) of tumour cells exhibited a ratio below a predetermined value (≤0.56), indicating a greater proportion of TROP2 in the cytoplasm.

The analysis showed a greater proportion of patients with nonsquamous NSCLC were considered TROP2-QCS biomarker positive than those with squamous NSCLC (66% versus 44%, respectively). The threshold for biomarker positivity was optimised for progression-free survival (PFS) in the subgroup of patients with nonsquamous NSCLC without actionable genomic alterations because it represents a population with significant unmet medical need and without actionable biomarkers.

In patients with TROP2-QCS biomarker positive tumours (60% of the biomarker evaluable population including patients with nonsquamous and squamous NSCLC), datopotamab deruxtecan reduced the risk of disease progression or death by 43% versus docetaxel (median PFS of 6.9 versus 4.1 months; hazard ratio [HR] 0.57; 95% confidence interval [CI] 0.41-0.79).

By comparison, in the primary analysis of the overall trial population, datopotamab deruxtecan reduced the risk of disease progression or death by 25% versus docetaxel (PFS of 4.4 versus 3.7 months; HR 0.75; 95% CI 0.62-0.91; p=0.004) as presented at the 2023 European Society for Medical Oncology Congress.5

In the subgroup of patients with nonsquamous NSCLC without actionable genomic alterations and with TROP2-QCS biomarker positive tumours, datopotamab deruxtecan reduced the risk of disease progression or death by 48% (PFS of 7.2 versus 4.1 months; HR 0.52; 95% CI 0.35-0.78).

Marina Garassino, MD, The University of Chicago, Professor of Medicine and investigator in the trial, said: “TROP2 is broadly expressed on solid tumour cells, including non-small cell lung cancer, but it has yet to be established as a predictive biomarker for any TROP2-directed antibody drug conjugate. We have shown with this analysis that the more precise quantitative measurement of TROP2 on and inside tumour cells, enabled by AstraZeneca’s computational pathology platform, can identify which patients with non-small cell lung cancer are most likely to benefit from treatment with datopotamab deruxtecan.”

Susan Galbraith, Executive Vice President, Oncology R&D, AstraZeneca, said: “This analysis demonstrates the power of our computational pathology platform to discover new predictive biomarkers and substantially improve patient selection for datopotamab deruxtecan. It also has great potential to help more precisely select patients across our broader antibody drug conjugate portfolio. ​We are excited to extend our collaboration with Roche Tissue Diagnostics with the aim of validating this exploratory approach for TROP2, developing the companion diagnostic and bringing it to the clinic as quickly as possible.”

Ken Takeshita, MD, Global Head, R&D, Daiichi Sankyo, said: “The results from the QCS analysis support the potential of TROP2, as measured by quantitative continuous scoring, as a predictive biomarker for datopotamab deruxtecan and begin to answer the question of why certain patients with non-small cell lung cancer respond better to treatment. These insights are critical to advancing our understanding of how we can more precisely identify patients with non-small cell lung cancer who may benefit from treatment with our TROP2-directed antibody drug conjugate.”

In the biomarker evaluable population, no new safety concerns were identified and rates of Grade 3 or higher treatment-related adverse events (TRAE) were similar regardless of TROP2 status. In patients with TROP2-QCS biomarker positive tumours, Grade 3 or higher TRAEs occurred in 30% and 46% of patients in the datopotamab deruxtecan and docetaxel arms, respectively. The most common Grade 3 or higher TRAEs were stomatitis (7%, 3%) and ocular surface events (3%, 0%). Grade 3 or higher adjudicated drug-related interstitial lung disease events occurred in 3% and 1% of patients in the datopotamab deruxtecan and docetaxel arms, respectively.

Summary of TROPION-Lung01 QCS analysis results

CI, confidence interval; HR, hazard ratio; ORR, objective response rate; PFS, progression-free survival

AstraZeneca and Roche Tissue Diagnostics collaborate to co-develop and commercialise the TROP2-QCS biomarker companion diagnostic

AstraZeneca and Roche Tissue Diagnostics are extending their existing collaboration to co-develop a novel companion diagnostic incorporating AstraZeneca’s proprietary computational pathology platform, QCS, which will be deployed within Roche's navify® Digital Pathology image management system.

Jill German, Head, Roche Tissue Diagnostics, said: “Our collaboration with AstraZeneca continues to push the boundaries of traditional cancer diagnostics. By developing an innovative Al tool that goes beyond human capabilities, the solution will be able to help determine which cancer patients are most likely to benefit from targeted therapies, potentially improving patient care.”

Under this expanded collaboration, Roche Tissue Diagnostics and AstraZeneca will co-develop and commercialise a novel companion diagnostic in Roche’s navify® Digital Pathology platform, based on the QCS computational pathology platform, to aid pathologists in interpreting an investigational VENTANA TROP2 assay.

As the leading provider of pathology lab solutions, Roche Tissue Diagnostics is delivering an end-to-end digital pathology workflow from tissue staining to producing high-quality digital images that can be reliably assessed using automated clinical image analysis algorithms.

Advanced non-small cell lung cancerNearly 2.5 million lung cancer cases were diagnosed globally in 2022.6 NSCLC is the most common type of lung cancer, accounting for about 80% of cases.7 Approximately 75% and 25% of NSCLC tumours are of nonsquamous or squamous histology, respectively.8 While immunotherapy and targeted therapies have improved outcomes in the 1st-line metastatic setting, most patients eventually experience disease progression and receive chemotherapy.9-11 For decades, chemotherapy has been the last treatment available for patients with advanced NSCLC, despite limited effectiveness and known side effects.9-11

TROP2 is a protein broadly expressed in the majority of NSCLC tumours.1 There is currently no TROP2-directed ADC approved for the treatment of lung cancer.12,13

TROPION-Lung01TROPION-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, 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.

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 collaborationAstraZeneca 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 cancerAstraZeneca 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 oncologyAstraZeneca 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.

References

  • 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.
  • Shvartsur A, et al. Trop2 and its overexpression in cancers: regulation and clinical/therapeutic implications. Genes & Cancer. 2015 Mar;6(3-4): 84-105.
  • Shimizu T, et al. J Clin Oncol 2023;41:4678-87.
  • Heist RS, et al. J Clin Oncol. 2017;35:2790-7.
  • Ahn M-J, et al. Datopotamab deruxtecan (Dato-DXd) vs doxetaxel in previously treated advanced/metastatic (adv/met) non-small cell lung cancer (NSCLC): results of the randomized phase 3 study TROPION-Lung01. Presented at: ESMO Congress 2023, 20-24 October 2023; Madrid, Spain. LBA12.
  • 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.
  • 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.
  • National Cancer Institute. SEER Cancer Statistics Factsheets: Lung and Bronchus Cancer, 1975-2017. Accessed September 2024.
  • Chen R, et al. Emerging therapeutic agents for advanced non-small cell lung cancer. J Hematol Oncol. 2020;13(1):58.
  • 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.
  • 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.
  • 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.
  • 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.

    • Source: AstraZeneca

    Posted : 2024-09-11 09:39

    Read more

    Disclaimer

    Every effort has been made to ensure that the information provided by Drugslib.com is accurate, up-to-date, and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. Drugslib.com information has been compiled for use by healthcare practitioners and consumers in the United States and therefore Drugslib.com does not warrant that uses outside of the United States are appropriate, unless specifically indicated otherwise. Drugslib.com's drug information does not endorse drugs, diagnose patients or recommend therapy. Drugslib.com's drug information is an informational resource designed to assist licensed healthcare practitioners in caring for their patients and/or to serve consumers viewing this service as a supplement to, and not a substitute for, the expertise, skill, knowledge and judgment of healthcare practitioners.

    The absence of a warning for a given drug or drug combination in no way should be construed to indicate that the drug or drug combination is safe, effective or appropriate for any given patient. Drugslib.com does not assume any responsibility for any aspect of healthcare administered with the aid of information Drugslib.com provides. The information contained herein is not intended to cover all possible uses, directions, precautions, warnings, drug interactions, allergic reactions, or adverse effects. If you have questions about the drugs you are taking, check with your doctor, nurse or pharmacist.

    Popular Keywords