AstraZeneca and Daiichi Sankyo’s datopotamab deruxtecan reduced the risk of disease progression or death by 25% in overall population and by 37% in patients with non-squamous tumors

Datopotamab deruxtecan is the first antibody drug conjugate to demonstrate statistically significant improvement in PFS over docetaxel in this setting of high unmet need

Positive results from the pivotal TROPION-Lung01 Phase III trial showed that datopotamab deruxtecan (Dato-DXd) demonstrated a statistically significant improvement for the primary endpoint of progression-free survival (PFS) compared to docetaxel, the current standard of care, in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) treated with at least one prior line of therapy.

These data will be shared today in the second of two late-breaking presentations for datopotamab deruxtecan in a Presidential Symposium at the European Society for Medical Oncology (ESMO) 2023 Congress in Madrid, Spain (LBA12).

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

Datopotamab deruxtecan reduced the risk of disease progression or death by 25% compared to docetaxel (hazard ratio [HR]=0.75; 95% confidence interval [CI] 0.62-0.91; p=0.004) as assessed by blinded independent central review (BICR). Median PFS was 4.4 months in patients treated with datopotamab deruxtecan versus 3.7 with docetaxel. Results also showed a confirmed objective response rate (ORR) of 26.4% in patients treated with datopotamab deruxtecan compared to an ORR of 12.8% with docetaxel.

In patients with non-squamous NSCLC, datopotamab deruxtecan demonstrated a clinically meaningful benefit, reducing the risk of disease progression or death by 37% compared to docetaxel (HR 0.63; 95% CI 0.51-0.78) as assessed by BICR. Median PFS was 5.6 months in patients treated with datopotamab deruxtecan versus 3.7 with docetaxel. A confirmed ORR of 31.2% was observed with datopotamab deruxtecan, including four complete responses (CRs), versus 12.8% with docetaxel which elicited no CRs. Datopotamab deruxtecan did not demonstrate a PFS benefit in patients with squamous NSCLC.

For the dual primary endpoint of overall survival (OS), interim results numerically favored datopotamab deruxtecan over docetaxel in the overall population (HR 0.90; 95% CI 0.72-1.13) and in patients with non-squamous tumors (HR 0.77 95% CI: 0.59-1.01), however, results did not reach statistical significance at the time of this data cut-off. The trial is ongoing and OS will be assessed at a final analysis.

Aaron Lisberg, MD, UCLA Health, Thoracic Medical Oncology and investigator in the trial, said: “For patients with advanced non-small cell lung cancer, current standard of care second-line docetaxel is associated with limited benefit and substantial toxicity. The improvement in progression-free survival observed with datopotamab deruxtecan, particularly in patients with non-squamous tumors, and the improved tolerability of this antibody drug conjugate compared to docetaxel, represent a meaningful advance for patients with lung cancer."

Susan Galbraith, Executive Vice President, Oncology R&D, AstraZeneca, said: “Datopotamab deruxtecan is central to the future we envision where antibody drug conjugates improve upon and ultimately displace entrenched standards of care, like chemotherapy, in multiple cancer types. The TROPION-Lung01 results demonstrate for the first time that an antibody drug conjugate can delay disease progression or death for longer than conventional chemotherapy in patients with advanced non-small cell lung cancer. This is particularly noteworthy considering datopotamab deruxtecan was also associated with a lower burden of treatment-related severe adverse events than chemotherapy.”

Ken Takeshita, MD, Global Head, R&D, Daiichi Sankyo, said, “These results shown at ESMO from the second of two pivotal trials of datopotamab deruxtecan provide further support for the practice-changing potential of our DXd antibody drug conjugate technology across different targets and types of cancer. The benefit seen in patients with non-squamous tumors is particularly impressive and, coupled with the data from TROPION-Lung05, provides promising evidence that datopotamab deruxtecan may play an important role in treating patients with non-small cell lung cancer who currently have limited effective options following initial treatment.”

In the TROPION-Lung01 trial, no new safety concerns were identified with datopotamab deruxtecan. The median treatment duration for datopotamab deruxtecan was 4.2 versus 2.8 months for docetaxel. Grade 3 or higher treatment-related adverse events (TRAEs) occurred in 25% and 41% of patients in the datopotamab deruxtecan and docetaxel arms, respectively. The most common Grade 3 or higher TRAEs were neutropenia (1%, 23%), stomatitis (6%, 1%), anemia (4%, 4%), asthenia (3%, 2%), nausea (2%, 1%) and fatigue (1%, 2%).

Grade 3 or higher adjudicated drug-related interstitial lung disease (ILD) events occurred in 3% and 1% of patients in the datopotamab deruxtecan and docetaxel arms, respectively. In the datopotamab deruxtecan arm, there were seven Grade 5 ILD events (2%) adjudicated as drug-related by an independent committee. The primary cause of death in four of these cases was attributed to disease progression by the treating investigator. Of the seven adjudicated Grade 5 ILD events, four (1.7%) were in patients with non-squamous NSCLC and three (4.6%) were in patients with squamous NSCLC. In the docetaxel arm, one adjudicated drug-related Grade 5 ILD event (0.3%) occurred.

Patient enrollment by tumor histology was consistent across treatment arms and with real world incidence with 78% and 77% of patients in the datopotamab deruxtecan and docetaxel arms, respectively, having non-squamous tumors.¹ In both arms, 17% of patients had tumors expressing actionable genomic alterations, such as epidermal growth factor receptor (EGFR) mutations. At the March 29, 2023 data cut-off, 52 patients remained on treatment with datopotamab deruxtecan and 17 remained on docetaxel.

Summary of TROPION-Lung01 Efficacy Results

CI, confidence interval; CR, complete response; DoR, duration of response; HR, hazard ratio; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; PR, partial response

ⁱ As assessed by BICR

ⁱⁱ p-value prespecified boundary of 0.008

ⁱⁱⁱ With median follow-up of 11.8 and 11.7 months for the datopotamab deruxtecan and docetaxel arms, respectively, OS data were not mature

^iv ORR is (complete response + partial response)

TROPION-Lung05 Results

Initial results from the TROPION-Lung05 Phase II trial showed datopotamab deruxtecan demonstrated encouraging antitumor activity in patients with heavily pretreated locally advanced or metastatic NSCLC with actionable genomic alterations including those with EGFR mutations and anaplastic lymphoma kinase (ALK) rearrangements. These data were presented at the ESMO 2023 Congress on Saturday, October 21 (1314MO).

In the overall population (n=137), datopotamab deruxtecan demonstrated a confirmed ORR of 35.8%, including four CRs and 45 partial responses, and a disease control rate (DCR) of 78.8%. Median PFS was 5.4 months. In patients with EGFR mutations (n=78), the largest subgroup, datopotamab deruxtecan demonstrated an ORR of 43.6% and DCR of 82.1%.

The most common Grade 3 or higher TRAEs were stomatitis (10%), anemia (6%), decreased appetite (4%) and fatigue (4%). There were five ILD events (4%) adjudicated as drug-related by an independent committee, including four Grade 1 or 2 events and one Grade 5 event.

Non-small cell lung cancer

More than one million people worldwide are diagnosed with advanced NSCLC each year.^2,3 Approximately 30% and 70% of NSCLC tumors are of squamous or non-squamous histology, respectively, the latter including adenocarcinoma and large cell carcinoma.¹ While immunotherapy and targeted therapies have improved outcomes in the first-line 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 in the absence of other treatment options and despite limited effectiveness and known side effects.^4-6

TROP2, a transmembrane glycoprotein, is broadly expressed in a large majority of NSCLC tumors.⁷ There are currently no TROP2-directed ADCs approved for the treatment of lung cancer.^8,9

TROPION-Lung01

TROPION-Lung01 is an ongoing global, randomized, multicenter, open-label Phase III trial evaluating the efficacy and safety of datopotamab deruxtecan (6.0 mg/kg) versus docetaxel (75 mg/m²) in patients with locally advanced or metastatic NSCLC with and without actionable genomic alterations previously treated with at least one therapy. Patients with actionable genomic alterations were 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 BICR and OS. Key secondary endpoints include investigator-assessed PFS, ORR, DoR, time to response, DCR as assessed by both BICR and investigator, and safety.

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

About TROPION-Lung05

TROPION-Lung05 is an ongoing global, multicenter, single-arm, open-label Phase II study evaluating the efficacy and safety of datopotamab deruxtecan (6.0 mg/kg) in patients with locally advanced or metastatic NSCLC with actionable genomic alterations with disease progression on or after at least one tyrosine kinase inhibitor and at least one regimen of platinum-based chemotherapy (with or without other systemic therapies). Patients with one or more genomic alterations including EGFR, ALK, ROS1, NTRK, BRAF, RET, or MET and who received up to four prior lines of treatment were eligible for the study.

The primary trial endpoint is ORR as assessed by BICR. Secondary efficacy endpoints include DoR, best percentage change in the sum of diameters of measurable tumors, DCR, clinical benefit rate, PFS, time to response and OS. Safety endpoints include treatment emergent adverse events and other safety parameters. TROPION-Lung05 enrolled 137 patients globally. 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 ADCs in the oncology pipeline of Daiichi Sankyo, and one of the most advanced programs in AstraZeneca’s ADC scientific platform. Datopotamab deruxtecan is comprised of a humanized 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 development program called TROPION is underway globally with more than 12 trials evaluating the efficacy and safety of datopotamab deruxtecan across multiple tumors, including NSCLC, triple-negative breast cancer and HR-positive, HER2-low or negative breast cancer. Beyond the TROPION program, datopotamab deruxtecan is also being evaluated in novel combinations in several ongoing trials. AstraZeneca is also researching a potential diagnostic test to help identify patients most likely to benefit from treatment with datopotamab deruxtecan.

Daiichi Sankyo collaboration

AstraZeneca and Daiichi Sankyo entered into a global collaboration to jointly develop and commercialize fam-trastuzumab deruxtecan-nxki 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 fam-trastuzumab deruxtecan-nxki 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 osimertinib and gefitinib; durvalumab and tremelimumab; fam-trastuzumab deruxtecan-nxki and datopotamab deruxtecan in collaboration with Daiichi Sankyo; 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 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 commercialization of prescription medicines in Oncology, Rare Diseases, and BioPharmaceuticals, including Cardiovascular, Renal & Metabolism, and Respiratory & Immunology. Based in Cambridge, UK, AstraZeneca operates in over 100 countries and its innovative medicines are used by millions of patients worldwide. Please visit www.astrazeneca-us.com and follow us on social media @AstraZeneca.

References

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3. World Health Organization. International Agency for Research on Cancer. Lung Fact Sheet. Available at: https://gco.iarc.fr/today/data/factsheets/cancers/15-Lung-fact-sheet.pdf. Accessed October 2023.
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 October 2023.

US-81577 Last Updated 10/23

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