Daiichi Sankyo, AstraZeneca Withdraw EU MAA for Dato-DXd in Advanced Nonsquamous NSCLC

Daiichi Sankyo and AstraZeneca have voluntarily withdrawn a marketing authorization application (MAA) seeking the approval of datopotamab deruxtecan (Dato-DXd) for the treatment of adult patients with locally advanced or metastatic nonsquamous non–small cell lung cancer (NSCLC) in the European Union (EU).1

The decision was based on feedback the companies received from the European Medicines Agency’s Committee for Medicinal Products for Human Use.

Notably, the companies’ MAA seeking the approval of Dato-DXd for the treatment of patients with hormone receptor–positive, HER2-negative metastatic breast cancer remains under review in the EU.

In November 2024, the companies also announced that they voluntarily withdrew a biologics license application (BLA) seeking FDA approval for Dato-DXd in patients with advanced or metastatic nonsquamous NSCLC.2 The companies submitted a new BLA seeking the approval of the antibody-drug conjugate for the treatment of adult patients with locally advanced or metastatic NSCLC harboring EGFR mutations who have received prior systemic therapies, including an EGFR-directed therapy.

The withdrawn MAA and BLA for Dato-DXd in advanced nonsquamous NSCLC were based on data from the phase 3 TROPION-Lung01 trial (NCT04656652). Data from the final overall survival (OS) analysis presented at the 2024 IASLC World Conference on Lung Cancer showed that in the intention-to-treat (ITT) population, the median OS was 12.9 months for Dato-DXd (n = 299) vs 11.8 months for docetaxel (n = 305); this difference did not reach statistical significance (HR, 0.94; 95% CI, 0.78-1.14; P = .530).3 In the subgroup of patients with nonsquamous NSCLC, the median OS was 14.6 months for Dato-DXd (n = 234) vs 12.3 months for docetaxel (n = 234; HR, 0.84; 95% CI, 0.68-1.05).

Results from the primary progression-free survival (PFS) analysis presented at the 2023 ESMO Congress showed that in the ITT population, the median PFS was 4.4 months (95% CI, 4.2-5.6) in the Dato-DXd arm vs 3.7 months (95% CI, 2.9-4.2) in the docetaxel arm (HR, 0.75; 95% CI, 0.62-0.91; P = .004).4 In the nonsquamous subgroup, the median PFS was 5.6 months (95% CI, 4.4-7.0) vs 3.7 months (95% CI, 2.9-4.2), respectively (HR, 0.63; 95% CI, 0.51-0.78).

TROPION-Lung01 was a global, multicenter, open-label trial that enrolled adult patients with locally advanced or metastatic NSCLC who did and did not harbor actionable genomic alterations and required systemic therapy following prior treatment.3 Those harboring actionable mutations needed to receive prior treatment with approved targeted therapy and platinum-based chemotherapy; patients without actionable alterations needed prior treatment with platinum-based chemotherapy and an immune checkpoint inhibitor, either in combination or sequentially.

Patients were randomly assigned to receive Dato-DXd at 6.0 mg/kg or docetaxel at 75 mg/m2.

PFS per blinded independent central review and OS served as the trial’s dual primary end points. Secondary end points included investigator-assessed PFS, objective response rate, duration of response, time to response, disease control rate, and safety.

Safety data from the final OS analysis showed that compared with docetaxel, Dato-DXd was associated with lower rates of dose reduction (20% vs 30%) and treatment discontinuation (8% vs 12%) due to adverse effects (AEs).

Grade 3 or higher treatment-related AEs (TRAEs) were reported in 26% of patients in the Dato-DXd arm vs 42% of patients in the docetaxel arm. The most common grade 3 or higher TRAEs included neutropenia (Dato-DXd, 1%; docetaxel, 23%), leukopenia (0%; 13%), stomatitis (7%; 1%), anemia (4%; 4%), interstitial lung disease (4%; 1%), and asthenia (3%; 2%).

References

1. Datopotamab deruxtecan application in the EU for patients with advanced nonsquamous non-small cell lung cancer voluntarily withdrawn. News release. Daiichi Sankyo. December 24, 2024. Accessed December 24, 2024. https://www.daiichisankyo.com/files/news/pressrelease/pdf/202412/20241224_E.pdf
2. Datopotamab deruxtecan new BLA submitted for accelerated approval in the US for patients with previously treated advanced EGFR-mutated non-small cell lung cancer. News release. AstraZeneca. November 12, 2024. Accessed December 24, 2024. https://www.astrazeneca.com/media-centre/press-releases/2024/dato-dxd-new-bla-submitted-nsq-bla-withdrawn.html
3. Datopotamab deruxtecan showed median overall survival of 14.6 months in patients with advanced nonsquamous non-small cell lung cancer in TROPION-Lung01 phase 3 trial. News release. Daiichi Sankyo. September 9, 2024. Accessed December 24, 2024. https://daiichisankyo.us/press-releases/-/article/datopotamab-deruxtecan-showed-median-overall-survival-of-14-6-months-in-patients-with-advanced-nonsquamous-non-small-cell-lung-cancer-in-tropion-lung0
4. Datopotamab deruxtecan improved progression-free survival versus chemotherapy in patients with previously treated non-small cell lung cancer in TROPION-Lung01 phase 3 trial. News release. Daiichi Sankyo. October 23, 2023. Accessed December 24, 2024. https://daiichisankyo.us/press-releases/-/article/datopotamab-deruxtecan-improved-progression-free-survival-versus-chemotherapy-in-patients-with-previously-treated-non-small-cell-lung-cancer-in-tropio