Results from TROPION-Lung05, TROPION-Lung01 Trials Lead to FDA Priority Review for Datopotamab Deruxtecan in NSCLC

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Positive efficacy and safety findings from the TROPION-Lung05 (NCT04484142) and TROPION-Lung01 (NCT04656652) clinical trials led the FDA to award Priority Review designation to a Biologics License Application (BLA) for datopotamab deruxtecan (Dato-DXd) in patients with locally advanced or metastatic EGFR-mutated non-small cell lung cancer (NSCLC) that was previously treated with systemic therapies.^1,2

Dato-DXd, an investigational trophoblast cell-surface antigen–2–d directed antibody-drug conjugate with a potent topoisomerase I inhibitor payload, was previously granted FDA Breakthrough Therapy Designation based on results from these trials.³ The BLA was also supported by data from the TROPION-PanTumor01 trial (NCT03401385).

“Acquired resistance to front-line therapies and, ultimately, disease progression are unfortunate realities for most patients with advanced EGFR-mutated non-small cell lung cancer,” said Susan Galbraith, executive vice president, Oncology R&D, AstraZeneca, in a press release. “This Priority Review, and the previously granted Breakthrough Therapy Designation, recognize the potential for datopotamab deruxtecan to provide a much-needed option to patients whose disease has become resistant to current treatments.”¹

Trial Design

TROPION-Lung01 is a global, randomized, multicenter, open-label Phase III trial that enrolled approximately 600 patients across sites in Asia, Europe, North America, and South America. Investigators compared the efficacy and safety of Dato-DXd at a dose of 6.0 mg/kg with docetaxel at a dose of 75 mg/m2 in adults with locally advanced or metastatic NSCLC, with and without actionable genomic alterations, who required systemic therapy after prior treatment with platinum-based chemotherapy and an approved targeted therapy. Those without known actionable genomic alterations received prior treatment, concurrently or sequentially, with platinum-based chemotherapy and a PD-1 or PD-L1 inhibitor.

The trial’s dual primary endpoints are progression-free survival (PFS) as assessed by blinded independent central review (BICR) and overall survival (OS), with key secondary endpoints that include investigator-assessed PFS, objective response rate (ORR), duration of response (DOR), time to response, BICR and investigator assessed disease control rate (DCR), and safety.

TROPION-Lung05 is a global, single-arm, open-label Phase II trial evaluating Dato-DXd in patients with advanced or metastatic NSCLC with actionable genomic alterations whose disease progressed on or following administration of targeted therapy and platinum-based chemotherapy.

The trial’s primary endpoint was ORR as assessed by BICR, as per RECIST v1.1. The trial’s secondary endpoints included DOR evaluation, DCR, clinical benefit rate, PFS, time to response, OS, and safety.

A total of 137 patients were administered therapy with Dato-DXd between March 29, 2021, and December 14, 2022, with a median study duration of 15.2 months (range, 9.1-20.5) and median treatment duration of 4.4 months (range, 0.7-20.6). Among patients enrolled in the trial, 71.5% were previously administered at least three lines of treatment for advanced or metastatic disease. Of these patients, 56.9% had EGFR mutations and 24.8% had ALK rearrangements.

As of the data cutoff date, 20 patients were still receiving treatment and 60 were ongoing in the trial. Findings from the trial were recently published by The Journal of Clinical Oncology.²

“First-line and second-line treatment approaches for NSCLC with actionable genomic alterations consist mostly of targeted treatment with tyrosine kinase inhibitors,” the study authors wrote. “Targeted therapies have significantly improved outcomes compared with conventional chemotherapy; however, resistance eventually develops, and subsequent treatment options remain limited. There remains an unmet need for novel therapies to treat patients with NSCLC with actionable genomic alterations in later-line settings.”²

Trial Results

Results of TROPION-Lung01 released in 2023 show that Dato-DXd lowered 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 BICR. Patients administered Dato-DXd had a median PFS of 4.4 months compared with 3.7 months in the docetaxel cohort. Confirmed ORR was 26.4% in the Dato-DXd cohort compared to 12.8% in the docetaxel cohort.⁴

Dato-DXd was found to reduce the risk of disease progression or death by 37% in patients with non-squamous NSCLC compared to docetaxel (HR 0.63; 95% CI 0.51-0.78), with a median PFS at 5.6 months in the Dato-DXd cohort compared with 3.7 in the docetaxel cohort. Confirmed ORR was 31.2% in the Dato-DXd cohort, which included four complete responses (CRs), compared with 12.8% in the docetaxel cohort with no CRs; however, Dato-DXd did not achieve a PFS benefit in patients with squamous NSCLC.⁵

In TROPION-Lung05, the results showed a confirmed ORR of 35.8% (95% CI, 27.8 to 44.4), with ORR at 43.6% (95% CI, 32.4 to 55.3) in patients with EGFR mutations and 23.5% (95% CI, 10.7 to 41.2) in those with ALK rearrangements. Median DOR was 7.0 months (95% CI, 4.2 to 9.8) and overall DCR was 78.8% (95% CI, 71.0 to 85.3).

Pooled data from both trials show a confirmed ORR of 42.7% (95% confidence interval [CI] 33.6-52.2) as assessed by BICR and median DOR of 7.0 months (95% CI 4.2-9.8). In terms of safety, the profile of Dato-DXd was consistent with findings from prior trials, with no new safety signals reported.

“Treating advanced EGFR-mutated non-small cell lung cancer presents a significant challenge due to the limited efficacy of available treatments once the disease has progressed following front-line therapies, including the use of an EGFR-tyrosine kinase inhibitor,” said Ken Takeshita, MD, global head, R&D, Daiichi Sankyo, in a press release. “If approved, datopotamab deruxtecan could become the first TROP2-directed antibody drug conjugate for lung cancer, providing a promising option for patients.”¹

References

1. Datopotamab deruxtecan granted Priority Review in the US for patients with previously treated advanced EGFR-mutated non-small cell lung cancer. News release. AstraZeneca. January 13, 2025. Accessed January 13, 2025. https://www.astrazeneca.com/media-centre/press-releases/2025/datopotamab-deruxtecan-granted-priority-review-in-the-us-for-patients-with-previously-treated-advanced-egfr-mutated-non-small-cell-lung-cancer.html#!

2. Jacob Sands et al. Datopotamab Deruxtecan in Advanced or Metastatic Non–Small Cell Lung Cancer With Actionable Genomic Alterations: Results From the Phase II TROPION-Lung05 Study. JCO 0, JCO-24-01349. DOI:10.1200/JCO-24-01349

3. Datopotamab deruxtecan granted breakthrough therapy designation in US for patients with previously treated advanced EGFR-mutated non-small cell lung cancer. AstraZeneca. December 9, 2024. Accessed January 13, 2025. https://www.astrazeneca.com/media-centre/press-releases/2024/datopotamab-deruxtecan-granted-breakthrough-therapy-designation-us-patients-previously-treated-advanced-egfr-mutated-non-small-cell-lung-cancer.html#!

4. Datopotamab deruxtecan showed clinically meaningful overall survival improvement vs. chemotherapy in patients with advanced nonsquamous non-small cell lung cancer in TROPION-Lung01 Phase III trial. News release. AstraZeneca. May 27, 2024. Accessed January 13, 2025. https://www.astrazeneca.com/media-centre/press-releases/2024/dato-dxd-improved-os-in-nonsquamous-lung-cancer.html#!

5. Datopotamab deruxtecan improved progression-free survival vs. chemotherapy in patients with previously treated non-small cell lung cancer in TROPION-Lung01 Phase III trial. News release. AstraZeneca. October 23, 2023. Accessed January 13, 2025. https://www.astrazeneca.com/media-centre/press-releases/2023/datopotamab-deruxtecan-improved-progression-free-survival-vs-chemotherapy-in-tropion-lung01-phase-iii-trial.html