Datopotamab Deruxtecan EU Application Is Voluntarily Withdrawn for NSCLC

Feedback from the European Medicines Agency following results of the phase 3 TROPION-Lung01 informed the marketing authorization application withdrawal.

The marketing authorization application (MAA) for datopotamab deruxtecan (Dato-DXd) as a treatment for adult patients with locally advanced or metastatic nonsquamous non–small cell lung cancer was voluntarily withdrawn, according to a news release from the drug’s developer, Daiichi Sankyo.¹

Feedback from the European Medicines Agency (EMA) Committee for Medicinal Products for Human Use following results of the phase 3 TROPION-Lung01 trial (NCT04656652) informed the decision to withdraw the MAA. In the study, Dato-DXd did not achieve statistical significance in the final overall survival (OS) analysis vs docetaxel.

The FDA previously received a new biologics license application (BLA) for dato-DXd in adult patients with EGFR-mutated metastatic or locally advanced NSCLC, based on results from the phase 2 TROPION-Lung05 study (NCT04484142).² The developers voluntarily withdrew the previous BLAfor the nonsquamous indication based on regulatory feedback.³

“TROPION-Lung01 was designed to test the potential to improve upon standard-of-care chemotherapy in a broad, previously treated, advanced lung cancer patient population,” said Susan Galbraith, MBBChir, PhD, executive vice president of oncology research and development at AstraZeneca, said in a separate news release.² “TROPION-Lung01 has also provided exciting exploratory data supporting our biomarker development, which will be validated in ongoing and planned phase 3 lung cancer trials.”

TROPION-Lung05

The single-arm, open-label TROPION-Lung05 trial assessed the safety and efficacy of dato-DXd among 137 patients with locally advanced or metastatic NSCLC harboring actionable genomic alterations.

The primary end point of the trial was ORR per blinded independent central review (BICR), with secondary end points including duration of response (DOR), clinical benefit rate, progression-free survival (PFS), OS, and safety.

Data from TROPION-Lung05 were presented at the 2023 ESMO Congress.⁴ Here, dato-DXd elicited a confirmed objective response rate (ORR) of 35.8% (95% CI, 27.8%-44.4%) in patients with advanced or metastatic NSCLC, including 43.6% among those with EGFR mutations.

Additionally, grade 3 or higher treatment-emergent adverse events (TEAEs) were reported in 47.4% of patients. Serious TEAEs were reported in 24.8% of patients. TEAEs leading to dose reduction, continuation, or death occurred in 21.9%, 9.5%, and 1.5% of patients, respectively.

TROPION-Lung01

The multicenter, open-label TROPION-Lung01 trial assessed the safety and efficacy of dato-DXd vs docetaxel in adults with locally advanced or metastatic NSCLC with or without actionable genomic alterations. The trial’s primary end points were PFS per BICR and OS, and secondary end points included ORR, DOR, time to response, and disease control rate.

According to final OS results presented at the 2024 IASLC World Conference on Lung Cancer (WCLC), the median OS was 12.9 months in all comers with dato-DXd vs 11.8 months with docetaxel (HR, 0.94; 95% CI, 0.78-1.14; P = .530).⁴ An OS improvement was observed in patients with nonsquamous histology regardless of actionable genomic alteration presence at 14.6 months with dato-DXd vs 12.3 months with docetaxel (HR, 0.84; 95% CI, 0.68-1.05).

Furthermore, among patients with actionable genomic alterations in the nonsquamous indication, median OS was 15.6 months with dato-DXd vs 9.8 months with docetaxel (HR, 0.65; 95% CI, 0.40-1.08).

Additionally, the safety profile of dato-DXd was consistent with previous analysis, with lower rates of TEAEs leading to dose reduction (20% vs 30%) and discontinuation (8% vs 12%) vs docetaxel. Grade 3 or higher TEAEs occurred in 26% and 42% of patients, respectively, with no new interstitial lung disease observed. Common grade 3 or higher TEAEs included neutropenia (1% vs 23%) and leukopenia (0% vs 13%).

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 January 2, 2025. https://tinyurl.com/5uf3rdvd
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 January 2, 2025. https://tinyurl.com/2knvb34p
3. Datopotamab deruxtecan biologics license application accepted in the US for patients with previously treated advanced nonsquamous non-small cell lung cancer. News release. AstraZeneca. February 19, 2024. Accessed January 2, 2025. http://tinyurl.com/2v5k3yhc
4. Paz-Ares L, Ahn M-J, Lisberg AE, et al. 1314MO TROPION-Lung05: datopotamab deruxtecan (Dato-DXd) in previously treated non-small cell lung cancer (NSCLC) with actionable genomic alterations (AGAs). Ann Oncol. 2023;34(suppl 2):S755-S756.
5. 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. News release. AstraZeneca. September 9, 2024. Accessed January 2, 2025. https://tinyurl.com/mvkp85dd