FDA Receives New BLA for Dato-DXd in Advanced EGFR+ NSCLC

The BLA for the new indication is based on findings from the phase 2 TROPION-Lung05 study (NCT04484142); it is also supported by data from the TROPION-Lung01 trial (NCT04656652) and the phase 3 TROPION-PanTumor01 trial (NCT03401385).

Developers AstraZeneca and Daiichi Sankyo have submitted a new biologics license application (BLA) to the FDA seeking accelerated approval for datopotamab deruxtecan (dato-DXd) as a therapy for adults with metastatic or locally advanced, previously treated non–small cell lung cancer (NSCLC) harboring EGFR mutations, according to a press release from the developers.¹

The FDA previously accepted a BLA for dato-DXd in advanced nonsquamous NSCLC in February 2024, which was supported by findings from the phase 3 TROPION-Luing01 trial (NCT04656652).² The developers have decided to voluntarily withdraw the BLA for the nonsquamous indication and submit a new BLA for the EGFR-mutated NSCLC population based on feedback from the regulatory agency.

The BLA for the new indication is based on findings from the phase 2 TROPION-Lung05 study (NCT04484142); it is also supported by data from the TROPION-Lung01 trial and the phase 3 TROPION-PanTumor01 trial (NCT03401385). Investigators will present pooled analysis results from the EGFR-mutant NSCLC cohorts from the TROPION-Lung05 and TROPION-Lung01 trials at the 2024 European Society for Medical Oncology (ESMO) Asia Congress.

“TROPION-Lung01 was designed to test the potential to improve upon standard-of-care chemotherapy in for patients with a broad, previously treated, advanced lung cancer patient population. The results, together with data from TROPION-Lung05, showed an especially pronounced benefit for patients with an EGFR mutation, which informed our discussions with the FDA and the decision to seek accelerated approval of datopotamab deruxtecan in this patient population,” Susan Galbraith, executive vice president of Oncology Research and Development at AstraZeneca, stated in the press release.¹ “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

According to data from the TROPION-Lung05 trial presented at the 2023 ESMO Congress, dato-DXd yielded a confirmed objective response rate (ORR) of 35.8% (95% CI, 27.8%-44.4%) among patients with advanced or metastatic NSCLC.³ Among those with EGFR mutations, the confirmed ORR was 43.6%.

Across the trial population, grade 3 or higher treatment-emergent adverse effects (TEAEs) affected 47.4% of patients, and serious TEAEs were reported in 24.8%. Additionally, 21.9% and 9.5% of patients required dose reductions and drug discontinuations due to TEAEs, respectively. TEAEs resulting in death were highlighted in 1.5% of patients.

Investigators of the international, 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 such as EGFR, ALK, and ROS1.

The trial’s primary end point was ORR per blinded independent central review (BICR). Secondary end points included duration of response (DOR), disease control rate (DCR), clinical benefit rate, progression-free survival (PFS), time to response, overall survival (OS), and safety.

TROPION-Lung01

Final OS findings from the TROPION-Lung01 trial were highlighted at the 2024 IASLC World Conference on Lung Cancer (WCLC).⁴ Across the overall trial population, the median OS was 12.9 months with dato-DXd vs 11.8 months with docetaxel (HR, 0.94; 95% CI, 0.78-1.14; P = .530). Among those with nonsquamous histology, an improvement in OS with dato-DXd occurred regardless of the presence of actionable genomic alterations such as EGFR, which were present in 17% of patients across both arms.

Investigators of the multi-center, open-label TROPION-Lung01 trial assessed the safety and efficacy of dato-DXd vs docetaxel in approximately 600 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. Secondary end points included ORR, DOR, time to response, and disease control rate.

References

1. 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 November 12, 2024. https://tinyurl.com/2knvb34p
2. 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 November 12, 2024. http://tinyurl.com/2v5k3yhc
3. 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.
4. 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 November 12, 2024. https://tinyurl.com/mvkp85dd