FDA Approval Sought for Dato-DXd in EGFR-Mutated NSCLC

• A new biologics license application (BLA) was submitted specifically for EGFR-mutated non–small cell lung cancer (NSCLC) after FDA feedback, replacing the earlier nonsquamous NSCLC application.
• This application draws from phase 2 and phase 3 data in TROPION-Lung01 (NCT04656652), TROPION-Lung05 (NCT04484142), and TROPION-PanTumor01 (NCT03401385) trials.
• Data has previously shown Dato-DXD’s enhanced efficacy in EGFR-mutant NSCLC.

A new BLA has been submitted to the FDA, seeking accelerated approval for datopotamab deruxtecan (Dato-DXd) as a treatment for adults with metastatic or locally advanced NSCLC with EGFR mutations, who have previously undergone treatment.1

In February 2024, the FDA accepted a BLA for dato-DXd in advanced nonsquamous NSCLC, as supported by data from the phase 3 TROPION-Lung01 study.2 However, feedback from the FDA guided the decision to submit a new BLA specifically for EGFR-mutated NSCLC and to withdraw the previously submitted BLA for nonsquamous NSCLC.¹

This new BLA is based on findings from the phase 2 TROPION-Lung05 study, the TROPION-Lung01 trial, and the phase 3 TROPION-PanTumor01 trial.

“TROPION-Lung01 was designed to test the potential to improve upon standard-of-care chemotherapy in 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. “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.”

Pooled analysis results from the EGFR-mutant NSCLC cohorts from the TROPION-Lung05 and TROPION-Lung01 trials are expected to be presented at the 2024 European Society for Medical Oncology (ESMO) Asia Congress.

Lung with cancer cells: © catalin - stock.adobe.com

About Dato-DXd

Dato-DXd is made of a human anti-TROP2 IgG1 monoclonal antibody that is covalently linked to a highly potent topoisomerase I inhibitor payload through a plasma-stable, tumor-selective, tetrapeptide-based cleavable linker.¹

A global clinical development program is ongoing and evaluating the safety and efficacy of the agent in over 20 trials across multiple cancers, including NSCLC, triple-negative breast cancer, and hormone receptor–positive, HER2-low or -negative breast cancer. Phase 3 trials in lung cancer and breast cancer are currently evaluating the agent as a monotherapy and in combination with other anticancer treatments.

Dato-DXd previously demonstrated antitumor activity with a manageable toxicity profile in heavily pretreated patients with advanced NSCLC enrolled in the phase 1 TROPION-PanTumor01 trial (NCT03401385).² In the group of patients who received Dato-DXd at 6 mg/kg every 3 weeks, the confirmed objective response rate (cORR) was 26% (95% CI, 14.6%-40.3%), the median duration of response (DOR) was 10.5 months (95% CI, 5.6-26.5), the disease control rate (DCR) was 70% (95% CI, 55.4%-82.1%), and the median progression-free survival (PFS) was 6.9 months (95% CI, 2.7-8.8).2

Results From TROPION-Lung05

The phase 2, single-arm TROPION-Lung05 study included patients with stage IIIB, IIIC, or IV NSCLC who had an ECOG performance status of 0 or 1 and at least 1 actionable genomic alteration, such as EGFR, ALK, ROS1, NTRK, BRAF, MET exon 14 skipping, or RET.³ Enrollment was open to patients who had received at least 1 line of targeted therapy and 1 or 2 cytotoxic agent–containing regimens, including platinum-based therapy in the metastatic setting. Further, patients were required to have experienced radiographic disease progression following targeted treatment.

Data from the TROPION-Lung05 trial presented at the 2023 ESMO Congress showed that Dato-DXd led to a cORR of 35.8% (95% CI, 27.8%-44.4%) among patients with advanced or metastatic NSCLC (n = 137), with 3% of patients achieving a complete response and 33% experiencing a partial response. For those with EGFR mutations (n = 78), the cORR was 43.6%.

The median DOR in all treated patients was 7.0 months (95% CI, 4.2-9.8), the confirmed DCR was 78.8% (95% CI, 71.0%-85.3%), and the median PFS was 5.4 months (95% CI, 4.7-7.0). Among patients with EGFR mutations, the median DOR was also 7.0 months (95% CI, 4.2-10.2), the confirmed DCR was 82.1% (95% CI, 71.7%-89.8%), and the median PFS 5.8 months (95% CI, 5.4-8.3).

For safety, grade 3 or higher treatment-emergent adverse events (TEAEs) were seen in 47.4% of all patients. Serious TEAEs were observed in 24.8%. A total of 21.9% and 9.5% of patients required dose reductions and drug discontinuations due to TEAEs, respectively, and TEAEs led to death in 1.5% of patients.

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/7x35dxz5

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. https://tinyurl.com/y9cjnbyz

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.