FDA Grants Breakthrough Therapy Designation to Dato-DXd for Previously Treated EGFR+ Advanced NSCLC

The FDA has granted breakthrough therapy designation to datopotamab deruxtecan (Dato-DXd; DS-1062a) for the treatment of adult patients with locally advanced or metastatic, EGFR-mutated non–small cell lung cancer (NSCLC) with disease progression on or after treatment with an EGFR TKI and platinum-based chemotherapy.1

The designation was supported by data from the phase 2 TROPION-Lung05 (NCT04484142) and the phase 3 TROPION-Lung01 (NCT04656652) trials. Findings from a pooled analysis of patients with EGFR-mutated NSCLC (n = 117) treated with Dato-DXd in TROPION-Lung05 (n = 78) and TROPION-Lung01 (n = 39) demonstrated that the antibody-drug conjugate produced an objective response rate (ORR) of 42.7% (95% CI, 33.6%-52.2%) per blinded independent central review (BICR) assessment, including a complete response (CR) rate of 4.3% and a partial response (PR) rate of 38.5%.2 Additionally, 41.0% of patients had stable disease (SD), and the disease control rate (DCR) was 86.3% (95% CI, 78.7%-92.0%).

Additional data showed the median duration of response (DOR) was 7.0 months (95% CI, 4.2-9.8). The median progression-free survival (PFS) was 5.8 months (95% CI, 5.4-8.2), and the median overall survival (OS) was 15.6 months (95% CI, 13.1-19.0).

“The breakthrough therapy designation granted by the FDA underscores the significant unmet need for new treatments for patients with previously treated EGFR-mutated NSCLC who have experienced disease progression,” Ken Takeshita, MD, global head, R&D, Daiichi Sankyo, stated in a news release.1 “Dato-DXd has the potential to play an important role in improving outcomes, and we look forward to working closely with the FDA to bring this medicine to patients as quickly as possible.”

In November 2024, AstraZeneca and Daiichi Sankyo submitted a new biologics license application (BLA) to the FDA seeking the accelerated approval of Dato-DXd 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.3 The companies also withdrew a BLA for Dato-DXd in the treatment of patients with advanced or metastatic nonsquamous NSCLC.

TROPION-Lung05 was a single-arm, open-label phase 2 study that enrolled patients at least 18 years of age with stage IIIB, IIIC, or IV NSCLC harboring at least 1 documented activating EGFR, ALK, ROS1, NTRK, BRAF, MET exon 14 skipping, or RET genomic alteration.4

All patients received Dato-DXd at a dose of 6.0 mg/kg once every 3 weeks. BICR-assessed ORR was the trial’s primary end point; secondary end points included DOR, PFS, OS, pharmacokinetics, and safety.

TROPION-Lung01 was a global, randomized, multicenter, open-label phase 3 trial that enrolled adult patients with locally advanced or metastatic NSCLC with or without actionable genomic alterations who required systemic therapy following prior treatment.2 Those harboring actionable genomic alterations needed to have received prior treatment with an approved targeted therapy and platinum-based chemotherapy.

Patients were randomly assigned to receive Dato-DXd or docetaxel. BICR-assessed PFS and OS served as the trial’s primary end points. Secondary end points comprised ORR, DOR, time to response, DCR, and safety.

Additional data from the pooled analysis of the 2 studies showed that patients previously treated with osimertinib (Tagrisso; n = 96) achieved an ORR of 44.8% (95% CI, 34.6%-55.3%), including CR, PR, and SD rates of 4.2%, 40.6%, and 38.5%, respectively. The median DOR was 6.9 months (95% CI, 4.2-9.8), and the DCR was 85.4% (95% CI, 76.7%-91.8%). The median PFS and OS were 5.7 months (95% CI, 5.4-7.9) and 14.7 months (95% CI, 13.0-18.3), respectively.

Pooled safety data showed the most common any-grade treatment-related adverse effects (TRAEs) included stomatitis (59%), alopecia (49%), nausea (46%), fatigue (18%), decreased appetite (16%), constipation (15%), vomiting (12%), rash (11%), and pruritus (10%). Twenty-three percent of patients had grade 3 or higher TRAEs. Notably, no instances of grade 4 or 5 stomatitis, ocular surface AEs, or adjudicated drug-related interstitial lung disease were reported.

"This breakthrough therapy designation reinforces Dato-DXd as a promising potential therapy for patients with EGFR-mutated lung cancer who continue to face significant unmet needs following disease progression on or after initial treatments,” Susan Galbraith, MBBChir, PhD, executive vice president, Oncology R&D, AstraZeneca, added in a news release.1 “We are proud to have long supported patients with EGFR-mutated lung cancer and look forward to the possibility of bringing another innovative treatment option to this community.”

References

1. Datopotamab deruxtecan granted breakthrough therapy designation in U.S. for patients with previously treated advanced EGFR-mutated non-small cell lung cancer. News release. Daiichi-Sankyo. December 9, 2024. Accessed December 9, 2024. https://www.daiichisankyo.com/files/news/pressrelease/pdf/202412/20241209_E.pdf
2. Datopotamab deruxtecan demonstrated meaningful clinical activity in patients with previously treated advanced EGFR-mutated non-small cell lung cancer in TROPION-Lung05 and TROPION-Lung01 pooled analysis. News release. Daiichi-Sankyo. December 6, 2024. Accessed December 9, 2024. https://www.daiichisankyo.com/files/news/pressrelease/pdf/202412/20241206_E.pdf
3. 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 9, 2024. https://www.astrazeneca.com/media-centre/press-releases/2024/dato-dxd-new-bla-submitted-nsq-bla-withdrawn.html
4. Study of DS-1062a in advanced or metastatic non-small cell lung cancer with actionable genomic alterations (TROPION-Lung05). ClinicalTrials.gov. Updated April 9, 2024. Accessed December 9, 2024. https://clinicaltrials.gov/study/NCT04484142