FDA Grants Datopotamab Deruxtecan Priority Review for EGFR-Mutated NSCLC

Datopotamab deruxtecan (Dato-DXd; AstraZeneca) was granted priority review by the FDA for treatment of adult patients with locally advanced or metastatic epidermal growth factor receptor-mutated (EGFRm) non-small cell lung cancer (NSCLC) who have received prior systemic therapies, including an EGFR-directed therapy.

AI x-ray illustration of lung cancer | Image Credit: © Moon Story - stock.adobe.com

NSCLC accounts for approximately 80% of all lung cancer diagnoses, with an estimated 10% to 15% in the US and Europe and 30% to 40% in Asia having an EGFR mutation. First-line treatment for EGFRm NSCLC are EGFR–tyrosine kinase inhibitors, which have improved outcomes in early settings. However, patients often experience disease progression and require subsequent therapies.¹

“Acquired resistance to front-line therapies and, ultimately, disease progression are unfortunate realities for most patients with advanced [EGFRm NSCLC],” 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 [dato-DXd] to provide a much-needed option to patients whose disease has become resistant to current treatments.”¹

Dato-DXd is an investigational TROP2-directed antibody drug conjugate (ADC) that is comprised of a humanized anti-TROP2 immunoglobulin G1 monoclonal antibody attached to multiple topoisomerase I inhibitor payloads (an exatecan derivative, DXd). In December 2024, it was granted a breakthrough therapy designation based on data from the TROPION-Lung05 phase 2 trial (NCT04484142) and supported by data from the TROPION-Lung01 phase 3 trial (NCT04656652). These data also led to FDA acceptance and priority review of the dato-DXd biologics license application.^1-4

As of January 2025, dato-DXd is only approved in Japan under the brand name Datroway for the treatment of patients with unresectable or recurrent hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer after prior chemotherapy.¹

In the global, multicenter, single-arm, open-label phase 2 TROPION-Lung05 trial, researchers evaluated the efficacy and safety of dato-DXd in patients with locally advanced or metastatic NSCLC with actionable genomic alterations who have progressed on at least 1 tyrosine kinase inhibitor and on or after 1 regimen of platinum-based chemotherapy. According to the data, patients in the overall population who received dato-DXd had a 35.8% overall response rate (95% CI, 27.8 to 44.4), compared with 43.6% of patients with EGFR mutations (95% CI, 32.4 to 55.3). There was a reported median duration of response of 7.0 months (95% CI, 4.2 to 9.8), with an overall disease control rate of 78.8% (95% CI, 71.0 to 85.3).^1,5

TROPION-Lung01 is a global, randomized, multicenter, open-label phase 3 trial evaluating the efficacy and safety of dato-DXd vs docetaxel (Docefrez; Sun Pharmaceutical Industries Europe BV) in adult patients with locally advanced or metastatic NSCLC with and without actionable genomic alterations who require systemic therapy following prior treatment. In this trial, dato-DXd treatment was associated with a median progression-free survival of 4.4 months (95% CI, 4.2 to 5.6) and overall survival of 12.9 months (95% CI, 11.0 to 13.9).^1,6

The FDA designations were also supported by data from the first-in-human, open-label, 2-part, multicenter phase 1 TROPION-PanTumor01 trial (NCT03401385) evaluating the safety and preliminary efficacy of dato-DXd in patients with advanced solid tumors who are relapsed or refractory to standard treatment.^1,7

“Treating advanced [EGFRm NSCLC] 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, [dato-DXd] could become the first TROP2-directed [ADC] 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. 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. 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

3. Study of DS-1062a in advanced or metastatic non-small cell lung cancer with actionable genomic alterations (TROPION-Lung05). Updated April 29, 2024. Accessed January 13, 2025. https://www.clinicaltrials.gov/study/NCT04484142?term=tropion-lung05&rank=1

4. Study of DS-1062a versus docetaxel in previously treated advanced or metastatic non-small cell lung cancer with or without actionable genomic alterations (TROPION-LUNG01). Updated December 18, 2024. Accessed January 13, 2025. https://clinicaltrials.gov/study/NCT04656652

5. Sands J, Ahn M, Lisberg A, 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. J Clin Oncol. January 6, 2025. doi:10.1200/JCO-24-01349

6. Ahn M, Tanaka K, Paz-Ares L, et al. Datopotamab deruxtecan versus docetaxel for previously treated advanced or metastatic non–small cell lung cancer: the randomized, open-label phase III TROPION-Lung01 study. J Clin Oncol. September 9, 2024. doi:10.1200/JCO-24-01544

7. First-in-human Study of DS-1062a for advanced solid tumors (TROPION-PanTumor01). Updated December 3, 2024. Accessed January 13, 2025. https://clinicaltrials.gov/study/NCT03401385?term=TROPION-PanTumor01&rank=1