How Dato-DXd and the TROPION Trials Are Transforming Solid Tumor Research

Dato-DXd is being assessed in numerous trials across the breast, lung, and bladder cancer spaces.

Datopotamab deruxtecan-dlnk (Dato-DXd; Datroway) has arrived on the breast cancer scene, showing positive results for patients within different indications. However, Dato-DXd is not solely for patients with breast cancer and is being investigated among patients with lung and bladder cancers.

In 2025, the FDA approved Dato-DXd for patients with unresectable or metastatic hormone receptor–positive, HER2-negative breast cancer as well as EGFR-mutated non–small cell lung cancer (NSCLC).1,2 These 2 approval indications show the diversity of the treatment.

In an overarching presentation at the 16th Annual World Antibody Drug Conjugate Conference in San Diego, CA, Federico Nasroulah, MD, executive director, Global Clinical Lead of Oncology Clinical Development at Daiichi Sankyo, highlighted various clinical trials assessing Dato-DXd.3

Throughout his presentation, Nasroulah covered top trials including the phase 3 TROPION-Breast01 (NCT05104866), the phase 1/2 BEGONIA (NCT03742102), the phase 3 TROPION-Breast02 (NCT05374512), and the phase 1 TROPION-PanTumor01 (NCT03401385) trials.

Dato-DXd’s Mechanism of Action

Dato-DXd is comprised of 3 components, including a humanized anti-TROP2 immunoglobulin 1 monoclonal antibody, a tetrapeptide cleavable linker, and a topoisomerase I inhibitor payload.4

Nasroulah said that TROP2 is highly expressed in solid tumors like lung and breast cancer. He also highlighted that Dato-DXd was created as a TROP2-directed antibody drug conjugate (ADC) with a stable linker that selectively targets and delivers a highly potent cytotoxic payload to the cells.

TROPION-Breast01

This trial assessed Dato-DXd at 6 mg/kg intravenously on day 1 every 3 weeks (n = 365) vs investigator’s choice of chemotherapy (ICC) as per protocol directions (n = 367) for patients with previously treated HR–positive/HER2-negative breast cancer.5

The median progression-free survival (PFS) was 6.9 months (95% CI, 5.7-7.4) in the Dato-Dxd arm vs 4.9 months (95% CI, 4.2-5.5) in the ICC arm (HR, 0.63; 95% CI, 0.52-0.76; P <.0001). The median overall survival (OS) was 18.6 months (95% CI, 17.3-20.1) vs 18.3 months (95% CI, 17.3-20.5) between either arm, respectively (HR, 1.01; 95% CI, 0.83-1.22). Nasroulah noted that this did not meet the primary end point of OS.6

The trial also looked at efficacy after adjusting for subsequent ADC therapy. The median OS was 19.1 months with Dato-DXd vs 17.5 months with ICC (HR, 0.86; 95% CI, 0.70-1.06).

The overall response rate (ORR) was 36.4% in the Dato-DXd arm vs 22.9% in the ICC arm.

Regarding safety, 22% vs 46% of patients in each arm had grade 3 or higher adverse effects (AEs), and serious AEs occurred in 6% vs 9%. The median treatment duration was 6.7 months vs 4.1 months. The most common treatment-related AEs (TRAEs) included nausea (51.9% vs 23.6%), stomatitis (51.4% vs 13.1%), alopecia (36.4% vs 21.4%), and fatigue (25.0% vs 18.2%).

“TROPION-Breast01 met its primary end point of PFS, with a statistically significant and clinically meaningful improvement with Dato-DXd vs ICC. The dual primary end point of OS was not statistically significant; subsequent ADC treatment may have affected survival results,” Nasroulah said.

BEGONIA

For this trial of patients with triple-negative breast cancer (TNBC), arms 7 and 8 were the focus of this presentation.7 In arm 7 (n = 62), patients with any PD-L1 expression were treated with Dato-DXd at 6 mg/kg intravenously every 3 weeks plus durvalumab (Imfinzi) at 1120 mg intravenously every 3 weeks. In arm 8 (n = 33), patients with PD-L1 high tumors were given Dato-DXd at 6 mg/kg intravenously every 3 weeks plus durvalumab at 1120 mg intravenously every 3 weeks.

Data showed that 11.3% of patients had PD-L1 high tumors vs 87.1% having PD-L1 low tumors. In arm 7, the confirmed ORR was 79.0% (95% CI, 66.8%-88.3%), with a complete response (CR) of 12.9%, a partial response (PR) rate of 66.1%, a stable disease rate of 12.9%, and a progressive disease rate of 6.5%. In arm 8, the confirmed ORR was 81.8% (95% CI, 64.5%-93.0%). The CR rate was 6.1%, the PR rate was 75.8%, the stable disease rate was 15.2%, and the progressive disease rate was 3.0%.

Any treatment-emergent AEs (TEAEs) occurred in 100% of patients in each arm. Serious AEs occurred in 29.0% vs 15.2%, and TEAEs leading to death were observed in 1.6% vs 0.0%. The most common any-grade TEAEs included stomatitis (69.4% vs 81.5%), nausea (67.7% vs 54.5%), alopecia (50.0% vs 39.4%), and constipation (50.0% vs 30.3%).

“The combination of Dato-DXd plus durvalumab demonstrated robust antitumor activity in patients with advanced/metastatic TNBC with any PD-L1 expression (arm 7) and in those with high PD-L1 expression (arm 8),” Nasroulah said.

TROPION-Breast02

Patients with locally recurrent inoperable or metastatic TNBC were treated with either Dato-DXd at 6 mg/kg on day 1 every 3 weeks (n = 323) or ICC (n = 321).8

The median PFS by BICR was 10.8 months (95% CI, 8.6-13.0) in the Dato-DXd arm and 5.6 months (95% CI, 5.0-7.0) in the ICC arm (HR, 0.57; 95% CI, 0.47-0.69; P <.0001). The median PFS by investigator assessment was 9.6 months (95% CI, 7.4-11.2) vs 5.2 months (95% CI, 4.2-5.6) between each arm (HR, 0.56; 95% CI, 0.47-0.67). The median OS was 23.7 months (95% CI, 19.8-25.6) vs 18.7 months (95% CI, 16.0-21.8; HR, 0.79; 95% CI, 0.64-0.98; P = .0291).

Response by BICR showed an ORR of 62.5% in the Dato-DXd arm vs 29.3% in the ICC arm (OR, 4.24; 95% CI, 3.03-5.95). Additionally, a CR was noted in 9.0% vs 2.5%, a PR in 53.6% vs 26.8%, stable disease in 26.9% vs 47.0%, and progressive disease in 8.4% vs 16.2%. The median duration of response was 12.3 months (95% CI, 9.1-15.9) vs 7.1 months (95% CI, 5.6-8.9).

Any grade TRAEs were noted in 93% of patients in the Dato-DXd arm vs 83% in the ICC arm, with serious TRAEs occurring in 9% vs 8%. The most common TRAEs included dry eye (24% vs 3%), stomatitis (57% vs 9%), and nausea (45% vs 17%).

AEs of special interest that were grade 1 included oral mucositis/stomatitis (24% vs 7%), ocular surface events (24% vs 3%), and adjudicated drug-related interstitial lung disease/pneumonitis (<1% vs <1%).

“TROPION-Breast02 enrolled patients who are representative of the real-world TNBC population, including those often excluded from clinical trials,” Nasroulah concluded.

Dato-DXd in Lung Cancer

Various TROPION-Lung trials are underway assessing Dato-DXd in patients with lung cancer. Results from the phase 2 TROPION-Lung05 trial (NCT04484142) led to the FDA approval of Dato-DXd in NSCLC.2

Bladder Cancer and Dato-DXd

The TROPION PanTumor01 trial assessed patients with different solid tumors. One of the cohorts includes patients with bladder cancer. Dato-DXd was given at 6 mg/kg every 3 weeks (n = 40).9

The ORR by BICR was 25.0% (95% CI, 12.7%-41.2%), with a disease control rate of 77.5% (95% CI, 61.5%-89.2%), a CR rate of 2.5%, a PR rate of 22.5%, a stable disease rate of 50.0%, and a progressive disease rate of 12.5%. The median duration of response (DOR) was not evaluable (NE). The ORR by investigator assessment was 30.0%, with all responses being PRs. The median PFS was 6.9 months (95% CI, 2.9-NE).

Any-grade TEAEs occurred in 98% of patients, of which 88% were treatment-related and 43% were serious. TEAEs associated with death occurred in 5% of patients. The 2 deaths that occurred were not related to Dato-DXd.

Grade 1 TRAEs were stomatitis (28%), nausea (28%), decreased appetite (23%), alopecia (18%), and fatigue (13%).

TROPION-PanTumor03

The phase 2 TROPION-PanTumor03 trial (NCT05489211) assessed patients with unresectable, locally advanced/metastatic urothelial carcinoma. Patients were given Dato-DXd at 6 mg/kg intravenously every 3 weeks plus rilvegostomig every 3 weeks.

For patients who were in the first-line setting and were platinum ineligible (n = 22), the confirmed ORR was 68.2% (95% CI, 45.1%-86.1%), with a DCR at 12 weeks of 95.5% (95% CI, 83.4%-99.5%). The median DOR was not calculable (NC). For patients in the second-line setting (n = 18), the confirmed ORR was 38.9% (95% CI, 17.3%-64.3%), with a DCR at 12 weeks of 83.3% (95% CI, 66.6%-93.7%). The median DOR was NC.

For patients in the first line who are cisplatin ineligible, the PFS by investigator response was NC (95% CI, 10.8-NC), the 6-month rate was 85.9% (95% CI, 62.4%-95.2%), and the 12-month rate was 73.5% (95% CI, 46.5%-88.4%). In the second line, the median PFS was 12.5 months (95% CI, 4.2-NC), with a 6-month rate of 72.2% (95% CI, 45.6%-87.4%) and a 12-month rate of 60.0% (95% CI, 33.7%-78.7%).

“These results warrant further exploration of Dato-DXd plus rilvegostomig in the first-line locally advanced/metastatic urothelial carcinoma setting,” Nasroulah concluded.

References

1. FDA approves datopotamab deruxtecan-dlnk for unresectable or metastatic, HR-positive, HER2-negative breast cancer. News release. FDA. January 17, 2025. Accessed November 5, 2025. https://tinyurl.com/yt69zyj8
2. FDA grants accelerated approval to datopotamab deruxtecan-dlnk for EGFR-mutated non-small cell lung cancer. News release. FDA. June 23, 2025. Accessed November 5, 2025. https://tinyurl.com/4mjxcsts
3. Nasroulah F. Exploring the clinical profile and journey of datopotamab deruxtecan from TROPION Breast trials & assessing future direction in solid tumors. Presented at the 16th Annual World Antibody Drug Conjugate Conference, San Diego, CA; November 3-6, 2025.
4. Okajima D, Yasuda S, Maejima T, et al. Datopotamab deruxtecan, a novel TROP2-directed antibody-drug conjugate, demonstrates potent antitumor activity by efficient drug delivery to tumor cells. Mol Cancer Ther. 2021;20(12):2329-2340. doi:10.1158/1535-7163.MCT-21-0206
5. Bardia A, Jhaveri K, Im SA, et al. Datopotamab deruxtecan versus chemotherapy in previously treated inoperable/metastatic hormone receptor-positive Human Epidermal Growth Factor Receptor 2-negative breast cancer: primary results from TROPION-Breast01. J Clin Oncol. 2025;43(3):285-296. doi:10.1200/JCO.24.00920
6. Pistilli B, Jhaveri K, Pernas Simon S, et al. VP1-2025: Datopotamab deruxtecan (Dato-DXd) vs chemotherapy (CT) in previously-treated inoperable or metastatic hormone receptor-positive, HER2-negative (HR+/HER2–) breast cancer (BC): Final overall survival (OS) from the phase III TROPION-Breast01 trial. Annal Oncol. 2023. doi:10.1016/j.annonc.2025.01.009
7. BEGONIA trial reports durable efficacy of datopotamab deruxtecan and durvalumab in advanced triple-negative breast cancer. News release. OncoDaily. October 19, 2025. Accessed November 5, 2025. https://tinyurl.com/4snknasj
8. Dent RA, Shao Z, Schmid P, et al. First-line datopotamab deruxtecan (Dato-DXd) vs chemotherapy in patients with locally recurrent inoperable or metastatic triple-negative breast cancer (TNBC) for whom immunotherapy was not an option: Primary results from the randomised, phase 3 TROPION-Breast02 trial. Presented at: 2025 ESMO Congress; October 17-21, 2025; Berlin, Germany. Abstract LBA21.
9. Meric-Bernstam F, Alhalabi O, Lisberg A, et al. Datopotamab deruxtecan (Dato-DXd) in locally advanced/metastatic urothelial cancer: updated results from the phase 1 TROPIONPanTumor01 study. J Clin Oncol. 2025;43(suppl 5):663. doi:10.1200/JCO.2025.43.5_suppl.663
10. Rha SY, Lim SH, Zhou Fangjian, et al. Datopotamab deruxtecan (Dato-DXd) + rilvegostomig (rilve) in patients (pts) with locally advanced or metastatic urothelial cancer (a/mUC): Results from the phase II TROPION-PanTumor03 study. Presented at the European Society for Medical Oncology 2025, Berlin, Germany; October 17-21, 2025. Abstract 3072MO