First-Line Dato-DXd Improves Intracranial Outcomes in Immunotherapy-Ineligible TNBC With Brain Metastases

First-line datopotamab deruxtecan-dlnk (Dato-DXd; Datroway) improved central nervous system (CNS) progression-free survival (PFS) and intracranial response vs investigator's choice of chemotherapy (ICC) in patients with locally recurrent inoperable or metastatic triple-negative breast cancer (TNBC) and baseline brain metastases for whom immunotherapy was not an option, according to an exploratory analysis of the phase 3 TROPION-Breast02 trial (NCT05374512) presented at the 2026 ESMO Congress.¹

Benefit was observed in patients with and without prior CNS-directed therapy, and Dato-DXd also showed consistent systemic efficacy across PFS, overall survival (OS), and objective response rate (ORR) in this subgroup.

Among patients with baseline brain metastases (n = 61), median CNS PFS was 9.5 months (95% CI, 6.9-19.3) with Dato-DXd (n = 35) vs 2.6 months (95% CI, 1.5-5.8) with ICC (n = 26; HR, 0.27; 95% CI, 0.13-0.56). In the subset with measurable intracranial disease, the confirmed intracranial ORR was 62.5% with Dato-DXd (n = 16) vs 37.5% with ICC (n = 8), and the intracranial disease control rate (DCR) at 12 weeks was 75.0% vs 50.0%, respectively.

“Dato-DXd also demonstrated higher intracranial response, … longer duration of response, and most importantly, CNS benefit vs ICC,” said lead study author Rebecca Dent, MD, MSc, of the National Cancer Centre Singapore and Duke-NUS Medical School.

Prior data from TROPION-Breast02 supported the May 2026 FDA approval of Dato-DXd for the treatment of adult patients with unresectable or metastatic TNBC who are not candidates for PD-1/PD-L1 inhibitor therapy.²

What did the intracranial analysis show?

CNS PFS events occurred in 18 patients (51.4%) in the Dato-DXd arm and 16 patients (61.5%) in the ICC arm.¹ Among patients with evaluable intracranial disease, defined as those with baseline and postbaseline brain scans and including both target and nontarget lesions, the confirmed intracranial ORR was 40.0% with Dato-DXd (n = 35; 5 complete responses [CRs] and 9 partial responses [PRs]) vs 13.6% with ICC (n = 22; 0 CRs and 3 PRs). The intracranial DCR at 12 weeks in this population was 85.7% vs 27.3%, respectively.

With Dato-DXd, the longest duration of response (DOR) observed was up to 117 weeks (approximately 27 months). Four of the 5 patients who achieved an intracranial CR with Dato-DXd had not received prior CNS-directed therapy, and responses in patients with measurable disease occurred regardless of prior locoregional therapy.

Investigators also presented the case of a 56-year-old patient with metastases to the brain, lung, and distant and regional lymph nodes who had received neoadjuvant taxane/anthracycline chemotherapy and no prior CNS-directed therapy. She experienced onset of intracranial response at 1.5 months, achieved an intracranial CR, and had an intracranial DOR of 17.8 months across 26 cycles of Dato-DXd.

How did systemic outcomes compare in patients with brain metastases?

Among all patients with baseline brain metastases, median PFS by blinded independent central review (BICR) was 7.7 months with Dato-DXd vs 3.5 months with ICC (HR, 0.37; 95% CI, 0.20-0.72). Median OS was 13.5 months vs 10.7 months, respectively (HR, 0.55; 95% CI, 0.29-1.05), and the respective ORRs by BICR were 62.9% vs 19.2% (odds ratio [OR], 7.11; 95% CI, 2.16-23.41).

In patients with previously treated brain metastases (n = 31), median PFS was 6.8 months with Dato-DXd vs 3.5 months with ICC (HR, 0.43; 95% CI, 0.17-1.11), median OS was 19.3 months vs 12.8 months, respectively (HR, 0.77; 95% CI, 0.28-2.08), and the respective ORRs were 62.5% vs 33.3%.

For patients with previously untreated brain metastases (n = 30), median PFS was 7.7 months for Dato-DXd vs 2.6 months for ICC (HR, 0.29; 95% CI, 0.12-0.76), median OS was 11.6 months vs 9.1 months, repsecitvely (HR, 0.35; 95% CI, 0.14-0.84), and the respective ORRs were 63.2% vs 0%. ORs were not calculated for subgroups with fewer than 20 events across both arms.

For comparison, among patients without baseline brain metastases (n = 583), median PFS was 11.1 months with Dato-DXd vs 5.6 months with ICC (HR, 0.56; 95% CI, 0.46-0.69), median OS was 23.7 months vs 19.3 months, respectively (HR, 0.80; 95% CI, 0.64-1.00), and the respective ORRs were 62.5% vs 30.2%.

How was TROPION-Breast02 designed?

Investigators randomly assigned 644 patients with previously untreated locally recurrent inoperable or metastatic TNBC for whom immunotherapy was not an option 1:1 to receive Dato-DXd at 6 mg/kg intravenously on day 1 of each 3-week cycle (n = 323) or ICC (n = 321), consisting of paclitaxel, nab-paclitaxel (Abraxane), capecitabine, eribulin mesylate, or carboplatin. No minimum disease-free interval (DFI) was required, and patients with asymptomatic treated or untreated brain metastases at baseline were eligible.

PFS by BICR per RECIST 1.1 criteria and OS were the dual primary end points. Randomization was stratified by geographic region, PD-L1 status, and DFI history.

Patients with brain metastases documented at baseline underwent mandated brain MRI or CT at baseline, every 6 weeks for 48 weeks, and every 9 weeks thereafter until RECIST 1.1 progression; intracranial response was assessed per CNS-modified RECIST 1.1 criteria. In the Dato-DXd arm, 16 patients had previously treated, and 19 had previously untreated brain metastases; in the ICC arm, those figures were 15 and 11, respectively.

Baseline characteristics were largely similar between patients with and without brain metastases, although 77% and 81% of patients with brain metastases in the Dato-DXd and ICC arms, respectively, had at least 3 metastatic sites compared with 31% and 29% of those without brain metastases. Prior CNS-directed therapy consisted of radiotherapy alone in 37% vs 58% of patients and radiotherapy plus surgery in 9% vs 0%.

Why do these data matter for patients with TNBC?

Approximately one-third of patients with metastatic TNBC develop brain metastases, with a real-world median OS of approximately 4 to 7 months and a 2-year real-world OS rate of 15%, according to the presentation.

In the overall TROPION-Breast02 population, Dato-DXd previously demonstrated a median PFS by BICR of 10.8 months vs 5.6 months with ICC (HR, 0.57; 99% CI, 0.44-0.73; P < .0001) and a median OS of 23.7 months vs 18.7 months (HR, 0.79; 95.01% CI, 0.64-0.98; P = .029).³

Dent noted that preclinical TNBC models of CNS metastases have shown accumulation of the DXd payload with sustained responses, adding to evidence of DXd activity in the CNS previously observed in patients with HER2-positive breast cancer. She also highlighted that a large proportion of patients in this analysis had not received prior CNS-directed therapy, a population often excluded from clinical trials.

References

1. Dent R, Cescon DW, Jung KH, 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: exploratory analysis of patients with brain metastasis in TROPION-Breast02. Presented at: 2026 ESMO Congress; October 23-27, 2026; Madrid, Spain. Abstract LBA96.
2. Datroway approved in the U.S. as first TROP2 directed antibody drug conjugate for first-line treatment of patients with metastatic triple negative breast cancer who are not PD-1/PD-L1 inhibitor candidates. News release. Daiichi Sankyo. May 22, 2026. Accessed October 24, 2026. https://daiichisankyo.us/web/dsi/press-releases/-/article/datroway-approved-in-the-us-as-first-trop2-directed-antibody-drug-conjugate-for-first-line-treatment-of-patients-with-metastatic-triple-negative-breast-cancer-who-are-not-pd-1pd-l1-inhibitor-candidates
3. Dent R, et al. First-line datopotamab deruxtecan vs chemotherapy in immunotherapy-ineligible metastatic triple-negative breast cancer: phase 3 TROPION-Breast02 results. Presented at: 2025 ESMO Congress; October 17-21, 2025; Berlin, Germany. Abstract LBA21.