What is the intracranial response rate of Tucatinib (Oral Tyrosine Kinase Inhibitor) vs TDxd (likely a chemotherapy regimen) in patients with HER2-positive breast cancer and brain metastases?

Intracranial Response Rates: T-DXd vs Tucatinib Combination

T-DXd demonstrates a higher intracranial objective response rate (71.7% overall) compared to tucatinib combination therapy (47.3%), based on the most recent 2025 guideline data from DESTINY-Breast12 and HER2CLIMB trials. 1

Comparative Intracranial Response Rates

T-DXd (Trastuzumab Deruxtecan)

In the DESTINY-Breast12 trial, T-DXd achieved superior intracranial response rates across all brain metastases populations: 1

• Overall brain metastases cohort: 71.7% (95% CI, 64.2–79.3) 1
• Stable brain metastases: 79.2% (95% CI, 70.2–88.3) 1
• Active brain metastases: 62.3% (95% CI, 50.1–74.5) 1

A pooled analysis of DEBBRAH, TUXEDO-1, and DFCI/Duke/MDACC cohorts confirmed these findings with an intracranial ORR of 64.9% (95% CI 47.5% to 79.8%) in patients with active brain metastases. 2

Tucatinib Combination (with Trastuzumab and Capecitabine)

In the HER2CLIMB trial, the tucatinib combination demonstrated lower but still clinically meaningful intracranial response rates: 3

• Intracranial ORR in measurable disease: 47.3% (95% CI, 33.7% to 61.2%) 3
• This represented a statistically significant improvement over placebo combination (20.0%; 95% CI, 5.7% to 43.7%; P = 0.03) 3

Clinical Context and Treatment Selection

Despite T-DXd's higher response rate, both agents demonstrate robust intracranial activity and the choice depends on clinical context: 1

When T-DXd May Be Preferred

• Predominantly extracranial disease burden with concurrent brain metastases 1
• Earlier lines of therapy (second-line setting after trastuzumab/pertuzumab) 4
• Both stable and active brain metastases show comparable efficacy 1

When Tucatinib Combination May Be Preferred

• Predominantly CNS disease burden 1
• After progression on T-DXd 1
• Superior CNS-specific progression-free survival data: median CNS-PFS of 9.9 months vs 4.2 months with placebo (HR 0.32; 95% CI, 0.22-0.48) 3
• Proven survival benefit: median OS 21.6 months vs 12.5 months with placebo in brain metastases population 5

Duration of Response Considerations

T-DXd demonstrates higher initial response rates, but tucatinib shows sustained CNS control: 1, 3

• Tucatinib combination achieved median duration of intracranial response of 8.6 months (95% CI, 5.5-10.3) 5
• The 12-month CNS-PFS rate with tucatinib was 61.6% in the overall brain metastases cohort 1
• T-DXd showed 12-month OS rate of 86.1% in patients with active brain metastases 1

Expert Consensus on Sequencing

Current expert consensus (98% agreement) supports the sequence: trastuzumab/pertuzumab → T-DXd → tucatinib/trastuzumab/capecitabine 4

This sequencing strategy maximizes the use of both highly active CNS-penetrant agents while reserving tucatinib combination for situations where its specific CNS activity profile may be most beneficial. 1

Important Caveats

Both agents can be used regardless of brain metastases status based on recent data, making the presence of brain metastases less determinative of treatment choice than previously thought. 1

Radiotherapy timing considerations: Recent evidence suggests potential increased radionecrosis risk when combining ADCs (like T-DXd) with stereotactic radiosurgery, warranting caution with concurrent administration. 1 Tucatinib with SRS appears safe with only 4% symptomatic radiation necrosis rate. 6