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Jan 20, 2025, 13:55

Paolo Tarantino: 10 facts to know on Dato-DXd

Paolo Tarantino, Advanced research fellow at Dana-Farber Cancer Institute, posted on LinkedIn:

“Dato-DXd is the third Topo1 ADC FDA-approved for treating breast cancer. Multiple ongoing phase 3 trials promise to expand its indication to earlier settings, including the curative setting.

Here’s 10 facts to know on Dato-DXd.

1. TARGET

Dato-DXd targets Trop2 (Trophoblast surface antigen 2), a calcium-transducing transmembrane protein with oncogenic potential. Trop2 is broadly expressed across solid tumors, but also expressed in multiple healthy tissues (e.g. skin, cornea and aerodigestive tract).

2. MOLECULE

Dato-DXd is the third DXd ADC to enter clinical testing (T-DXd in 2015, HER3-DXd in 2016, Dato-DXd in 2018). It consists of an anti-Trop2 IgG1 antibody linked to DXd via a tetra peptide linker (same linker-payload vs other DXd ADCs).

3. DAR

Dato-DXd has a lower drug-to-antibody ratio (DAR=4) compared to T-DXd (DAR=8) and SG (DAR=8). This choice was based on preclinical studies in non human primates, which found a higher DAR version of Dato-DXd to cause excessive skin and esophageal toxicity.

4. PK

Dato-DXd has a half life of 4.8 days. This is similar to the half-life of T-DXd (5.7 days) but much longer than the half-life of SG (< 1 day)

5. ACTIVITY

The current approval of Dato-DXd is based on TROPION-Breast01, enrolling pts with chemo-refractory HR+/HER2- MBC. PFS was 6.9 months with Dato-DXd vs 4.9 months with chemo (HR 0.63, p<0.001). OS was 18.6 months with Dato-DXd vs 18.3 months with chemo (HR 1.01, ns).

6. TOXITY

The most common toxicities with Dato-DXd are a mix of DXd-related (nausea 51%, alopecia 36%) or Trop2-related (stomatitis 50%, ocular tox 40%). ILD seems rare (3.3%) but a fatal ILD event did occur in TB-01, as well as in other trials. Warrants proactive monitoring.

7. COMPARISON WITH T-DXd/SG

In similar patients (DB-04), T-DXd showed a larger benefit in PFS (10.1 vs 5.4 mo, HR 0.51, p<0.001) and positive OS. SG was tested in a more pretreated population (TROPiCS-02), and showed a similar PFS improvement (5.5 vs 4 mo; HR 0.66, p=0.0003) and positive OS.

8. ACTIVITY AFTER PRIOR ADCs

In TROPION-Pantumor01, some pts received Dato-DXd after prior T-DXd or SG. Some activity was seen in this setting, but the response rate was lower in Topo1-ADC pretreated (ORR 14% vs 40% in Topo1 naive). TRADE-DXd trial ongoing to address this question.

9. BRAIN METS

Preliminary data suggests intracranial activity for Dato-DXd, with 3/8 intracranial responders in TUXEDO-2 (all in Topo1 ADC naive pts).
At DFCI we’re currently conducting DATO-Base, which evaluates Dato-DXd in patients with HER2- brain mets and/or LMD (n=58).

10. ONGOING DEVELOPMENT

The next Dato-DXd phase 3 trial expected to report in breast oncology is TROPION-Breast02, comparing Dato-DXd to chemo in 1L mTNBC. Additional phase 3 trials are testing Dato-DXd in the neoadjuvant (TB-04), adjuvant (TB-03) setting and in combo with IO for the 1L treatment of PD-L1+ mTNBC (TB-05).”