KATHERINE Final Analysis: Trastuzumab Emtansine Superior to Trastuzumab Post-Neoadjuvant

Adjuvant T-DM1 significantly improves long-term invasive disease–free and overall survival versus trastuzumab in residual HER2-positive early breast cancer post-neoadjuvant therapy, a new study finds.

In a pivotal update to the phase 3 KATHERINE trial, published in NEJM (January 2025), trastuzumab emtansine (T-DM1) has demonstrated sustained superiority over trastuzumab in patients with residual invasive HER2-positive early breast cancer following neoadjuvant therapy. With a median follow-up of 8.4 years, T-DM1 significantly improved both invasive disease–free survival (IDFS) and overall survival (OS), reinforcing its role as standard adjuvant therapy in this high-risk population.

The KATHERINE trial randomized 1486 patients with HER2-positive early breast cancer who had residual invasive disease post-neoadjuvant taxane-based chemotherapy and trastuzumab. Patients received either adjuvant T-DM1 (3.6 mg/kg IV q3w) or trastuzumab (6 mg/kg IV q3w) for 14 cycles. Final analysis reports a 46% relative reduction in the risk of invasive disease or death with T-DM1 versus trastuzumab (HR, 0.54; 95% CI, 0.44–0.66), with 7-year IDFS rates of 80.8% and 67.1%, respectively—an absolute benefit of 13.7 percentage points.

Importantly, this updated report marks the first time the overall survival benefit with adjuvant T-DM1 has reached statistical significance. The hazard ratio for death was 0.66 (95% CI, 0.51–0.87; P = 0.003), translating to a 7-year OS of 89.1% with T-DM1 versus 84.4% with trastuzumab—a clinically meaningful absolute gain of 4.7 percentage points.

Subgroup analyses reaffirmed benefit across multiple high-risk cohorts, including those with inoperable disease at baseline, residual nodal positivity post-neoadjuvant therapy, and both hormone receptor–positive and –negative subtypes. However, patients with IHC 2+ and ISH-amplified tumors derived less IDFS benefit (HR, 0.84) than the IHC 3+ group (HR, 0.47), aligning with prior findings that HER2 expression heterogeneity may modulate response to T-DM1.

Safety outcomes remained consistent with prior reports. Grade ≥3 adverse events occurred more frequently with T-DM1 (26.1%) than with trastuzumab (15.7%), primarily due to thrombocytopenia and elevated transaminases. However, no new safety signals emerged with long-term follow-up. Post-treatment adverse cardiac events and hepatobiliary toxicity were rare and manageable.

Of note, the incidence of CNS recurrence as first metastatic event was higher in the T-DM1 group (7.0% vs. 5.1%); however, cumulative CNS events were similar between arms, likely reflecting a shift in metastatic pattern due to improved extracranial control.

These findings solidify adjuvant T-DM1 as the standard of care in patients with residual HER2-positive disease following neoadjuvant therapy. Nevertheless, the residual risk of recurrence in certain subsets—particularly those with IHC 2+ tumors or high nodal burden—underscores the need for further intensification strategies.

Ongoing trials such as DESTINY-Breast05 (trastuzumab deruxtecan vs T-DM1), CompassHER2 RD (T-DM1 ± tucatinib), and ASTEFANIA (T-DM1 ± atezolizumab) aim to address these unmet needs in the adjuvant setting.

Reference: Geyer CE Jr. et al. N Engl J Med. 2025;392:249–257. DOI:10.1056/NEJMoa2406070.