Subgroup Analyses of KATHERINE Trial Promote T-DM1 Use in High-Risk Groups

The KATHERINE trial found a clinical benefit without increasing the risk of CNS recurrence for patients with HER2-positive early breast cancer treated with T-DM1.

Compared with trastuzumab (Herceptin), adjuvant trastuzumab emtansine (T-DM1; Kadcyla) did not increase the risk of central nervous system (CNS) recurrence while offering a clinical benefit for patients with HER2-positive early breast cancer across subgroups, according to data published in Annals of Oncology.

The subgroup analyses in the KATHERINE trial (NCT01772472) included patients with residual invasive disease after neoadjuvant chemotherapy plus trastuzumab, focusing on small tumors and particularly high-risk disease.

Patients were enrolled and randomized to receive either adjuvant T-DM1 (n = 743) or trastuzumab (n = 743) over a period of 14 cycles.

The research team found there was a decreased risk of recurrence or death for patients treated with T-DM1 compared with trastuzumab, including those who received anthracycline-based neoadjuvant chemotherapy (HR, 0.51; 95% CI, 0.38–0.67) or nonanthracycline-based neoadjuvant chemotherapy (HR, 0.43; 95% CI, 0.22–0.82), presented with cT1, cN0 tumors (0 versus 6 invasive disease-free survival events [IDFS]), or presented with high-risk tumors.

While there was no observed association between T-DM1 and a difference in the risk of CNS recurrence, the data showed that the CNS was more commonly the first site of recurrence for patients in the experimental arm (5.9%) compared with the trastuzumab arm (4.3%).

“In KATHERINE, there was a numerically higher incidence of CNS recurrence as the first IDFS event in the T-DM1 versus the trastuzumab arm. The data presented here suggest that this increased incidence is a result of competing risk as observed in trastuzumab trials,” wrote the investigators. “Specifically, substantial reduction in the incidence of non-CNS recurrences as a first event observed with T-DM1 resulted in an increased likelihood of a CNS recurrence as a first event and as the only site of recurrence.”

Focusing on treatment-emergent peripheral neuropathy, patients receiving T-DM1 had a higher incidence rate (32.3%) compared with patients receiving trastuzumab (16.9%). More, an increase in all-grade peripheral neuropathy was observed for patients with baseline peripheral neuropathy who were treated with T-DM1 (36.3%) versus those without baseline peripheral neuropathy (31.1%). For patients treated with trastuzumab, similar rates were observed with (17.5%) or without (16.8%) baseline peripheral neuropathy.

“In our analysis, patients with baseline peripheral neuropathy (grade 1) who received T-DM1 had a higher incidence of grade 2 and 3 peripheral neuropathy,” wrote the investigators. “However, regardless of treatment group, baseline peripheral neuropathy was associated with longer duration and lower resolution rates of peripheral neuropathy, suggesting that pre-existing peripheral neuropathy is a risk factor irrespective of HER2-targeted treatment type.”

Overall, baseline peripheral neuropathy was associated with extended median duration of peripheral neuropathy (105-109 days longer) and lower resolution rates of neuropathy (65% vs 83%) regardless of treatment arm.

More, an association was found between prior platinum therapy and increased grade 3/4 thrombocytopenia for patients receiving T-DM1 (13.5%) compared with those treated with trastuzumab (3.8%).

Limitations of the research included statistical and methodological issues, although the investigative team was reassured with the results as they aligned well with previously reported data in this area of research.

Moving forward, the investigators emphasized that these data have the potential to support clinicians in their use of adjuvant T-DM1 as the new standard of care for patients with this tumor type.


Mamounas EP, Untch M, Mano MS, et al. Adjuvant T-DM1 versus Trastuzumab in Patients with Residual Invasive Disease after Neoadjuvant Therapy for HER2-Positive Breast Cancer: Subgroup Analyses from KATHERINE. Ann Oncol. April 28, 2021. doi:10.1016/j.annonc.2021.04.011