Episode 17: Insights from the KATHERINE Trial: iDFS surrogate endpoint is predictive for OS in breast cancer patients

In this episode of WND Breast, Dr Kevin Punie from GZA Hospitals and Prof Evandro de Azambuja from Institut Jules Bordet will discuss the updated findings of the KATHERINE trial.

The KATHERINE trial recently provided updated results from its phase 3 investigation comparing ado-trastuzumab emtansine (T-DM1) versus trastuzumab among patients with HER2-positive breast cancer. Patients presenting with residual invasive disease after neo-adjuvant treatment and surgery were randomly assigned in a 1:1 ratio within 12 weeks of surgery to receive either 14 cycles of T-DM1 or trastuzumab.

The interim analysis in 2018 revealed a remarkable absolute reduction of 11.3% in iDFS. This statistically significant but also clinically relevant outcome initiated the approval of the drug. Since then, it has been the standard treatment for early HER2+ breast cancer in the neo-adjuvant setting alongside chemotherapy and anti-HER2 agents with invasive disease.

In this latest update, after 8.4 years, there was a slight increase in the magnitude of the benefit on recurrence. Patients treated with 14 cycles of T-DM1 experienced an absolute benefit of 13.7% for iDFS at 7 years, with an HR between 0.5-0.6, compared to those receiving 14 cycles of trastuzumab alone.

There was a 4.5% absolute benefit in OS at a median follow-up of 7 years indicating that effectively more patients are cured, even at stage 4 disease. This outcome is statistically significant and clinically relevant since it translates into a 34% significant reduction in the risk of death.

These findings confirm the current standard treatment and provide an important lesson on the concept of surrogate outcomes in oncology. If only OS, and not iDFS, had been considered as an endpoint, patients may have been hindered from using TDM-1 in positive and urgent settings. Now, this treatment option was available in 2018, following publication and approval based on iDFS, resulting in almost 5% of patients being cured by the drug, while extending the time to recurrence for many more. The acceptance of surrogate outcomes is critical, especially when high-magnitude benefits and good tolerability are achieved and there is a consistent benefit for all subgroups.