Update on HER2-Targeted Therapy in Early Breast Cancer - Episode 6

Adjuvant T-DM1 Therapy for Early-Stage HER2+ Breast Cancer

May 11, 2020
Sara M. Tolaney, MD, MPH

Sara M. Tolaney, MD, MPH: The KATHERINE trial was a study that looked at patients who had residual disease after receiving preoperative chemotherapy and trastuzumab and randomized them to receive 14 cycles of T-DM1 [trastuzumab emtansine] or trastuzumab in the adjuvant setting. Then they looked to see if T-DM1 [trastuzumab emtansine] resulted in fewer recurrences relative to trastuzumab. What was found was that there was a dramatic reduction associated with the use of T-DM1 [trastuzumab emtansine] instead of trastuzumab, with a hazard ratio of about 0.5. So there was a 50% reduction in recurrences from using T-DM1 [trastuzumab emtansine] relative to trastuzumab.

This trial was very exciting because it found benefit regardless of hormone receptor status and regardless of whether patients had received dual HER2 [human epidermal growth factor receptor 2]–directed therapy in the preoperative setting versus not. Really, there wasn’t a subgroup that didn’t benefit from the use of T-DM1 [trastuzumab emtansine] relative to trastuzumab in this study.

One challenge, however, was that T-DM1 [trastuzumab emtansine] did not reduce rates of CNS [central nervous system] recurrence relative to trastuzumab. Rates of CNS recurrence were the same in both arms. I think this continues to be an area that we need to work on. We need to further explore ways to prevent CNS recurrence. Even though T-DM1 [trastuzumab emtansine] is doing a great job at preventing recurrence, in general, we’re not doing very well in regard to preventing those CNS events.

There is further work being done in this area. There is an arm of the COMPASS trial that is taking patients who have residual disease and is randomizing them to receive either T-DM1 [trastuzumab emtansine] or T-DM1 [trastuzumab emtansine] and tucatinib. We know tucatinib is a HER2-directed tyrosine kinase inhibitor that does have CNS penetration and has had activity in the CNS in patients with metastatic disease. We’re hoping that adding tucatinib in this setting may also help prevent CNS recurrences. Certainly, there’s more to come in this area.

There was work done to look at patient-reported outcomes in the KATHERINE study that really showed there was no overall global deterioration in health in the T-DM1 [trastuzumab emtansine] arm relative to the trastuzumab arm. While there were some small changes in the T-DM1 [trastuzumab emtansine] arm with particular symptoms that were slightly worse than with trastuzumab, global health was maintained across both arms.

This is particularly important because we are giving 14 cycles of additional therapy. While T-DM1 [trastuzumab emtansine] is an antibody drug conjugate, technically it is chemotherapy. With prolonged exposure to treatment, we really want to make sure we’re able to maintain patients’ quality of life. In general, I think this shows that T-DM1 [trastuzumab emtansine] is generally well tolerated.

There were some patients who did need to discontinue T-DM1 [trastuzumab emtansine] early. In KATHERINE, approximately 18% of patients did not complete all 14 cycles of therapy. I think this was for a myriad of different reasons. There wasn’t 1 particular toxicity driving discontinuation. But generally speaking, T-DM1 [trastuzumab emtansine] has been very well tolerated. Again, the patient-reported outcomes show very good preservation in global health.

Transcript edited for clarity.