Update on HER2-Targeted Therapy in Early Breast Cancer - Episode 4

Neoadjuvant T-DM1 in Early-Stage HER2+ Breast Cancer

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

Sara M. Tolaney, MD, MPH: The KRISTINE study looked to explore whether T-DM1 [trastuzumab emtansine] and pertuzumab would be as good as the TCHP [docetaxel, carboplatin, trastuzumab, pertuzumab] regimen. In this trial, patients were randomized to receive 6 cycles of TCHP [docetaxel, carboplatin, trastuzumab, pertuzumab] or 6 cycles of T-DM1 [trastuzumab emtansine] and pertuzumab, and then go to surgery. At the time of surgery, we did see that TCHP [docetaxel, carboplatin, trastuzumab, pertuzumab] was superior to T-DM1 [trastuzumab emtansine] and pertuzumab. We saw higher rates of pathologic complete response in patients getting TCHP [docetaxel, carboplatin, trastuzumab, pertuzumab] relative to T-DM1 [trastuzumab emtansine] and pertuzumab.

However, I think it’s important to note, there was less toxicity in the T-DM1 [trastuzumab emtansine]–pertuzumab arm. Interestingly, this study also followed patients after surgery. Patients on TCHP [docetaxel, carboplatin, trastuzumab, pertuzumab] continue on trastuzumab and pertuzumab, whereas patients who got T-DM1 [trastuzumab emtansine] and pertuzumab continued on that treatment. Then investigators looked at long-term outcomes. One interesting thing that was seen was that there were more patients on the T-DM1 [trastuzumab emtansine] and pertuzumab who experienced local-regional recurrences prior to going to surgery.

Interestingly, when you dug down into those patients who experienced local-regional recurrence, you can see that about two-thirds of those patients actually had HER2 [human epidermal growth factor receptor 2] 2+ tumors. This suggested that patients with HER2 heterogeneity are experiencing local-regional progression on T-DM1 [trastuzumab emtansine] and pertuzumab, which probably contributed to the differences we were seeing in terms of pathologic complete response rates between the 2 arms.

When you actually follow those patients long-term and look at invasive disease-free survival, the invasive disease-free survival is similar in the 2 arms, with the curves overlapping. Event-free survival was certainly better with TCHP [docetaxel, carboplatin, trastuzumab, pertuzumab] compared with T-DM1 [trastuzumab emtansine] and pertuzumab, but the invasive disease-free survival is actually quite similar. What this really tells me is that a patient without a heterogeneous HER2-positive tumor may do just as well with T-DM1 [trastuzumab emtansine] and pertuzumab as they would do with TCHP [docetaxel, carboplatin, trastuzumab, pertuzumab], regarding long-term outcomes.

This is quite important, because T-DM1 [trastuzumab emtansine] and pertuzumab is so much better tolerated than TCHP [docetaxel, carboplatin, trastuzumab, pertuzumab]. If we could identify those patients who do not have HER2 heterogeneity, these are potentially the patients who could omit standard chemotherapy and do just as well with T-DM1 [trastuzumab emtansine] and pertuzumab.

There was also the PREDIX HER2 trial that compared THP [docetaxel, trastuzumab, pertuzumab] to T-DM1 [trastuzumab emtansine], and found very similar rates of pathologic complete response—45% and 47% in each arm. Again, this suggested that T-DM1 [trastuzumab emtansine] performs quite similarly to chemotherapy and trastuzumab and pertuzumab.

The THP [docetaxel, trastuzumab, pertuzumab] regimen is probably not quite as good as the TCHP [docetaxel, carboplatin, trastuzumab, pertuzumab] regimen that was looked at in the KRISTINE trial. In KRISTINE, we did see a higher pathologic complete response compared with T-DM1 [trastuzumab emtansine]. But I think the study just suggests that T-DM1 [trastuzumab emtansine]–based therapy can be very effective, even in early HER2-positive disease. We really need to move forward trying to best select those patients who don’t have heterogeneous HER2 positivity, because those patients may potentially be able to de-escalate from a standard chemotherapy regimen to T-DM1 [trastuzumab emtansine] in the future.

Transcript edited for clarity.