Safety Analysis Supports Adjuvant T-DM1 Use in Early HER2+ Breast Cancer

Michael Untch, MD, PhD

Findings from a secondary analysis of the phase III KATHERINE trial showed that adjuvant ado-trastuzumab emtansine (T-DM1; Kadcyla) has a comparable safety profile with adjuvant trastuzumab (Herceptin) regarding the rate of peripheral neuropathy, thrombocytopenia, and CNS recurrence in patients with HER2-positive early breast cancer.¹

Previous data from KATHERINE² demonstrated a 50% reduction in the risk of invasive disease recurrence or death with the use of adjuvant ado-trastuzumab emtansine in women with residual HER2-positive early breast cancer following neoadjuvant trastuzumab and chemotherapy, which led to the regimen’s approval for this indication in May 2019.

According to results from the secondary analysis, baseline neuropathy was not associated with a higher incidence of peripheral neuropathy in the T-DM1 or trastuzumab arms, but did correlate with a longer median duration of peripheral neuropathy and a lower resolution rate in the T-DM1 arm compared with the trastuzumab arm (352-337 days, 66%-64% vs 243-232 days, 81%-83%, respectively).

Additionally, prior platinum was associated with a higher incidence of all-grade thrombocytopenia in the T-DM1 arm versus the trastuzumab arm, at 36% versus 27%, respectively. However, investigators reported that for grade 3/4 thrombocytopenia, the median duration and resolution were similar between the 2 arms, regardless of prior platinum.

In terms of CNS recurrence, patients who received T-DM1 had a numerically higher rate of CNS recurrence compared with those who received trastuzumab. However, T-DM1 was not associated with an adverse impact on overall survival.

“We don't have to worry about long-term adverse events with [T-DM1], said Michael Untch, MD, PhD, professor and chief physician, Obstetrics and Gynecology, Helios Hospital Berlin-Buch. We now have a blueprint for adjuvant treatment with the data from KATHERINE; these data have given us perspective on how to treat our patients.”

In an interview with OncLive, Untch, discussed the primary findings from the phase III KATHERINE trial and the added impact of long-term safety data regarding the use of adjuvant T-DM1 in early-stage HER2-positive breast cancer.

OncLive: Could you discuss the initial results of the KATHERINE trial?

Untch: The KATHERINE trial changed the treatment paradigm for patients with aggressive [early-stage HER2-positive] breast cancer by introducing [a new adjuvant] therapy. Patients with aggressive triple-negative breast cancer or HER2-positive breast cancer need neoadjuvant therapy. In the setting of HER2-positive breast cancer, patients will receive at least 6 cycles of chemotherapy plus the addition of an anti-HER2 treatment: either trastuzumab or the combination of trastuzumab and pertuzumab (Perjeta). Patients who have a pathologic complete response (pCR) [to neoadjuvant therapy] do well, whereas patients who do not have a pCR need additional treatment. In the KATHERINE trial, investigators evaluated the use of standard-of-care trastuzumab in patients with residual disease following neoadjuvant therapy versus the antibody-drug conjugate (ADC) T-DM1.

The primary results were published in the New England Journal of Medicine in December 2018 and showed that patients with residual disease in the breast or lymph nodes after neoadjuvant therapy, had a 50% relative reduction in the risk of recurrence and metastasis with adjuvant T-DM1 versus trastuzumab. Since these data were published, national and international guidelines have introduced T-DM1 as a standard adjuvant therapy in patients who have residual disease after neoadjuvant therapy.

At the 2019 ESMO Congress, you presented results from a secondary analysis regarding the safety of this approach. What were the key takeaways from this trial?

The second analysis focused on 3 events: peripheral neuropathy, thrombocytopenia, and CNS metastasis. We saw that patients who finished their neoadjuvant therapy still had some degree of peripheral neuropathy due to the taxanes. We wanted to see whether the addition of T-DM1 had an influence on the development of peripheral neuropathy and the resolution rate compared with trastuzumab. We found that patients who received T-DM1 had a somewhat higher incidence of peripheral neuropathy versus trastuzumab. However, the resolution rate was very good. [The peripheral neuropathy resolved] after approximately 1 year. Notably, we didn’t see a high level of high-grade peripheral neuropathy caused by T-DM1.

We knew that patients who received platinum as part of their neoadjuvant therapy had a higher incidence of thrombocytopenia, especially if they were treated with T-DM1. Encouragingly, after about 30 days, we saw a 90% to 95% resolution rate [of this event].

Finally, we know CNS recurrence is a major problem in approximately 5% of patients with high-risk TNBC or HER2-positive breast cancer. In the KATHERINE trial, we saw that approximately 5% of patients had CNS metastasis in both arms. T-DM1 did not have an effect on CNS metastasis. It seemed that the first event of CNS metastasis was somewhat higher in the T-DM1 arm compared with the trastuzumab arm. This is caused by a concurrent risk, meaning that peripheral metastasis, not CNS metastasis, are kept under control with T-DM1. In our analysis, we demonstrated that the occurrence of CNS metastasis was similar in both arms. Unfortunately, these patients have a bad prognosis. We’re still looking for methods to [delay] CNS metastasis.

What are the implications of these findings?

Peripheral neuropathy and thrombocytopenia are not major long-term problems for patients treated with T-DM1, especially those who have had previous platinum.

We still have to look for drugs that can prevent the development of CNS metastasis. We have several drugs in development in this setting, that appear to be quite promising. One example is [fam-] trastuzumab deruxtecan (DS-8201), which is being evaluated in phase II/III trials.

Could you discuss the next phase of research in this space?

Patients with HER2-overexpressing cancer did very poorly 25 years ago. Today, with the addition of neoadjuvant and adjuvant therapy, we are not very far from cure. The next step would be to use adjuvant treatment in patients with TNBC and luminal hormone receptor—positive breast cancer, which is still an unmet medical need.

For example, for patients who had a pCR to neoadjuvant treatment, we can de-escalate surgery, radiotherapy, and medical treatment. For patients who have residual disease in the breast or in the lymph nodes after neoadjuvant therapy, we know to treat with escalated treatment approaches. We have immune checkpoint inhibitors, PARP inhibitors, and ADCs, so I look forward to [addressing these] current unmet medical needs in the near future.

References

1. Untch M, Geyer C, Huang C, et al. Peripheral neuropathy (PN), thrombocytopenia (TCP) and central nervous system (CNS) recurrence: an update of the phase III KATHERINE trial of post-neoadjuvant trastuzumab emtansine (T-DM1) or trastuzumab (H) in patients with residual invasive HER2-positive breast cancer (BC). Ann Oncol. 2019;30(5 suppl; abstr LBA19). doi: 10.1093/annonc/mdz394.005.
2. von Minckwitz G, Huang CS, Mano MS, et al. Trastuzumab emtansine for residual invasive HER2-positive breast cancer. N Eng J Med. 2019;380(7):617-628. doi: 10.1056/NEJMoa1814017.