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Novel Agents, Approaches Drive Progress in HER2+ Breast Cancer

Caroline Seymour
Published: Friday, Mar 01, 2019

Erika P. Hamilton, MD
Erika P. Hamilton, MD
Several data sets from studies presented at the 2018 San Antonio Breast Cancer Symposium (SABCS) had an immediate impact on patients with HER2- positive breast cancer, explained Erika P. Hamilton, MD. For patients with low HER2 expression, with brain metastases, and those with hormone- and HER2-driven disease, therapies such as antibody– drug conjugates (ADCs), HER2-directed agents, and CDK4/6 inhibitors are showing potential.

For example, based on findings from the phase III KATHERINE trial, the ADC ado-trastuzumab emtansine (T-DM1; Kadcyla) could replace adjuvant trastuzumab (Herceptin) as the standard of care in patients with residual invasive disease following neoadjuvant therapy. Results presented at the meeting showed a 50% reduction in the risk of invasive disease recurrence or death with T-DM1 versus trastuzumab.1

Also presented at the meeting was the final data set from the phase III PHARE trial, which failed to show noninferiority between a 6-month and 12-month course of adjuvant trastuzumab, findings which differed from the 5-year follow-up data from the phase III PERSEPHONE trial. PERSEPHONE did demonstrate noninferiority between the 6- and 12-month durations of therapy (HR, 1.07; 90% CI, 0.93-1.24; P = .01).2

For more difficult-to-treat populations, Hamilton explained that DS-8201 has shown unique activity in patients with low HER2-expressing tumors. The ADC was granted a breakthrough therapy designation by the FDA in August 2017 and showed a 29% objective response rate and a 93% disease control rate in an ongoing, dose-escalation/dose-expansion phase I study (NCT02564900).3

Additionally, the small molecule HER2 inhibitor tucatinib has shown promising central nervous system activity in both the phase II HER2CLIMB trial with capecitabine and trastuzumab (NCT02614794)4 and a phase Ib trial which is testing its use in combination with T-DM1 (NCT01983501).5

Finally, palbociclib (Ibrance), a CDK4/6 inhibitor indicated for patients with hormone receptor (HR)–positive breast cancer, is being investigated in combination with T-DM1 for patients with metastatic HER2-positive disease (NCT03530696).

“We used to think that HER2-positive tumors were very aggressive, and they are, but with the new medicines we have for patients with HER2-positive breast cancer, [the disease] has become easier to treat,” said Hamilton.

In an interview during the 2019 OncLive® State of the Science Summit™ on Breast Cancer, Hamilton, director of the Breast and Gynecologic Research Program at Sarah Cannon Research Institute, shared insight on the management of patients with HER2-positive breast cancer and strategies aimed at targeting treatment resistance and toxicity.

OncLive: What are some of the latest treatment approaches in HER2-positive breast cancer?

Hamilton: Several new [agents] have come into the HER2 arena over the past few months. At the 2018 SABCS, we saw data from PHARE, which contrasted with what we saw from PERSEPHONE. Both of these studies looked at a shorter duration of trastuzumab—specifically, 6 months of therapy versus the traditional 12 months. Although the hazard ratios were quite similar, [there were] different conclusions based on the statistical design of the 2 trials. PHARE concluded that 6 months of therapy was inferior to 12, whereas PERSEPHONE concluded noninferiority between the 2 treatment durations.

My takeaway is that probably a real difference exists [between 6 months of therapy and 12 months of therapy], but it’s probably very small. In my practice, I would continue to use 12 months of trastuzumab. However, in patients who have an ejection fraction drop, who are elderly, or who have trouble coming to the clinic, you’re probably not losing a lot by using 6 months of trastuzumab.

Additionally, novel agents are on the horizon, and that’s something exciting in the space right now. We have new TKIs, antibodies, bispecifics, and ADCs. We’re all very interested in these targeted compounds after T-DM1.




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2017 Year in Review™: Clinical Impact of Immunotherapies in the Treatment of CancerMar 30, 20191.75
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