Novel Agents, Approaches Drive Progress in HER2+ Breast Cancer

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.

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

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.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.

Are strategies being developed to overcome resistance to HER2-directed therapies?

The other important data to come from SABCS were from the KATHERINE trial, which showed a really big improvement in disease-free survival for women who did not receive a pathologic complete response to their neoadjuvant chemotherapy. They were randomized to finish a year of their antibody or receive a year of T-DM1; T-DM1 was the winner by far. We’re all excited to get that option into the clinic.HER2 resistance is very interesting—it’s not all a single type of resistance. We have patients who are HER2-low; these are women with [lower HER2 expression than] the traditional woman who comes in with a ratio of 18, where you know that her tumor is completely HER2-driven; those are the women who tend to do really well on the HER2-directed agents. In women with a lower HER2 ratio, that’s where other pathways such as HER3, or even PI3K, may come into play. [In those patients], combination therapies are probably going to become most effective.

Could the PI3K inhibitor alpelisib have any impact in this space?

What cardiac toxicities are associated with some of the targeted agents being used in the space, and how are they managed?

Some of the newer ADCs are also exciting; DS-8201 is among them. [This agent] has shown activity and has been the first to do so dramatically in the HER2-low space.Potentially. The PI3K inhibitors have a lot of interest, not only for patients with HER2-positive breast cancer, but also for patients who have tumors that are both HR-driven and HER2-driven. Trials are out there that will give us some of those answers.We all are well familiar with the risk with trastuzumab. In my clinic, I do echocardiograms about every 3 months. If the patient’s ejection fraction drops, the recommendation is to stop trastuzumab or reimage and see if that value comes back up. I’ve certainly been successful in rechallenging women with trastuzumab so that they’re able to finish their course. Some patients have an ejection fraction drop that does [allow the reintroduction of trastuzumab].

Does the combination of palbociclib and trastuzumab have a future in this space?

Is any research with immunotherapy ongoing or planned?

Although the prognosis for patients with HER2- positive disease has improved, what is a challenge that clinicians are still facing?

I work closely with my cardio-oncology colleagues, and they’re more than happy to see those patients. Sometimes we can put patients on other medicines to optimize their cardiac health. With other HER2-targeted drugs, a theoretical risk always exists. It’s something we’re very concerned about in clinical trials; [however], drugs that use the same binding site as trastuzumab haven’t shown the same cardiotoxicity. That’s encouraging for the drugs to come.We know that a decent percentage of patients are both hormonally driven and HER2-driven. It’s always been a bit confusing as to what to do for those women because they don’t fall completely into one bucket or another. Most of the time we treat them as a traditional HER2-positive patient, so that they go through taxane chemotherapy, trastuzumab, and pertuzumab (Perjeta). Then, they may go onto T-DM1. The idea of combining endocrine therapies with trastuzumab has certainly been very successful. There’s no reason to think that [combining palbociclib with trastuzumab] won’t [have] the same [success]. Thus far, the trial data have shown that this can be a very active regimen.Immunotherapy got off the ground with triple-negative breast cancer for a variety of reasons. First, we tend to have fewer drugs in the triple-negative space, and specifically, fewer targeted agents. Also, there’s the phenomenon that triple-negative disease tends to be a more highly mutated tumor compared with a HR-positive tumor. We’ve participated in a study that combined immunotherapy with HER2-targeted agents, and [that approach] looks quite encouraging. As with immunotherapy across all tumors, a subset of patients respond and a subset doesn’t respond. It’s up to us to define the women who will benefit.One challenge that we are seeing more of is brain metastases. Unfortunately, many of our drugs don’t cross the blood— brain barrier well, although they’re great at eradicating and controlling disease below the neck. Up to 50% of women with metastatic disease will eventually have HER2-positive brain metastases. I’m very excited about some new drugs in that space, and tucatinib is among them; it’s an oral HER2 TKI that crosses the blood–brain barrier very well. Unlike some other TKIs that inhibit both HER2 and HER1, or EGFR, it only inhibits HER2. As a result, we’ve been able to dose it a little bit higher. It’s extremely well tolerated.

References

1. Geyer CE Jr, Huang C-S, Mano MS, et al. Phase III study of trastuzumab emtansine (T-DM1) vs trastuzumab as adjuvant therapy in patients with HER2-positive early breast cancer with residual invasive disease after neoadjuvant chemotherapy and HER2-targeted therapy including trastuzumab: primary results from KATHERINE. Presented at: 2018 San Antonio Breast Cancer Symposium; December 4-8, 2018; San Antonio, TX. Abstract GS1-10. abstracts2view.com/sabcs18/view. php?nu=SABCS18L_1226&terms=.
2. Earl HM, Hiller L, Vallier A-L, et al. PERSEPHONE: 6 versus 12 months (m) of adjuvant trastuzumab in patients (pts) with HER2 positive (+) early breast cancer (EBC): randomised phase 3 non-inferiority trial with definitive 4-year (yr) disease-free survival (DFS) results. J Clin Oncol. 2018;36(suppl 15; abstr 506). doi: 10.1200/JCO.2018.36.15_suppl.506.
3. Doi T, Iwata H, Tsurutani J, et al. Single agent activity of DS-8201a, a HER2-targeting antibody-drug conjugate, in heavily pretreated HER2 expressing solid tumors. J Clin Oncol. 2017;35(suppl 15; abstr 108). doi: 10.1200/JCO.2017.35.15_suppl.108.
4. Hamilton E, Borges VF, Conlin A, et al. Efficacy results of a phase 1b study of tucatinib (ONT-380), an oral HER2-specific inhibitor, in combination with capecitabine and trastuzumab in HER2+ metastatic breast cancer, including patients with brain metastases. Presented at: 2016 San Antonio Breast Cancer Symposium; December 6-10, 2016; San Antonio, TX. Poster P4-21-01. sabcs16.posterview. com/nosl/i/P4-21-01.
5. Borges VF, Ferrario C, Aucoin N, et al. Efficacy results of a phase 1b study of ONT-380, a CNS-penetrant TKI, in combination with T-DM1 in HER2+ metastatic breast cancer (MBC), including patients (pts) with brain metastases. J Clin Oncol. 2017;34(suppl 15; abstr 513). doi: 10.1200/JCO.2016.34.15_suppl.513.