Incorporating Neoadjuvant and Adjuvant Data in Early-Stage HER2+ Breast Cancer

Yee Chung Cheng, MD

Given the number of positive neoadjuvant and adjuvant trials that have surfaced in early-stage HER2-positive breast cancer in recent years, it can be difficult to properly integrate these agents into practice. However, with careful consideration of the data, physicians can optimize available anti-HER2 therapy for their patients, said Yee Chung Cheng, MD.

“One very exciting thing about HER2-positive breast cancer is we have many trials in the neoadjuvant setting as well as the adjuvant setting,” said Cheng. “The most difficult thing is [healthcare providers] do not know how to incorporate all these study results together in practice.”

In the neoadjuvant setting, data from the phase II NeoSphere trial and TRYPHAENA trials served as the basis for the FDA approval of neoadjuvant pertuzumab (Perjeta), trastuzumab (Herceptin), and chemotherapy for patients with node-positive disease who are at high risk or for those with tumors ≥2 cm.

Although pertuzumab can be continued into the adjuvant setting when used in combination with trastuzumab and chemotherapy, per the results of the phase III APHINITY trial, it may be better used in patients at high risk for recurrence. Similarly, neratinib (Nerlynx), demonstrated a superior rate of invasive disease-free survival versus placebo in patients with residual disease following neoadjuvant therapy and prior exposure to adjuvant trastuzumab and chemotherapy.

Physicians should also look to data from the phase III KATHERINE trial, which indicated a 50% reduction in the risk of invasive disease recurrence or death when ado-trastuzumab emtansine (T-DM1; Kadcyla) was substituted for trastuzumab as adjuvant therapy. In May 2019, the FDA approved T-DM1 for use as an adjuvant treatment of patients with HER2-positive early breast cancer who have residual invasive disease following neoadjuvant trastuzumab and chemotherapy.

In an interview during the 2019 OncLive^® State of the Science Summit™ on Breast Cancer, Cheng, associate professor, Medical College of Wisconsin, discussed the importance of integrating these trial data into practice in order to optimize outcomes for patients with early-stage HER2-positive breast cancer.

OncLive^®: How should clinicians approach treatment for patients with early-stage HER2-positive breast cancer?

Cheng: I get many calls from community doctors who sometimes do not know which agent should be used first or which agent comes after another therapy. [In my presentation at the State of the Science Summit^TM,] I tried to shed some light on how we can incorporate all these data into practice in order to help community doctors really utilize all of the anti-HER2 therapies [that are available].

Could you discuss the neoadjuvant data and adjuvant data in this space?

The 2 major neoadjuvant trials are the NeoSphere and TRYPHAENA studies. These trials established the use of pertuzumab in the neoadjuvant setting. I also focused on 3 adjuvant trials—specifically, the APHINITY, ExteNET, and KATHERINE trials. These 3 trials also give us information about the use of pertuzumab in addition to neratinib and T-DM1. I tried to incorporate all of these results and come up with an algorithm on how to use all these drugs [effectively].

How do you decide which patients should receive a particular regimen in the neoadjuvant and adjuvant settings?

It's difficult because all of the trials did not enroll the same patient population. We tried to look at the best outcome. I always say we need to try to [look at] the neoadjuvant setting first, as there is a priority to try to find patients who fit into the neoadjuvant setting in HER2-positive breast cancer. For those patients whose do not fit into the neoadjuvant setting, then we can move on to the adjuvant setting.

Regarding the neoadjuvant setting, we have data from the KATHERINE trial, which showed that if patients are not in a complete response (CR), they have the option of using T-DM1. This is the first time [we have seen data like this]. In the past, we only knew that a patient who is not in a CR has a high risk of recurrence, but we did not know what to do. This is the first time that data have shown that patients who are not in CR can use a given drug, which is very exciting.

Could you discuss the data from the KATHERINE trial? What are the next steps for T-DM1?

Investigators looked at patients who finished neoadjuvant therapy with trastuzumab. The majority of patients only received trastuzumab alone. Only about 20% of the population received trastuzumab and another anti-HER2 treatment, which is a little bit different from our general practice. Now, with the data from the neoadjuvant trials, most [healthcare providers] use dual anti-HER2 therapy. Nevertheless, the data were positive. The investigators did look at the 20% of patients who received the dual anti-HER2 treatment and those data showed a positive result [with adjuvant T-DM1 as well].

In the future, we’ll need to look at T-DM1 again following neoadjuvant dual anti-HER2 treatment. Secondly, we’ll also need to look at what we should do after T-DM1. Do we still need to give patients neratinib? There are a lot of opportunities to run a new trial as there are many unanswered questions.

What are your thoughts on the utility of neratinib?

The most important thing to note regarding neratinib is we have to preemptively manage the diarrhea. If you wait until the patient develops diarrhea, it's too late. The best approach is to give patients a [prophylaxis] regimen upfront to prevent the diarrhea from happening.

The CONTROL trial looked into that. The investigators looked into using different antidiarrheal medications and showed a very good result [with those interventions]. It decreased the rate of significant diarrhea down to approximately less than 10%. The key is to preemptively or proactively treat the diarrhea instead of waiting until it happens.

Is there any rationale to explore neratinib in combination with other agents?

Now we know that dual anti-HER2 treatment is better than single-agent therapy, so there is an opportunity to look into the combination of, let's say, trastuzumab and neratinib. In terms of the diarrhea management, once you learn how to manage it, it should not be a big problem.

Following its demonstrated efficacy in the metastatic setting, should [fam-] trastuzumab deruxtecan (DS-8201) be explored in earlier settings?

It's a new antibody-drug conjugate, a class of drugs which are very exciting. It's a new approach to many of these anti-HER2 treatments and could also be applied in triple-negative breast cancer. It's definitely very exciting.

What do you hope oncologists take away from your presentation?

The most important message is [understanding] how to combine the current anti-HER2 drugs in clinical practice, as we now have several trials in different settings and in different patient populations. For community doctors, it can be difficult to incorporate these drugs together. I tried to share how to combine these drugs together and how to use them in the clinical setting.