Targeted Agents Allow for Individualized Approaches in HER2+ Breast Cancer Treatment Arsenal

Denise A. Yardley, MD

HER2-targeted therapy has become more personalized, allowing patients with early-stage HER2-positive breast cancer to receive de-escalated or escalated treatment according to their risk status, explained Denise Yardley, MD, who added that this has become especially important as it relates to neratinib’s (Nerlyx) availability in the extended adjuvant setting.

“Neratinib comes to mind as an extended [adjuvant] HER2-directed therapy for higher-risk patients,” said Yardley. "Patients with HER2-positive disease have done so well, but that’s still a subgroup [of patients who] benefits from the addition of extended [adjuvant] therapy.”

In an interview with OncLive, Yardley, senior investigator at Sarah Cannon Research Institute, shed light on individualized treatment approaches for patients with HER2-positive breast cancer, the importance of early intervention strategies for neratinib-associated adverse events, and treatment adjustments that have been made during the coronavirus disease 2019 (COVID-19) pandemic.

OncLive: How do you approach treatment for patients with HER2-positive breast cancer? Which patients should receive extended adjuvant therapy?

Yardley:How to essentially de-escalate [and escalate] therapy has really predominated the management of patients with HER2-positive disease. We’re really trying to tailor therapy for these patients. We are increasingly trying to identify the patients who we think are at higher risk for recurrence, and those who are at lower risk.

One group that stands out as a higher-risk population is patients who had neoadjuvant therapy and have evidence of residual disease. In these patients, we’ve increased our consideration for neoadjuvant therapy, so we can utilize ado-trastuzumab emtansine (TDM-1; Kadcyla), which is now approved [as an adjuvant therapy] for patients with residual HER2-positive disease. [It’s become an incentive for us to use] neoadjuvant therapy for patients who might be on the cusp of going to surgery because T-DM1 has shown an improvement in outcomes among patients who have residual disease after neoadjuvant therapy.

Now, for our earlier-stage patients who, for the most part, go to surgery first and then [come to us] for adjuvant therapy, we have great data from the ATEMPT and APT trials looking at weekly paclitaxel for 12 [weeks] with trastuzumab (Herceptin) for patients with lower-risk, T0N0 tumors.

We look at the estrogen receptor—positive, node-positive patient population and offer [neratinib] to them. Overall, patients do so well with HER2-directed therapy that these patients are still a minority of the early-stage HER2-positive patient population. However, neratinib is out there and has offered an advantage for those groups. Now, we are able to further characterize [patient’s risk and response to treatment] to tailor that discussion and treatment approach to the patient. Node-positive, hormone receptor–positive [patients benefit from] neratinib. Now, [we’re really able to] focus on the groups that may benefit from extended therapy.

The challenge is, at some point, patients are going to get tired of being on therapy and additional monitoring. We’re seeing patient fatigue with additional therapy. It becomes a more detailed patient physician discussion in terms of the advantages or disadvantages [of additional treatment], so that patients can incorporate [additional treatment they can tolerate] into their lifestyle.

Are the toxicities associated with neratinib easily managed with dose-escalation strategies?

The [diarrhea] clearly impacts activities of daily living for patients. While it can be managed with dose modifications and additional supportive care medications, I do find that patients have a little less interest in pursuing an extended course if we do not get that regimen very well worked out in the first couple weeks of treatment.

These patients have been on therapy for at least 1 year. We’re also trying to figure out the population [who received] neoadjuvant [therapy and] may get T-DM1. Is there a role for neratinib [in patients who received T-DM1] as that wasn’t the population that was studied? We look at the really high-risk population and have that discussion [about the ExteNET and CONTROL trials] with the patients. We try very hard to manage [the diarrhea], and we are successful most of the time. It’s a limited number of patients who are that high-risk these days.

Has treatment been impacted by the pandemic?

We take it on a case-by-case basis depending on where the patient is in terms of their treatment algorithm. For patients in the neoadjuvant setting, we move forward with their treatment. Looking at treatment selection, we’ve used weekly paclitaxel maybe a little bit more frequently in a few patients up front. That’s balanced by the fact that patients need to come into the clinic more often but with less immunosuppression.

Other patients have been very well versed and have a network of providers that help them outside of their treatment, so they're staying on their every 3-week regimen, but they are confined to their home. Someone’s doing their shopping, every need they have, [so that the only time they have to go out is when] they return to the clinic. Our clinic has all the appropriate measures for both visitors and patients [in place]. The patients have largely adapted very well in their home environment, meeting those challenges as well, so that they can continue to move forward with their treatment.

Would you use an oral agent like neratinib during the pandemic?

I would. We struggle with COVID-19 and [struggle with] determining how that affects the management of our patients with cancer. We’re trying to balance risk reduction and ultimate outcomes after COVID-19 [has passed]. I haven’t actually been faced with a patient who has finished their adjuvant HER2-targeted therapy [and is ready] to move on to neratinib. Right now, I would probably give the patients a couple weeks off.

In our own community, we seem to be on the downtrend [trend of COVID-19 cases]. Most of those patients have been coming back in several weeks after their last visit to pick up that discussion [about extended treatment]. Where traditionally I may have transitioned right into [discussing additional treatment in] their last visit, I have given a little bit more space. This is just because of the visits, the monitoring, and the additional unpredictable toxicity that may expose that patient to needing to come back to a health care environment. In that aspect, you have given them a little bit more time in sequencing, [after which you can] still discuss and offer [neratinib] as a treatment strategy.