Updated ExteNET Data Raise Questions Over TKI Utility in HER2+ Breast Cancer With Brain Metastases


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Adam M. Brufsky, MD, PhD, discusses the updated findings from the ExteNET trial, the role of TKIs in treating patients with brain metastases, and unanswered questions that future research efforts should aim to address.

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Adam M. Brufsky, MD, PhD

Updated findings from the phase 3 ExteNET trial have raised questions regarding the optimal role of neratinib (Nerlynx) in patients with early-stage HER2-positive breast cancer that need to be fleshed out, according to Adam M. Brufsky, MD, PhD.

During the 2020 San Antonio Breast Cancer Symposium (SABCS), updated findings from the study were presented in a virtual poster showing fewer deaths and improved cumulative incidence of central nervous system (CNS) recurrences with adjuvant neratinib compared with placebo among patients with early-stage HER2-positive breast cancer after trastuzumab (Herceptin)-based therapy. 

At 8 years of follow-up, 8.9% of patients who received neratinib in the intention-to-treat (ITT) population died prior to the analysis cutoff date versus 9.6% of patients who received placebo. 

Regarding CNS events, the cumulative incidence of CNS recurrences in the ITT population was 1.3% with neratinib versus 1.8% with placebo.

Although overall survival (OS) was not statistically significant with neratinib compared with placebo, OS was numerically improved with neratinib versus placebo among the subgroup of patients with hormone receptor–positive disease.

Ultimately, these findings raise other questions regarding the utility of other HER2-directed TKIs, such as tucatinib (Tukysa), which has the potential to make its way into the early-stage setting, explained Brufsky. Moreover, as the story of TKIs continues to evolve, developing a predictive biomarker to inform which patients are likely to develop brain metastases could fill a significant unmet need in the field. 

“[Currently], we don’t know, clinically/pathologically, who gets brain metastases,” said Brufsky. “Some of us who have seen a lot of patients have a hint, but there is nothing in the literature that says a patient with this presentation of HER2-positive early-stage breast cancer is going to develop brain metastases. It would be nice to have some way of figuring that out.”

In an interview with OncLive®, Brufsky, a professor of medicine and associate chief in the Division of Hematology/Oncology at the University of Pittsburgh School of Medicine, medical director of the Magee-Women’s Cancer Program, co-director of the Comprehensive Breast Cancer Center, and associate director for Clinical Investigations at the University of Pittsburgh Medical Center Hillman Cancer Center, discussed the updated findings from the ExteNET trial, the role of TKIs in treating patients with brain metastases, and unanswered questions that future research efforts should aim to address. 

OncLive®: What notable findings were presented from the updated ExteNET analysis?

Brufsky: The key findings of ExteNET are that the invasive disease-free survival (iDFS) benefit is maintained. [Also,] an OS benefit was seen in the subgroups that are most relevant to us today. Most women with HER2-positive early-stage breast cancer will get neoadjuvant therapy with pertuzumab [Perjeta], trastuzumab, and some sort of chemotherapy combination. If patients have residual disease, they get T-DM1 [ado-trastuzumab emtansine; Kadcyla] for 17 doses. 

The issue really becomes that these patients are at a higher risk of recurrence. What do you do? The ExteNET trial showed that a prespecified subgroup of patients who get 1 year of neratinib post trastuzumab have a 7% to 8% iDFS benefit and a 7% OS benefit, with the caveat that patients were not treated with post-neoadjuvant T-DM1. These are patients who are really at the highest risk of recurrence. [ExteNET showed] some pretty strong data, suggesting that if a patient can tolerate the drug, it is reasonable to offer [neratinib] to those at the highest risk of recurrence. 

Would you offer neratinib to most patients with early-stage HER2-positive breast cancer?

No, but I would take certain patients with a lot of lymph nodes involved, a large tumor, or a lot of residual disease. I would probably offer [neratinib] even after a year of T-DM1 even though that is not the study population. The reason for that was teased out in very preliminary data, with very small numbers in the ExteNET update. It appears that patients who got neratinib had fewer brain metastases. When we go back and look at [data from the] KATHERINE trial, we see that there is an 11% distant-relapse rate, half of which are brain metastases. This means that the T-DM1 doesn’t get into the CNS. These are extraordinarily preliminary data. 

On the other hand, if we look at metastatic breast cancer and the NEfERT-T trial, which was basically paclitaxel and trastuzumab versus paclitaxel and neratinib, the neratinib cut the incidence of brain metastases as first recurrence in half. [Neratinib] is doing something. 

Plus, we know from the HER2CLIMB trial that tucatinib is doing something in the metastatic setting. TKIs [have some efficacy] in the brain and [are potentially] stopping the progression of brain metastases. It makes perfect sense [that neratinib would have efficacy in the early-stage setting].

There is a trial called Compass[HER2 RD], which is going to [evaluate] T-DM1 with or without tucatinib that is going to [begin enrollment] in the not-too-distant future. That trial will help us answer the question [of whether tucatinib in this setting is an advantage], but until we get those data, [neratinib] is something to consider because brain metastases are devastating in patients who [develop them] as the first site of recurrence even though they’ve done well systemically. It is important for us to give that some thought, although, again, these are very preliminary data. [The data] have people talking about whether [the ExteNET investigators] extended themselves beyond what [data] were there, but on the other hand, it was all hypothesis-generating data. It’s very intriguing. To me, the survival benefit is clear because it was a prespecified [subgroup] and [the ExteNET data are] something we can use to justify [giving neratinib in the early-stage setting].

What is next for TKIs in this space?

The COMPASS trial has just started and will evaluate TDM-1 with or without tucatinib. There are a lot of nonrandomized trials in the metastatic setting of T-DM1 with or without neratinib. 

The concept of TKIs [has led to] the hope that one day we will have a genetic predictor, or a clinical pathologic predictor of which patients are going to be more susceptible to brain metastases. We’ll be able to look at a patient’s primary tissue and focus our HER2[-directed] TKIs on those individuals. That is where all of this is going, but again, that depends on getting a predictor, which is the hard part.

If tucatinib moves into the early-stage setting, will treatment decisions become more complex? 

We always have these problems. We had them with aromatase inhibitors; we have them with CDK4/6 inhibitors now. Everything has a safety profile. The diarrhea with neratinib can be managed very successfully with dose escalation. We start with 120 mg or 160 mg per day of neratinib and gradually dose escalate over the first month. During that time, we are very liberal with antidiarrheals, such as loperamide [Diamode], colestipol [Colestid], and budesonide [Entocort]. These are available and [Puma Biotechnology Inc.] provides [antidiarrheals] to patients for free when they get [neratinib].

Although the diarrhea can be controlled, there are people who just can’t tolerate [neratinib]. I have maybe 1 in 10 or 1 in 5 patients who just cannot tolerate [neratinib], and we have to stop [the drug]. However, the remainder of patients get through it and want to continue it.

[Overall], this is why tucatinib is a potential option because it has less [severe] diarrhea.

Is there anything else you would like to add regarding the future utility of TKIs in HER2-positive breast cancer?

The big problem in HER2-positive early-stage [and] metastatic breast cancer is that all of us are starting to come to the conclusion that we are doing a really good job of controlling systemic disease. However, [HER2-positive breast cancer is] just like pediatric leukemia where 40 or 50 years ago we realized there were sanctuary sites [of cancer] that our therapies cannot get to. Now, we have therapies like HER2[-directed] TKIs that can get into those sanctuary sites. 

Now [it becomes a matter] of which [drugs] do we use, and how do we use them? If a patient is resistant to one TKI in the metastatic setting, do they respond to another? Does it depend on what kind of mutation the patient has, if they have any? Does it depend on [HER2] amplification? These are the sort of questions that investigators are going to be exploring in this field over the next couple of years.


  1. Holmes FA, Moy B, Delaloge S, et al. Continued efficacy of neratinib in patients with HER2-positive early-stage breast cancer: final overall survival analysis from the randomized phase 3 ExteNET trial. Presented at: 2020 San Antonio Breast Cancer Symposium; December 8-11, 2020; virtual. Poster PD3-03. https://bit.ly/377gMaq

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