Neratinib Shows Strong Benefit in Early-Stage, Metastatic HER2+ Breast Cancer

Joyce A. O'Shaughnessy, MD

Neratinib’s (Nerlynx) greatest impact is in the early-stage setting in women with high-risk, HER2-positive breast cancer, said Joyce A. O'Shaughnessy, MD, who added that the agent can also be of benefit to patients with metastatic disease.

“The ExteNET data [provide compelling evidence] that giving 1 year of neratinib along with endocrine therapy [in the extended adjuvant setting] is of great value to patients, particularly those with estrogen receptor (ER)–positive disease,” said O’Shaughnessy. “[In the metastatic setting], we have the newly approved combination of neratinib/capecitabine, which is another option, especially for patients with brain metastases.”

In an interview with OncLive, O'Shaughnessy, chair of Breast Cancer Research and the Celebrating Women Chair in Breast Cancer at Baylor-Sammons Cancer Center, Texas Oncology, and chair of The US Oncology Network, and 2016 Giant of Cancer Care® in Community Outreach, shed light on the current paradigm of HER2-positive breast cancer and the optimal role of neratinib in the early-stage and advanced settings.

OncLive: Could you provide an overview of the early-stage HER2-positive breast cancer landscape?

O’Shaughnessy: HER2-positive breast cancer has a lot of excellent therapies starting with, in most patients, preoperative trastuzumab (Herceptin) and pertuzumab (Perjeta) with chemotherapy, which very commonly is docetaxel and carboplatin (TCHP). TCHP has the highest pathologic complete response (pCR) rate of all the regimens we have [in this setting]. Patients who don’t get a pCR go on to receive ado-trastuzumab emtansine (T-DM1; Kadcyla) for 14 cycles because they get an 11% additional improvement in disease-free survival (DFS). Women who do get a pCR finish out their year of trastuzumab and pertuzumab along with endocrine therapy if they’re ER-positive.

After that, women who were quite high-risk to start, such as those who had positive nodes up front, or positive nodes at the time of surgery, women who had preoperative TCHP and still have residual disease, are at very high risk for recurrence—even though they’ve gotten the benefit of additional T-DM1. Going out 5 years, [we see] an 8% absolute improvement in DFS in the HER2-confirmed patients and those who received preoperative therapy, which is very significant. We don’t know for sure that the benefit is exactly 8% in women who received prior pertuzumab and T-DM1, but we do know that neratinib is non–cross-resistant with those agents. We have good evidence of that.

We also know that there’s a lot of synergy with pan-HER blockade and blocking the ER. We know there’s a lot of synergistic cell kill to be had there. For patients who remain high risk, we have to make sure we give every woman the opportunity to have her highest chances of benefit.

Neratinib’s greatest impact is in the curative setting. That’s where we always want to optimize care. Neratinib is very important for high-risk, ER-positive patients. We’ve seen, in a number of trials, that neratinib can reduce the risk of progression of brain metastasis, which remains a big problem for patients with HER2-positive disease. That’s another reason to use neratinib up front in combination with endocrine therapy.

Patients with very serious ER-negative, HER2-positive breast cancer who don’t get a pCR with preoperative TCHP and go on to receive T-DM1 are very high-risk individuals. These women have a high-risk of brain metastasis. Treating those patients with 1 year of neratinib is very reasonable. A subset analysis from the ExteNET study looking at the ER-negative, HER2-positive patients who started the neratinib within a year of finishing adjuvant trastuzumab showed a split in the curves. We saw an improvement in DFS.

Moreover, the curves stayed apart; they did not come back together again. If we started neratinib soon after a patient finished T-DM1, it would be very reasonable to expect that they would benefit from neratinib. That is important for these patients that remain at high risk.

How do you approach treatment in the metastatic setting?

Unfortunately, in spite of all that, patients will recur. Additionally, about half of patients with metastatic disease in the first-line setting have de novo metastatic HER2-positive [disease]. Those women will get the CLEOPATRA regimen in the first-line setting, which is a taxane, trastuzumab, and pertuzumab. In the second-line setting, generally speaking, they’ll receive T-DM1. However, the new National Comprehensive Cancer Network guidelines gives a list of the options for second-line treatment, which include T-DM1, trastuzumab deruxtecan-nxki (Enhertu; DS-8201), and tucatinib (Tukysa) plus capecitabine/trastuzumab, so there is a menu of options now for the second-line setting.

Most physicians will continue to use T-DM1 in the second-line setting. In the third-line setting, most doctors will use tucatinib plus capecitabine/trastuzumab because of the survival advantage, particularly for patients with brain metastasis. Trastuzumab deruxtecan is another excellent option. We have very limited data about its activity in the brain, so for patients with central nervous system metastasis, [the use of trastuzumab deruxtecan] is uncertain. Then, we have the newly approved combination of neratinib/capecitabine, which is another option, especially for patients with brain metastases.

If a woman gets tucatinib/capecitabine/trastuzumab, does well for a while and then has disease progression, continuing capecitabine, switching to neratinib at that point and stopping the trastuzumab is entirely reasonable if the brain metastasis is the patient’s most serious site of disease.

The survival advantage with tucatinib plus capecitabine/trastuzumab is really quite impressive in the metastatic setting. [The data are] fairly compelling that we need to use that triplet earlier in metastatic disease. The triplet also has an improvement in progression-free survival, even for patients with untreated brain metastasis. We’ve seen quite an impressive level of activity. We’ll see more data on [that triplet in patients with] brain metastasis at the 2020 ASCO Virtual Scientific Program in an oral presentation. That has to be the priority for patients with brain metastasis.

Tucatinib is a pure inhibitor of HER2. If patients with brain metastasis initially benefit from tucatinib and then progress, it’s a pretty fair bet they’re going to have upregulation of other HER family members, such as HER1, HER3, heterodimerization with HER2, and HER4. It makes a great deal of sense to give those patients neratinib at that point, particularly if the brain is really the patient’s life-limiting site of metastatic disease.

However, should you stop capecitabine and just give single-agent neratinib? I probably wouldn’t. I would probably continue the capecitabine inhibition of the cancer proliferation of the MAPK pathway and utilize neratinib for the pan-HER family inhibition to shut down the PI3K pathway. That’s how I envision neratinib will be used, according to the FDA label.

There’s room for all the new options that we have. Some [agents] will be particularly [useful] for patients with brain metastasis. Other agents, such as trastuzumab deruxtecan, works very quickly and has a very high response rate will be used in patients who have severe disease in the lungs or liver where an immediate response is needed. We have options for all different scenarios.

Lastly, there’s the issue of HER2 mutations, particularly in ER-positive, HER2-nonamplified breast cancer. HER2 mutations are one of the mechanisms of resistance to endocrine therapy. You’ll find them 5% to 8% of the time in patients with metastatic disease. We have very nice data now from a number of trials, including the SUMMIT trial, which shows that fulvestrant and neratinib in ER-positive, HER2-mutant breast cancer is highly active.

Now, there are emerging data that adding trastuzumab and making a triplet against those HER2-mutant breast cancers can be of benefit. That is something I always look for in the metastatic setting. I’ll get serial circulating tumor DNA from patients, or I will biopsy patients with next-generation sequencing, so that I can look for HER2 mutations. There are a number of places we can utilize neratinib for the patients benefit.

How have you managed the diarrhea associated with neratinib?

Dose escalation has made a huge difference [in managing diarrhea]. I usually start with 4 pills a day which is 160 mg, and wait 2 weeks, to make sure the woman is not going to have significant diarrhea. Then, I’ll go up to 5 pills, which is 200 mg. If the woman starts getting diarrhea, I stay there. If she continues to have diarrhea, I don’t go up to 6 pills, and I don’t escalate. Of course, we use loperamide. My approach is to give 2 loperamide after the first loose stool of a day and then 1 loperamide after each subsequent loose stool that day. That’s made a huge difference.

I had a patient who was an older woman in her 70s with high-risk disease. She’s a very gung-ho woman. She received preoperative TCHP and T-DM1. She said, “You had mentioned neratinib to me. Let’s get on with it.” She was spot on, so we started with 4 pills. This was right on the heels of a great deal of therapy that she had just had. She got very substantial diarrhea even with the 4 pills, so we let her recover. When she came back in, we went down to 3 pills, and she had 0 problems. We went to 4 pills, and she had 0 problems. She’s up to 6 pills now, which is unbelievable. Spacing the neratinib a little bit after preoperative therapy might be of some use. I don’t think we have good data on what that spacing might be, but if at first you don’t succeed, try again.

For someone who has had a lot of therapy, it might be reasonable to start with 3 pills a day. The key in the high-risk extended adjuvant setting is to keep women on neratinib in combination with endocrine therapy for the year. Even if patients can only get 5 pills in, certainly they’re going to benefit. That has been shown in the ExteNET study. Even 4 pills a day [is reasonable]. If the patient still has some degree of diarrhea, that means she’s still pharmacodynamically getting a lot of inhibition of the HER family; that is evidenced by her diarrhea.

The key is to find the dose of the neratinib that patients can tolerate and keep them on it. We have to go for the year in combination with endocrine therapy. We can almost always find a dose that works. I have another patient, a young woman who we started on 4 pills. We went to 5 pills and then 6 pills, and she never batted an eyelash. She never had any diarrhea, so it’s very variable. It’s really incumbent on us for the high-risk patients to utilize all the tools we have.

Has the coronavirus disease 2019 (COVID-19) impacted treatment selection for patients with HER2-positive breast cancer?

It hasn’t. In Dallas, we have not been greatly impacted by the pandemic. We have not changed our therapy recommendations. Certainly, not in the curative setting, but not even in the metastatic setting because we haven’t had a single case of COVID-19 among our staff in our cancer center. We’ve kept our patients extremely safe, so we have not really had to [make any adjustments to therapy]. We’ve been fortunate in that regard so far.

Could neratinib be a preferred agent because it is an oral agent?

One certainly could [say so] if we have a very substantial rise [in cases], and we’re very concerned of having patients stay at home. One could certainly [give neratinib] as a way to either temporize [the disease] if it’s not safe for patients to come in for their therapy. If a patient had a good response, and you just don’t want them to come in again for T-DM1 or trastuzumab and pertuzumab, it would potentially be very reasonable to utilize capecitabine and neratinib. One could potentially just use the neratinib. It would certainly be an option for patients who we are really concerned may be putting their life at risk by coming into a very high-risk situation.