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.”

, 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.

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

: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.

Articles

Denise Yardley, MD, sheds light on individualized treatment approaches and other key developments in HER2-positive breast cancer.

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

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.”

, 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.

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

: 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.

 mutations, particularly in ER-positive, HER2-nonamplified breast cancer. 

 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, 

Now, there are emerging data that adding trastuzumab and making a triplet against those 

-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 

 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.

Joyce A. O'Shaughnessy, MD, sheds light on the current paradigm of HER2-positive breast cancer and the optimal role of neratinib in the early-stage and advanced settings.

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

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 

, 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.



: 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.





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 

-mutant breast cancer is highly active.

Now, there are emerging data that adding trastuzumab and making a triplet against those 

 mutations. There are a number of places we can utilize neratinib for the patients benefit.





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.





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.





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.

Over the past few years, the armamentarium in early- and late-stage HER2-positive breast cancer has become more robust with antibody-drug conjugates (ADCs) and the pan-HER inhibitor neratinib (Nerlynx), the latter of which has emerged as a standard of care for patients with metastatic disease, said Adam M. Brufsky, MD, PhD.

In 2019, the FDA approved ado-trastuzumab emtansine (T-DM1; Kadcyla) as adjuvant therapy for patients with residual HER2-positive breast cancer following neoadjuvant trastuzumab (Herceptin) and chemotherapy. The agency also approved fam-trastuzumab deruxtecan-nxki (Enhertu; DS-8201) for patients with unresectable or metastatic HER2-positive breast cancer who have received ≥2 prior anti—HER2-based regimens in the metastatic setting.

approved a supplemental new drug application for neratinib in combination with capecitabine (Xeloda)

 for the treatment of patients with advanced or metastatic HER2-positive breast cancer who have received ≥2 prior anti—HER2-based regimens in the metastatic setting, augmenting its indication as extended adjuvant therapy for patients with early HER2-positive breast cancer following trastuzumab-based therapy.

Findings from the phase III NALA trial served as the basis for the approval. Data showed a 24% reduction in the risk of disease progression or death with the neratinib combination compared with lapatinib (Tykerb) and capecitabine (HR, 0.76; 95% CI, 0.63-0.93; log-rank 

"The bottom line is that [neratinib] is a new standard of care if one is comfortable managing the diarrhea,” said Brufsky, who is a professor of medicine and associate division chief for the Division of Hematology/Oncology in the Department of Medicine at the University of Pittsburgh School of Medicine.

, Brufsky, who is also codirector of the Comprehensive Breast Cancer Center at the University of Pittsburgh Medical Center Hillman Cancer Center, highlighted the treatment landscape in HER2-positive breast cancer, remaining sequencing questions, and the growing utility of neratinib in the paradigm.

: Could you shed light on the current treatment paradigm in early-stage HER2-positive breast cancer?

: Generally, the way we treat patients with early-stage metastatic HER2-positive breast cancer is based on the size of the tumor. If the tumor is >2 cm, we tend to give neoadjuvant chemotherapy, usually with trastuzumab and pertuzumab (Perjeta). If the patient has a pathologic complete response (pCR), they will get trastuzumab or pertuzumab to complete 1 year of treatment. If they do not have a pCR, they will receive T-DM1.

For patients with tumors <1 cm, we will [perform] surgery and then make a decision about what to do. If they have tumors <2 cm and are node negative, they will likely get adjuvant paclitaxel and trastuzumab for 12 cycles or 12 weeks.

Some clinicians will give T-DM1 for 1 year, but I think that is a little controversial right now.

What options are available for patients in the adjuvant setting?

The big problem is what to do with a patient who had substantial residual disease after [surgery]. Normally, we do not give those patients 1 year of T-DM1. The problem is that data from the KATHERINE trial revealed about a 10% to 12% relapse rate, about half of which are in the central nervous system (CNS).

After T-DM1 is [completed], should these patients be given 1 year of neratinib? There are data that support this; however, [not in the context of] T-DM1 or pertuzumab. The ExteNET study showed about a 5% to 6% disease-free survival benefit in the patients who had residual disease after neoadjuvant therapy and [went on to] receive neratinib for 1 year.

Could dose-escalation strategies be used to mitigate treatment-emergent adverse events (AEs) with neratinib?

The biggest concern with [neratinib] is its toxicity, particularly diarrhea. As it turns out, there was a nice trial called CONTROL that may or may not get published in the next few months that looked at various strategies such as dose-escalation, as well as the use of colestipol, and loperamide. It turned out that a combination of dose-escalation and perhaps adding 1 of the other agents ameliorated the vast majority of diarrhea.

There will always be patients who [have significant] diarrhea, so neratinib should be used judiciously. On the other hand, there is evidence that we can ameliorate a lot of the AEs [with dose-escalation and adding other agents].

How do you approach treatment for patients with late-stage disease?

Patients with late-stage disease will likely get docetaxel, trastuzumab, and pertuzumab [to start]. If they progress, they will get T-DM1.

The real mystery right now is what to give patients after that. That [decision] is going to revolve around whether patients have brain metastases or not. If they do, we tend to try to use TKIs. I'm using neratinib and capecitabine as 1 option. It is better than lapatinib and capecitabine. At some point in the not-to-distant future, tucatinib (Tukysa), capecitabine and trastuzumab [will be another] option.

If the patient does not have substantial CNS disease, we are likely to [give] trastuzumab deruxtecan. That is really where we are going as long as we understand that a certain number of patients may get lung inflammation while on trastuzumab deruxtecan.

How have data from the NALA trial and the FDA approval of neratinib/capecitabine impacted the treatment of patients with metastatic HER2-positive breast cancer?

The combination of neratinib and capecitabine was compared with the combination of lapatinib and capecitabine in the NALA trial. Both median and mean PFS were evaluated, because it looked like the curves separated late. Because of that, median PFS is not a great end point.

It turned out there was about a 25% improvement in mean PFS in the women who received neratinib/capecitabine versus lapatinib/capecitabine—–that was statistically significant.

There was also an improvement in duration of response and time to progression [with neratinib/capecitabine]. There was also an improvement in the time to treatment failure in the brain, which was measured as the need for CNS intervention with radiation, steroids, or another modality.

The reason that end point was chosen was because we didn't require a baseline MRI to [enroll patients in] the trial. This study started around 2013, when we didn't understand that a substantial number of women had CNS progression. Had we known that, the trial would have been designed like the tucatinib studies, in which patients would have been required to have an MRI at baseline. Unfortunately, it is what it is, and we have to go with the study.

There was a clear improvement of about 10% in the number of patients who did not require CNS intervention.

While there was some grade 3 diarrhea, it only lasted about 4 days. I believe that only about 3% of patients in both arms of the trial discontinued treatment.

We will have to see what happens when tucatinib [gets approved] because that agent does not lead to diarrhea. The nice thing is that we now have an [agent in an area of] HER2-positive breast cancer, which historically didn't have a lot of proven therapies. Now, we have at least 3 agents that are going to be FDA approved.

What drugs in the pipeline look promising?

There are other drugs that are coming down the pike such as margetuximab, which is basically trastuzumab that has been reengineered to have more binding to the Fc receptor and macrophages. That [drug] may work better [than trastuzumab], but we will have to see. There are some trials that demonstrated a progression-free survival (PFS) but not an overall survival benefit [with margetuximab], so we will see [what longer-term data show].

(Vic-)trastuzumab duocarmazine (SYD985) is a similar drug. It is an ADC with a slightly different payload. It is currently in phase III clinical trials.

How has the coronavirus disease 2019 (COVID-19) pandemic impacted treatment for patients with HER2-positive breast cancer?

It is hard to know where the COVID-19 pandemic is going. The science is increasing at an enormous pace. We are doing years-worth of science and debate about varying topics in about 4 weeks.

The good thing is that it looks like the initial wave [of the pandemic] is going to resolve in the future. Our efforts are going to be centered around what we think is going on scientifically. How do we take that science and figure out how to move forward? That is the real debate.

Could neratinib be a preferred agent during the pandemic since it is an oral agent?

It's a good point for patients with metastatic disease. It is a very good idea, although patients would require close and frequent monitoring over the phone during this time.

Saura C, Oliveira M, Feng Y-H, et al. Neratinib + capecitabine versus lapatinib + capecitabine in patients with HER2+ metastatic breast cancer previously treated with ≥ 2 HER2-directed regimens: findings from the multinational, randomized, phase III NALA trial. 

. 2019;37(suppl 15; abstr 1002). doi: 10.1200/JCO.2019.37.15_suppl.1002

Adam M. Brufsky, MD, PhD, highlightes the treatment landscape in HER2-positive breast cancer, remaining sequencing questions, and the growing utility of neratinib in the paradigm.

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