CE / CME
Pharmacists: 1.00 contact hour (0.1 CEUs)
Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™
Nurses: 1.00 Nursing contact hour
Released: May 12, 2021
Expiration: May 11, 2022
Given the abundance of data that has been generated in both the neoadjuvant and the adjuvant setting during the past decade, how do we incorporate all of this into a proposed strategy for managing patients with stage I-III HER2+ 3EBC?
This module does not focus on low-risk HER2+ EBC patients, but patients with T1a/b, clinical N0 disease should have surgery. For small, T1a tumors, I typically observe those patients following surgery, and for patients with T1b disease, I recommend surgery followed by trastuzumab-based therapy. Generally, these patients do well on 12 cycles of trastuzumab and weekly paclitaxel and then trastuzumab to complete a year of therapy.
Patients with T1c lesions with node-negative disease and who are lower risk (based on age, grade, and hormone receptor status) could also receive the paclitaxel and trastuzumab regimen. For patients who may be higher risk, one might consider a strategy similar to patients with larger or node-positive disease.
For patients who have cT2 or cN1 or greater disease, I advocate neoadjuvant treatment with either doxorubicin/cyclophosphamide followed by a taxane with trastuzumab and pertuzumab or TCHP. Based on the TRAIN-2 data, I have stopped using the anthracycline-containing regimen in most cases because of the decreased risk of cardiac AEs long term with the nonanthracycline approach.
After neoadjuvant therapy, if patients achieve a pCR, they should continue to receive anti-HER2 therapy, with trastuzumab with or without pertuzumab to complete a total of 1 year. Right now, it is still unclear whether we should de-escalate patients to trastuzumab alone or continue with the dual HER2-targeted combination for a full year, although the 3-year data from TRAIN-2 suggest that the pCR outcomes are promising even with single HER2-targeted therapy with trastuzumab. However, we need additional data in this setting to further inform clinical practice. For patients whose disease is hormone receptor positive, they should also receive endocrine therapy for at least 5 years according to standard practice.
Patients with residual invasive disease after appropriate neoadjuvant treatment do not do as well, as shown by analyses of pCR vs non-pCR outcomes. For patients with residual disease who are hormone receptor positive, I would generally treat with T-DM1 followed by extended adjuvant therapy with neratinib.
There are currently no data supporting the use of neratinib therapy after T-DM1, but for patients with hormone receptor–positive disease, the rate of IDFS with adjuvant T-DM1 is still less than 90%, and extended adjuvant therapy with neratinib may be a reasonable strategy to improve outcomes further. For patients with residual disease who have hormone receptor–negative disease, I would recommend treatment with T-DM1 as adjuvant therapy.
Each of the HER2-targeted therapies has AEs of interest. For the anti-HER2 antibody combination of trastuzumab/pertuzumab, AEs tend to be diarrhea and, more rarely, cardiac toxicity or infusion reactions.9,10 Diarrhea is particularly a problem when trastuzumab/pertuzumab is combined with chemotherapy like carboplatin and taxanes.
Neratinib is predominantly associated with diarrhea, rash, and rare cardiac and liver toxicity.8 As an oral molecule, there can be some drug interactions that need to be noted and paid attention to.
T-DM1 is an antibody–drug conjugate and, therefore, has a different profile of AEs, including thrombocytopenia, increased liver enzymes, sensory neuropathy, and rarely, acute hepatic toxicity or cardiac toxicity or infusion reactions.12
In the phase III APHINITY trial, the addition of pertuzumab to trastuzumab increased the rate of diarrhea from 45.2% with trastuzumab and placebo to 71.2% (for any grade).11 The incidence of grade ≥3 diarrhea was approximately 10% with trastuzumab/pertuzumab vs 3.7% for trastuzumab and placebo.
Generally, diarrhea was most frequent during cycle 1 and when trastuzumab/pertuzumab is given concurrently with chemotherapy. Treatment with taxane/carboplatin plus trastuzumab/pertuzumab resulted in 18% of patients experiencing grade ≥3 diarrhea compared with 8% of patients receiving an anthracycline-based regimen with trastuzumab/pertuzumab.28
Diarrhea is not a trivial toxicity, and patients should be monitored carefully, particularly during cycle 1 of therapy. Diarrhea can generally be managed with antidiarrheals and diet modification if it is caught early, and treatment delay or discontinuation is generally not necessary for pertuzumab-associated diarrhea.
It was clear from the ExteNET trial that diarrhea was the major toxicity for neratinib even when it was given as a single agent. The rate of grade ≥3 diarrhea in ExteNET led to the CONTROL trial, which is an ongoing, open-label, sequential cohort trial in which different interventions were tried sequentially to manage diarrhea associated with neratinib therapy.29 Patients on the CONTROL trial all received neratinib for 1 year. The first 4 cohorts received neratinib 240 mg/day with a prophylactic antidiarrheal regimen. Cohort 1 started with loperamide 4 mg as a motility controlling agent, given routinely. Cohorts 2 and 3 received loperamide plus additional agents (budesonide or colestipol), and cohort 4 received colestipol with loperamide as needed. Finally, 2 cohorts assessed different neratinib dose-escalation strategies. Dose-escalation cohort 1 began with either neratinib 120 mg/day for 7 days followed by dose escalation to 160 mg/day for Days 8-14, and then up to full dose at 240 mg/day. Dose-escalation cohort 2 started treatment with neratinib 160 mg/day for Days 1-14, followed by 200 mg/day for Days 15-28, and then increasing 240 mg/day in cycle 13. The dose-escalation cohorts also received loperamide as needed.
The neratinib dose-escalation cohort 2 of the CONTROL study is still ongoing, but the other intervention cohorts are complete.29,30 As the cohorts progressed, there was less discontinuation of neratinib before the fully prescribed 1 year, and that reduced to 20%-28% for the combination therapies. For the loperamide-only cohort, the discontinuation rate before 1 year of neratinib therapy was 44.5% and that improved to 20%-30% with combination prophylaxis. The median duration of neratinib treatment across the completed cohorts was 11.60-11.96 months.
For the first neratinib dose-escalation cohort, 78% of patients completed 1 year of neratinib and 22% discontinued prior to 1 year of therapy, for a median duration of 11.96 months of neratinib treatment.
As the CONTROL trial progressed, there was a reduction in the incidence of diarrhea.30 In the dose-escalation cohort 1, only 13% of patients had grade 3 diarrhea. The rate of grade 3 diarrhea was higher for the cohort that received loperamide alone (31%), followed by the cohorts that received budesonide with loperamide (28%), colestipol with loperamide (21%), colestipol with as needed loperamide (32%), or the dose-escalation cohort 2 with as needed loperamide (26%).
The discontinuation rate due to diarrhea was quite low (≤11%) in most arms but was highest (20%) for those treated with loperamide alone.
Most treatment discontinuation due to diarrhea in the CONTROL study occurred in the first month of neratinib therapy, and discontinuation was particularly high (16.8%) in the loperamide-alone arm, so that would not be recommended as the standard approach.
All of the other approaches could be considered for patients, but in my own practice, I find that the dose-escalation strategy of starting at 120 mg/day for a week, then going up another 40 mg to 160 mg/day for a week, and then going up to full dose after 2-3 weeks results in a low discontinuation rate. Since the overall treatment course for neratinib is a full year of therapy, starting at a lower dose and escalating should not have any impact on the overall exposure to neratinib or on the overall impact for patient outcomes.
Based on these data, the best approach for management of neratinib-induced diarrhea would be to start neratinib at a lower dose (120 mg/day) and titrate up to 160 mg/day in Week 2 and 240 mg/day in Week 3. Loperamide can also be added as needed or used early with budesonide or colestipol. If diarrhea still occurs, there are also dose modifications to help manage this AE.8 Neratinib should be held for any grade 2 events that last more than 5 days or for grade 3 events that last more than 2 days. If the diarrhea resolves to grade ≤1 within a week, neratinib treatment can be resumed. If it takes longer to resolve, neratinib can be resumed at a lower dose (200 mg/day) and the dose can be further reduced by 40 mg/day if grade 3 diarrhea recurs. If grade 4 diarrhea occurs, treatment delay lasts longer than 3 weeks, or diarrhea recurs at grade ≥2 at 120 mg/day dose, neratinib should be permanently discontinued.
There are considerations for cardiac dysfunction during adjuvant trastuzumab, pertuzumab, or T-DM1 therapy.9,10,12 All of these drugs can result in decreased LVEF and even congestive heart failure, which can either be subclinical or clinical. All patients should receive a baseline assessment of LVEF before starting any anti-HER2 therapy. For patients receiving trastuzumab/pertuzumab, the baseline LVEF should be ≥55%, or 50% if they have received previous anthracyclines. LVEF should be monitored every 12 weeks during anti-HER2 therapy. If LVEF is reduced to <50% or if there is a ≥10% decrease from baseline, the HER2-targeted therapy should be held for at least 3 weeks. The LVEF should be rechecked, and typically, it does resolve and come back up to normal or near normal. If it improves to >50% or <10% below the baseline, the anti-HER2 therapy can be resumed with careful monitoring. I also recommend a cardiac evaluation by a cardiologist with an interest in cardio-oncology for any patient who has even an asymptomatic drop in LVEF. A cardiologist may prescribe beta-blockers or other cardiac medications that have a protective effect.
For adjuvant T-DM1 therapy, the pretreatment LVEF should be >50%. T-DM1 should be held if LVEF decreases to 40% or 45% with ≥10% decrease from baseline, and treatment can be resumed when cardiac function gets back up to ≥40% or within 10% of baseline.
There are many trials that are ongoing in HER2+ EBC. There are additional neoadjuvant trials (IMPassion050 and APTneo) adding the immune checkpoint inhibitor atezolizumab to standard therapy.31,32 This is a very interesting strategy that could enhance our ability to keep patients from relapsing and improve their pCR rate.
The PALTAN and NA-PHER2 trials are 2 neoadjuvant studies in patients with estrogen receptor–positive/HER2+ EBC that are looking at using the CDK4/6 inhibitor palbociclib with endocrine therapy and anti-HER2 therapy (trastuzumab or pertuzumab and trastuzumab) in a chemotherapy-free environment.33-35
So, we are looking both at strategies of intensification with the addition of atezolizumab to standard therapy and de-escalation strategies trying to achieve similar pCR rates without chemotherapy in selected populations. It will be interesting to see the results of these trials.
For patients with HER2+ breast cancer, the availability of HER2-targeted agents has markedly and rapidly improved overall outcomes. Survival rates for patients with early stage disease are >90% with up to 10 years of follow-up, depending on the study.
Neoadjuvant chemotherapy plus trastuzumab/pertuzumab for patients with HER2+ EBC and a tumor size ≥2 cm in diameter or with node-positive disease regardless of the size of the primary tumor has become the standard. We are now moving most patients to a nonanthracycline regimen with pertuzumab and trastuzumab, which appears to deliver similar efficacy with less cardiac toxicity.
For adjuvant therapy, either after surgery, after neoadjuvant chemotherapy, or after HER2 therapy with less than a pCR after surgery, we reviewed 3 trials in this commentary. APHINITY showed that dual HER2 therapy with trastuzumab/pertuzumab in the adjuvant setting improved the outcome for patients with node-positive disease. In the KATHERINE trial, T-DM1 adjuvant therapy for patients with residual invasive disease after neoadjuvant taxane and trastuzumab-based treatment improved the outcome for patients with residual disease. The ExteNET trial evaluated extended adjuvant therapy with neratinib after anti-HER2 antibody therapy, particularly in patients with hormone receptor–positive disease, and those who received neoadjuvant therapy who did not achieve a pCR showed substantial benefit.
I look forward to additional trials for our patients with HER2+ breast cancer to further improve on patient outcomes.
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