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: August 10, 2020
Expiration: August 09, 2021
The most common toxicity associated with neratinib and trastuzumab plus pertuzumab is diarrhea.24,25 Neratinib can also cause a rash and, rarely, can cause liver toxicity. T-DM1 can also rarely cause severe hepatic toxicity, but more commonly results in increased aspartate aminotransferase and alanine aminotranferase levels and thrombocytopenia.15 Neuropathy is also seen with T-DM1. Cardiotoxicity is rare but possible with any of these 3 approaches, particularly with trastuzumab/pertuzumab when combined with anthracycline-based chemotherapy. As with any agent given as IV infusion, infusion-related reactions can occur with trastuzumab/pertuzumab and T-DM1, particularly during the first dose.
Neratinib, because it is an oral agent, does not result in infusion-related reactions but it can have drug interactions. Clinicians need to be cautious about using this TKI in patients who are taking gastric acid–reducing agents, or CYP3A4 inhibitors or inducers, and the potential for P-glycoprotein to interact with neratinib.
Diarrhea is the most common and most problematic AE for patients receiving pertuzumab and trastuzumab. In the APHINITY trial, an increase in the rate of diarrhea was observed with the addition of pertuzumab to trastuzumab compared with trastuzumab alone: 71.2% of any grade vs 45.2%, respectively. Likewise, grade ≥ 3 diarrhea was seen in 9.8% vs 3.7% of cases, respectively. Of note, the rate of diarrhea was higher with the nonanthracycline regimen of docetaxel, carboplatin, trastuzumab, and pertuzumab: grade ≥ 3 diarrhea occurred in 18% of patients in this treatment arm vs 8% of patients receiving anthracycline-based chemotherapy followed by a taxane plus trastuzumab/pertuzumab.
Episodes of diarrhea were most frequent during cycle 1 of pertuzumab and when given concurrently with chemotherapy. The incidence of grade ≥ 3 diarrhea from the onset of the first dose of any study treatment was 9.8% and 0.5% with an onset during treatment with the HER2-targeted agents after chemotherapy was complete.
Regardless, even for patients who experienced grade 3 diarrhea, treatment delays or discontinuations were generally not necessary to mitigate the diarrhea. Most incidences of diarrhea were low grade and also decreased in frequency in subsequent treatment cycles. To manage pertuzumab-related diarrhea, antidiarrheal medications and dietary modifications are often sufficient, along with adequate hydration. Although dose delays or reductions in chemotherapy can be considered to manage diarrhea, dose reductions of pertuzumab are not recommended.
After the ExteNET trial, in which 55% of patients receiving neratinib experienced grade 1/2 diarrhea and 40% experienced grade 3 diarrhea, the phase II CONTROL study was designed to evaluate antidiarrheal prophylaxis for neratinib-associated diarrhea using sequential cohorts with different drugs (N = 501).35 The first cohort of patients was given loperamide alone at initiation of neratinib 240 mg/day and additional sequential cohorts received loperamide with budesonide, loperamide with colestipol, or colestipol and loperamide as needed.
In addition, the study included 2 neratinib dose-escalation cohorts. In 1, patients received neratinib starting with a half dose of 120 mg/day in Week 1, 160 mg/day in Week 2, and then the full dose of 240 mg/day for 13 cycles with loperamide as needed. In the other dose-escalation cohort, patients received neratinib starting at 160 mg/day for 2 weeks, then 200 mg/day for 2 weeks, then 240 mg/day for 13 cycles with loperamide as needed.
If diarrhea did occur after prophylaxis, episodes were managed with standard approaches including loperamide or diphenoxylate plus atropine along with dietary changes, drinking 8-10 large glasses of clear liquids/day, and neratinib dose modifications as needed.
Results showed that the addition of budesonide or colestipol to loperamide as antidiarrheal prophylaxis in patients receiving neratinib was associated with higher rates of completing 1 year of treatment, as well as lower rates of neratinib discontinuation during the year of therapy.35,36
In patients receiving loperamide alone, only 55.5% completed a year of treatment and 44.5% discontinued neratinib within the first year. By contrast, with the addition of budesonide and colestipol, more than 70% of patients were able to complete a year of neratinib and fewer than 30% discontinued within the first year.
Of note, the data for the neratinib dose-escalation cohorts are not yet mature, with 37% of patients still receiving neratinib therapy. However, thus far 20% have discontinued neratinib for any reason before completing a year of therapy.
In CONTROL, all the prophylaxis approaches reduced diarrhea incidence and severity, including overall rates of diarrhea, but particularly the rate of high-grade diarrhea.
The best results, to date, have been seen with the combination of loperamide and colestipol or the neratinib dose escalation with loperamide PRN. In the group receiving loperamide and colestipol, the incidence of grade 3 diarrhea was 21% (vs approximately 30% with loperamide alone or with budesonide) and the rate of discontinuation due to diarrhea was 4%. Although the rate of grade 3 diarrhea (15%) appears even lower with neratinib dose escalation and loperamide as needed, as mentioned, those data remain immature and additional follow-up is needed in this cohort.
Overall, however, it is clear that all preventive strategies evaluated in CONTROL reduced the incidence of grade 3 diarrhea compared with the 40% rate seen in the ExteNET study.
It is also important to recognize that the incidence of diarrhea is highest during the first month of therapy.37 As seen here, after Month 1 those numbers reduced substantially, particularly when prophylactic measures outlined in the CONTROL trial are implemented.
As shown here, even in the first month, adding any of these antidiarrheal agents provided a meaningful reduction in both grade 2 and grade 3 neratinib-associated diarrhea. For the patients who received loperamide and colestipol, rates of grade 2 and grade 3 diarrhea were approximately 50% lower vs ExteNET in Month 1. Over the next 11 months, no grade 3 diarrhea was reported with loperamide and colestipol, and only minimal or no grade 2/3 diarrhea was reported after Month 2. No grade 4 events were reported from CONTROL.
These data guidelines have been suggested to manage neratinib-induced diarrhea. In general, loperamide 4 mg should be given prophylactically to all patients at the first dose of neratinib and taken 3 times a day in Weeks 1 and 2, twice daily in Weeks 3 to 8, and as needed (up to 4 times a day) starting in Week 9.24 Either budesonide or colestipol can be added to manage loperamide-refractory diarrhea as needed, and care should be taken to adjust the dose of antidiarrheal medications if constipation occurs.
In addition, neratinib dose modifications can be considered as appropriate. Neratinib should be held if grade 2 diarrhea lasts 5 days or longer, if grade 3 diarrhea lasts 2 days or longer, or diarrhea of any grade is accompanied by complicating features such as dehydration, fever, hypotension, renal failure, or grade 3/4 neutropenia. Once the diarrhea (and any other AEs) resolve to grade 1 or less, neratinib can be restarted.
If the diarrhea resolves to grade 1 or less in less than a week after holding neratinib therapy, neratinib can be restarted at the same dose. If it takes longer to resolve to grade 1, reduce the neratinib dose to 200 mg/day once neratinib can be restarted, and consider additional reductions to 160 mg/day or 120 mg/day for additional recurrence of diarrhea. If grade 4 diarrhea occurs or diarrhea recurs at grade ≥ 2 at 120 mg neratinib dose, permanently discontinue neratinib.
Cardiac dysfunction is an uncommon event seen during adjuvant treatment with trastuzumab plus pertuzumab or with T-DM1.15,25 The anti-HER2–targeted antibody therapy alone, or with chemotherapy (particularly anthracyclines), can result in decreased LVEF and congestive heart failure.
When considering therapy with trastuzumab and pertuzumab, clinicians should ensure that patients have a baseline LVEF assessment of at least 55%, or 50% after anthracyclines. During treatment, LVEF should be monitored every 12 weeks.
If the LVEF reduces to lower than 50% with a greater than 10% decrease from baseline, hold trastuzumab and pertuzumab for at least 3 weeks and obtain a repeat echocardiogram or evaluation of LVEF by other means. If LVEF improves to greater than 50% or lower than 10% below baseline, trastuzumab and pertuzumab can be reinitiated with careful monitoring.
With regard to T-DM1, clinicians should ensure that patients have a baseline LVEF assessment of at least 50% before beginning therapy. Once treatment has started, LVEF should be monitored and if the LVEF decreases to lower than 40% or 45% with a 10% decrease or greater from baseline, treatment should be held for at least 3 weeks. T-DM1 treatment can be resumed when the LVEF increases to greater than 40% or is within 10% of baseline.
Going forward, in the setting of HER2-positive EBC, the goal is to continue to meaningfully improve rates of invasive DFS. As shown in this table, key ongoing neoadjuvant trials include immunotherapy in IMpassion050 and APTneo, which are evaluating atezolizumab combination regimens, and CDK4/6 inhibition in the PALTAN and NA-PHER2 studies of palbociclib combination therapy.38-42 We await the results of these studies with great interest.
For patients with HER2-positive EBC, the availability of HER2-targeted agents have markedly and rapidly improved overall outcomes. The first major advance was the approval of trastuzumab, and this was followed by lapatinib, pertuzumab, T-DM1, and neratinib.
Based on the APT trial, the combination of paclitaxel and trastuzumab became a new standard of care for patients with small (< 3 cm), node-negative, HER2-positive EBCs. Then, the ATEMPT trial, although technically a negative trial, suggested that T-DM1 may also be reasonable for selected patients with stage I, node negative HER2-positive EBC who want to avoid traditional chemotherapy.
For patients with more extensive or higher-risk HER2-positive EBC, neoadjuvant systemic therapy with trastuzumab and pertuzumab in combination with chemotherapy has become increasingly more important based on the phase II NeoSphere and TRYPHAENA trials. The APHINITY trial led to the approval of dual HER2 therapy with trastuzumab and pertuzumab in the adjuvant setting (either continued for a total of 1 year after neoadjuvant chemotherapy or with adjuvant chemotherapy and continuing for a total of 1 year in patients at a high risk of recurrence). The phase III KATHERINE trial led to the approval of T-DM1 as adjuvant therapy for patients with residual invasive disease after neoadjuvant taxane and trastuzumab-based treatment.
Finally, the ExteNET trial has highlighted the importance of extended adjuvant therapy with neratinib for some patients following the completion of 1 year of anti-HER2 antibody therapy. Neratinib is particularly important for patients with hormone receptor–positive disease and for those without pCR after neoadjuvant therapy.
As we continue to advance the standard of care, by enhancing the safety and tolerability of current treatment options as well as by researching novel agents and treatment strategies, outcomes for our patients with HER2-positive EBC will likely continue to improve.
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