Dose Escalation & Managing Toxicities of Neratinib

Joyce O'Shaughnessy, MD: When neratinib as seen in the ExteNET trial became FDA approved, it immediately became an option for patients who had finished up their year of trastuzumab, or pertuzumab if they were treated with pertuzumab either preoperatively or in the adjuvant setting. This is because at 5 years, particularly in the ER [estrogen receptor]-positive patients, you had more than a 5% absolute improvement in remaining disease free. That immediately became a standard of care. The optimal selection of patients are those with high-risk disease who either started with node-positive disease or who did not have a pathologic complete response to preoperative therapy. Now, most patients are treated with preoperative therapy if they have node-positive disease or larger cancers, T2 or greater. So we’re going to know their pathologic status.

If they have residual disease, they’re high risk by definition, and I think they should be afforded every opportunity to reduce their risk of recurrence. The other issue with neratinib is it does cross the blood-brain barrier, and patients who have residual disease who had high risk to start off with, particularly stage III disease and ER-negative disease, unfortunately they’re at risk for brain metastasis. In the KATHERINE trial, utilization of the T-DM1 [trastuzumab emtansine], though it was very impressive in terms of improving invasive disease-free survival, unfortunately did not reduce the risk of brain recurrence. Even for patients who started off stage III disease, ER-negative and had a pathologic complete response, unfortunately they’re really at risk. In the KATHERINE trial, of the recurrences, about half of them were in the brain, basically.

I’m thinking increasingly about what tools do I have that are proven to improve disease-free survival. We don’t have data from the ExteNET trial showing reduction in brain metastasis, but I think anyone who had stage III disease, even if they’re a pathologic complete response, could very reasonably be considered for the adjuvant neratinib. But I think where most doctors would agree would be those with residual disease and those who had nodes positive to start off with, who for whatever reason may have just been treated in the adjuvant setting, didn’t get the opportunity to have preoperative therapy.

For women to benefit from the neratinib, we know they need to take it for the year or close to the year in looking at the ExteNET data. Our job is to get it into the women and have them be able to tolerate it and stay with it. It’s only 1 year. The main toxicity of neratinib is diarrhea, and the labeled dose is 240 mg. Each pill is 40 mg. That’s 6 pills. Starting with that leads to about a 40% grade 3 diarrhea rate. It’s not very feasible. What has been done is there’s a large study called the CONTROL trial, which is very helpful, looking at prophylactic loperamide, starting from day 1 of the neratinib to prevent diarrhea or to decrease the frequency of it. That has been shown to be useful. Colestipol, the bile acid binder, has also shown to be useful if a second agent is needed.

More recently, the approach has been studied prospectively in the CONTROL trial, not starting with 6 pills but starting with 4 pills, so 160 mg for a week or two. If it’s well tolerated, it goes up to 5 pills, 200 mg for a week or 2 or 3, and then going up to 240 mg if tolerated. It’s OK to stay at the 160 mg or the 200 mg if women are still having some loose stools. I always tell my patients to take 2 loperamides after the first loose stool of each day and then 1 loperamide after each subsequent loose stool. Write it down, keep a log for me.

In the CONTROL trial, loperamide was utilized just prophylactically, like 1 loperamide 3 or 4 times a day for the first couple of weeks. The thing about the diarrhea is it’s really the first 30 days. It substantially goes down after the first 30 days. In part that could be due to dose reduction, but the dose escalation is quite a clever approach because you’re getting less severe diarrhea and less need for dose reduction because you’re not going to go up until someone is tolerating it quite well. There is a tachyphylaxis, there is an accommodation. Patients get used to it, then you might be able to go up.

But in a subset analysis of the ExteNET trial, patients who could stay on for 11 months, who could at least receive 160 mg for 11 months, receive benefit. They don’t have to get 240 mg for the full year to benefit, which is really good. That’s really the main toxicity, the diarrhea. The rest is a little mild fatigue. There can be a little nausea in the beginning. There’s a small risk of rash, which can be helped with non-drowsy antihistamines, for example. Dose reduction can also help in that regard.

But we can get this in, and I think it’s very good to start with 4 pills, work their way up, and to have the loperamide if they’re ready, either starting 2 or 3 times a day. Or what I do, is 2 after the first loose stool of the day and 1 after each subsequent loose stool because then you’d really know if they need it or not. This is so they don’t get too constipated, and to keep a log, keep track of it. That is quite manageable for most patients if you do that.

Transcript edited for clarity.

Case: A 54-Year-Old Woman With Stage 2HER2+ Breast Cancer

Initial presentation

• A 54-year-old, postmenopausal woman presented with a painless palpable mass on the right upper outer quadrant of her right breast
• PMH/SH: unremarkable, no family history of cancer
• PE: ~ 4-cm palpable right breast mass, clinically node negative, no visible sink involvement

Clinical workup

• Labs: WNL
• Ultrasound showed a right breast mass, and two axillary lymph nodes
• Mammogram confirmed a right—sided, poorly defined speculated 4.2-cm mass
• PET/CT showed increased uptake in the right breast diffusely, with 2 FDG—avid axillary lymph node involvement; no evidence of distant metastases
• Ultrasound—guided FNA biopsy of the breast mass confirmed grade 3 infiltrative ductal carcinoma
  • Hormone receptor/HER2 Status:HER2+:3+ by IHC,80%ER+, PR-
• Stage T2N1M0; ECOG PS 0

Treatment and Follow-Up

• The patient was started on preoperative docetaxel + carboplatin + trastuzumab + pertuzumab (TCHP), and pegfilgrastim every 3 weeks for 6 cycles;
  • Achieved clinical complete response
• She underwent right mastectomy; residual disease: 1 positive axillary lymph node, and 1-cm RD in the right breast; 4 sentinel lymph nodes removed, 1 positive for disease; she also received post mastectomy radiation therapy of her chest wall and regional lymphatics
• She was started on trastuzumab emtansine every 3 weeks for 14 cycles + aromatase inhibitor PMRT + letrozole planned for 10 years
• Extended adjuvant neratinib was initiated
  • Week 1: 160 mg (4 tablets) PO qDay; week 2: 200 mg (5 tablets) PO qDay; week 3: 240 mg (6 tablets) PO qDay for 1 year
  • IV zoledronic acid every 6 months was added to her regimen for 3-5 years