Neratinib + Capecitabine in HER2+ Breast Cancer

Julie R. Gralow, MD: Let’s move on to another combination that received recent FDA approval in the metastatic setting. Let’s talk a bit about neratinib and capecitabine in metastatic breast cancer. What is it? What’s neratinib? How does it differ from the other targeted therapies?

Mark Pegram, MD: Neratinib is an orally bioavailable dual actually pan-HER [human epidermal growth factor] receptor kinase inhibitor, so it blocks EGF receptor as well as HER2 and also HER4. HER3 lacks a kinase active domain in the carboxy terminus of that protein, so it doesn’t hit the 3 per se. This agent has been tested in patients with HER2 mutations in the kinase domain, has been shown to have activity in that setting, particularly when combined with antiestrogen such as fulvestrant. This combination of neratinib in combination with capecitabine was put to the test head-to-head against lapatinib plus capecitabine, which was approved by the FDA many years ago. This head-to-head trial was called the NALA trial.

It was presented first at ASCO [American Society of Clinical Oncology Annual Meeting] in 2019, and in that analysis the difference between the 2 arms in terms of the PFS [progression-free survival] was about 2.2 months. Oddly in that analysis, because the proportional hazard assumption did not hold, the separation between the curves didn’t occur until roughly after about 6 months. The statistical analysis plan for that trial prespecified that a restricted mean survival analysis at 24 months would be performed. In this prespecified analysis, the mean PFS for patients on the neratinib-plus-capecitabine arm was 8.8 months, and the mean PFS for patients treated with lapatinib-capecitabine was 6.6 months and that met statistical confidence.

Now the FDA has granted approval for neratinib in combination with capecitabine for HER2-positive metastatic breast cancer patients who have received 2 or more prior anti–HER2-based regimens in the metastatic setting. It’s of note that when you use this combination, the drugs are to be taken orally once a day with food. The capecitabine is given on a 14-day on, 7-day off cycle—a 21-day cycle—while the neratinib is given continuously. Since neratinib blocks EGF receptor as well as HER2, it is associated with EGFR kinase inhibition adverse effects, particularly diarrhea. But it also can cause stomach upset, such as nausea, vomiting, anorexia, constipation, fatigue, weight loss, dizziness, back pain, arthralgia, and other troublesome adverse effects.

It’s of note that concomitant use with proton pump inhibitors is discouraged with this regimen. Patients requiring gastric acid–reducing agents are to use H2 receptor antagonists, but even then separated by at least 3 hours or so from the neratinib administration. Also remember neratinib is a CYP3A4-metabolized drug, so you’re to avoid strong CYP3A4 inhibitors. Because of the potential for this drug combination to cause diarrhea, it’s required to use a high-dosage loperamide prophylaxis starting at 12 mg per day for the first couple of weeks, then 4 mg twice a day from day 15 all the way to 56 and as needed thereafter. This can be a quite toxic regimen. There was no OS [overall survival] benefit—21 versus 18.7 months—and no statistically significant difference in response rate, about 33% versus 27% for the control arm.

Interestingly, the TBCRC [Translational Breast Cancer Research Consortium] has presented data on this regimen prior to the pivotal NALA trial, and it noted some CNS [central nervous system] responses. In about 49% of those patients without prior lapatinib exposure, they saw objective responses, and about a third even with prior lapatinib exposure had response to this regimen with median survivals in the range of 13 to 15 months, respectively. This regimen is available technically in as much as it’s approved by the FDA. In my opinion, given the challenging toxicities with lapatinib, I would argue that it has been trumped by the tucatinib HER2CLIMB trial regimen, which is tucatinib in combination with capecitabine and trastuzumab. I don’t currently use neratinib in the late-stage setting for HER2-positive metastatic disease, because I don’t think the therapeutic index is there anymore compared with some of these more recently approved approaches.

Julie R. Gralow, MD: Based on the control trial, which was in the extended adjuvant setting, our group has actually taken to starting colestipol with the loperamide as we initiate the drug, which seems to really help control the diarrhea early on. You can quickly get it off after a few cycles as you’re tapering the loperamide. While we learned how to help our patients manage the most significant adverse effect, I would agree with you that while neratinib has a role, it has some activity in the brain. The FDA gave it orphan drug status for HER2-positive brain metastases, based on that TBCRC-022 trial that you described. But I do think that based on the adverse-effect profile, tucatinib probably wins out here, although the 2 haven’t been head-to-head compared in terms of efficacy.

Mark Pegram, MD: Julie, there was a cohort 5 in the control trial, which was gradual escalation of the neratinib dose, first starting at about 120 mg/day. Have you ever used that either in the metastatic setting or in the extended adjuvant setting?

Julie R. Gralow, MD: I’ve used it a couple of times in the metastatic setting when I’ve had frail patients who have had a lot of treatment, and I just wanted to slowly ease them into this. Have you had much experience with it?

Mark Pegram, MD: Yeah, I have tried it a few times since that cohort 5 was presented at a poster session. I forget which meeting, but it was about a year or so ago. It does seem to help. Most of the diarrhea from neratinib happens in the first 2 to 3 months, and consequently if you can just gradually escalate the dose during that interval, you can generally get by with it, albeit still with PRN [as-needed] loperamide and/or colestipol as you point out.

Transcript edited for clarity.