Defining Value for the Treatment of Brain Metastases in Metastatic HER2-Positive Breast Cancer - Episode 9

Phase 3 NALA Study

A review of the NALA study looking at the use of capecitabine plus neratinib in patients with pretreated metastatic HER2-positive breast cancer.

Kevin M. Kalinsky, MD, MS: The NALA study was a study of patients with pretreated metastatic HER2 [human epidermal growth factor receptor 2]–positive breast cancers who had progressed, for instance, on trastuzumab. It randomized patients to capecitabine plus neratinib vs capecitabine plus lapatinib. The study demonstrated an improvement in terms of reduction of CNS [central nervous system] brain metastases, and this study led to actualization, including its inclusion in NCCN [National Comprehensive Cancer Network] Guidelines for patients with CNS metastases.

As you can see in the conversations we’ve had, with various other agents, like lapatinib and tucatinib, these are given with capecitabine, which is a chemotherapy that we know has good CNS penetration.

As I mentioned, neratinib had some associated toxicities, in particular gastrointestinal issues. There have been other studies with various agents that you can give to prevent the likelihood of developing gastrointestinal adverse effects and other things like budesonide and other agents. This seems to be a way that you can prevent the significant gastrointestinal issues that you can see with neratinib. This was a study that did lead to the utilization of capecitabine plus neratinib.

Sarah Sammons, MD: The NALA trial was a phase 3 randomized clinical trial of patients with advanced HER2-positive metastatic breast cancer who had received at least 2 lines of prior therapy. Patients were randomized to either neratinib, which is a pan-HER inhibitor, plus capecitabine or lapatinib plus capecitabine. The clinical trial showed that there was a modest improvement in progression-free survival with neratinib and capecitabine vs lapatinib and capecitabine. They also looked at an end point, which was time to CNS intervention: time to needing intracranial, surgery, or something like that. They showed that neratinib prolonged time to CNS intervention modestly over lapatinib and capecitabine.

Neratinib and capecitabine has a bit worse diarrhea than lapatinib and capecitabine. About 86% of patients in the trial had all-grade diarrhea. When you’re prescribing neratinib and capecitabine, it’s extremely important to consider diarrhea prophylaxis. The CONTROL trial also looked at several different ways that you can mitigate the diarrhea with this regimen. Dose escalation can be effective in mitigating diarrhea as well as prophylactic loperamide. That trial also looked at prophylactic budesonide and colestipol, which we’ll sometimes use in drastic cases as well.