Neratinib Regimens Elicit CNS Responses in HER2+ Breast Cancer

Nancy U. Lin, MD

A combined analysis of data from the NALA, NEfERT-T, and TBCRC 022 trials demonstrated potential with neratinib (Nerlynx) regimens for patients with HER2-positive breast cancer who have brain metastases, explained Nancy U. Lin, MD.

In cohort 3a of the phase II TBCRC 022 trial, the combination of neratinib plus capecitabine (Xeloda) showed a composite CNS objective response rate (ORR) of 49% in patients with HER2-positive breast cancer who had brain metastases and were naïve to lapatinib (Tykerb).

Data from the phase II NEfERT-T trial, which enrolled treatment-naïve patients with HER2-positive metastatic breast cancer, showed a CNS ORR of 100% with neratinib and paclitaxel compared with 33.3% with trastuzumab (Herceptin)/paclitaxel.

In the phase III NALA study, the CNS ORR with neratinib plus capecitabine was 26.3%, which included 1 complete response, compared with 15.4% with lapatinib/capecitabine in patients with HER2-positive metastatic breast cancer who previously received ≥2 HER2-directed regimens.

In September 2019, the FDA accepted a supplemental new drug application for neratinib for use in combination with capecitabine for the treatment of patients with HER2-positive metastatic breast cancer who have failed ≥2 prior lines of HER2-directed treatments, based on the overall NALA data. The FDA is expected to decide on the application by the end of April 2020.

In a landmark analysis compiling data from all 3 studies, results showed that patients who experienced CNS objective responses had improvements in progression-free survival (HR, 0.58; 95% CI, 0.31-1.10; P = .087) and overall survival (HR, 0.43; 95% CI, 0.24- 0.76; P = .003).

Research efforts focused on therapeutic regimens that target CNS metastases continue, with the hope to eventually prevent brain metastases altogether, said Lin.

“Systemic therapy for patients with HER2-positive breast cancer and brain metastases can be effective. This is not limited to just neratinib plus capecitabine. There are a number of other agents, including tucatinib, lapatinib, and hopefully others in the future that have CNS activity,” said Lin. “One of the most important things that we can try to work on are developing strategies to prevent CNS metastases in the first place.”

In an interview with OncLive, Lin, associate chief in the Division of Breast Oncology at the Susan F. Smith Center for Women's Cancers, director of the Metastatic Breast Cancer Program, senior physician at Dana-Farber Cancer Institute, and an associate professor of medicine at Harvard Medical School, discussed research focusing on CNS penetration in HER2-positive metastatic breast cancer.

OncLive: Could you provide an overview on the compiled CNS data in the NALA, NEfERT-T, and TBCRC 022 trials?

Lin: This was an analysis to pull together the CNS data that were available from 3 trials. The first was NALA, a randomized phase III trial comparing lapatinib/capecitabine versus neratinib/capecitabine in patients with previously treated, HER2-positive metastatic breast cancer. The second was NEfERT-T, which was a first-line trial comparing neratinib/paclitaxel versus trastuzumab/paclitaxel in HER2-positive metastatic breast cancer. Finally, the third trial was TBCRC 022, which was a single-arm, multicohort study that specifically enrolled only patients with progressive CNS disease. In that study, the primary endpoint was CNS ORR. The goal of this analysis was to put together the CNS-focused data in one place, focusing on CNS progression as well as the data on CNS response.

What were the results of the analysis?

In terms of CNS-specific outcomes, if we look at TBCRC 022, which enrolled only patients with progressive brain metastases, the ORR in the brain was 49% in lapatinib-naïve patients. There was also a subset of patients who previously received lapatinib; the CNS ORR was 33% in those patients.

If we look at NALA and NEfERT-T, because the trials enrolled patients who had stable or treated brain metastases—they couldn't have progressive brain metastases at the start of the trial—the data focus on time-to-event outcomes. Both trials showed that the combination of neratinib and capecitabine was associated with a prolongation to CNS events. Specifically, in the NEfERT-T trial, the cumulative incidence of CNS metastases was 20% in the trastuzumab/paclitaxel arm compared with 10% in the neratinib/paclitaxel arm; therefore, there is some signal of potential CNS prevention.

What impact will these data have on the breast cancer paradigm?

They further solidify the idea that neratinib and capecitabine do have CNS activity in patients with HER2-positive breast cancer, and CNS prevention is a potential goal. In a larger sense, trying to prevent CNS metastases is important for the breast cancer community and for our patients.

Patients with brain metastases are often excluded from clinical trials. Why is it important to perform research on this patient population?

We have previously conducted a study of lapatinib, which is another HER2-based TKI, in patients with HER2-positive breast cancer who have brain metastases. It showed that the combination of lapatinib and capecitabine has CNS activity. We were very motivated to see whether other HER2 TKIs, including neratinib, might also have CNS activity. This is because if we look at HER2-positive disease—in thinking about the development plan of new HER2-targeted TKIs—one of the main, potential, differentiating factors can be CNS activity. There are several compounds that are currently in late stages of development and that were reported at the 2019 San Antonio Breast Cancer Symposium. If there is a compound that shows activity in the CNS, that becomes a very important differentiating factor.

What does the future treatment of patients with HER2-positive metastatic breast cancer with brain metastases look like?

When we think about the paradigm of how we treat patients with brain metastases, we don't always have to reach for radiation therapy first, especially in those patients who have had multiple prior rounds of radiation therapy—a patient population where it makes sense to consider systemic approaches.

We will have to see how everything plays out in terms of the HER2 TKIs. Lapatinib is currently on the market and both neratinib and tucatinib are being reviewed by the FDA. We will have to see how the next few months and year play out.

Awada AH, Brufsky AM, Saura C, et al. Impact of neratinib on development and progression of central nervous system (CNS) metastases in patients with HER2-positive metastatic breast cancer (MBC): findings from the NALA, NEfERT-T, and TBCRC 022 trials. Presented at: 2019 San Antonio Breast Cancer Symposium; December 10-14; San Antonio, TX. Abstract P2-20-01. https://bit.ly/2uQPowJ.