Neratinib Generates CNS Responses Across HER2+ Breast Cancer Brain Metastases Subgroups

Neratinib (Nerlynx)–based combinations demonstrated consistent central nervous system (CNS) efficacy across treatment settings in patients with HER2-positive breast cancer with untreated/active or asymptomatic/stable brain metastases, according to findings from a literature review that were presented at the 42nd Annual Miami Breast Cancer Conference.1

This literature review included prospective clinical trials that reported CNS-specific data for neratinib-based combination regimens from patients with HER2-positive breast cancer from the phase 2 TBCRC 022 trial (NCT01494662), which only enrolled patients with untreated or active brain metastases; as well as from the phase 3 NALA (NCT01808573) and phase 2 NEfERT-T (NCT00915018) trials, which comprised patients with asymptomatic or stable brain metastases.

“The combination of neratinib with other FDA-approved drugs represents a promising approach for the treatment of patients with HER2-positive breast cancer brain metastases in clinical practice, although the optimal sequencing of treatments following tucatinib [Tukysa], fam-trastuzumab deruxtecan-nxki [Enhertu], and/or ado-trastuzumab emtansine [T-DM1; Kadcyla] progression has yet to be established,” the study authors wrote in a poster of the findings.

Overview of Literature Review

Breast cancer brain metastases are a common site of disease recurrence and are associated with high rates of morbidity and mortality among patients with HER2-positive metastatic breast cancer, the authors noted.

For instance, a retrospective meta-analysis demonstrated that the pooled cumulative incidence of brain metastases in patients with HER2-positive breast cancer was 31% at a median follow-up of 30.7 months (interquartile range, 24.0-34.0).2 Furthermore, a United States real-world analysis showed that 21.5% to 36.3% of patients with HER2-positive breast cancer had developed brain metastases by their third line of therapy for metastatic disease.1

“There is a paucity of FDA-approved systemic treatments specifically targeting HER2-positive breast cancer brain metastases,” the authors explained. “Clinical trials explicitly designed to evaluate active CNS disease remain limited, highlighting an unmet need for novel systemic drug combinations in this setting.”

The irreversible pan-HER TKI neratinib is FDA approved as monotherapy for the extended adjuvant treatment of adult patients with early-stage HER2-positive breast cancer, as well as in combination with capecitabine for the treatment of adult patients with advanced or metastatic HER2-positive breast cancer who have received at least 2 prior lines of anti-HER2–based regimens in the metastatic setting.3

Notably, the CNS activity of neratinib in combination with other agents has been observed across several clinical trials.1

Trial Designs Included in This Analysis

This analysis included data from cohorts 3 and 4 of TBCRC 022. In cohort 4, patients with measurable CNS metastases were assigned to 1 of 3 arms: cohort 4A (n = 6), which consisted of patients with previously untreated brain metastases; cohort 4B (n = 17), which consisted of those with progressive brain metastases and no prior T-DM1 exposure; and cohort 4C (n = 21), which consisted of those with progressive brain metastases and prior T-DM1 exposure. All patients in cohort 4 received neratinib at 160 mg per day plus intravenous T-DM1 at 3.6 mg/kg every 3 weeks.

In cohort 3, patients with measurable, progressive CNS metastases were assigned to 1 of 2 arms: cohort 3A (n = 37) included patients with no prior lapatinib (Tykerb) exposure, and cohort 3B (n = 12) included those with prior lapatinib exposure. All patients in cohort 3 received neratinib at 240 mg per day plus capecitabine at 1500 mg/m2 for 14 days of each 21-day cycle.

In the NALA trial, patients with HER2-positive metastatic breast cancer who had previously received at least 2 lines of HER2-directed therapy for metastatic disease and were permitted to have asymptomatic or stable brain metastases were randomly assigned 1:1 to receive either neratinib at 240 mg per day plus capecitabine at 1500 mg/m2 for 14 days of each 21-day cycle (n = 307; CNS subgroup, n = 51); or lapatinib at 1250 mg per day plus capecitabine at 2000 mg/m2 for 14 days on of each 21-day cycle (n = 314; CNS subgroup, n = 50).

In the NEfERT-T trial, patients with previously untreated HER2-positive locally recurrent or metastatic breast cancer who were permitted to have a history of brain metastases or current asymptomatic/stable brain metastases were randomly assigned 1:1 to receive either neratinib at 240 mg per day plus paclitaxel at 80 mg/m2 in days 1, 8, and 15 of every 28-day cycle (n = 242; CNS subgroup, n = 3); or trastuzumab (Herceptin) at a 4-mg/kg loading dose then at 2 mg/kg weekly in combination with paclitaxel at 80 mg/m2 in days 1, 8, and 15 of every 28-day cycle (n = 237; CNS subgroup, n = 3).

Each trial included in this analysis reported CNS overall response rates (ORRs) for all patients with measurable baseline CNS lesions. Other CNS-related outcomes in NALA and NEfERT-T included time to intervention for CNS disease and incidence of progressive CNS disease.

CNS ORR Outcomes Across Trials

In TBCRC 022 cohort 4, the CNS ORRs in cohorts 4A, 4B, and 4C, respectively, were 50.0%, 29.4%, and 23.8%. One complete response (CR) each occurred in cohorts 4B and 4C; the remainder of responses were partial responses (PRs). Five additional unconfirmed PRs were observed in cohorts 4B (n = 1) and 4B (n = 4). The Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) ORRs in cohorts 4A, 4B, and 4C, respectively, were 33.3%, 35.3%, and 28.6%. One CR occurred in cohort 4B; the remainder of responses were PRs. Four additional unconfirmed responses were observed in cohorts 4A (n = 1), 4B (n = 1), and 4C (n = 2).

In TBCRC 022 cohort 3, the CNS ORRs in cohorts 3A and 3B were 48.6% and 33.3%, respectively; all CNS responses in these cohorts were PRs. The RANO-BM ORRs in these respective cohorts were 24.3% and 16.7%. Two additional patients in cohort 3A had unconfirmed RANO-BM responses that did not persist for at least 4 weeks.

In the NALA CNS subgroup, the CNS ORRs were 26.3% in the neratinib arm and 15.4% in the lapatinib arm. One CR was observed in the neratinib arm; all other responses were PRs.

In the NEfERT-T CNS subgroup, the CNS ORRs were 100.0% and 33.3% in the neratinib and trastuzumab arms, respectively. All responses were PRs.

Additional CNS-Related End Points in NALA and NEfERT-T

In the NALA CNS subgroup, the median CNS progression-free survival was 12.4 months in the neratinib arm vs 8.3 months in the lapatinib arm. At 1 year of follow-up, 25.5% of patients in the neratinib arm required intervention for CNS disease compared with 36.0% of those in the lapatinib arm. The 1-year cumulative incidences of progressive CNS disease in these respective arms were 26.2% and 41.6%, respectively.

In the NEfERT-T intention-to-treat population, the 2-year cumulative incidence of progressive CNS disease was 10.0% in the neratinib arm vs 20.2% in the trastuzumab arm.

CNS Responses in TBCRC 022 by Prior Therapy

“The intracranial activity for neratinib-based combinations persisted even in patients previously exposed to TKIs or previously exposed to the antibody-drug conjugate [T-DM1] partnered with neratinib,” the authors emphasized.

In TBCRC 022 cohort 4C, among patients with prior T-DM1 exposure who received neratinib plus T-DM1, the best CNS responses per volumetric criteria at a data cutoff of October 31, 2023 included CR (n = 1), PR (n = 4), stable disease (n = 9), and progressive disease (n = 2).

In TBCRC 022 cohort 3B, among patients with prior lapatinib exposure who received neratinib plus capecitabine, 4 patients had a response per volumetric criteria at the data cutoff of July 1, 2017.

Safety Findings

Across all trials, the most common grade 3 or higher toxicity was diarrhea, which occurred in approximately 1 out of every 4 patients. Primary diarrhea prophylaxis was required during cycle 1 in TBCRC 022 and NALA. Grade 4 adverse effects (AEs) of any type were rare.

Specifically, in TBCRC 022 cohort 4, 22.7% of patients reported grade 3 diarrhea; no grade 4 diarrhea was observed. Patients in this cohort were required to receive loperamide and colestipol prophylaxis in cycle 1. Overall, the any-grade AEs that occurred in more than 10% of patients in cohort 4 included diarrhea (grade 2, 32%; grade 3, 23%; grade 4, 0%), fatigue (25%; 2%; 0%), increased aspartate aminotransferase levels (14%; 9%; 0%), nausea (16%; 2%; 0%), increased alanine aminotransferase levels (5%; 5%; 2%), anorexia (11%; 0%; 0%), and decreased platelet counts (9%; 2%; 0%).

The most common reasons for treatment-related discontinuation in this cohort were CNS progression or relapse (n = 26), and toxicity (n = 5). No treatment-attributed deaths were reported in this cohort.

The authors added that diarrhea is now commonly managed in clinical practice using neratinib dose escalation or antidiarrheal prophylaxis initiated in cycle 1 and continued through cycle 2. However, these strategies have not been formally explored in patients receiving neratinib plus T-DM1.

Analysis Limitations and Next Steps

The study authors noted that key limitations of this research include its retrospective nature; the fact that cross-trial analyses are complicated by heterogeneous patient populations, trial designs, and standards of care; the inconsistent definitions of CNS-specific end points across trials; and the absence of patients who had received prior tucatinib.

“Further prospective studies with standardized methodologies and larger patient cohorts are warranted to better assess the clinical impact of sequencing treatments for patients with breast cancer brain metastases,” the authors concluded.

References

1. Sammons S, Freedman RA, Awada A, et al. Neratinib-based combination treatments for patients with HER2-positive breast cancer brain metastases. Presented at: 42nd Annual Miami Breast Cancer Conference. March 6-9, 2025; Miami, Florida. Poster 107.
2. Kuksis M, Gao Y, Tran W, et al. The incidence of brain metastases among patients with metastatic breast cancer: a systematic review and meta-analysis. Neuro Oncol. 2021;23(6):894-904. doi:10.1093/neuonc/noaa285
3. Prescribing information. Neratinib. Puma Biotechology, Inc. Updated February 2020. Accessed March 10, 2025. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/208051s005s006lbl.pdf