107 Neratinib-Based Combination Treatments for Patients With HER2-Positive Breast Cancer Brain Metastases

107 Neratinib-Based Combination Treatments for Patients With HER2-Positive Breast Cancer Brain Metastases

Background

Breast cancer brain metastases (BCBM) contribute to substantial morbidity and mortality in patients with HER2-positive (HER2+) metastatic breast cancer. The central nervous system (CNS) is a common site of recurrence in patients with HER2+ breast cancer, and there is an ongoing need for safe and effective treatments. Neratinib, an oral, irreversible pan-HER tyrosine kinase inhibitor, is FDA-approved for the extended adjuvant treatment of early-stage HER2+ breast cancer and in combination with capecitabine for HER2+ advanced or metastatic breast cancer. We summarize prospective data of neratinib-based combinations in HER2+ BCBM.

Materials and Methods

We conducted a literature review of neratinib combinations for HER2+ BCBM, focusing on prospective trials reporting CNS outcomes. CNS-specific data were extracted from studies restricted to patients with untreated/active brain metastases (phase 2 TBCRC 022 [NCT01494662]) or asymptomatic/stable brain metastases (phase 3 NALA [NCT01808573] and phase 2 NEfERT-T [NCT00915018]). TBCRC 022, a dedicated HER2+ BCBM trial, assessed neratinib combinations in patients with no prior lapatinib (cohort 3A; neratinib plus capecitabine) or with prior lapatinib (cohort 3B; neratinib plus capecitabine), in patients with previously untreated brain metastases (cohort 4A; neratinib plus T-DM1), and in patients progressing after CNS-directed therapies with no prior T-DM1 (cohort 4B; neratinib plus T-DM1) or in patients with prior T-DM1 (cohort 4C; neratinib plus T-DM1). Also available were descriptive CNS outcomes for (1) patients with baseline CNS metastases previously treated with HER2-directed therapy in NALA (neratinib plus capecitabine vs lapatinib plus capecitabine) and (2) patients who are metastatic treatment-naive in NEfERT-T (neratinib plus paclitaxel vs trastuzumab plus paclitaxel). End points included CNS objective response rate (CNS-ORR) per composite/volumetric (TBCRC 022) or RECIST (NALA and NEfERT-T) (assessed locally or centrally), or ORR per Response Assessment in Neuro-Oncology-Brain Metastases (RANO-BM; assessed centrally). Cumulative 1-year incidence ofintervention for CNS disease or incidence of progressive CNS disease were reported for the NALA CNS subgroup.

Results

The analysis includes 212 patients: 93 with untreated/active BCBM from TBCRC 022; 101 (16.3% of ITT) from NALA; and 18 (3.8% of ITT) from NEfERT-T. No patients had received prior tucatinib and only 2 patients in TBCRC 022 cohort 4 had received prior trastuzumab deruxtecan.Across all 3 studies, 131 patients had measurable/target CNS lesions at baseline and were evaluable for CNS-ORR (TBCRC 022: n = 49 in cohort 3 and n = 44 in cohort 4; NALA: n = 32; NEfERT-T: n = 6). In TBCRC 022, CNS-ORRs were 49% (18/37 in cohort 3A; neratinib plus capecitabine), 33% (4/12 in cohort 3B; neratinib plus capecitabine), 50% (3/6 in cohort 4A; neratinib plus T-DM1), 29% (5/17 in cohort 4B; neratinib plus T-DM1), and 24% (5/21 in cohort 4C; neratinib plus T-DM1). In NALA, CNS-ORRs were 26% (5/19 pts; neratinib plus capecitabine) vs 15% (2/13; lapatinib plus capecitabine). In NEfERT-T, CNS-ORRs were 100% (3/3; neratinib plus paclitaxel) vs 33% (1/3; trastuzumab plus paclitaxel). In TBCRC 022, RANO-BM ORRs were 24% (9/37; cohort 3A), 17% (2/1; cohort 3B), 33% (2/6; cohort 4A), 35% (6/17; cohort 4B), and 29% (6/21; cohort 4C). In the NALA CNS subgroup (n = 101), 1-year cumulative incidence of intervention for CNS disease was 26% for neratinib plus capecitabine vs 36% for lapatinib plus capecitabine, and 1-year cumulative incidence of progressive CNS disease was 26% (neratinib plus capecitabine) vs 42% (lapatinib plus capecitabine). Diarrhea was the most common grade 3 or higher toxicity.

Conclusion

Data from prospective trials of neratinib-based combinations show consistent intracranial activity across various treatment settings in untreated/active and asymptomatic/stable HER2+ BCBM. Clinical guidelines and real-world analyses further support the use of neratinib combinations for HER2+ BCBM. Notably, neratinib plus T-DM1 had intracranial efficacy in patients with previously untreated brain metastases and patients who had undergone multiple local CNS-directed and/or systemic therapies, including prior T-DM1. In addition to the established CNS activity of tucatinib and trastuzumab deruxtecan, the combination of neratinib with other FDA-approved drugs represents a promising approach to the treatment of HER2+ BCBM in clinical practice, although the optimal sequence of treatments is not known.