Both patients with heavily pre-treated HR-positive/HER2-negative, HER2-mutated, metastatic breast cancer and patients with heavily pre-treated HER2-mutated metastatic triple-negative breast cancer (TNBC) have encouraging responses to treatment with neratinib/trastuzumab(/fulvestrant), results from the SUMMIT trial show.
HER2 mutations in the absence of gene amplification or protein overexpression are a unique mechanism of oncogenic addiction to HER2 signaling [1]. Neratinib is an oral, irreversible pan-HER tyrosine kinase inhibitor that has demonstrated encouraging clinical activity either as a single agent or in combination with fulvestrant in HER2-mutated, HER2-non-amplified metastatic breast cancer [2]. The addition of trastuzumab to neratinib/fulvestrant showed encouraging clinical activity with durable responses in the phase 2 SUMMIT trial (NCT01953926) in heavily pre-treated HR-positive, HER2-mutant, metastatic breast cancer, including patients who had previously received CDK4/6 inhibitors. Early data also suggested that neratinib/fulvestrant/trastuzumab might be more effective [3]. On the basis of these findings, and in order to better understand the contribution of neratinib to the activity of the neratinib/fulvestrant/trastuzumab combination (‘triplet’), SUMMIT has recently been expanded to include a randomized comparison of neratinib/fulvestrant/trastuzumab (‘triplet’) versus fulvestrant/trastuzumab (‘doublet’) versus fulvestrant (‘mono’) in 21 patients with HR-positive/HER2-negative, HER2-mutated, metastatic breast cancer who were exposed to CDK4/6 inhibitors. Prior to starting this randomized portion of the trial, 26 patients were already enrolled in a non-randomized cohort receiving neratinib/fulvestrant/trastuzumab. In another SUMMIT cohort, 18 patients with HER2-mutant triple-negative breast cancer (TNBC) were enrolled in a non-randomized cohort and received neratinib/trastuzumab. Dr. Komal Jhaveri (Memorial Sloan Kettering Cancer Center, NY, USA) presented the results [4]. In the 26 non-randomized, triplet-treated patients, ORR was 46.2% (all partial response [PR]), clinical benefit rate (CBR) was 57.7%, and median progression-free survival (PFS) was 8.2 months. In the 7 randomised triplet-treated patients, ORR was 28.6% (14.3% complete response [CR], 14.3% PR), CBR was 28.6%, and median PFS was 6.2 months. In the combined randomized and non-randomized triplet cohort (n=33), ORR was 42.4% (3% CR, 39.4% PR), CBR was 51.5%, and median PFS was 7.0 months. No responses were seen in de doublet- and mono-treated patients. “This is in line with the hypothesis that niraparib is critical for the inhibition of HER2-mutations. Based on these results, the doublet- and mono-cohorts were closed.” In the TNBC cohort (n=18), ORR was 33.3% (5.6% CR, 27.8% PR), CBR was 38.9%, and median PFS was 6.2 months. Diarrhea was the most commonly reported adverse event: 90.9% any grade, 45.5% grade 3 in the HR-positive/HER2-negative, HER2-mutated cohort and 89.9% any grade, 16.7% grade 3 in the TNBC cohort. Based on these results, Dr. Jhaveri concluded that “the combination neratinib/fulvestrant/trastuzumab demonstrates encouraging clinical activity in patients with heavily pretreated patients with HR-positive/HER2-negative, HER2-mutated, metastatic breast cancer who had previously received CDK4/6 inhibitors. In addition, the combination neratinib/trastuzumab shows promising clinical activity in heavily pre-treated HER2-mutated TNBC.”
- Nayar U, et al. Nat Genet 2019;51:207-216.
- Smyth LM, et al. Cancer Discov 2020;10:198-213.
- Jhaveri K, et al. SABCS 2020, Abstract PD1-05
- Jhaveri K, et al. Neratinib + fulvestrant + trastuzumab for hormone receptor-positive, HER2-mutant metastatic breast cancer and neratinib + trastuzumab for triple-negative disease: Latest updates from the SUMMIT trial. SABCS 2021 Virtual Meeting, abstract GS4-10.
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