Neratinib plus trastuzumab plus fulvestrant shows encouraging clinical activity

Both patients with heavily pretreated hormone receptor (HR)-positive/HER2-mutated, HER2-negative metastatic breast cancer and patients with heavily pretreated HER2-mutated metastatic triple-negative breast cancer (TNBC) have encouraging responses to treatment with neratinib plus trastuzumab plus fulvestrant.

HER2 mutation in the absence of gene amplification or protein overexpression is a unique mechanism of oncogenetic addiction to HER2 signalling [1]. Neratinib 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]. Addition of trastuzumab to neratinib plus fulvestrant showed encouraging clinical activity with durable responses in the phase 2 SUMMIT trial (NCT01953926). Early data also suggest that neratinib plus fulvestrant plus trastuzumab improves clinical benefit in patients with HER2-mutated, HER2-non-amplified metastatic breast cancer [3].

Based on these findings, SUMMIT has recently been expanded to include a randomised comparison of neratinib plus fulvestrant plus trastuzumab (‘triplet’) versus fulvestrant plus trastuzumab (‘doublet’) versus fulvestrant alone (‘mono’) in 21 patients with HR-positive/HER2-mutated, HER2-negative metastatic breast cancer who were exposed to CDK4/6 inhibitors. Prior to starting this randomised portion of the trial, 26 patients were already enrolled in a non-randomised cohort receiving neratinib plus fulvestrant plus trastuzumab. In another SUMMIT cohort, 18 patients with HER2-mutant TNBC were enrolled in a non-randomised cohort and received neratinib plus trastuzumab. Dr Komal Jhaveri (Memorial Sloan Kettering Cancer Center, NY, USA) presented the results [4].

In the non-randomised, triplet-treated patients (n=26) objective response rate was 46.2% (all partial response), clinical benefit rate was 57.7%, and median progression-free survival was 8.2 months. In the randomised, triplet-treated patients (n=7) objective response rate was 28.6% (14.3% complete response, 14.3% partial response), clinical benefit rate was 28.6%, and median progression-free survival was 6.2 months. No responses were seen in de doublet-treated and mono-treated patients.

These results are in line with the hypothesis that neratinib is critical for the inhibition of HER2 mutations. Based on these results the doublet-cohort and mono-cohort were closed. In the combined randomised and non-randomised triplet cohort (n=33) objective response rate was 42.4% (3% complete response, 39.4% partial response), clinical benefit rate was 51.5%, and median progression-free survival was 7.0 months. In the TNBC cohort (n=18) objective response rate was 33.3% (5.6% complete response, 27.8% partial response), clinical benefit rate was 38.9%, and median progression-free survival was 6.2 months (see Table).

Table: Baseline characteristics and efficacy of TNBC patients treated with neratinib plus trastuzumab [4].



 

 

 

 

 

 

 

 

CR, confirmed response; PR, partial response; CI, confidence interval; DOR, duration of response; NE, not estimable; PFS, progression-free survival

Based on these result, Dr Jhaveri concluded that “the combination regimen of neratinib plus fulvestrant plus trastuzumab demonstrates encouraging clinical activity in patients with heavily pretreated HR-positive/HER2-mutated, HER2-negative metastatic breast cancer who had previously received CDK4/6 inhibitors.”

1. Nayar U, et al. Nat Genet 2019;51:207–216.
2. Smyth LM, et al. Cancer Discov 2020;10:198–213.
3. Jhaveri K, et al. PD1-05, SABCS 2020 Virtual Symposium, 8–11 December.
4. 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. GS4-10, SABCS 2021 Virtual Meeting, 7–10 December.

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Posted on 31 January, 202225 March, 2024