Neratinib + fulvestrant + trastuzumab for HR-positive, HER2-negative, HER2-mutant metastatic breast cancer: outcomes and biomarker analysis from the SUMMIT trial

Abstract

Background: HER2 mutations are targetable alterations in patients with hormone receptor-positive (HR+) metastatic breast cancer (MBC). In the SUMMIT basket study, patients with HER2-mutant MBC received neratinib monotherapy, neratinib + fulvestrant, or neratinib + fulvestrant + trastuzumab (N + F + T). We report results from 71 patients with HR+, HER2-mutant MBC, including 21 (seven in each arm) from a randomized substudy of fulvestrant versus fulvestrant + trastuzumab (F + T) versus N + F + T.

Patients and methods: Patients with HR+ HER2-negative MBC with activating HER2 mutation(s) and prior cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) therapy received N + F + T (oral neratinib 240 mg/day with loperamide prophylaxis, intramuscular fulvestrant 500 mg on days 1, 15, and 29 of cycle 1 then q4w, intravenous trastuzumab 8 mg/kg then 6 mg/kg q3w) or F + T or fulvestrant alone. Those whose disease progressed on F + T or fulvestrant could cross-over to N + F + T. Efficacy endpoints included investigator-assessed objective response rate (ORR), clinical benefit rate (RECIST v1.1), duration of response, and progression-free survival (PFS). Plasma and/or formalin-fixed paraffin-embedded tissue samples were collected at baseline; plasma was collected during and at end of treatment. Extracted DNA was analyzed by next-generation sequencing.

Results: ORR for 57 N + F + T-treated patients was 39% [95% confidence interval (CI) 26% to 52%); median PFS was 8.3 months (95% CI 6.0-15.1 months). No responses occurred in fulvestrant- or F + T-treated patients; responses in patients crossing over to N + F + T supported the requirement for neratinib in the triplet. Responses were observed in patients with ductal and lobular histology, 1 or ≥1 HER2 mutations, and co-occurring HER3 mutations. Longitudinal circulating tumor DNA sequencing revealed acquisition of additional HER2 alterations, and mutations in genes including PIK3CA, enabling further precision targeting and possible re-response.

Conclusions: The benefit of N + F + T for HR+ HER2-mutant MBC after progression on CDK4/6is is clinically meaningful and, based on this study, N + F + T has been included in the National Comprehensive Cancer Network treatment guidelines. SUMMIT has improved our understanding of the translational implications of targeting HER2 mutations with neratinib-based therapy.

Trial registration: ClinicalTrials.gov NCT01953926 NCT01670877 NCT03734029 NCT04639219 NCT05372614.

Keywords: ERBB2; HER2-mutant; hormone receptor-positive; metastatic breast cancer; neratinib.

Figure 1.. (A) Best change in tumor from baseline and corresponding histology and central biomarker analysis. (B) Duration of treatment and best response in patients randomized to F + T or F, before and after cross-over to N + F + T. (C) HER2 expression in patients treated with N + F + T. (D) HER2 H-score, FISH ratio, or mRNA expression, and response to N + F + T.

The solid horizontal line represents the median. BOR, best overall response; CEN-17, centromere of chromosome 17; CI, confidence interval; CDK4/6i, cyclin-dependent kinase 4/6 inhibitor; CNA, copy number amplification; CR, complete response; ctDNA, circulating tumor DNA; dup, duplication; F, fulvestrant; FFPE, formalin-fixed paraffin-embedded; FISH, fluorescence in situ hybridization; IHC, immunohistochemistry; KD, kinase domain; mut, mutation; N, neratinib; NE, not evaluable; NGS, next-generation sequencing; PD, progressive disease; PFS, progression-free survival; PR, partial response; SD, stable disease; T, trastuzumab; TMD, transmembrane domain. ^aObjective response defined as either a CR or PR that is confirmed no less than 4 weeks after the criteria for response are initially met. ^bKaplan–Meier analysis. For cross-over patients, calculated from time of cross-over to N + F + T. ^cClinical benefit is defined as confirmed CR or PR or SD for ≥24 weeks (within a ±7-day visit window).

Figure 1.. (A) Best change in tumor from baseline and corresponding histology and central biomarker analysis. (B) Duration of treatment and best response in patients randomized to F + T or F, before and after cross-over to N + F + T. (C) HER2 expression in patients treated with N + F + T. (D) HER2 H-score, FISH ratio, or mRNA expression, and response to N + F + T.

The solid horizontal line represents the median. BOR, best overall response; CEN-17, centromere of chromosome 17; CI, confidence interval; CDK4/6i, cyclin-dependent kinase 4/6 inhibitor; CNA, copy number amplification; CR, complete response; ctDNA, circulating tumor DNA; dup, duplication; F, fulvestrant; FFPE, formalin-fixed paraffin-embedded; FISH, fluorescence in situ hybridization; IHC, immunohistochemistry; KD, kinase domain; mut, mutation; N, neratinib; NE, not evaluable; NGS, next-generation sequencing; PD, progressive disease; PFS, progression-free survival; PR, partial response; SD, stable disease; T, trastuzumab; TMD, transmembrane domain. ^aObjective response defined as either a CR or PR that is confirmed no less than 4 weeks after the criteria for response are initially met. ^bKaplan–Meier analysis. For cross-over patients, calculated from time of cross-over to N + F + T. ^cClinical benefit is defined as confirmed CR or PR or SD for ≥24 weeks (within a ±7-day visit window).

Figure 2.. Longitudinal HER2 mutation VAFs in patients with response to N + F + T.

Blood draw and ctDNA sequencing: (A) before treatment, on treatment, and at the end of treatment in patients who progressed; and (B) before treatment and in two on-treatment samples for patients who had not yet progressed. Solid and dotted lines represent original and emergent mutations, respectively. (C) Prevalence of notable mutations throughout the course of treatment with N + F + T; size of the bubble corresponds with VAF. Empty circle indicates mutation not detectable. CR, complete response; ctDNA, circulating tumor DNA; dup, duplication; F, fulvestrant; N, neratinib; PR, partial response; T, trastuzumab; VAF, variant allele frequency. ^aPatient remained on treatment as of data cut-off.

Figure 3.. Cross-over case studies.

(A) patient crossed over from F to N + F + T. The patient was enrolled on tissue-based NGS (FoundationOne CDx), which reported HER2 D769Y. The patient was initially randomized to F alone; upon progression, she crossed over to receive N + F + T. HER2 D769Y VAF increased upon initial treatment with F then decreased upon cross-over. (B) Patient crossed over from F + T to N + F + T. The patient was enrolled on ctDNA (Guardant 360), which detected HER2 G776V at 0.04% VAF. HER2 E1145 and E717Q, but not G776V, were centrally detected in pretreatment ctDNA. The patient was initially randomized to F + T; upon progression she crossed over to receive N + F + T. HER2 VAFs of both mutations increased upon initial treatment with F + T, then decreased upon addition of N. HER2 copy number gain was also detected upon initial treatment, but not after the patient crossed over to receive the triplet. Upon progression to N + F + T, the HER2 T798I gatekeeper mutation emerged, along with PIK3CA-activating mutations E542K and E545K. After progression on N + F + T, the patient was treated with A + F and experienced a PR. A, alpelisib; CNV, copy number variation; ctDNA, circulating tumor DNA; F, fulvestrant; N, neratinib; NGS, next-generation sequencing; PD, progressive disease; PR, partial response; SD, stable disease; T, trastuzumab; VAF, variant allele frequency. ^aHER2 CNV only detected at second timepoint. Solid lines indicate Tempus xF+ results; dotted lines indicate Guardant360 results.