Tucatinib and trastuzumab in HER2-mutated metastatic breast cancer: a phase 2 basket trial

Abstract

Human epidermal growth factor receptor 2 (HER2, also known as ERBB2) signaling promotes cell growth and differentiation, and is overexpressed in several tumor types, including breast, gastric and colorectal cancer. HER2-targeted therapies have shown clinical activity against these tumor types, resulting in regulatory approvals. However, the efficacy of HER2 therapies in tumors with HER2 mutations has not been widely investigated. SGNTUC-019 is an open-label, phase 2 basket study evaluating tucatinib, a HER2-targeted tyrosine kinase inhibitor, in combination with trastuzumab in patients with HER2-altered solid tumors. The study included a cohort of 31 heavily pretreated female patients with HER2-mutated metastatic breast cancer who were also HER2 negative per local testing. Hormone receptor (HR)-positive patients also received fulvestrant. The overall response rate (primary endpoint) was 41.9% (90% confidence interval (CI): 26.9-58.2). Secondary endpoints of duration of response and progression-free survival were 12.6 months (90% CI: 4.7 to not estimable) and 9.5 months (90% CI: 5.4-13.8), respectively. No new safety signals were detected. Responses were observed across various HER2 mutations, including mutations in the tyrosine kinase and extracellular domains. The chemotherapy-free regimen of tucatinib and trastuzumab showed clinically meaningful antitumor activity with durable responses and favorable tolerability in heavily pretreated patients with HER2 mutations. These data support further investigation of HER2-targeted therapies in this patient population. ClinicalTrials.gov registration: NCT04579380 .

Fig. 1. CONSORT diagram of the SGNTUC-019 study.

Flow diagram detailing patients enrolled in the SGNTUC-019 study (NCT04579380) HER2-mutated MBC cohort.

Fig. 2. Response to study treatment and HER2 biomarker assessments.

a, Maximum percentage reduction in the sum of the diameters of target lesions per investigator and HER2 biomarker assessments. Only patients who had baseline and post-baseline target lesion measurements are included (n = 30). The asterisks indicate patients that were excluded from any analysis of local results because their eligibility (HER2-negative status and HER2 mutations) was determined by central blood-based NGS (B-NGS). T-NGS denotes tissue-based NGS testing by central lab assay. In all assays, ‘ND’ (not determined) indicates that there was no assay result, which may have been due to failed assay, failed quality control or no assay run due to sample issues, and ‘NE’ denotes non-evaluable. In the ‘Amp’ (amplification) panel, ‘central’ indicates overall HER2-amplification status as determined by IHC with FISH reflex, both by central lab testing; whereas ‘local’ denotes local testing results. In the ‘Domain’ panel, patients had mutations exclusively in the domains indicated (that is, the tyrosine kinase (TK) or extracellular domains of HER2). The dashed line at 20% indicates progressive disease (PD). The dashed line at −30% indicates the threshold for a partial response (PR). D, ductal; L, lobular. b, Duration of treatment of patients in the HER2-mut MBC cohort.

Fig. 3. Kaplan–Meier curves for PFS and OS per investigator in the HER2-mut MBC cohort.

The vertical lines indicate censoring.

Extended Data Fig. 1. Response versus presence of L755 and/or S310F mutations.

B-NGS, blood-based NGS testing by central lab assay; CR, complete response; D, ductal; L, lobular; Local, local testing results; Mut, Mutation; ND, not determined; NE, non-evaluable; NGS, next-generation sequencing; PD, progressive disease; PR, partial response; SD, stable disease; T-NGS, tissue-based NGS testing by central lab assay. Only subjects who had baseline and post-baseline target lesion measurements are included (n = 30). * indicates patients that were excluded from any analysis of local results because their eligibility (HER2-negative status and HER2 mutations) was determined by central blood-based NGS.

Extended Data Fig. 2. Concomitant genomic alterations from central tissue-based NGS.

CNV, copy number variant; D, ductal; INDEL, insertion and deletion; L, lobular; ND, not determined; NGS, next-generation sequencing; SNV, single nucleotide variant.

Extended Data Fig. 3. Waterfall plot vs concomitant gene alterations from central blood-based NGS.

CNV, copy number variant; CR, complete response; D, ductal; INDEL, insertion and deletion; L, lobular; ND, not determined; NE, non-evaluable; NGS, next-generation sequencing; PD, progressive disease; PR, partial response; SD, stable disease; SNV, single nucleotide variant. Only subjects who had baseline and post-baseline target lesion measurements are included (n = 30).