Tucatinib/Trastuzumab Yields Durable Responses in HER2-Mutated Metastatic Breast Cancer

HER2-Mutated Breast Cancer
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Findings from the final analysis of the phase 2 SGNTUC-019 trial (NCT04579380) demonstrated durable antitumor activity and a high disease control rate (DCR) with the combination of tucatinib (Tukysa) and trastuzumab (Herceptin) in patients with HER2-mutated metastatic breast cancer who had received prior systemic therapy in the advanced/metastatic setting.

Among 31 evaluable patients, the confirmed objective response rate (ORR) was 41.9% (90% CI, 26.9%-58.2%). The median duration of response (DOR) was 18.2 months (90% CI, 4.7-23.1), and the DCR was 80.6% (90% CI, 65.3%-91.2%). The median time to response (TTR) was 1.4 months (range, 1.2-6.2). The median follow-up at the time of the final analysis was 24.9 months.

"With an additional 10 months of follow-up, tucatinib in combination with trastuzumab has demonstrated clinically meaningful efficacy with durable response to study treatment while continuing to show favorable tolerability in patients with heavily pretreated, HER2-mutated metastatic breast cancer," lead study author Alicia Okines, MD FRCP, a consultant medical Oncologist, Royal Marsden Hospital, explained in her presentation.

SGNTUC-019 Study Design and Background

SGNTUC-019 was an open-label, phase 2, global basket trial evaluating the safety and efficacy of tucatinib in combination with trastuzumab, with or without fulvestrant (Faslodex), in patients with previously treated, locally advanced, unresectable, or metastatic HER2-altered solid tumors. The breast cancer cohort specifically enrolled patients across North America, Europe, and Asia.

Eligible patients for the breast cancer cohort were required to have unresectable, locally advanced or metastatic disease harboring next-generation sequencing (NGS)–identified HER2 mutations in the absence of HER2 overexpression or amplification. Additional key inclusion criteria included disease progression during or following at least 1 prior systemic therapy for locally advanced or metastatic disease, prior CDK4/6 inhibitor use if the patient had hormone receptor (HR)–positive disease, measurable disease per RECIST 1.1 criteria, and an ECOG performance status of 0 or 1.

Patients received oral tucatinib at 300 mg twice daily in 21-day cycles. Intravenous trastuzumab was administered at 8 mg/kg on day 1 of cycle 1, followed by 6 mg/kg on day 1 of subsequent cycles. For patients with HR-positive tumors, intramuscular fulvestrant was given at a dose of 500 mg once every 4 weeks, with an additional dose on day 15 of cycle 1.

The primary end point of the trial was confirmed ORR as assessed by investigators. Secondary end points included DOR, progression-free survival (PFS), overall survival (OS), and safety. Disease assessments were conducted every 6 weeks for the first 24 weeks, followed by assessments every 12 weeks thereafter, with response determined based on RECIST 1.1 criteria.

Baseline patient characteristics showed that 87% of enrolled patients were HR-positive, and all received fulvestrant. Additionally, 58% had lobular histology, and the median number of prior lines of therapy in the advanced/metastatic setting was 3.

Initial findings, reported at a median follow-up of 15 months, showed a confirmed ORR of 41.9% with a median DOR of 12.6 months. The median PFS was reported at 9.5 months, and the median OS was 20.1 months. Diarrhea emerged as the most common adverse effect (AE), occurring in 65% of patients overall, with grade 3 or higher diarrhea reported in 13% of patients. Notably, there were no treatment discontinuations attributed to AEs.

Safety Analysis

Treatment with tucatinib in combination with trastuzumab was generally well tolerated. Among the 31 patients included in the safety population, treatment-emergent AEs (TEAEs) of any grade occurred in all patients, and 52% experienced grade 3 or higher TEAEs. Serious TEAEs were reported in 29% of patients.

No TEAEs led to death, and there were no discontinuations of all study treatments due to toxicity. Discontinuation of any single study treatment due to TEAEs occurred in 2 patients (6%), both of whom discontinued tucatinib; no patients discontinued trastuzumab or fulvestrant. Importantly, no additional discontinuations were reported since the primary analysis.

Dose modifications of tucatinib due to TEAEs were relatively common, with 39% of patients requiring treatment interruption and 23% requiring dose reduction. The median duration of tucatinib treatment was 9.0 months (range, 0.7-31.7), with a mean treatment duration of 10.7 months (standard deviation, 9.1 months).

"[The] treatment was well tolerated, with a low rate of tucatinib discontinuation at 6% and no deaths due to TEAEs. These results support tucatinib plus trastuzumab as a potential treatment option for patients with previously treated HER2-mutated metastatic breast cancer," Okines added.

Reference

Okines A, Curigliano G, Mizuno N, et al. Tucatinib and trastuzumab for previously treated HER2-mut MBC: final analysis of a phase 2 basket study (SGNTUC-019). Presented at: 2025 ESMO Breast Cancer Congress; May 15-17, 2025; Berlin, Germany. Abstract 304MO.