Tucatinib Combo Shows Meaningful Activity in HER2+ Metastatic Breast Cancer

Tucatinib plus trastuzumab was well tolerated in patients with metastatic breast cancer and consistent with the combination’s established safety profile.

Tucatinib (Tukysa) in combination with trastuzumab (Herceptin) showcased clinically meaningful antitumor activity and enduring responses in a small cohort of patients with heavily pretreated HER2-mutant metastatic breast cancer who were HER2 negative per local testing, according to results from the phase 2 SGNTUC-019 basket trial (NCT04579380) published in Nature Medicine.1

Data from the study revealed that in patients evaluable for efficacy analysis (n = 31), the combination regimen elicited a confirmed objective response rate (ORR) of 41.9% (n = 13; 90% CI, 26.9%-58.2%), including 2 (6.5%) patients attaining a complete response (CR) and 11 (35.5%) patients attaining a partial response (PR). Additionally, the disease control rate (DCR) was 80.6% (n = 25; 90% CI, 65.3%-91.2%), with 12 (38.7%) patients reported to have stable disease. The median duration of response (DOR) was 12.6 months (90% CI, 4.7-not estimable [NE]) in this patient population.

Additional efficacy data revealed that the median progression-free survival (PFS) for patients treated with the combination regimen was 9.5 months (90% CI, 5.4-13.8). Furthermore, the median overall survival (OS) in this patient group was 20.1 months (90% CI, 15.9-NE).

“In the SGNTUC-019 study, the combination of tucatinib and trastuzumab (with fulvestrant in patients with [HR–positive disease]) is active in patients with heavily pretreated HER2-mutant metastatic breast cancer, with a confirmed ORR of 41.9%,” Alicia F.C. Okines, MBChB, MD, FRCP, consultant medical oncologist at The Royal Marsden NHS Foundation Trust, wrote in the publication with study coinvestigators.1 “This clinically meaningful activity was seen despite patients having been heavily pretreated with a median of 4 previous lines of systemic therapy in any setting and 3 previous lines in the locally advanced or metastatic setting.”

The open-label phase 2 basket study enrolled patients with previously treated, locally advanced, unresectable, or metastatic HER2-mutant solid tumors, with the breast cancer cohort comprising patients without evidence of HER2 overexpression or amplification. To be eligible for treatment, patients in the locally advanced or metastatic disease setting had to have progressed after at least 1 prior line of therapy and had to have progressed or have been intolerant to the most recent line of systemic therapy. Patients with HR–positive disease must have received a CDK4/6 inhibitor in the metastatic setting.

Those in the metastatic breast cancer cohort (n = 31) received 300 mg of oral tucatinib twice daily plus 8 mg/kg-1 of intravenous trastuzumab then 6 mg/kg-1 every 3 weeks in 21-day cycles. Additionally, 500 mg of intramuscular fulvestrant was received by patients with HR–positive disease every 4 weeks starting cycle 1, day 1 and once on day 15 of cycle 1.

The median age of efficacy evaluable patients was 64.0 years (range, 43-76). All patients were female, and most were White (48%) or Asian (35%) and non-Hispanic (77%). Most patients had an ECOG performance status of 0 (61%), HR–positive disease (87%), a lobular tumor type (58%), and stage III (42%) or IV disease (23%).

The primary efficacy end point was confirmed ORR. Secondary end points included DCR, DOR, PFS, OS, the maximum and trough concentration of tucatinib, and safety.2

Safety results revealed that any-grade treatment-emergent adverse events (TEAEs) were observed in all evaluable patients (n = 31; 100%), with 15 (48%) patients experiencing at least 1 grade 3 or higher TRAE. The most common any-grade TRAEs included diarrhea (65%), nausea (35%), vomiting (29%), pruritus (29%), and infusion-related reactions (26%). The most common grade 3 or higher TRAEs included diarrhea (13%), alanine aminotransferase increases (10%), hypertension (10%), back pain (6%), appetite decreases (6%), and aspartate aminotransferase increases (6%).

No TEAEs resulted in treatment discontinuation of all study treatments, with TEAEs resulting in tucatinib discontinuations in 2 patients; a grade 4 aspartate aminotransferase increase and a grade 2 instance of pseudocirrhosis. No TEAE-related discontinuations of trastuzumab or fulvestrant occurred. TEAEs led to dose reductions of tucatinib in 7 patients and 1 in fulvestrant. No TEAEs were related to deaths, with all 11 deaths occurring as a result of disease progression.

References

1. Okines AFC, Curigliano G, Mizuno N, et al. Tucatinib and trastuzumab in HER2-mutated metastatic breast cancer: a phase 2 basket trial. Nat Med. Published online January 17, 2025. doi:10.1038/s41591-024-03462-0
2. Basket study of tucatinib and trastuzumab in solid tumors with HER2 alterations. ClinicalTrials.gov. Updated November 13, 2024. Accessed January 30, 2025. https://tinyurl.com/3ed8u2vh