Tucatinib Combo Produces Meaningful Activity in HER2+ Biliary Tract Cancer

"The results from the [biliary tract cancer] cohort of SGNTUC-019 study [NCT04579380] further validate HER2 as an actionable biomarker in [metastatic biliary tract cancer], and additional investigations of HER2-directed agents are warranted in patients with [HER2-positive metastatic biliary tract cancer]," according to the study authors.

Combining tucatinib (Tukysa) with trastuzumab (Herceptin) led to clinically significant anti-tumor activity and appeared to be tolerable among patients with previously treated HER2-positive metastatic biliary tract cancer, according to findings from the phase 2 SGNTUC-019 basket study (NCT04579380).

Based on investigator assessment, the confirmed objective response rate (ORR) was 46.7% (90% CI, 30.8%-63.0%) in patients receiving tucatinib plus trastuzumab. Additionally, the disease control rate (DCR) was 76.7% (90% CI, 60.6%-88.5%), and 70.0% of patients experienced tumor shrinkage. Investigators reported a median time to first response of 2.1 months (range, 1.2-4.3). The median duration of response (DOR) was 6.0 months (90% CI, 5.5-6.9).

Patients experienced a median progression-free survival (PFS) of 5.5 months (90% CI, 3.9-8.1), and the estimated PFS rates at 6 and 12 months were 49.8% (90% CI, 34.1%-63.6%) and 16.1% (90% CI, 5.9%-30.6%), respectively. Additionally, investigators noted a median overall survival (OS) of 15.5 months (90% CI, 6.5-16.7). The estimated OS rates at 6 and 12 months, respectively, were 73.0% (90% CI, 56.9%-83.9%) and 53.6% (90% CI, 36.8%-67.8%).

Overall, 90.0% of patients were not on study treatment as of the data cutoff point, including 25.9% who received at least 1 additional line of anti-cancer therapy. Of those treated with subsequent therapy, 11.1% received a HER2-targeting agent.

“The results from the [biliary tract cancer] cohort of SGNTUC-019 study further validate HER2 as an actionable biomarker in [metastatic biliary tract cancer], and additional investigations of HER2-directed agents are warranted in patients with [HER2-positive metastatic biliary tract cancer],” the study authors wrote.

In the biliary tract cancer cohort of the open-label SGNTUC-019 basket study, patients received 300 mg of tucatinib orally twice a day plus 8 mg/kg of trastuzumab intravenously followed by 6 mg/kg every 3 weeks as part of a 21-day cycle.

The study’s primary end point was confirmed ORR according to investigator assessment per RECIST v1.1 criteria. Secondary end points included DCR, DOR, PFS, and safety. Time to first response, agreement between different local and central testing methods of HER2 expression, and the confirmed ORR of those with HER2-positive tumors based on specific testing methods were selected as exploratory end points.

Patients with measurable disease per RECIST v1.1 criteria and disease progression following 1 or more prior lines of systemic treatment were able to enroll on the biliary tract cancer cohort of the study. Additional eligibility criteria included having an ECOG performance status of 0 or 1 and adequate cardiac, hepatic, renal, and hematologic function at baseline.

The biliary tract cancer cohort included a total of 30 patients with a median age of 68.5 years (range, 33-79). Additionally, 76.7% of patients were Asian, 80.0% had locally advanced or metastatic disease at the time of initial diagnosis, and all (100.0%) had a history of metastatic disease.

Patients received a median of 2.0 (range, 1-4) prior lines of therapy in any setting and 1.0 (range, 1-4) line in the locally advanced or metastatic setting. Investigators also reported that 6.7% of patients received prior treatment with a PD-1 or a PD-L1 inhibitor.

The confirmed ORR was 57.1% (n = 12/21; 90% CI, 37.2%-75.5%) in patients with HER2-positive disease as determined by central immunohistochemistry or FISH and 63.6% (n = 14/22; 90% CI, 43.9%-80.4%) in those with HER2 positivity as assessed via blood-based next-generation sequencing.

Any-grade treatment-emergent adverse effects (TEAEs) occurred in all patients (100.0%), the most common of which included pyrexia (43.3%), diarrhea (40.0%), blood creatinine increases (26.7%), infusion-related reactions (26.7%), and alanine transaminase increases (26.7%). Investigators also reported that grade 3 or higher TEAEs affected 60.0% of the biliary tract cancer cohort, most of which were not associated with study treatment. The most common higher-grade toxicities included nausea (10.0%), decreased appetite (10.0%), and cholangitis (10.0%).

One patient discontinued treatment with trastuzumab due to grade 3 interstitial lung disease; no patients died because of TEAEs.

Reference

Nakamura Y, Mizuno N, Sunakawa Y, et al. Tucatinib and trastuzumab for previously treated human epidermal growth factor receptor 2–positive metastatic biliary tract cancer (SGNTUC-019): a phase II basket study. J Clin Oncol. Published online September 26, 2023. doi:10.1200/JCO.23.00606