Tucatinib and Trastuzumab for Previously Treated Human Epidermal Growth Factor Receptor 2-Positive Metastatic Biliary Tract Cancer (SGNTUC-019): A Phase II Basket Study

Abstract

Purpose: To evaluate the efficacy and safety of tucatinib and trastuzumab in patients with previously treated human epidermal growth factor receptor 2-positive (HER2+) metastatic biliary tract cancer (mBTC).

Methods: SGNTUC-019 (ClinicalTrials.gov identifier: NCT04579380) is an open-label phase II basket study evaluating the efficacy and safety of tucatinib and trastuzumab in patients with HER2-altered solid tumors. In the biliary tract cancer cohort, patients had previously treated HER2 overexpressing or amplified (HER2+) tumors (identified with local testing) with no prior HER2-directed therapy. The primary end point was confirmed objective response rate (cORR) per investigator assessment. Patients were treated on a 21-day cycle with tucatinib (300 mg orally twice daily) and trastuzumab (8 mg/kg intravenously followed by 6 mg/kg every 3 weeks).

Results: Thirty patients were enrolled. As of data cutoff (January 30, 2023), the median duration of follow-up was 10.8 months. The cORR was 46.7% (90% CI, 30.8 to 63.0), with a disease control rate of 76.7% (90% CI, 60.6 to 88.5). The median duration of response and progression-free survival were 6.0 months (90% CI, 5.5 to 6.9) and 5.5 months (90% CI, 3.9 to 8.1), respectively. At data cutoff, 15 patients (50.0%) had died, and the estimated 12-month overall survival rate was 53.6% (90% CI, 36.8 to 67.8). The two most common treatment-emergent adverse events (TEAEs) were pyrexia (43.3%) and diarrhea (40.0%). Grade ≥3 TEAEs were reported in 18 patients (60.0%), with the most common being cholangitis, decreased appetite, and nausea (all 10.0%), which were generally not treatment related. TEAEs led to treatment regimen discontinuation in one patient, and there were no deaths due to TEAEs.

Conclusion: Tucatinib combined with trastuzumab had clinically significant antitumor activity and was well tolerated in patients with previously treated HER2+ mBTC.

FIG 1.

Flow diagram of the BTC cohort. BTC, biliary tract cancer; HER2+, human epidermal growth factor receptor 2–positive.

FIG 2.

Maximum percentage reduction in the sum of tumor diameters from baseline per investigator assessment and local HER2 testing results for each patient. One patient was excluded because of missing postbaseline measurement. ^aNumbers refer to the IHC scores. NA indicates a missing evaluable sample, including quality control fails. ^b+ is defined as amplification. NA indicates a missing evaluable sample, including quality control fails. B, blood-based; CISH, chromogenic in situ hybridization; IHC, immunohistochemistry; FISH, fluorescence in situ hybridization; HER2, human epidermal growth factor receptor 2; NA, not available; NGS, next-generation sequencing; T, tissue-based.

FIG 3.

Percentage change from baseline in sum of diameter of target lesions per investigator assessment. One patient was excluded because of no postbaseline measurement.

FIG 4.

Kaplan-Meier curves for (A) PFS and (B) OS. Associated 90% CIs were calculated on the basis of the complementary log-log transformation. OS, overall survival; PFS, progression-free survival.

FIG A1.

Summary of HER2 testing results and best overall response. Each column represents one patient. One patient was not included because of missing postbaseline measurement. The one excluded patient had IHC 3+ tumor per local testing (NA for FISH/CISH and NGS). Per central testing, this patient had IHC 1+ and no amplification per FISH and blood-based NGS. ^aNumbers refer to the IHC scores. NA indicates a missing evaluable sample, including quality control fails. ^bNo scoring criteria were specified for local IHC. ^c+ is defined as amplification. NA indicates a missing evaluable sample, including quality control fails. ^dEvaluated by using the ASCO-College of American Pathologists Gastric Scoring criteria. ^e+ is defined as amplification. – is defined as no amplification. NA indicates a missing evaluable sample, including quality control fails. B, blood-based; CISH, chromogenic in situ hybridization; CR, complete response; FISH, fluorescence in situ hybridization; HER2, human epidermal growth factor receptor 2; IHC, immunohistochemistry; NA, not available; NGS, next-generation sequencing; PD, progressive disease; PR, partial response; SD, stable disease; T, tissue-based.