Groisberg, Roman

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.

4007 Background: Biliary tract cancer (BTC) is an aggressive malignancy with a poor prognosis, and current treatment options for advanced BTC are limited, with second-line therapy, FOLFOX and S-1 offering an objective response rate (ORR) of 5.0% and 7.5%, respectively. Up to 20% of BTCs overexpress human epidermal growth factor receptor 2 (HER2). Tucatinib (TUC) is a highly selective HER2-directed TKI approved for HER2-positive (HER2+) metastatic breast and colorectal cancer. Discussed here are the efficacy and safety results of TUC combined with Trastuzumab (Tras) in pts with previously treated HER2+ metastatic BTC. Methods: SGNTUC-019 (NCT04579380) is an open-label phase 2 basket study evaluating efficacy, safety, and tolerability of TUC and Tras in pts with HER2-altered solid tumors. Pts in the BTC cohort had been previously treated with and progressed after ≥1 line of systemic therapy for metastatic disease. Eligible pts had locally determined HER2+ (defined as HER2 overexpression determined by immunohistochemistry [IHC] 3+ or HER2 amplification determined by in situ hybridization assay or next-generation sequencing) metastatic BTC. Pts were treated on a 21-day cycle with TUC (300 mg orally twice a day) and Tras (8 mg/kg IV followed by 6 mg/kg every 3 wks). Disease status was determined based on RECIST v1.1 with assessments performed every 6 wks for 24 wks and every 12 wks thereafter. The primary endpoint is confirmed objective response rate (cORR) per investigator assessment. Secondary endpoints include overall survival (OS), disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), and safety. Results: Thirty pts were enrolled in the BTC cohort as of data cutoff date of 30 Nov 2022. The median duration of follow-up was 8.3 months. cORR was 46.7% (90% CI, 30.8, 63.0), with 14 responses including 1 complete and 13 partial responses. Median DOR was 6.0 months (90% CI, 5.5, not estimable). DCR was 76.7% (n=23; 90% CI, 60.6, 88.5), and median PFS was 5.5 months (90% CI, 3.9, 8.1). At data cutoff, 13 (43.3%) patients had died, and the 12-months OS rate was 53.8% (90% CI, 35.2, 69.1%). Overall, the most common treatment-emergent adverse events (TEAEs) reported were pyrexia (43.3%) and diarrhea (40.0%). Grade ≥3 TEAEs were reported in 18 (60.0%) of 30 pts; however, only 6 (20.0%) and 2 (6.7%) of these pts had Grade ≥3 TEAEs related to TUC and Tras, respectively. Two (6.7%) pts discontinued TUC due to TEAEs, cholangitis and liver disorder. No deaths were due to TEAEs. Conclusions: The combination of TUC and Tras was well tolerated in pts with previously treated HER2+ metastatic BTC. The observed antitumor activity supports the combination of TUC and Tras as a future chemotherapy-free treatment option for this population with historically poor outcomes. Clinical trial information: NCT04579380 .