Dose-escalation and dose-expansion study of trastuzumab deruxtecan (T-DXd) monotherapy and combinations in patients (pts) with advanced/metastatic HER2+ gastric cancer (GC)/gastroesophageal junction adenocarcinoma (GEJA): DESTINY-Gastric03.
Authors: Yelena Y. Janjigian, Do-Youn Oh, Sun Young Rha, Keun Wook Lee, Neeltje Steeghs, Yee Chao, Maria Di Bartolomeo, Marc Díez Garcia, Nadia Haj Mohammad, Alexander Stein, William McAdoo, Megan Winter, Liz Croydon, Jeeyun Lee
Journal: Journal of Clinical Oncology (2022)

295 Background: T-DXd is an antibody-drug conjugate composed of a humanized anti-HER2 monoclonal antibody, a tetrapeptide-based cleavable linker, and a topoisomerase I inhibitor payload. T-DXd is approved for HER2+ advanced/metastatic GC/GEJA after a prior trastuzumab-based regimen (US/Israel) and GC after chemotherapy (Japan). In DESTINY-Gastric01, T-DXd showed improved efficacy vs standard chemotherapy in Japanese and Korean pts (≥2 prior therapies) with advanced HER2+ GC/GEJA. Preclinical data of T-DXd combinations suggest encouraging antitumor activity. DESTINY-Gastric03 is the first study of T-DXd combinations in GC/GEJA. Methods: DESTINY-Gastric03 (NCT04379596) is a 2-part, phase 1b/2, multicenter, open-label, 3+3 dose-escalation (part 1) and -expansion (part 2) study in advanced/metastatic HER2+ GC/GEJA. In part 1, pts with locally confirmed HER2+ GC/GEJA (IHC 3+ or IHC 2+/ISH+) who progressed on/after ≥1 prior therapy including a trastuzumab-containing regimen received T-DXd intravenously (IV) every 3 weeks + assigned combination. Primary objectives were safety and recommended phase 2 dose (RP2D). Preliminary antitumor activity was a secondary objective; confirmed objective response rate (ORR) was a secondary endpoint. We report the T-DXd + fluoropyrimidine cohorts. Results: In part 1, 15 pts were assigned to T-DXd + IV 5-fluorouracil (5-FU) and 10 pts to T-DXd + oral capecitabine (Cap). In addition to trastuzumab, all pts had received prior treatment with 5-FU and/or Cap and a median of 2 (range, 1-5) prior lines of therapy. The most common grade ≥3 AEs (%) were anemia (33), decreased neutrophil count (33), nausea (13), and stomatitis (13) with T-DXd + 5-FU and decreased neutrophil count (40), anemia (30), and nausea (20) with T-DXd + Cap. Starting doses were T-DXd 5.4 mg/kg + 5-FU 800 mg/m 2 and T-DXd 5.4 mg/kg + Cap 1000 mg/m 2 twice daily (BID). There were 2 dose-limiting toxicities of grade 3 stomatitis with T-DXd 6.4 mg/kg + 5-FU 800 mg/m 2 ; this exceeded the maximum tolerated dose and was discontinued. RP2Ds were T-DXd 6.4 mg/kg + 5-FU 600 mg/m 2 and T-DXd 6.4 mg/kg + Cap 1000 mg/m 2 BID. Preliminary confirmed and confirmed + unconfirmed ORR at the RP2D for T-DXd + Cap were 3/7 and 5/7, respectively; 3/3 pts at the starting dose of T-DXd + Cap had confirmed ORR. ORR data for T-DXd + 5-FU are not yet mature. Conclusions: In the first T-DXd + fluoropyrimidine combination study in HER2+ GC/GEJA, preliminary part 1 results suggest tolerability and feasibility of the RP2Ds for T-DXd + 5-FU and T-DXd + Cap. Preliminary ORR with the T-DXd + Cap RP2D (n = 7) showed efficacy with this combination in heavily pretreated, trastuzumab- and fluoropyrimidine-refractory, HER2+ GC/GEJA. This study is ongoing, with further combinations and follow-up planned. Clinical trial information: NCT04379596.