Characterization and management of gastrointestinal (GI) adverse events (AEs) with zanidatamab + chemotherapy (CT) ± tislelizumab in first-line (1L) HER2-positive (HER2+) locally advanced or metastatic gastroesophageal adenocarcinoma (mGEA): Analysis from HERIZON-GEA-01.

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4042 Background: In HERIZON-GEA-01, replacing 1L trastuzumab (tras) + CT with zanidatamab + CT ± tislelizumab significantly improved progression-free survival and, with tislelizumab, yielded a statistically significant overall survival benefit in HER2+ mGEA. The safety profile was manageable; diarrhea was the most common AE. Here we further characterize GI AEs and diarrhea management. Methods: Eligible patients (pts) with previously untreated HER2+ mGEA were randomized 1:1:1 to zanidatamab (1800 mg [<70 kg]/2400 mg [≥70 kg] IV Q3W) + tislelizumab (200 mg IV Q3W) + capecitabine/oxaliplatin (CAPOX) or 5-FU/cisplatin (FP); zanidatamab + CAPOX or FP; or tras + CAPOX or FP. CT could be discontinued per physician preference after cycle 6. Tras dose reductions were not permitted. Diarrhea prophylaxis (loperamide 4 mg orally BID) was mandatory in zanidatamab-containing arms for the first 7 days of cycle 1. Results: Median treatment duration was 43.1 wk with zanidatamab + tislelizumab + CT, 31.0 with zanidatamab + CT, and 30.0 with tras + CT. Median number of CT cycles was 6, 6, and 7, respectively. Diarrhea was the most common GI AE in all arms; other GI AEs were generally similar across arms. Among pts who experienced diarrhea, most had first onset in cycle 1 (76% in ≤3 wk) with median duration <2.5 wk (Table). Few pts had their first onset of diarrhea occur after cycle 6 when pts could discontinue CT. HER2-targeted therapy discontinuations (4.1%, 1.3%, 0.3%, respectively) and dose reductions (9.9%, 10.8%, NA) or delays (13.6%, 13.4%, 7.6%) due to diarrhea were infrequent. Diarrhea was more often managed with CT dose reduction (21.8%, 23.6%, 14.2%, respectively). Immune-mediated colitis occurred in 2.7% of pts with zanidatamab + tislelizumab + CT. Additional incidence and management data will be presented. Conclusions: In zanidatamab-treated pts, most diarrhea events were grade 1/2, and first-onset events tended to occur in cycle 1 and resolved in <3 wk. Diarrhea rarely led to zanidatamab discontinuation. The safety of zanidatamab-containing regimens appears favorable given the survival benefits; diarrhea should be managed with prophylactic loperamide and CT dose modifications as needed. Clinical trial information: NCT05152147 . Diarrhea Zanidatamab + Tislelizumab + CT n = 294 Zanidatamab + CT n = 305 Tras + CTn = 302 Any-grade, n (%) 244 (83.0) 241 (79.0) a 161 (53.3) Grade 1 79 (26.9) 80 (26.2) 84 (27.8) Grade 2 92 (31.3) 99 (32.5) 38 (12.6) Grade ≥3 73 (24.8) 61 (20.0) 39 (12.9) Time to first onset, n (%), wk ≤3 188 (77.0) 192 (79.7) 108 (67.1) >3 to ≤6 25 (10.2) 27 (11.2) 22 (13.7) >6 to ≤9 7 (2.9) 14 (5.8) 11 (6.8) >9 to ≤12 4 (1.6) 4 (1.7) 2 (1.2) >12 to ≤18 8 (3.3) 3 (1.2) 7 (4.3) >18 12 (4.9) 1 (0.4) 11 (6.8) Duration of first onset, median (95% CI), wk 2.0 (1.6, 2.6) 2.4 (1.9, 2.9) 1.4 (1.0, 2.1) a Grade missing for 1 pt.

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