Sugimoto, Naotoshi

100 Background: HER2 is overexpressed in various GI tumors. Tucatinib (TUC), which is approved in combination with trastuzumab (Tras) in the US for previously treated RAS WT HER2+ metastatic colorectal cancer (mCRC), is a tyrosine kinase inhibitor highly selective for HER2. Preliminary safety and antitumor activity results of TUC + trastuzumab + FOLFOX in patients (pts) with HER2+ GI cancers are presented. Methods: The phase 1b/2 SGNTUC-024 (NCT04430738) study evaluated TUC + Tras + FOLFOX in pts with HER2+ metastatic GI cancers in Cohorts 1A, 1B, 1D (pts in Japan), and 2B. For Cohorts 1A, 1B, and 1D (enrolled sequentially), eligible pts had unresectable or metastatic HER2+ GI malignancies, including mCRC. Cohort 2B is still enrolling, and pts with HER2+ mCRC are eligible. Pts received a combination of TUC 150 mg orally twice a day (PO BID; Cohort 1A) or TUC 300 mg PO BID (Cohorts 1B, 1D, and 2B) + Tras + FOLFOX. Pts in Cohort 2B were enrolled to further assess the study regimen. Antidiarrheal prophylaxis was required for Cohort 1D. Results: As of July 10, 2023, 25 pts were treated (5, 11, 7, and 2 in Cohorts 1A, 1B, 1D, and 2B, respectively). In Cohort 1A (TUC 150 mg PO BID), the most common TEAEs were diarrhea, fatigue, nausea, and proteinuria (each in 60.0% [3/5]). For pts receiving TUC 300 mg PO BID, the most common TEAEs were diarrhea (90.0% [18/20]) and fatigue (65.0% [13/20]). Table 1 presents the overall summary of adverse events. In Cohort 1A, Treatment-emergent adverse events (TEAEs) leading to any treatment discontinuation were reported in 40.0% (2/5) pts, with 20.0% (1/5) discontinuing tucatinib. For pts treated with TUC 300 mg, TEAEs leading to treatment discontinuation were reported in 35.0% (7/20), with 15.0% (3/20) discontinuing tucatinib. One TEAE leading to death (aspiration) in Cohort 1A was unrelated to study treatment. Grade ≥3 diarrhea was observed in 45.5% (5/11) pts in Cohort 1B; most were observed in elderly pts or pts with gastric, gastroesophageal, or esophageal cancer or pts who were generally noncompliant with antidiarrheal treatment. No grade ≥3 diarrhea was observed in Cohort 1D. Among pts receiving TUC 300 mg, confirmed objective response rate was 83.3% (5/6) for mCRC, 40.0% (4/10) for gastroesophageal cancers, and 0% (0/4) for biliary tract cancer. Conclusions: TUC + Tras + FOLFOX showed manageable safety in the enrolled pt population and preliminary antitumor activity in pts with HER2+ mCRC and gastroesophageal cancer. This regimen will be compared with the standard of care (FOLFOX with or without bevacizumab/cetuximab) in the ongoing randomized, phase 3 study (MOUNTAINEER-03; NCT05253651) for pts with HER2+ RAS WT mCRC. Clinical trial information: NCT04430738 . [Table: see text]

102 Background: This phase II study aimed to investigate the safety and efficacy of XP compared to SP in the first-line treatment of HER2 negative AGC. Methods: Patients were randomly assigned to receive either SP (S-1 at 40–60 mg twice daily for 21 days plus cisplatin at 60 mg/ m2 on day 8, every 5 weeks) or XP (capecitabine 1,000 mg/m2 twice daily for 14 days plus cisplatin 80 mg/m2 on day 1, every 3 weeks). Primary endpoint was response rate (RR), and secondary endpoints were progression-free survival (PFS), overall survival (OS), time to treatment failure (TTF), and adverse events. Results: 84 eligible patients were randomly assigned to receive SP ( N = 41) or XP ( N = 43). No statistical difference was observed in overall RR between the SP and XP groups [51.2% (95% CI, 35.1% to 67.1%) vs. 53.5% (95% CI, 37.7% to 68.8%), P = 1.000]. Despite not significant, however, SP vs. XP showed a trend toward better PFS [median, 5.9 months vs. 4.1 months; hazard ratio (HR), 0.763; 95% CI, 0.462 to 1.259; P = .284] and OS (median, 13.5 months vs. 10.0 months; HR, 0.776; 95% CI, 0.485 to 1.244; P = .290). This trend in the SP vs. XP comparison was more pronounced in TTF (median, 4.5 months vs. 3.1 months; HR, 0.651; 95% CI, 0.421 to 1.006; P = .052). Common grade 3 to 4 hematological toxicities were neutropenia and anemia (SP group, 23% and 23%; XP group, 35% and 28%). Grade 3-4 anorexia and hyponatremia were more frequently seen in the XP group (31% and 16%) compared to the SP group (13% and 5%). Treatment-related deaths occurred in one patient (2.3%) in the XP group. Conclusions: XP failed to demonstrate the superior efficacy over SP. Higher incidence of severe toxicities by XP suggests SP as the standard 1st line chemotherapy for HER2 negative AGC in Japan. Clinical trial information: UMIN000006755.