GI Oncology Daily Digest

First-line HER2-positive gastric cancer has run on trastuzumab plus chemotherapy for over a decade, and this single-arm Phase 2 trial asks whether a HER2-directed antibody-drug conjugate plus a checkpoint inhibitor can do better up front. Fifty-seven patients with advanced HER2-overexpressing (IHC 3+, or 2+ regardless of ISH status) gastric or gastroesophageal junction adenocarcinoma received disitamab vedotin, tislelizumab, and oral S-1 in 21-day cycles. The confirmed objective response rate by central review was 89.5%, and at a median follow-up of 28.2 months the median progression-free survival was 13.8 months and median overall survival reached 31.9 months — numbers that sit well above the historical 1L benchmark of roughly 13–15 months mOS for trastuzumab-based therapy. Notably, activity held up even in PD-L1-low tumors: the CPS <1 subgroup (54% of the cohort) still achieved an 87.1% ORR and 25.4-month mOS. Grade ≥3 treatment-related adverse events occurred in 64.9%, driven mainly by hematologic toxicity and peripheral neuropathy. This is single-arm data and not yet practice-changing, but the magnitude of response and the survival tail are striking enough to make the planned randomized validation one to watch closely.

"Early-onset" colorectal cancer is usually defined as diagnosis before 50, but this multicenter Italian analysis asks whether the very youngest patients are biologically distinct from those merely under 50. Among 264 patients with metastatic CRC, the authors compared a very early-onset group aged 30–39 (n=65) against an early-onset group aged 40–49 (n=199). The ultra-young patients fared worse, with a median overall survival of 30.0 versus 38.0 months (HR 0.67, p=0.027), and their tumors carried a different molecular fingerprint: KRAS mutations were more common (55.4% vs 42.0%, p=0.041), APC mutations were less frequent (69.2% vs 82.0%, p=0.024), and peritoneal metastases were more prevalent (32.3% vs 19.6%, p=0.041). The work, built on FoundationOne comprehensive genomic profiling and authored by a heavyweight Italian GI group, argues that very early-onset mCRC is not just early-onset CRC in younger packaging but a more aggressive, genomically divergent subtype. For practice, it reinforces that age at diagnosis carries prognostic and biological information, and that the under-40 cohort may warrant particularly careful molecular characterization and follow-up.

When intrahepatic cholangiocarcinoma recurs after curative resection — which it often does — the question is whether anything done before surgery shapes what happens afterward. This single-institution Mayo Clinic study analyzed 343 patients who underwent curative-intent resection for iCCA between 2000 and 2024, comparing those who received neoadjuvant therapy (NAT) against those taken straight to surgery. Patients who had NAT showed markedly longer post-recurrence overall survival: 31.9 versus 16.4 months (HR 0.506, p=0.008). Part of the explanation appears to be selection and biology — the NAT group was enriched for targetable IDH1 and FGFR2 alterations (48.2% vs 13.9%) and was more likely to receive curative-intent local and systemic therapies at the time of recurrence. As a retrospective single-center series, this cannot establish that neoadjuvant therapy causes the survival difference, and confounding by patient selection is real. Still, the analysis adds to a growing argument that a neoadjuvant approach in resectable iCCA may identify favorable biology, improve downstream treatment options, and is worth testing prospectively rather than reserving systemic therapy for after surgery.