Background/Aim: The usefulness of angiogenesis inhibitors as second-line treatment after the progression of anti-epidermal growth factor receptor antibody drug-containing regimens for RAS wild-type metastatic colorectal cancer (mCRC) has not been fully investigated. Therefore, we conducted a phase II study to verify the efficacy and safety of the combination of S-1 and irinotecan plus bevacizumab (SIRB regimen) as second-line treatment for patients with oxaliplatin and cetuximab-refractory KRAS wild-type mCRC. Patients and Methods: Patients with mCRC who had previously received oxaliplatin and cetuximab-containing regimen were eligible for this study. Patients were infused with bevacizumab 7.5 mg/kg and irinotecan 150 mg/m² intravenously on day 1, whereas S-1 80 mg/m² was administered orally twice daily until day 15, followed by a 7-day drug holiday period. The primary end point was 6-month progression-free survival (PFS) rate. Results: In total, 17 patients were enrolled in this study. The 6-month PFS rate was 64.7% [95% confidence interval (CI)=41.99-87.43], median PFS was 10.1 months (95%CI=4.11-17.28), and median overall survival was 21.8 months (95%CI=9.79-37.91). The response rate was 23.5% (95%CI=6.81-49.90%). Grade ≥3 adverse events were observed in 10% of patients, and included leukopenia [3 (17.6%)], neutropenia [5 (29.4%)], anorexia [2 (11.8%)], diarrhea [2 (11.8%)], and hypertension [3 (17.6%)]. No treatment-related deaths or febrile neutropenia were observed. Conclusion: The SIRB regimen might be a promising second-line treatment option for patients with oxaliplatin and cetuximab-refractory KRAS wild-type mCRC in terms of efficacy and safety.

Background: Platinum-based doublets are standard first-line therapy for advanced gastric cancer (GC) in the Western Pacific region, but oxaliplatin frequently induces persistent peripheral sensory neuropathy (PSN). Whether residual PSN compromises the feasibility and efficacy of subsequent paclitaxel (PTX)-based therapy remains unclear. Methods: The IVY study was a prospective, multicenter observational trial conducted across 16 Japanese institutions. Patients with advanced GC progressing after fluoropyrimidine–platinum therapy received second-line PTX ± ramucirumab. Baseline PSN was assessed by CTCAE, PNQ, and FACT/GOG-Ntx. The primary endpoint was the incidence of grade ≥ 3 PSN during second-line therapy. Secondary endpoints included progression-free survival (PFS), overall survival (OS), time to treatment failure (TTF), tumor response, and patient-reported outcomes. Results: Among 156 patients (90 PSN-positive, 66 PSN-negative), grade ≥ 3 PSN occurred more frequently in the PSN-positive group (16.7% vs. 4.5%; p = 0.02). Median PFS was 4.0 vs. 3.9 months (p = 0.20), and median OS was 10.3 vs. 8.1 months (p = 0.04). In multivariable analysis, residual PSN was not an independent predictor of OS (HR = 0.68 for PSN-positive vs. PSN-negative, 95% CI [0.46–1.01]; p = 0.06). Patient-reported instruments captured greater and earlier QoL impairment in PSN-positive patients, though trajectories stabilized by 12 weeks. Conclusions: Residual PSN increases the risk of clinically relevant neurotoxicity—particularly in patients with baseline grade ≥ 2—but, in this cohort, did not appear to preclude paclitaxel-based second-line therapy when monitoring and dose modification were available. The apparent survival difference was exploratory and, after adjustment for baseline imbalance, should not be interpreted as a benefit attributable to residual PSN. Residual neuropathy should therefore prompt structured baseline assessment and early-cycle monitoring rather than routine reassurance.