The ICH S1B(R1) guideline addendum, adopted by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) in August 2022, introduces a comprehensive Weight of Evidence (WoE)-based approach into the traditional framework for drug carcinogenicity risk assessment. This method aims to conduct an integrated analysis by incorporating multiple key factors to evaluate whether the two-year rat carcinogenicity study can provide additional valuable information for human carcinogenicity risk assessment. Consequently, under certain circumstances, the two-year rat carcinogenicity study may be waived, allowing resources to be focused on more scientific, mechanism-based carcinogenicity assessments. This transformation is grounded in scientific advances since the release of ICH S1B in 1997, retrospective analyses of drug databases, and an international prospective study, confirming that the WoE approach can adequately assess risks in specific contexts and aligns with the 3R principles (Replacement, Reduction, Refinement) aimed at reducing animal use. The addendum emphasizes a systematic evaluation of factors such as target biology, secondary pharmacology, histopathology from long-term toxicity studies, hormonal effects, genotoxicity, and immunomodulation, encouraging a mechanism-driven risk assessment strategy. However, its implementation faces scientific and procedural challenges, and there may be disagreements between regulatory authorities and applicants regarding WoE conclusions. Promoting practical application requires early communication, standardized documentation submission, and international experience sharing. Although current implementation experience is limited and both regulators and industry remain cautious, coordinated efforts by the ICH Implementation Working Group (IWG) and accumulating case studies are expected to advance WoE-based carcinogenicity assessment, optimize drug development processes, reduce unnecessary animal testing, and foster the safe and ethical development of innovative drugs.