RAS wild-type

P1/2, N=151, Recruiting, Takeda | Not yet recruiting --> Recruiting

P1, N=47, Completed, M.D. Anderson Cancer Center | Active, not recruiting --> Completed | N=33 --> 47

P2, N=31, Fudan University Shanghai Cancer Center; Fudan University Shanghai Cancer Center

P1, N=180, Recruiting, R-Pharm

KRAS-mutant LUAD patients exhibit inferior pathological responses and survival after neoadjuvant immunotherapy compared to KRAS-wildtype patients. A CD4T_Treg_TNFRSF4 subset is enriched in non-responders, defining an immunosuppressive microenvironment. Responders are characterized by a synergistic network between Th1 cells and a novel exhausted-like B-cell (Bex) state. The balance between immunosuppressive Tregs and the Th1/Bex axis determines therapeutic efficacy in KRAS-mutant LUAD.

P1, N=387, Not yet recruiting, Shanghai Henlius Biotech

Importantly, EGFR sialylation affected Cetuximab binding and receptor activation in a cell line-dependent manner, with cells bearing α2,6-sialylation showing modified antibody responsiveness. Overall, these findings demonstrate that EGFR sialylation modulates receptor behaviour and Cetuximab response in CRC, highlighting the inhibition of sialylation as a potential strategy to overcome glycosylation-mediated therapeutic resistance.

P2, N=38, Recruiting, Emory University | Not yet recruiting --> Recruiting

P2, N=29, Terminated, Aurigene Discovery Technologies Limited | N=90 --> 29 | Trial completion date: May 2027 --> Feb 2026 | Recruiting --> Terminated | Trial primary completion date: Sep 2026 --> Feb 2026; Patient recruitment problems.

Patients were randomized (1:1) to FOLFIRI-cetuximab then mFOLFOX6-bevacizumab (arm A) or OPTIMOX-bevacizumab then FOLFIRI-bevacizumab followed by EGFR monoclonal antibody +/- irinotecan (arm B)...Adverse events were consistent with the well-known safety profiles. STRATEGIC-1 did not meet its primary endpoint and was inconclusive in identifying the optimal treatment strategy in wild-type RAS/BRAFV600E mCRC.

This case underscores the importance of early response evaluation in ICI-treated MSI-H tumors. Rapid disease progression requires prompt differentiation between HPD and pseudoprogression, emphasizing the necessity of timely therapeutic modification.

Anti-EGFR monoclonal antibodies, cetuximab and panitumumab, have demonstrated survival benefit in selected patients, particularly those with left-sided, RAS wild-type tumors. We also discuss mechanisms of resistance such as pathway reactivation, receptor mutations, and epithelial-to-mesenchymal transition, alongside emerging approaches, including combination regimens, ctDNA-guided rechallenge, and genotype-specific inhibitors. Collectively, these insights highlight the evolving landscape of precision oncology in CRC and the importance of molecular stratification to optimize EGFR-targeted therapy and overcome resistance.