RAS wild-type

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.

In an HCT116 xenograft model, oral administration of SL43 (20 and 40 mg/kg) also significantly suppressed tumor growth (TGI = 57.2% and 74.9%, respectively), outperforming MRTX0902 (60 mg/kg, TGI = 47.1%) with no observable systemic toxicity. In conclusion, SL43 represents a potent and orally bioavailable SOS1 inhibitor that effectively suppresses KRAS signaling and exerts strong antitumor efficacy, highlighting its potential as a promising candidate for KRAS-mutant colorectal cancer.

P1, N=39, Recruiting, National Cancer Institute (NCI) | Trial completion date: Apr 2026 --> Apr 2027 | Trial primary completion date: Apr 2026 --> Apr 2027

The study underscores the importance of integrating NGS-based molecular testing with PD-L1 evaluation for personalised management of NSCLC. Distinct patterns of PD-L1 expression across molecular subtypes, particularly lower in EGFR-mutated tumours and higher in KRAS-mutated tumours, underscore the need for tailored therapeutic strategies and informed sequencing of targeted therapies and immunotherapies.

P1/2, N=90, Recruiting, Universita Degli Studi Di Padova | Not yet recruiting --> Recruiting

Pharmacological inhibition of these pathways, in combination with a K-RasG12C inhibitor, led to either addictive or synergistic reduction in tumor cell viability, in an allele-specific manner. These findings highlight the distinct biological consequences of individual K-Ras G12 mutations in colonic tumorigenesis and underscore therapeutic relevance of allele-specific signaling dependencies, offering a foundation for the development of effective, allele-informed therapeutic strategies for K-Ras mutant cancers.