cetuximab (Lupitux / Cetuxa / ENZ124)

Integrated Evaluation of Survival, Surgical Conversion, and Toxicity for Induction Therapy in Initially Unresectable Colorectal Liver Metastases: An Individual Patient Data Network Meta-analysis.

Nie Guilin G, Li Xinming X, Wang Yaoqun Y, Xu Jianrong J et al.

Patients with initially unresectable colorectal cancer liver metastases (CRLM) could derive benefits from active induction regimens by increasing the likelihood of surgical conversion. However, the comparative benefit-risk profiles of currently available regimens remain unclear. We performed an individual patient data (IPD) and network meta-analysis (NMA) to compare the efficacy of active induction regimens. IPD was reconstructed from randomized controlled trials (RCTs). The primary outcome was progression-free survival (PFS). Secondary outcomes included R0-1 resection rate, overall survival (OS), and grade ≥ 3 adverse events (AEs). Subgroup analyses were conducted according to KRAS/BRAF status and primary tumor sidedness. An entropy-weighted TOPSIS model was used to integrate efficacy and safety outcomes. Seven RCTs involving 1368 patients were included. IPD-based network analysis suggested that bevacizumab + triplet-chemotherapy was associated with the highest probability of improving R0-1 resection rate (0.99) and prolonging PFS (0.99). No significant differences in OS were observed among targeted therapy-based regimens. For patients with KRAS/BRAF wild-type tumors, cetuximab + doublet-chemotherapy is the only therapy performed better than chemotherapy in prolonging PFS. Bevacizumab + triplet-chemotherapy demonstrated superior efficacy among patients with KRAS/BRAF-mutant tumors. No significant PFS differences were observed among therapies in both left-sided and right-sided. Bevacizumab + doublet-chemotherapy demonstrated a more balanced benefit-risk profile with the highest Topsis scores (0.67). Bevacizumab plus triplet chemotherapy improves disease control and surgical conversion benefits but is associated with greater toxicity. Bevacizumab plus doublet chemotherapy showed the most favorable benefit-risk balance and may represent an optimal compromise for patients with initially unresectable CRLM.

Monitoring pharmacodynamic and molecular drug targets in liquid biopsy: Exploratory study in liver cancer with modelling of EGFR Receptor engagement.

Al-Majdoub Zubida M ZM, Sepp Armin A, Rostami-Hodjegan Amin A, Achour Brahim B

Liquid biopsy is minimally invasive (compared with tissue biopsy) and has previously been used to generate systems data regarding drug elimination via hepatic enzymes and transporters. This study extends quantitative assessment of systems parameters in liquid biopsy to pharmacodynamic (PD) and disease markers relevant to cancer development and therapeutics. Plasma extracellular vesicles (EVs) were extracted from 29 liver cancer donors. Cell-free RNA from EVs was subjected to RNAseq, allowing differential expression of PD/disease markers to be investigated relative to healthy baseline. Proteomics of matched liver membrane fractions was used to assess correlation of hepatic abundance with expression in plasma EVs. As a case example, quantitative systems pharmacology (QSP) modelling was used to evaluate EGFR occupancy with its ligand EGF and the EGFR-specific mAb, cetuximab. Expression of 406 PD markers and drug targets was monitored in plasma-derived EVs (including >130 molecular drug targets and >240 disease markers). Differential expression analysis revealed 18 dysregulated pathways involved in cell growth, proliferation, invasion, apoptosis, angiogenesis and immune regulation. EV expression of 33 markers with corresponding liver abundance lacked correlation, reflecting ubiquitous/extrahepatic expression of PD markers. QSP modelling of EGFR receptor occupancy with standard-dose cetuximab in the presence of EGF demonstrated suboptimal receptor blockade by the mAb (~80%) in patients with high EGFR expression. This study demonstrated the utility of liquid biopsy in monitoring PD targets and informing QSP models of disease. The approach may be used to guide drug dosing adjustment based on disease progression or remission.

Case Report: A case of carbapenem hypersensitivity and tigecycline-associated coagulopathy after immunotherapy for advanced oral cancer.

Peng Yifei Y, Peng Rui R

Managing complex infections after immunotherapy in patients with advanced head and neck cancer is clinically challenging, especially when severe adverse drug reactions like carbapenem hypersensitivity and tigecycline-associated coagulopathy further limit treatment options. This case demonstrates the potential contribution of clinical pharmacists in such difficult scenarios. A 74-year-old man with oral squamous cell carcinoma developed severe sepsis after one cycle of PD-1 inhibitor (penpulimab) plus EGFR inhibitor (cetuximab). The clinical pharmacist sequentially recommended escalation to meropenem, switch to piperacillin-tazobactam, and addition of vancomycin. Later, the pharmacist recognized possible imipenem-related central nervous system effects, leading to discontinuation of all carbapenems due to possible cross-hypersensitivity. Subsequently, tigecycline was initiated, its associated coagulopathy was managed, and a switch to doxycycline was made. The patient's fever resolved, and coagulation substantially improved; the infection was finally controlled. Causality was assessed using the Naranjo scale (imipenem 7, meropenem 5) and the RUCAM scale (penpulimab 6). In this case, the clinical pharmacist's dynamic assessment and use of quantitative adverse reaction tools (Naranjo and RUCAM scales) contributed to successful infection control and management of drug toxicity.

Methylglyoxal Scavengers Resensitize KRAS-Mutated Colorectal Tumors to Cetuximab.

Bellier Justine J, Nokin Marie-Julie MJ, Caprasse Maurine M, Tiamiou Assia A et al.