Dynamic nature of BRAF or KRAS p.G12C mutations in second-line therapy for advanced colorectal cancer patients: do early and late effects exist?

INTRODUCTION: The mitogen-activated protein kinase (MAPK) signalling network aberrations in metastatic colorectal cancer (mCRC) generate intrinsic dynamic effects and temporal variations that are crucial but often overlooked in clinical trial populations. Here, we investigate the time-varying impact of MAPK pathway mutation genotype on each treatment line's contribution to the overall clinical course. METHODS: The PROMETEO study focused on mCRC patients undergoing second-line treatment at 20 hospitals. We evaluated genotypes and employed flexible models to analyse the dynamic effect of each mutation. RESULTS: We examined data derived from 1160 patients. The effects of KRAS G12C or G12V, and BRAF V600E are clearly time-varying, with unexpected consequences such as the deleterious effect of BRAF V600E vs other genotypes dissipating over time when subjects receive antiangiogenics, or KRAS G12V and G12C showing increasing aggressiveness over time. Thus, contrary to expectations, the 12-month survival rate from the second line for those who survived >6 months was 49.9% (95% CI, 32.7-67.3) for KRAS G12C and 59% (95% CI, 38.5-80.6) for BRAF V600E. CONCLUSIONS: The dynamic perspective is essential for understanding the behaviour of tumours with specific genotypes, especially from the second line onward. This may be relevant in patient monitoring and treatment decision-making, particularly in cases with distinct mutations.

Potential treatment strategy for the rare osimertinib resistant mutation EGFR L718Q.

Epidermal growth factor receptor (EGFR) L718Q is a rare resistant mutation which independently leads to third-generation tyrosine kinase inhibitor (TKI) resistance. Although a few studies have examined its resistance mechanisms, no effective treatment strategy has yet been proposed for patients with this mutation. Here, we report an effective treatment strategy for the rare EGFR L718Q mutation for the first time. A 44-year-old Chinese male patient initially presented with the sensitizing EGFR L858R mutation, and the progression-free survival (PFS) time after initial icotinib treatment was 9 months. When the progression of the disease (PD) and the EGFR T790M mutation were identified, he did not respond to the osimertinib treatment. Through comprehensive next-generation sequencing (NGS) of the surgical specimen, the rare EGFR L718Q mutation was eventually identified as having a frequency of 68.84%, together with an EGFR amplification with a copy number of 11.54. The previous treatment response was retrospectively explained, and the patient faced the challenge of not being able to benefit from any targeted therapy. Following chemotherapy with a personalized regimen which effectively modified the proportion of sensitive and resistant cells, significant response to osimertinib re-challenge was observed, and another PFS of 4.7 months was achieved. Unfortunately, four EGFR mutations, EGFR L858, T790M, L718Q, and C797S, were simultaneously detected in his late stage, and led to further progression of disease.

Are patients in haemodialysis good candidates for immunotherapy treatment?

The effectiveness and safety of nivolumab, an anti-programmed cell death protein 1 mAbmonoclonal antibody, in patients with renal replacement therapy is unclear, with limited evidence supporting its usefulness in this context. Therefore, we report a case of recurrent metastatic melanoma in a patient on haemodialysis successfully treated with nivolumab. As seen in patients without renal impairment, significant regression of the lesions was observed after 8 weeks of treatment, reaching complete clinical response after 4 months. During follow-up, no dose adjustment, delay, or treatment suspension due to toxicity were required.