The results of Study LIBRETTO-431, an ex-US multiregional, open-label, randomized, active-controlled trial of selpercatinib versus platinum-based and pemetrexed chemotherapy with or without pembrolizumab in patients with treatment-naïve advanced rearranged during transfection fusion-positive non-small cell lung cancer, highlight the challenges of interpreting OS in trials with high crossover rates and variable postprogression therapies. Trial results demonstrated a large improvement in progression-free survival with an acceptable safety profile, but were accompanied by an immature OS analysis with a hazard ratio of 1.26, favoring the chemoimmunotherapy arm. Regardless of the position of OS in the end point hierarchy, it is critical that OS analyses include prespecified plans for data collection and analytical methods to account for the potential impact of postprogression therapies on the interpretation of study results.

We present the case of a 74-year-old man with Stage IVB lung adenocarcinoma who developed changes in his psychiatric symptoms following three cycles of treatment with cisplatin, pemetrexed, and pembrolizumab. This is the first documented case of anti-titin antibody-positive encephalitis in a patient with non-small cell lung cancer (NSCLC). This case highlights the importance of considering immune-mediated neurological complications during Immune Checkpoint Inhibitor (ICI) treatment and the value of early antibody detection and prompt immunosuppressive therapy.

The standard first-line treatment for patients with driver mutation-negative non-small cell lung cancer (NSCLC) is chemotherapy and immunotherapy, including chemotherapy plus anti-programmed death-1 (PD-1)/programmed cell death ligand 1 (PD-L1) antibody (C + PD-1/PD-L1) or anti-PD-1 antibody (nivolumab) and anti-cytotoxic T-lymphocyte antigen-4 antibody (ipilimumab) (C + NI)...In the C + PD-1/PD-L1 group, platinum doublets were administered for up to four cycles, with pemetrexed maintenance permitted when the initial regimen included pemetrexed, whereas in the C + NI group, platinum doublets were limited to a maximum of two cycles with no maintenance chemotherapy...C + NI did not demonstrate superior effectiveness compared with C + PD-1/PD-L1 treatment across the PD-L1 TPS subgroups and was associated with increased toxicity, suggesting no clear clinical advantage of prioritizing C + NI in routine practice. C + NI should be reserved for selected cases in which the potential benefits outweigh the risks.

In contrast, chemotherapy-induced seizures, particularly those associated with high-dose methotrexate, arise from disrupted folate metabolism, intracellular oxidative stress, and subsequent N-methyl-D-aspartate (NMDA) receptor-mediated excitotoxicity. We provide a comparative analysis of these pathways, integrating current evidence on pharmacogenomic susceptibility-including polymorphisms in methylenetetrahydrofolate reductase (MTHFR) and drug transporter genes-as well as epigenetic factors. By synthesizing these molecular insights, we propose a mechanistic framework for precise clinical differentiation, which may inform biomarker-driven diagnostic approaches and targeted neuroprotective strategies in this vulnerable population.

The rs7421861G-allele is associated with poorer outcomes in pembrolizumab-treated MLA patients and warrants further validation.

The patient received high-dose methotrexate-based chemotherapy according to the DeAngelis protocol, combined with rituximab, selected to optimise disease control while minimising the neurotoxicity associated with whole-brain radiotherapy. She achieved visual recovery to 6/9 and regression of the central nervous system (CNS) lesion. This case underscores the importance of recognising pathognomonic retinal signs and employing molecular immunophenotyping to enable timely, life-saving, neuro-sparing therapy.

Taxane‑based chemotherapy was associated with more favorable outcomes than pemetrexed in dramatic progression after osimertinib resistance, with higher non‑hematologic toxicity. These findings, supported by exploratory in vitro sensitivity, warrant prospective validation.

In elderly PCNSL patients, R-MPV without routine WBRT provides effective disease control while being associated with less structural brain change. CSF IL-10 may represent a potential biomarker of susceptibility to treatment-related brain structural alterations.

Patients received either pemetrexed plus cisplatin (control group, n=56) or the same regimen with osimertinib (experimental group, n=56). The incidence of adverse reactions did not differ significantly between groups (P>0.05). In this retrospective cohort, the addition of osimertinib to platinum-based chemotherapy was associated with improved disease control and prolonged survival, along with greater reductions in angiogenesis-related and tumor marker levels, without increasing treatment-related toxicity.

He received afatinib as frontline treatment and showed a partial response; however, the right lung lesion progressed after 14 months of treatment...Because EGFR testing using resected tissue showed only the original mutation, we switched his regimen to pemetrexed and carboplatin...Although an association between MET amplification and rapidly progressive lung cancer has been predicted previously, to the best of our knowledge, this is the first report on the potential contribution of other mutations, such as those in RNA-binding motif 10, during MET-driven rapid progression. Our report highlights the importance of more active utilization of molecular profiling for the emergence of resistance during tyrosine kinase inhibitor use and the early identification of MET amplification and timely initiation of MET-targeted therapy, such as MET inhibitors in combination with EGFR-TKIs, to potentially mitigate rapid disease progression and clinical deterioration.

However, epcoritamab induced a rapid systemic response along with partial neurological improvement. This case highlights the potential role of bispecific antibody therapy in refractory DLBCL with CNS involvement, an area of significant unmet clinical need.

P4, N=108, Recruiting, Chinese University of Hong Kong