International Journal of Molecular Medical Science, 2025, Vol.15, No.5, 224-234 http://medscipublisher.com/index.php/ijmms 2 30 6.2 Overlapping toxicity of chemotherapy and immunotherapy When PD-1/PD-L1 inhibitors are used in combination with chemotherapy, the risk of certain adverse events increases, especially severe toxic reactions. Compared with chemotherapy alone, the combination of chemotherapy and immunotherapy leads to a higher incidence of treatment-related adverse events (AES) of grade 3 or above, treatment discontinuation, and death due to AES (Aburaki et al., 2024). Overlapping toxic reactions include gastrointestinal symptoms (vomiting, diarrhea, constipation), fatigue, hematological toxicity, and an increased risk of pneumonia at all levels (especially severe pneumonia) (Jiang et al., 2021; Takada et al., 2024). Despite these risks, the overall safety of the combination therapy was manageable. No unexpected or unforeseen toxic reactions were found except for the known toxicity of each of the two treatment methods (Hoffner et al., 2020). Importantly, compared with immunotherapy alone, the addition of chemotherapy may reduce the occurrence of certain irAEs, such as pneumonia and endocrination-related events, by regulating the overactivated immune system (Wang et al., 2020). However, doctors still need to be vigilant about immune-mediated toxicity and toxicity related to conventional chemotherapy. 6.3 Monitoring and management strategies for adverse events For patients with non-small cell lung cancer who receive chemotherapy combined with immunotherapy, to effectively handle adverse events, it is necessary to detect them early, have multiple departments cooperate, and take timely measures. Regular check-ups are crucial, including clinical evaluations by doctors and laboratory tests for organ functions such as the thyroid, liver, and lungs, especially in the first few months of treatment - this is the period when irAEs are most likely to occur. It is also very important for patients to understand how to report physical discomfort for the timely detection of adverse events. The treatment plan should be formulated based on the severity of the adverse event and the organs involved. Most irAEs improve after temporary drug withdrawal and the use of corticosteroids. Only for cases that are difficult to control or severe will additional immunosuppressants be considered. Endocrine-related irAEs may require long-term hormone supplementation rather than immunosuppressants. For overlapping toxic reactions, it is important to distinguish whether they are caused by immunotherapy or chemotherapy for taking the correct intervention measures. Proactive supportive care and personalized risk assessment can minimize complications and lead to better treatment outcomes for patients (Hoffner et al., 2020). 7 Predictive Factors Affecting Therapeutic Effect 7.1 Molecular biomarkers (PD-L1, TMB, MSI, etc.) PD-L1 expression is the most commonly used biomarker for predicting the response of non-small cell lung cancer to PD-1/PD-L1 inhibitors. The higher the PD-L1 level, the more benefits patients usually obtain from immunotherapy (especially immunotherapy alone). However, due to different detection methods, inherent differences in tumors themselves, and changes in PD-L1 expression, its predictive effect is not good enough. So even if the PD-L1 level is low or negative, patients can still benefit from the combination regimen of chemotherapy and immunotherapy (Huo et al., 2022). Tumor mutational burden (TMB) is another promising biomarker. The higher the TMB, the better the objective response, more lasting clinical benefits, and longer progression-free survival (PFS) of patients after PD-1 blockade therapy. This may be because the increase in neoantigens makes it easier for the immune system to recognize tumors. However, in different studies, the predictive effect of TMB is inconsistent, and there is a lack of a unified detection standard. It also interacts with other factors such as smoking history. All these limit its clinical use (Huo et al., 2022). Microsatellite instability (MSI) and other new biomarkers (including specific oncogenic mutations such as KRAS, EGFR, BRAF, etc.) are still under investigation, but their role in non-small cell lung cancer compared with other cancers remains unclear (Akers et al., 2023; Chen et al., 2024). 7.2 Clinical characteristics and stratification factors of patients Clinical characteristics such as age, smoking history, physical activity ability and the presence or absence of specific driver mutations can significantly affect the efficacy of PD-1/PD-L1 inhibitors. Meta-analysis found that
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