In recent years, Immune Checkpoint Inhibitors (ICIs) have revolutionized the treatment landscape of Non-Small Cell Lung Cancer (NSCLC).[11] However, a subset of patients experiences primary resistance to ICIs or develops resistance after an initial response, posing a significant clinical challenge.[2,12] In such cases, alternative treatment strategies are urgently needed to improve outcomes. in this study, we observed the efficacy and safety of anlotinib combined with single-agent chemotherapy[9] in patients with primary immune resistance in Non-Small Cell Lung Cancer (NSCLC).[13]

The primary endpoint of the study, Progression-Free Survival (PFS) and Overall Survival (OS), serves as a critical measure of treatment efficacy in oncology trials. The observed median PFS and OS of 4.0 months and 8.0 months in our trial exceeded expectations, indicating that the combination of anlotinib with single-agent chemotherapy effectively delayed disease progression in this challenging patient population. This finding is particularly noteworthy given the aggressive nature of immune-resistant NSCLC, underscoring the potential of this treatment approach to provide meaningful clinical benefit.[5,14]

Moreover, Other endpoints such as the Objective Response Rate (ORR) and Disease Control Rate (DCR) further support the efficacy of this regimen. The ORR of 23% and DCR of 65% reflect substantial tumor response and disease stabilization, respectively, highlighting the therapeutic potential of combining anlotinib with chemotherapy.[4] These outcomes are crucial as they suggest not only tumor shrinkage but also sustained disease control, which is essential for improving long-term patient outcomes in advanced NSCLC. Further research has found that its therapeutic efficacy is closely associated with the occurrence of toxic side effects such as hypertension, proteinuria, and hand-foot syndrome, indicating that the occurrence of toxic side effects can serve as potential biomarkers for predicting the efficacy of this regimen.[15,16]

The safety profile of the combination therapy was manageable, with common adverse events including bone marrow suppression, hypertension, fatigue, and proteinuria et al.[17] These adverse events were mostly grade 1 or 2 in severity and were effectively managed through dose adjustments or supportive care measures.[15] Importantly, no treatment-related deaths occurred during the study period, underscoring the safety and tolerability of the anlotinib plus chemotherapy combination in this patient population.[4,7,9] Regular monitoring of hematologic, hepatic, and renal functions facilitated early detection and management of treatment-related toxicities, ensuring that patients received appropriate supportive care throughout the treatment course.[18] This proactive approach to toxicity management is critical in maintaining treatment adherence and optimizing patient quality of life during cancer therapy.[16]

The findings from this study have several important clinical implications for the management of advanced primary immune-resistant NSCLC. Firstly, the efficacy demonstrated by the anlotinib plus chemotherapy combination highlights its potential as a salvage therapy.[19] for patients who have failed or progressed on ICIs. This expands the therapeutic options available to oncologists and provides hope for patients facing limited treatment alternatives.[20,21] Secondly, the safety profile observed in our trial supports the feasibility of combining anlotinib with chemotherapy in clinical practice. With appropriate monitoring and supportive care strategies, clinicians can effectively manage treatment-related adverse events, thereby enhancing patient safety and treatment tolerability.[15] Furthermore, our mechanistic study also revealed for the first time that patients with primary resistance exhibit generally higher proportions of Treg cells and lower proportions of NK cells, indicating a likely negative immune microenvironment in these individuals. This could potentially be a significant factor contributing to immune resistance, especially primary resistance. Following the adoption of combination therapy, however, there was a significant decrease in peripheral blood Treg proportions and an increase in NK cell proportions, suggesting a shift towards a positive immune microenvironment. This indicates that the regimen likely operates by reducing immune suppression to further activate immune responses and enhance synergistic anti-tumor effects.[3] Nevertheless, given the complexity of the immune microenvironment,[22,23] the precise mechanisms of action require further investigation. Looking ahead, future research efforts should focus on elucidating biomarkers predictive of response to anlotinib-based combinations, as well as exploring novel treatment strategies to further improve outcomes in immune-resistant NSCLC, These are also the current focus and direction of the research.[24,25]