NSCLC First Line Therapy Chemotherapy Combinations
Overview
This retrospective study explores optimal first-line treatments for non-small cell lung cancer (NSCLC) patients with brain metastases (BMs) lacking driver gene alterations. The research compares the effectiveness of immunotherapy plus chemotherapy (ICI+Chemo) against bevacizumab plus chemotherapy (Beva+Chemo). The study, conducted between March 2017 and May 2022, includes 155 eligible patients. Results indicate that ICI+Chemo outperforms Beva+Chemo in terms of median intracranial progression-free survival (iPFS) and systemic PFS (sPFS) with hazard ratios of 0.626 and 0.634, respectively.
Specifically, ICI+Chemo demonstrates iPFS and sPFS of 14.4 and 12.1 months compared to 10.0 and 8.4 months for Beva+Chemo. This PFS advantage is particularly significant in patients with programmed cell death-ligand 1 (PD-L1)-positive expression. However, the median overall survival (OS) remains comparable between the two groups at 26.9 and 23.1 months for ICI+Chemo and Beva+Chemo, respectively (HR, 0.790; P = 0.335). Objective response rates (ORR) are similar, and both regimens are well-tolerated without additional adverse events.
The study also analyzes subsequent treatments after progression, revealing that patients receiving immunotherapy throughout treatment exhibit significantly improved OS compared to those naive to immunotherapy (P < 0.001). OS is similar between patients receiving immunotherapy alone and those receiving both immunotherapy and bevacizumab (P = 0.394). In conclusion, ICI+Chemo emerges as a superior first-line treatment for NSCLC patients with BMs lacking driver gene alterations, offering notable improvements in iPFS and sPFS, particularly for those with PD-L1-positive expression. Additionally, ongoing immunotherapy contributes significantly to enhancing the overall survival of these patients.
Introduction
This retrospective study addresses the pressing issue of non-small cell lung cancer (NSCLC), responsible for a significant portion of global cancer-related deaths. Brain metastases (BMs) afflict 20-40% of NSCLC patients, notably those with adenocarcinoma, leading to a particularly grim prognosis. Bevacizumab, a monoclonal antibody targeting vascular endothelial growth factor (VEGF), has demonstrated efficacy in preventing BMs formation in preclinical models. Earlier trials revealed improved outcomes with bevacizumab in advanced NSCLC, but these excluded patients with untreated BMs.
Preliminary evidence suggests enhanced intracranial responses and prolonged progression-free survival (PFS) with bevacizumab in combination with epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) for EGFR-mutant NSCLC. Additionally, bevacizumab plus chemotherapy (Beva+Chemo) demonstrated efficacy in reducing BMs incidence compared to chemotherapy alone.
Immune checkpoint inhibitors (ICI), particularly anti-programmed cell death 1 (PD-1) antibodies, have revolutionized cancer treatment. Immunotherapy has shown promise in NSCLC patients with BMs, with studies indicating benefits from pembrolizumab alone or in combination with chemotherapy. Previous data also supports positive outcomes with camrelizumab plus pemetrexed-carboplatin.
Despite these advancements, it remains unclear whether upfront systemic therapy, specifically ICI plus chemotherapy (ICI+Chemo), surpasses the efficacy of Beva+Chemo in NSCLC patients with BMs. This retrospective study seeks to provide a direct comparison, aiming to ascertain the superior treatment approach and quantify the associated benefits for this challenging patient population.
Result
In this retrospective analysis conducted at Sun Yat-Sen University Cancer Center (SYSUCC), a cohort of 155 advanced non-small cell lung cancer (NSCLC) patients with brain metastases (BMs) and lacking targetable driver mutations was examined. The patients, who were treated between March 2017 and May 2022, received either a combination of immunotherapy and chemotherapy (ICI+Chemo) or bevacizumab plus chemotherapy (Beva+Chemo) as their first-line treatment.
The demographic characteristics of the patients included a median age of 60 years, with a predominant male representation (80%). Most patients exhibited an Eastern Cooperative Oncology Group (ECOG) performance status of 0–1 (55%), and a significant portion were current or former smokers (61%). Additionally, the majority of patients had nonsquamous carcinoma (93%), and various clinical parameters, such as the number of brain metastatic lesions, presence of central nervous system (CNS) symptoms, and programmed cell death-ligand 1 (PD-L1) expression status, were considered in the analysis.
The key findings revealed that patients in the ICI+Chemo group experienced superior outcomes in terms of median intracranial progression-free survival (iPFS) and systemic PFS (sPFS) compared to those receiving Beva+Chemo. Notably, overall survival (OS) did not significantly differ between the two treatment groups. Subsequent treatments after disease progression were also examined, showing that patients who received immunotherapy throughout the course of treatment demonstrated significantly improved OS compared to those who were immunotherapy-naïve.
In the safety analysis, adverse events (AEs) were reported in both groups, with the most common being neutropenia, thrombocytopenia, and elevated aspartate aminotransferase/alanine aminotransferase (AST/ALT) levels. Two patients in the ICI+Chemo group experienced grade 3 or higher elevated AST/ALT and pneumonia, considered immune-mediated AEs. Notably, both treatment regimens were generally well-tolerated.
Further exploration through subgroup analyses indicated that the benefits of ICI+Chemo were particularly pronounced in specific patient groups, including those with PD-L1-positive expression, those who received locoregional therapy for BMs, and those without CNS symptoms. Cox regression analysis identified better performance status and the use of ICI+Chemo as independent prognostic factors for iPFS.
In summary, this study provides comprehensive insights into the efficacy and safety profile of different first-line treatment approaches in advanced NSCLC patients with BMs lacking targetable driver mutations. The findings contribute valuable information for clinicians in selecting optimal therapeutic strategies for this patient population.
Conclusion
The groundbreaking nature of this study lies in its focus on a critical and underexplored aspect of lung cancer treatment—non-small cell lung cancer (NSCLC) patients with brain metastases (BMs) lacking sensitizing mutations. Lung cancer, particularly NSCLC, stands as a significant global health concern, and the prevalence of BMs in NSCLC patients poses unique challenges, often leading to poor prognosis. This study addresses the dearth of specific clinical data for this patient subgroup, shedding light on optimal treatment strategies.
The research, conducted at Sun Yat-Sen University Cancer Center, delves into the comparison of two frontline treatment approaches—immunotherapy plus chemotherapy (ICI+Chemo) and bevacizumab plus chemotherapy (Beva+Chemo). The study’s focus on PD-L1-positive NSCLC patients with BMs adds a nuanced layer, considering the importance of personalized treatment in the era of precision medicine.
The findings of the study resonate with the broader landscape of lung cancer treatment. Notably, ICI+Chemo emerges as a powerful contender, significantly extending intracranial progression-free survival (iPFS) and reducing the risk of systemic disease progression when juxtaposed with Beva+Chemo. The importance of immunotherapy is underscored by the clear OS benefit observed in patients who received immunotherapy throughout their treatment course, compared to those who did not.
Beyond clinical outcomes, the study engages with the biological complexities of brain metastases. It challenges the conventional notion of the brain as an “immune-privileged” organ due to the presence of the blood-brain barrier. The hypothesis that BMs might disrupt this barrier, allowing immune cells and therapeutic antibodies to migrate into the brain, adds a layer of understanding to the intricate interplay between the immune system and brain metastatic lesions.
Comparisons with meta-analyses bring forth the unique challenges posed by BMs in traditional clinical trial settings. The study emphasizes the need for specific investigations tailored to this patient population, highlighting the inadequacy of extrapolating findings from studies excluding NSCLC patients with BMs.
Subgroup analyses further enrich the narrative by pinpointing specific cohorts that derive significant benefits from ICI+Chemo. PD-L1-positive expression, receipt of locoregional therapy for BMs, and absence of central nervous system (CNS) symptoms emerge as key factors associated with improved outcomes. This granularity in analysis not only provides clinicians with valuable insights for treatment decision-making but also lays the groundwork for future research directions.
The study’s recognition of the impact of subsequent treatments on overall survival outcomes introduces a critical nuance to the interpretation of results. Imbalances in subsequent treatment rates between ICI+Chemo and Beva+Chemo groups prompt reflection on the broader treatment landscape and the need for meticulous consideration of treatment sequencing.
Despite the valuable contributions, the study acknowledges its limitations, including its retrospective nature and the relatively modest sample size. This humility underscores the necessity for further validation through larger cohorts and potentially sets the stage for prospective studies to corroborate these findings.
In conclusion, this study not only adds to the growing body of evidence supporting the efficacy of ICI+Chemo in NSCLC but, more crucially, tailors these insights to the unique challenges posed by brain metastases. By emphasizing the significance of immunotherapy and delineating specific patient subsets that stand to gain the most, the study paves the way for more personalized and effective treatment approaches for NSCLC patients with BMs lacking sensitizing mutations.
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