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Impact of clinicopathological features on the efficacy of immune checkpoint inhibitors plus conventional treatment in patients with advanced lung cancer.

ABSTRACT: Background:To investigate the impact of different immune checkpoint inhibitors (ICI), programmed-death ligand 1 (PD-L1) expression and clinical characteristics on clinical outcome of ICI plus conventional treatment in advanced lung cancer patients. Methods:Randomized clinical trials that compared combination therapy versus control group were screened in PubMed, EMBASE, Web of Science, Cochrane Library and included. The pooled hazard ratio (HR) with a 95% confidence interval (95% CI) were used to estimate associations. Cochrane Collaboration tool was used for quality assessment. Results:Thirteen clinical trials were included (n=9,241). The pooled results indicated that combination strategy based on ICI significantly improved PFS (HR =0.66, P<0.001) and OS (HR =0.77, P<0.001) in overall population. Greatest PFS improvement was seen in group of PD-1 based combination (HR =0.54, P<0.001), followed by PD-L1 based (HR =0.66, P<0.001) and CTLA-4 based combination (HR =0.86, P=0.002) (interaction: P<0.001).The improvement in PFS did proportionally differ by PD-L1 expression (interaction: P<0.001). OS HRs favored combination in patients with negative or strong positive group of PD-L1 expression not in the group of weak positive group (HR =0.77, P=0.12). Subgroup analysis demonstrated that OS benefit could be observed in male (HR =0.82, P=0.03), current or former smokers (HR =0.74, P=0.04), non-squamous (HR =0.71, P<0.001) and patients without driver mutations (HR =0.73, P<0.001). OS benefit rather than PFS benefit was appeared in patients with liver metastasis treated with ICI-based combination (HR =0.74, P=0.005). Conclusions:ICI plus conventional treatment could significantly improve PFS and OS in overall advanced lung cancer patients. PD-1-based combination leads to the greatest improvement in both PFS and OS. More data are warranted to address the association of PD-L1 staining intensity with OS improvement. Male, current or former smokers, non-squamous and patients without driver mutations do benefit from ICI-based combination.

SUBMITTER: Gao G

PROVIDER: S-EPMC6790436 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Impact of clinicopathological features on the efficacy of immune checkpoint inhibitors plus conventional treatment in patients with advanced lung cancer.

Gao Guanghui G Qiao Meng M Liu Hongcheng H Jiang Tao T Zhou Fei F Li Xuefei X Zhao Chao C Chen Xiaoxia X Su Chunxia C Ren Shengxiang S Zhou Caicun C

Journal of thoracic disease 20190901 9

<h4>Background</h4>To investigate the impact of different immune checkpoint inhibitors (ICI), programmed-death ligand 1 (PD-L1) expression and clinical characteristics on clinical outcome of ICI plus conventional treatment in advanced lung cancer patients.<h4>Methods</h4>Randomized clinical trials that compared combination therapy versus control group were screened in PubMed, EMBASE, Web of Science, Cochrane Library and included. The pooled hazard ratio (HR) with a 95% confidence interval (95% C ...[more]

PMID: 31656652

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Project description:BackgroundHistorically, tumor burden has been considered an impediment to efficacy of immunotherapeutic agents, including vaccines, stem cell transplant, cytokine therapy, and intravesical bacillus Calmette-Guérin. This effect has been attributed to hypoxic zones in the tumor core contributing to poor T-cell infiltration, formation of immunosuppressive stromal cells, and development of therapy-resistant cell populations. However, the association between tumor burden and efficacy of immune checkpoint inhibitors is unknown. We sought to determine the association between radiographic tumor burden parameters and efficacy of immune checkpoint inhibitors in advanced lung cancer.Materials and methodsWe performed a retrospective analysis of patients with advanced lung cancer treated with immune checkpoint inhibitors. Demographic, disease, and treatment data were collected. Serial tumor dimensions were recorded according to RECIST version 1.1. Associations between radiographic tumor burden (baseline sum of longest diameters, longest single diameter) and clinical outcomes (radiographic response, progression-free survival, and overall survival) were determined using log-rank tests, Cox proportional-hazard regression, and logistic regression.ResultsAmong 105 patients, the median baseline sum of longest diameters (BSLD) was 6.4 cm; median longest single diameter was 3.6 cm. BSLD was not associated with best radiographic, progression-free survival, or overall survival. In univariate and multivariate analyses, no significant associations were observed for the other radiographic parameters and outcomes when considered as categorical or continuous variables.ConclusionAlthough tumor burden has been considered a mediator of efficacy of earlier immunotherapies, in advanced lung cancer it does not appear to affect outcomes from immune checkpoint inhibitors.Implications for practiceHistorically, tumor burden has been considered an impediment to the efficacy of various immunotherapies, including vaccines, cytokines, allogeneic stem cell transplant, and intravesical bacillus Calmette-Guérin. However, in the present study, no association was found between tumor burden and efficacy (response rate, progression-free survival, overall survival) of immune checkpoint inhibitors in advanced lung cancer. These findings suggest that immune checkpoint inhibitors may provide benefit across a range of disease burden, including bulky tumors considered resistant to other categories of immunotherapy.

Project description:BackgroundAlthough predictive value of immune-related adverse events (irAEs) induced by immune checkpoint inhibitors (ICIs) have been suggested by several studies, their assessments were insufficient because patients were categorized only by the occurrence of irAEs. It has not been elucidated whether irAEs also play a significant role even in responders.Materials and methodsBetween December 2015 and September 2018, 106 patients with advanced non-small cell lung cancer treated with ICIs were enrolled in our prospective biomarker study. Twenty-three of these were responders, defined as those with complete or partial response. We investigated the proportion of irAEs among overall and responders. For responders, progression-free survival (PFS) and overall survival of ICIs were compared between those with and without irAEs. As an exploratory analysis, we measured 41 proteins from peripheral blood before and after ICI treatment.ResultsThe proportion of irAEs was significantly higher in responders than nonresponders (65.2% vs. 19.3%, p < .01). Among responders, clinical characteristics did not differ regardless of the occurrence of irAEs. However, there was a significant difference in PFS among responders (irAE group 19.1 months vs. non-irAE group 5.6 months; hazard ratio: 0.30 [95% confidence interval: 0.10-0.85]; p = .02). Of 41 protein analyses, fibroblast growth factor-2 at baseline and monocyte chemoattractant protein fold change showed significant differences between them (p < .04).ConclusionAlthough this is a small sample-sized study, irAE might be a predictive factor of durable efficacy, even in patients who responded to ICIs. Investigation into the significance of irAEs in responders will contribute to the establishment of optimal administration of ICI.Implications for practiceAlthough the predictive value of immune-related adverse events (irAEs) induced by immune checkpoint inhibitors (ICIs) has been suggested by several studies, it has not been elucidated whether irAEs also play a significant role even in responders. This study showed that more than 60% of responders had irAEs. It demonstrated the strong correlation between irAEs and efficacy even in responders. Investigation into the significance of irAEs in responders will contribute to the establishment of optimal administration of ICI.

Dataset Information

Impact of clinicopathological features on the efficacy of immune checkpoint inhibitors plus conventional treatment in patients with advanced lung cancer.

Publications

Impact of clinicopathological features on the efficacy of immune checkpoint inhibitors plus conventional treatment in patients with advanced lung cancer.

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