Predictors of Survival Benefit From Immune Checkpoint Inhibitors in Patients With Advanced Non–small-cell Lung Cancer: A Systematic Review and Meta-analysis

Raphael, Jacques; Batra, Anupam; Boldt, Gabriel; Shah, Prakesh S.; Blanchette, Phillip; Rodrigues, George; Vincent, Mark

doi:10.1016/j.cllc.2019.11.004

Cited by 24 publications

(19 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Patients who are heavy smokers have better PFS (progression-free survival) and DOR (duration of response) in the treatment of PD-1 ( Gainor et al, 2020 ). Several meta-analyses also show that previous or current smokers are more likely to benefit from treatment with ICIs than non-smokers ( El-Osta and Jafri, 2019 ; Raphael et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

The Effect of Smoking on the Immune Microenvironment and Immunogenicity and Its Relationship With the Prognosis of Immune Checkpoint Inhibitors in Non-small Cell Lung Cancer

Sun

Yang

Shen

et al. 2021

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

Background: The emergence of immune checkpoint inhibitors (ICIs) has opened a new chapter for the treatment of non-small cell lung cancer (NSCLC), and the best beneficiaries of ICI treatment are still being explored. Smoking status has been repeatedly confirmed to affect the efficacy of ICIs in NSCLC patients, but the specific mechanism is still unclear.Methods: We performed analysis on the Memorial Sloan Kettering Cancer Center (MSKCC) clinical NSCLC cohort receiving ICI treatment, The Cancer Genome Atlas (TCGA) Pan-Lung Cancer cohort, and Gene Expression Omnibus (GEO) database GSE41271 lung cancer cohort that did not receive ICI treatment, including survival prognosis, gene mutation, copy number variation, immunogenicity, and immune microenvironment, and explored the impact of smoking status on the prognosis of NSCLC patients treated with ICIs and possible mechanism. In addition, 8 fresh NSCLC surgical tissue samples were collected for mass cytometry (CyTOF) experiments to further characterize the immune characteristics and verify the mechanism.Result: Through the analysis of the clinical data of the NSCLC cohort treated with ICIs in MSKCC, it was found that the smokers in NSCLC receiving ICI treatment had a longer progression-free survival (HR: 0.69, 95% CI: 0.49–0.97, p = 0.031) than those who never smoked. Further analysis of the TCGA and GEO validation cohorts found that the differences in prognosis between different groups may be related to the smoking group’s higher immunogenicity, higher gene mutations, and stronger immune microenvironment. The results of the CyTOF experiment further found that the immune microenvironment of smoking group was characterized by higher expression of immune positive regulatory chemokine, and higher abundance of immune activated cells, including follicular helper CD4+ T cells, gamma delta CD4+ T cells, activated DC, and activated CD8+ T cells. In contrast, the immune microenvironment of non-smoking group was significantly enriched for immunosuppressive related cells, including regulatory T cells and M2 macrophages. Finally, we also found highly enriched CD45RAhighCD4+ T cells and CD45RAhighCD8+ T cells in the non-smoking group.Conclusion: Our research results suggest that among NSCLC patients receiving ICI treatment, the stronger immunogenicity and activated immune microenvironment of the smoking group make their prognosis better.

show abstract

Section: Introductionmentioning

confidence: 99%

The Effect of Smoking on the Immune Microenvironment and Immunogenicity and Its Relationship With the Prognosis of Immune Checkpoint Inhibitors in Non-small Cell Lung Cancer

Sun

Yang

Shen

et al. 2021

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

show abstract

“…Small cell lung cancer (SCLC) has become one of the most malignant and deadly cancers around the world, with more than 30 000 newly diagnosed cases in the USA annually [ 1–3 ]. The heterogeneity and diversity of tumor cells composed of SCLC lead to the frequent acquirement of radiotherapy resistance and poor prognosis, with an estimated 5-year survival rate of <7% in North America [ 4 , 5 ].…”

Section: Introductionmentioning

confidence: 99%

hTERT promoter methylation promotes small cell lung cancer progression and radiotherapy resistance

Zhai

Zheng

et al. 2020

Journal of Radiation Research

View full text Add to dashboard Cite

Small cell lung cancer (SCLC) has been a devastating actuality in clinic and the molecular mechanisms underlying this disease remain unclear. The epigenetic alterations located in the promoter region of human telomerase reverse transcriptase (hTERT) have been demonstrated as one of the most prevalent non-coding genomic modifications in multiple cancers. However, alteration of hTERT promoter methylation in SCLC and the subsequently induced change in tumor cell behavior remains unclear. In this research, we hypothesized that abnormal methylation of hTERT promotor enhanced the progression of SCLC and the outcome of radiotherapy resistance. Quantitative real-time PCR and western blot assays were performed to evaluate the RNA and protein levels of hTERT and enhancer of zeste homolog 2 (EZH2), respectively. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was used to estimate the viability and X-ray sensitivity of H20 and H446 cell lines. Functionally, upregulation of hTERT promoted the proliferation and migration of H20 and H446 cells, and the high-level of methylation in the promoter region of hTERT induced by radiation caused radio-resistance in SCLC. Mechanically, methylation of hTERT promoter enhanced the progression and radio-resistance of SCLC through upregulating the expression of its downstream effector EZH2.

show abstract

“…In previous randomized controlled trials, the clinical benefits of immune checkpoint inhibitors (ICIs) were not significantly better in patients aged 65 or over, and nonsmokers, as compared to placebo or chemotherapy. Recent meta-analyses, pooling all published randomized trials of standard-dose ICIs, showed consistent clinical benefits among elderly and non-elderly patients [ 31 ]. However, ICIs might be less effective in nonsmokers at the standard dose, and lower dosing of ICIs might worsen clinical outcomes.…”

Section: Discussionmentioning

confidence: 99%

Comparative Effectiveness and Safety of Standard-Dose and Low-Dose Pembrolizumab in Patients with Non-Small-Cell Lung Cancer: A Multi-Institutional Cohort Study in Taiwan

Chang

Shao

Chen

et al. 2022

Cancers

View full text Add to dashboard Cite

Fixed doses at 200 mg of pembrolizumab or 2 mg/kg every 3 weeks are the standard dosages for first- and second-line treatment of non-small-cell lung cancer (NSCLC); however, in clinical practice, patients with NSCLC may receive lower doses of pembrolizumab due to drug product availability or economic factors. To date, the comparative effectiveness and safety of the standard dose and lower doses of pembrolizumab in these patients still remains limited. We conducted a retrospective cohort study by analyzing electronic medical records data from the largest multi-institutional hospital system in Taiwan. Advanced NSCLC patients newly receiving pembrolizumab with or without chemotherapy were included. Patients were classified into: (1) the standard-dose group (≥2 mg/kg), and (2) the low-dose group (<2 mg/kg). We applied inverse probability of treatment weighting (IPTW) to compare the overall survival (OS) and immune-related adverse events (irAEs) between the two treatment groups, and to evaluate the minimum clinically effective dose of pembrolizumab. We included a total of 147 NSCLC patients receiving standard-dose pembrolizumab (mean [range] age: 63.7 [58.0–73.0] years; male: 62.6%; mean [range] body weight: 60.5 [58.0–73.0] kg) and 95 patients receiving low-dose pembrolizumab (mean [range] age: 62.0 [50.0–68.8] years; male: 64.2%; mean [range] body weight: 63.9 [55.0–73.8] kg). After IPTW adjustments, the median OS was similar for both the standard-dose and low-dose pembrolizumab groups (19.3 vs. 14.3 months, log-rank p = 0.15). Also, the rate for all classes of irAEs was similar for both groups. We found that patients with a pembrolizumab dose ≥1.8 mg/kg were associated with better OS than those receiving <1.8 mg/kg. Our findings suggested no significant difference in OS and irAEs between patients receiving pembrolizumab ≥2 mg/kg and <2 mg/kg in clinical practice. A pembrolizumab dose ≥1.8 mg/kg may be the clinically most efficient dose.

show abstract

Predictors of Survival Benefit From Immune Checkpoint Inhibitors in Patients With Advanced Non–small-cell Lung Cancer: A Systematic Review and Meta-analysis

Cited by 24 publications

References 20 publications

The Effect of Smoking on the Immune Microenvironment and Immunogenicity and Its Relationship With the Prognosis of Immune Checkpoint Inhibitors in Non-small Cell Lung Cancer

The Effect of Smoking on the Immune Microenvironment and Immunogenicity and Its Relationship With the Prognosis of Immune Checkpoint Inhibitors in Non-small Cell Lung Cancer

hTERT promoter methylation promotes small cell lung cancer progression and radiotherapy resistance

Comparative Effectiveness and Safety of Standard-Dose and Low-Dose Pembrolizumab in Patients with Non-Small-Cell Lung Cancer: A Multi-Institutional Cohort Study in Taiwan

Contact Info

Product

Resources

About