Clinical and Molecular Correlates of Tumor Mutation Burden in Non-Small Cell Lung Cancer

Sharpnack, Michael F.; Cho, Ju Hwan; Johnson, Travis; Shields, Peter G.; Huang, Kun; Carbone, David P.; He, Kai

doi:10.1016/j.lungcan.2020.05.021

Cited by 13 publications

(17 citation statements)

References 26 publications

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“…In this way, the efficacy of EGFR‐TKIs might decrease due to the decreased exposure in smokers than never‐smokers. What is more, the tumour mutation burden was negatively correlated with the efficacy of EGFR‐TKI 33 while smoking displays a strong correlation with increased tumour mutational burden 34,35 . In this way, the efficacy of EGFR‐TKI might decrease in smoking patients.…”

Section: Discussionmentioning

confidence: 96%

The impact of smoking status on the progression‐free survival of non‐small cell lung cancer patients receiving molecularly target therapy or immunotherapy versus chemotherapy: A meta‐analysis

Huang

Xie

et al. 2020

J Clin Pharm Ther

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What is known and Objective Smoking has a notable influence on the efficacy of medications for lung cancer. Previous studies illustrated the correlation between smoking and the efficacy of first‐line Epidermal Growth Factor Receptors‐Tyrosine Kinase Inhibitors (EGFR‐TKIs). The benefit of smokers in immunotherapy was still controversial. Here, we investigated the impact of smoking on clinical outcomes of molecularly targeted therapies or immunotherapy in Non‐Small Cell Lung Cancer (NSCLC). Methods We performed meta‐analysis including trials comparing EGFR‐TKIs, Anaplastic Lymphoma Kinase (ALK) inhibitors or Immune Checkpoint Inhibitors (ICIs) against chemotherapy in NSCLC. The Progression‐Free Survival (PFS)‐Hazard Ratios (HRs) of two groups served as the index and we used random effects to pool outcomes. Results and discussion Twenty randomized trials were selected. Compared with chemotherapy, treatment with EGFR‐TKIs had similar benefit in never‐smokers (PFS: HR = 0.46, 95% CI 0.30 to 0.69) and smokers (PFS: HR = 0.68, 95% CI 0.50 to 0.91; p = 0.135) while non‐smokers (PFS: HR = 0.32, 95% CI 0.23 to 0.44) had better benefit from first‐line EGFR‐TKIs than smokers (PFS: HR = 0.54, 95% CI 0.41 to 0.71; p = 0.02). Treatment with ALK inhibitors had similar benefits in never‐smokers (PFS: HR = 0.43, 95% CI 0.35 to 0.53) and smokers (PFS: HR = 0.56, 95% CI 0.44 to 0.71; p = 0.406). The benefit of ICIs in smokers (PFS: HR = 0.79, 95% CI 0.64 to 0.98) was significantly greater than never‐smokers (PFS: HR = 1.81, 95% CI 1.27 to 2.57; p = 0.004). What is new and Conclusion Smoking status is an important clinical predictor of therapy in NSCLC. Never‐smokers and smokers have similar benefit with EGFR‐TKIs therapy compared with chemotherapy, while never‐smokers have greater benefit after first‐line EGFR‐TKIs therapy. There was similar benefit in never‐smokers and smokers when using ALK inhibitors over chemotherapy. Additionally, ICIs treatment over chemotherapy leads to more favourable PFS in smokers both in first‐line and second‐line settings.

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Section: Discussionmentioning

confidence: 96%

The impact of smoking status on the progression‐free survival of non‐small cell lung cancer patients receiving molecularly target therapy or immunotherapy versus chemotherapy: A meta‐analysis

Huang

Xie

et al. 2020

J Clin Pharm Ther

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“…The next logical question is why does a smoking history contribute to a better response to immunotherapy. The first and most obvious explanation is the correlation between smoking and TMB ( 47 ). TMB is another widely accepted biomarker for predicting the immunotherapy response among patients ( 48 ).…”

Section: Discussionmentioning

confidence: 99%

Impact of Smoking History on Response to Immunotherapy in Non-Small-Cell Lung Cancer: A Systematic Review and Meta-Analysis

et al. 2021

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ObjectivesTo evaluate the impact of smoking history on the clinical benefit of immunotherapy in patients with non-small cell lung cancer (NSCLC).MethodsTwenty-three randomized clinical trials and seven real-world studies were included in this meta-analysis. Hazard ratios (HRs) and 95% confidence intervals (CIs) for overall survival (OS) and progression-free survival (PFS) and odds ratios for the overall response rate (ORR) were extracted. A fixed-effects or random-effects model was applied to obtain pooled estimates.ResultsData from 16 high-quality trials involving 10,643 NSCLC patients receiving either immunotherapy or chemotherapy/placebo enabled direct comparison of the survival impact of smoking. Anti-PD-1/PD-L1/CTLA-4 immunotherapy was found to significantly prolong OS and PFS as compared to chemotherapy/placebo in smokers (HR for OS, 0.76 [0.69–0.83], P<0.00001; HR for PFS, 0.65 [0.56–0.75], P<0.00001), and these trends were less or not significant in non-smokers (HR for OS, 0.91 [0.78–1.06], P=0.25; HR for PFS, 0.68 [0.45–1.03], P=0.07). Consistent results were obtained for the first-line or second/third-line use of immunotherapy and for non-squamous NSCLC patients only. Furthermore, the data from 7 trials and 7 real-world studies involving 4,777 patients receiving immunotherapy allowed direct comparison of therapeutic outcomes between smokers and non-smokers. Prolonged OS (HR 0.86 [0.75–0.99], P=0.04) and PFS (HR 0.69 [0.60–0.81], P<0.0001) and a higher response rate (ORR 1.20 [0.94–1.53], P=0.15) were observed in smokers compared to non-smokers receiving immunotherapy.ConclusionsImmunotherapy was found to have a greater benefit in NSCLC patients with a smoking history than in those who had never smoked.

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“…In the clinical treatment of advanced NSCLC, ICI targeting PD1/PD‐L1 has made rapid progress, 17 PD1/PD‐L1 inhibitor monotherapy or combination therapy with chemotherapy/antiangiogenic therapy has become one of the main treatment especially for NSCLC patients without the presence of driver gene mutation 18 . However, currently there is no effective biomarkers for the efficacy prediction of combination immunotherapy, and the relationship between TMB and smoking status in NSCLC is controversial 11,19 . In this study, we retrospectively recruited 711 cases NSCLC patients who received two different NGS panel tests to analyze the relationship between TMB and smoking status, and we further evaluated the efficacy predictive value of smoking status and TMB in 90 cases NSCLC patients who received ICI therapy combined with chemotherapy/anti‐angiogenesis therapy.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, the TMB value in smoking patients is supposed to be increased 24 . However, the correlation between the smoking index and the TMB value of NSCLC patients is still controversial 11 . Previous studies have shown that smoking patients receiving ICI monotherapy have better response rates and PFS than non‐smokers, but there is no difference in overall survival between two groups 25 .…”

Section: Discussionmentioning

confidence: 99%

“…Smoking is well known as the primary cause of NSCLC 10 . However, the correlation between smoking history and TMB is still contentious, and its role in efficacy prediction in ICI treatment of NSCLC needs additional study as well 11,12 . One study showed that NSCLC patients who smoked could benefit more from second‐line immunotherapy than non‐smoking patients after resistance to first‐line targeted therapy 13 .…”

Section: Introductionmentioning

confidence: 99%

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Smoking status combined with tumor mutational burden as a prognosis predictor for combination immune checkpoint inhibitor therapy in non‐small cell lung cancer

et al. 2021

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Background This study aimed to explore the prognostic value of tumor mutational burden (TMB) combined with smoking status in advanced non‐small cell lung cancer (NSCLC) patients who received immune checkpoint inhibitor therapy (anti PD‐1/PD‐L1 therapy) combined with chemotherapy or anti‐angiogenesis therapy. Methods We conducted a retrospective analysis of NSCLC patients who underwent next‐generation sequencing test (either 295‐gene panel NGS or 1021‐gene panel NGS) from September 2017 to November 2020. The relationship between TMB and smoking status was investigated. Kaplan–Meier survival analysis was used to compare progression‐free survival (PFS) of the NSCLC patients who received combination immunotherapy grouped by TMB value and smoking status. Results We enrolled 323 cases and 388 cases of NSCLC patients in the 295‐gene panel cohort and 1021‐gene panel cohort, respectively. Positive correlation between TMB and smoking status was found in lung adenocarcinoma, but not in lung squamous cell carcinoma. Participants with both high TMB and smoking status who received immune checkpoint therapy combined with chemotherapy or anti‐angiogenesis therapy had longer PFS than other participants (p < 0.05). Conclusions The combination of TMB with smoking status might be a potential predictor for the efficacy of combination immunotherapy in advanced NSCLC.

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Clinical and Molecular Correlates of Tumor Mutation Burden in Non-Small Cell Lung Cancer

Cited by 13 publications

References 26 publications

The impact of smoking status on the progression‐free survival of non‐small cell lung cancer patients receiving molecularly target therapy or immunotherapy versus chemotherapy: A meta‐analysis

The impact of smoking status on the progression‐free survival of non‐small cell lung cancer patients receiving molecularly target therapy or immunotherapy versus chemotherapy: A meta‐analysis

Impact of Smoking History on Response to Immunotherapy in Non-Small-Cell Lung Cancer: A Systematic Review and Meta-Analysis

Smoking status combined with tumor mutational burden as a prognosis predictor for combination immune checkpoint inhibitor therapy in non‐small cell lung cancer

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