Impact of Smoking Status in Combination Treatment with EGFR Tyrosine Kinase Inhibitors and Anti-Angiogenic Agents in Advanced Non-Small Cell Lung Cancer Harboring Susceptible EGFR Mutations: Systematic Review and Meta-Analysis

Abstract

Patients with advanced non-small cell lung cancer (NSCLC) who harbor susceptible epidermal growth factor receptor (EGFR) mutations and are treated with EGFR tyrosine kinase inhibitors (TKIs) show longer progression-free survival (PFS) than those treated with chemotherapy. However, developed EGFR-TKI resistance limits PFS improvements. Currently, combination treatment with EGFR-TKIs and anti-angiogenic agents is considered a beneficial regimen for advanced-stage NSCLC harboring susceptible EGFR mutations. However, several trials reported osimertinib plus bevacizumab failed to show superior efficacy over osimertinib alone. However, subgroup analysis showed significantly longer PFS among patients with a history of smoking over those who never smoked. We performed a comprehensive systematic review and meta-analysis to evaluate the smoking status impact. At the end of the process, a total of 2068 patients from 11 randomized controlled trials (RCTs) were included in our meta-analysis. Overall, combination EGFR-TKI plus anti-angiogenic agent treatment showed significantly better PFS among patients with a smoking history (Hazard Ratio (HR) = 0.59, 95% confidence interval (CI) = 0.48–0.73). Erlotinib-based combination therapy showed positive PFS benefits regardless of smoking status (HR = 0.54, 95%CI = 0.41–0.71 for ever smoker, HR = 0.69, 95%CI = 0.54–0.87 for never smoker). Combination therapy prolonged PFS significantly regardless of ethnicity (HR: 0.64, 95% CI: 0.44–0.93 for Asian RCTs, HR: 0.55, 95% CI: 0.41–0.74 for global and non-Asian RCTs). PROSPERO registration number is CRD42022304198).

Comparison of osimertinib plus bevacizumab against osimertinib alone in NSCLC harboring EGFR mutations: a systematic review and meta-analysis

“…These findings are in line with conclusions from previous meta-analyses. 13 – 15 The underlying rationale is not yet fully understood. A possible explanation is that TP53 mutations are associated with increased VEGF-A expression, 22 supporting the concept of better efficacy with bevacizumab in tumors with TP53 mutations that are more frequently observed among lung cancer patients with a history of tobacco exposure.…”

“… 10 – 12 Several past meta-analyses have assessed the efficacy of osimertinib plus bevacizumab but they focused only on the smoker population and included other combination regimens. 13 – 15 There is no relevant systematic review yet evaluating the effectiveness and safety of this combination modality. Herein, we performed a systematic review and meta-analysis focusing on the efficacy and safety of osimertinib plus bevacizumab in patients with advanced EGFR-mutated NSCLC.…”

Cumulative antitumor effect of bismuth lipophilic nanoparticles and cetylpyridinium chloride in inhibiting the growth of lung cancer

“…Currently, combination treatment to obtain higher efficacy is a popular strategy to treat LC patients. 31 The combination of amlodipine with the novel anticancer drug gefitinib reduced A549 proliferation by altering the cell cycle. 32 Also, doxorubicin-loaded iron oxide nanoparticles generated excellent results against glioblastoma.…”

Clinical value of peripheral blood circulating tumor DNA in predicting the efficacy of immunotherapy for non-small cell lung cancer

“…Nearly 85% of lung cancer patients have non-small cell lung cancer (NSCLC), among which adenocarcinoma and squamous cell carcinoma are the most common subtypes ( 2 - 4 ). The most common epidemiologically pathogenic factor of lung cancer is smoking ( 5 , 6 ). In the past 20 years, the emergence of multiple targeted therapies and the effective application of immunotherapy in some patients with advanced NSCLC have brought hope to the field of lung cancer treatment ( 7 - 9 ).…”