Impact of smoking status on the relative efficacy of the EGFR TKI/angiogenesis inhibitor combination therapy in advanced NSCLC—a systematic review and meta-analysis

Dafni, Urania; Soo, Ross A.; Peters, Solange; Tsourti, Zoi; Zygoura, Panagiota; Vervita, Katerina; Han, Ji‐Youn; Castro, Javier de; Coate, Linda; Früh, Martin; Hashemi, S.; Nadal, Ernest; Carcereny, Enric; Sala, María; Bernabé, R.; Provencio, Mariano; Cuffe, Sinéad; Roschitzki-Voser, Heidi; Ruepp, Barbara; Rosell, Rafael; Stahel, Rolf A.

doi:10.1016/j.esmoop.2022.100507

Cited by 8 publications

(5 citation statements)

References 32 publications

(47 reference statements)

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“…The finding is echoed with the same subgroup analyses in the study of Deng et al, 2021 . In addition, we found that combination bevacizumab and EGFR-TKI therapy significantly improved the PFS and OS result in smokers rather than those who never smoked, which is in line with the findings of Dafni et al, 2022 . One possible explanation of this phenomenon is that TP53 mutation triggered by cigarette exposure would lead to increased sensitivity to anti-VEGF therapy ( Schwaederlé et al, 2015 ).…”

Section: Discussionsupporting

confidence: 89%

“…Subgroup analyses showed that the PFS benefit was consistently observed in EGFR-mutant advanced NSCLC patients of different gender (male or female), patients with different ECOG PS (0 or 1), baseline CNS metastasis (presence or absence) and EGFR mutation type (19del or 21L858R). The finding is echoed with the same subgroup analyses in the study of Deng et al, 2021. In addition, we Frontiers in Pharmacology frontiersin.org found that combination bevacizumab and EGFR-TKI therapy significantly improved the PFS and OS result in smokers rather than those who never smoked, which is in line with the findings of Dafni et al, 2022. One possible explanation of this phenomenon is that TP53 mutation triggered by cigarette exposure would lead to increased sensitivity to anti-VEGF therapy (Schwaederlé et al, 2015). Moreover, we also noticed a significantly improved PFS in patients younger than 75 years old, as compared with those aged equal or more than 75 years.…”

Section: Discussionsupporting

confidence: 79%

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Addition of bevacizumab to EGFR tyrosine kinase inhibitors in advanced NSCLC: an updated systematic review and meta-analysis

Zheng,

Qin,

Zheng

et al. 2024

Front. Pharmacol.

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Background: The synergistic effects of antiangiogenic inhibitor bevacizumab and epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKI) therapy were encouraging in patients with EGFR-mutant advanced NSCLC, though some controversy remains. The specific subgroup of patients who might benefit most from the EGFR-TKI and bevacizumab combination therapy is yet to be determined.Methods: Randomized clinical trials (RCTs) that had compared the clinical efficacy of EGFR-TKI and bevacizumab combination therapy with EGFR-TKI monotherapy in treating EGFR-mutant advanced NSCLC patients published before 23 December 2022 were searched in the Cochrane, PubMed and Embase. We performed a meta-analysis for the overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and treatment-related adverse events with a grade equal or more than 3 (grade≥3 TRAEs). Subgroup analyses of PFS and OS stratified by clinical characteristics and treatment were conducted.Results: We included 10 RCTs involving 1520 patients. Compared with EGFR-TKI monotherapy, addition of bevacizumab to EGFR-TKI resulted in a significantly higher PFS (hazard ratio (HR) = 0.74, 95% confidence interval (95% CI): 0.62–0.87)) and ORR (risk ratio (RR) = 1.07, 95% CI: 1.01–1.13). However, no significant difference in OS (HR = 0.96, 95% CI: 0.83–1.12) was noticed. Patients with EGFR-mutant advanced NSCLC receiving combination therapy showed PFS improvement regardless of gender (male or female), Eastern Cooperative Oncology Group performance status (0 or 1), baseline central nervous system (CNS) metastasis (presence or absence) and EGFR mutation type (19del or 21L858R). Subgroup analyses showed that, with the treatment of bevacizumab and EGFR-TKI, patients who ever smoked achieved significantly better OS and PFS benefits (HR = 0.68, 95% CI: 0.48–0.95; HR = 0.59, 95% CI: 0.46–0.74, respectively), and those aged <75 years and the Asian population had significantly prolonged PFS (HR = 0.69, 95% CI: 0.52–0.91; HR = 0.71, 95% CI: 0.58–0.87; respectively). The superiority of EGFR-TKI and bevacizumab combination therapy against EGFR-TKI monotherapy in improving PFS was more significant in the erlotinib regimen subgroup. The risk of grade≥3 TRAEs was remarkably higher in the combination therapy group (HR = 1.73, 95% CI: 1.39–2.16).Conclusion: Addition of bevacizumab to EGFR-TKI therapy provided significantly better PFS and ORR for EGFR-mutant advanced NSCLC patients, though with higher risk of grade≥3 TRAEs. Patients who ever smoked, aged <75 years, and Asian population might benefit more from the combination regimen.Systematic Review Registration: This systematic review and meta-analysis was registered in the PROSPERO database (CRD42023401926)

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Section: Discussionsupporting

confidence: 89%

Section: Discussionsupporting

confidence: 79%

Addition of bevacizumab to EGFR tyrosine kinase inhibitors in advanced NSCLC: an updated systematic review and meta-analysis

Zheng,

Qin,

Zheng

et al. 2024

Front. Pharmacol.

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“…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.…”

Section: Discussionmentioning

confidence: 99%

“… 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.…”

Section: Introductionmentioning

confidence: 99%

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

Zhou,

Guo,

et al. 2024

Ther Adv Med Oncol

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Background: Frequent failures observed in some trials comparing the efficacy and safety of osimertinib plus bevacizumab to osimertinib monotherapy in advanced non-small-cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) alterations have brought questions. Objectives: To evaluate the efficacy and safety of these two treatment regimens in advanced NSCLC patients harboring EGFR mutations. Design: This study is a systematic review and meta-analysis. Data sources and methods: PubMed, Embase, Cochrane Library, Web of Science, CNKI, Wanfang, and VIP databases were extensively searched for relevant randomized controlled trials (RCTs) on 14 May 2023. Two researchers independently screened the literature, assessed quality, and extracted data. The primary outcomes were progression-free survival (PFS), overall survival (OS), and objective response rate (ORR). The secondary outcomes were adverse events (AEs) and PFS stratified by patients’ characteristics. STATA 17.0 software (StataCorp LLC, USA) was adopted for meta-analysis. Results: A total of four RCTs involving 390 patients were included. Overall, the risk of bias across the studies was moderate to low. Pooled results showed that compared to osimertinib alone, the addition of bevacizumab to osimertinib failed to show prolongation of PFS [hazard ratio (HR) = 1.00, 95% confidence interval (CI): 0.78–1.27], OS (HR = 1.01, 95% CI: 0.73–1.41), or improvement of the ORR (risk ratio = 1.12, 95% CI: 0.90–1.38), while an increased incidence of some AEs was observed, such as nausea, oral mucositis, hypertension, and proteinuria. Notably, combination treatment did significantly prolong the PFS in the subset of smokers (HR = 0.64, 95% CI: 0.44–0.94). A mild trend toward PFS benefit under the combined regimen was also noted in patients with brain metastases and first-line treatment, though not reaching statistical significance. Conclusion: Based on the available evidence, the addition of bevacizumab to osimertinib could not provide additional survival benefits with higher but manageable toxicity for EGFR-mutant NSCLC patients. Osimertinib monotherapy remains the prioritized treatment. Further investigation is warranted.

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“… 44 Also, the effect might be affected by for example baseline TP53 co-mutation or smoking status. 42 , 45 Another study showed that addition of chemotherapy to gefitinib enhanced OS in patients with del19, whereas this was not significant for L858R, at cost of a higher rate of grade ≥3 treatment-related adverse events. 46 The results of the addition of immune checkpoint inhibition to TKI treatment are disappointing.…”

Section: Discussionmentioning

confidence: 99%

Overall survival in advanced epidermal growth factor receptor mutated non-small cell lung cancer using different tyrosine kinase inhibitors in The Netherlands: a retrospective, nationwide registry study

Gijtenbeek

Damhuis

Wekken

et al. 2023

The Lancet Regional Health - Europe

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Impact of smoking status on the relative efficacy of the EGFR TKI/angiogenesis inhibitor combination therapy in advanced NSCLC—a systematic review and meta-analysis

Cited by 8 publications

References 32 publications

Addition of bevacizumab to EGFR tyrosine kinase inhibitors in advanced NSCLC: an updated systematic review and meta-analysis

Addition of bevacizumab to EGFR tyrosine kinase inhibitors in advanced NSCLC: an updated systematic review and meta-analysis

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

Overall survival in advanced epidermal growth factor receptor mutated non-small cell lung cancer using different tyrosine kinase inhibitors in The Netherlands: a retrospective, nationwide registry study

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