Targeted combination of Bevacizumab demonstrates superior efficacy for stage IV Adenocarcinoma of the lung with EGFR mutation: A Real World Study

doi:10.21203/rs.3.rs-3238070/v1

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Research Article

Targeted combination of Bevacizumab demonstrates superior efficacy for stage IV Adenocarcinoma of the lung with EGFR mutation: A Real World Study

https://doi.org/10.21203/rs.3.rs-3238070/v1

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Background

Research on bevacizumab combined with EGFR-TKIs is limited to erlotinib, and the NCCN guidelines only recommend erlotinib combined with bevacizumab as a nonfirst-line option. Consequently, To address the real-world efficacy of various treatment regimens, we conducted this study.

Methods

A total of 11,893 patients were screened. The patients were divided into three distinct groups: single targeted group(T), targeted combined chemotherapy group(TC) and targeted combined bevacizumab group(TB), and. The targeted therapy plans encompassed the utilization of first-, second-, and third-generation targeted drugs, namely, Iresa, Ireko, Echtenib, Afatinib, and Osimertinib. The chemotherapy regimen consisted of pemetrexed in combination with platinum, administered in a 21-day cycle for a total of 4–6 cycles. Subsequently, the patients continued receiving targeted drugs until disease progression. Statistical analysis was performed using the R programming language. The survival analysis compared patients treated with the three groups and who received first-generation combined targeted bevacizumab with single T. Subgroup analysis was performed for each factor.

Results

The study included a total of 822 patients, comprising 308 males (36.2%) and 542 females (63.8%), with ages ranging from 26 to 88 years (mean age of 58.9 ± 11.0 years). A total of 591 cases were group T, 152 cases were TC, and 107 cases were TB. The five-year survival of TB (78.5%, 95% CI: 0.625–0.985) was found to be significantly higher than TC (63.1%, 95% CI: 0.54.7-0.728) and T (44.1%, 95% CI: 0.387–0.503). Subgroup analysis revealed that among patients with stage IV adenocarcinoma of the lung with EGFR-sensitive mutations, women (p = 0.05), ≤ 65 years old (p = 0.05), no history of hypertension (p = 0.04), no history of diabetes (p = 0.04), no history of smoking (p = 0.05), smoking index ≤ 200 years (p = 0.04), and no brain metastasis (p = 0.05) who treated with TB experienced a survival advantage. The combination of bevacizumab with first-generation targeted drugs demonstrated superior efficacy compared to first-generation and third-generation targeted drugs (HR = 1.63, 95% CI: 1.47–1.81, p < 0.0001).

Conclusion

In patients diagnosed with stage IV adenocarcinoma of the lung with EGFR-sensitive mutations, TB demonstrates superior efficacy compared to TC and T. Furthermore, the efficacy of first-generation targeting combined with bevacizumab surpasses that of single targeting.

Adenocarcinoma of the lung

stage IV

RGFR mutation

Targeted therapy

EGFR-TKI

Bevacizumab

Chemotherapy

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related mortality, as the majority of stage IV NSCLC patients have a low likelihood of achieving a cure. The pathogenesis of NSCLC is closely linked to the presence of epidermal growth factor receptor (EGFR). Certain subgroups of NSCLC patients, such as women, nonsmokers, East Asians, and those with adenocarcinoma, exhibit higher rates of EGFR mutations, rendering them more responsive to EGFR tyrosine kinase inhibitors (TKIs), such as gefitinib, erlotinib, and afatinib. Consequently, EGFR-TKI therapy plays a crucial role in the management of stage IV NSCLC patients with positive EGFR mutations in a clinical setting[1]. Previous studies [2, 3] have demonstrated that EGFR TKIs, namely, erlotinib, gefitinib, and Ikotinib, exhibit a greater propensity for extending progression-free survival (PFS) in patients diagnosed with EGFR variant-positive NSCLC than conventional chemotherapy. Consequently, the current clinical guidelines, including Chinese society of clinical oncology (CSCO) and National Comprehensive Cancer Network (NCCN), advocate for the administration of EGFR-TKI treatment in EGFR variant-positive NSCLC patients. However, the CSCO guidelines also acknowledge the possibility of recommending alternative protocols, such as targeted combination chemotherapy or targeted combination of bevacizumab, as the category II recommendation. The category II recommendation is supported by a multicenter, prospective randomized controlled phase II clinical study with a small sample size (n = 126 for pemetrexed + gefitinib group and n = 65 for gefitinib group). The study findings indicate that PFS for the two groups is 15.8 vs 10.9 months, with a statistically significant p value of 0.014[4]. Additional reports from the same research team suggest a median survival time of 43.4 vs 36.8 months, although the p value of 0.105 does not reach statistical significance[5]. Nevertheless, this study did not yield any data pertaining to overall survival outcomes. Furthermore, other studies have demonstrated that the combination of chemotherapy and targeted therapy outperforms single targeted therapy in patients with EGFR mutation positivity. Despite this, the estimated survival time (not reached vs. 17 months, p < 0.001) failed to provide significant findings regarding overall survival[6]. Bevacizumab functions as a vascular endothelial factor inhibitor, primarily exerting its antitumor efficacy through the inhibition of angiogenesis mediated by vascular endothelial growth factor receptors 2 (VEGFR2) [7]. This mechanism effectively retards the growth of neovascularization, thereby impeding the supply of oxygen and nutrients to tumors. Additionally, the inhibition of vascular endothelial growth factor (VEGF) signaling can enhance the transportation of cytotoxic drugs by mitigating tumor interstitial fluid pressure and diminishing the presence of nonfunctional tumor blood vessels.

The utilization of a combination of chemotherapy drugs has yielded noteworthy efficacy in the initial treatment of advanced NSCLC. Prior to the introduction of bevacizumab, the median survival duration for patients with advanced lung adenocarcinoma treated solely with chemotherapy was merely 7–8 months [8]. Bevacizumab stands as the pioneering drug to extend patient survival beyond one year when compared to other drugs employed in concurrent combination chemotherapy for advanced lung adenocarcinoma. The E4599 study demonstrated a significant 21% reduction in mortality risk (HR = 0.79, p = 0.003), leading to its approval as a first-line treatment for advanced lung cancer [9]. Numerous studies have also provided evidence supporting the efficacy of bevacizumab in combination with first-line chemotherapy, resulting in improved PFS and overall survival (OS) for patients [10–15]. These findings indicate that bevacizumab, whether used in conjunction with targeted drugs or first-line chemotherapy agents, offers benefits to patients. However, research on bevacizumab combined with EGFR-TKIs is limited to erlotinib, and the NCCN guidelines solely recommend the combination of erlotinib and bevacizumab. To assess the effectiveness of various treatment regimens for patients with EGFR gene mutations, this study was conducted.

This was a retrospective study and involved screening a total of 11,893 patients who were admitted to our hospital between August 2005 and March 2021. Patients with stage IV adenocarcinoma of the lung who received targeted therapy(T), targeted combined chemotherapy (TC), or targeted therapy combined with bevacizumab (TB) were included in the study based on the predefined inclusion criteria. All patients underwent enhanced computed tomography (CT) scans of the chest and abdomen, enhanced magnetic resonance imaging (MRI) scans of the head, bone scans, and other examinations for pretreatment staging evaluation. Assessments of liver and kidney function, cardiac ultrasound, and other examinations were conducted to evaluate the functioning of major organs. Based on the varying treatment plans, the patients were categorized into three groups: targeted combined chemotherapy treatment group, targeted combined bevacizumab group, and simple targeted group. The targeted therapy regimen encompasses the utilization of first-, second-, and third-generation targeted drugs (Iresa, Ireko, Echtinib, Afatinib, and Osimertinib). Conversely, the chemotherapy regimen involves the administration of pemetrexed in conjunction with platinum, with a treatment cycle spanning 21 days and a recommended total of 4–6 cycles. Following this, patients are advised to continue orally taking targeted drugs until disease progression occurs. Subsequently, patients will make an informed decision regarding the subsequent treatment steps and the formulation of a tailored treatment plan, taking into account their individual physical condition. Inclusion criteria encompass the following: 1) The patient exhibits EGFR gene mutation and lacks T790 and exon 20 mutation. 2) The initial treatment of patients adheres to one of three schemes: oral targeted drug therapy or targeted combined chemotherapy (including bevacizumab). 3) Patients who have not undergone radiotherapy are included. Conversely, exclusion criteria consisted of the following: 1) Absence of EGFR mutation or presence of T790 and EGFR20 mutation. 2) The initial treatment of patients does not involve targeted therapy. 3) The patient has received radiotherapy or alternative treatments.

A statistical analysis was performed on the clinicopathological characteristics of the three groups. Categorical variables are presented as totals and percentages. Chi-square or Fisher exact tests were conducted using the R language for the two groups of variables. Kaplan‒Meier survival analysis was performed on the three groups using the "ggsurvplot" package in R. Additionally, hierarchical survival analysis was conducted based on the gene mutation point (exons 19 and 21 and unknown mutations). In addition, we will conduct a comparative analysis of patient survival between those who received a combination of first-generation targeted therapy and bevacizumab and those who received only first-generation or third-generation targeted therapy. This analysis will be performed using the "pairwise_survdiff" package in R, and the results will be presented through subgroup analysis and a forest plot using the "forestplot" package in R. Statistical significance will be determined by a p value of less than 0.05 in the two-tailed test.

A total of 822 patients admitted to our hospital between August 2005 and March 2021 were selected as the study subjects. Among them, 308 (36.2%) were male and 542 (63.8%) were female, with an age range of 26 to 88 years (mean age: 58.9 ± 11.0 years). The treatment modalities included 591 patients receiving simple targeted therapy, 152 patients receiving targeted combined chemotherapy, and 107 patients receiving targeted combined bevacizumab. Further patient information can be found in Table 1. The five-year survival rate of the targeted combined bevacizumab group (78.5%, 95% CI: 0.625–0.985) exhibited a statistically significant increase compared to both the targeted combined chemotherapy group (63.1%, 95% CI: 0.547–0.728) and the simple targeted group (44.1%, 95% CI: 0.387–0.503). Additionally, the targeted combined chemotherapy group demonstrated superior survival rates compared to the simple targeted group (p < 0.0001, HR = 0.701, 95% CI: 0.523–0.939) (Fig. 1). The survival analysis, which focused on the gene mutation site, revealed that patients with 19 exon mutations in the targeted combination with bevacizumab group had a significantly higher 5-year survival rate than patients receiving simple targeted therapy or targeted combination chemotherapy alone (p = 0.0001, HR = 0.814, 95% CI: 0.54–1.225). Additionally, there was no significant difference in survival between the latter two groups (p = 0.29042) (see Fig. 2 and Table 3). Similarly, for patients with 21 favorable exon mutations, the 5-year survival rate in the targeted combined bevacizumab group was significantly higher than that in the other two groups (p < 0.001, HR = 0.648, 95% CI: 0.412–1.019). There was no significant difference observed between the targeted combined chemotherapy group and the single targeted group in terms of statistical analysis (p = 0.0663) (Fig. 2, Table 4). Subgroup analysis revealed that among patients with stage IV adenocarcinoma of the lung with EGFR-sensitive mutations, certain characteristics, such as being female (p = 0.05), being ≤ 65 years old (p = 0.05), having no history of hypertension (p = 0.04), no history of diabetes (p = 0.04), no history of smoking (p = 0.05), having a smoking index ≤ 200 years (p = 0.04), and having no brain metastasis (p = 0.05), were associated with survival benefits when utilizing targeted combined bevacizumab therapy (Fig. 3). The combination of bevacizumab with first-generation targeted drugs demonstrated superior efficacy compared to both third-generation targeted drugs and single-generation targeted drugs (HR = 1.63, 95% CI: 1.47–1.81, p < 0.0001). Furthermore, there was no significant difference in survival between the latter two groups (p = 0.185), as depicted in Table 6 and Fig. 4. Supplement Table 1 showed the incidence of grade 3–4 adverse events of erlotinib combined with bevacizumab in each previous study (Supplement Table 1).

This study conducted a comprehensive examination and analysis of the practical application of targeted therapy for stage IV adenocarcinoma of the lung with EGFR mutation. The findings revealed that the effectiveness of combining targeted therapy with bevacizumab surpassed that of combining targeted therapy with chemotherapy, with statistical significance (p < 0.001). Furthermore, the combined efficacy of targeted therapy and bevacizumab was superior to that of targeted therapy alone. Additionally, when comparing first-generation targeted therapy combined with bevacizumab to third-generation targeted therapy alone, the former exhibited greater efficacy.

Targeted therapy is the primary treatment modality for patients diagnosed with stage IV adenocarcinoma of the lung harboring sensitive mutations, as advocated by both the Chinese Society of Clinical Oncology (CSCO) guidelines and the National Comprehensive Cancer Network (NCCN) guidelines. The CSCO guidelines additionally suggest secondary treatment options such as targeted combined chemotherapy, targeted combined bevacizumab, and chemotherapy combined bevacizumab. Conversely, the NCCN guidelines exclusively recommend targeted therapy as the initial approach or as a subsequent intervention if the disease progresses, followed by appropriate follow-up care. Patients harboring EGFR-sensitive mutations are typically managed with EGFR-TKI monotherapy; however, the development of resistance is nearly inevitable. To counteract acquired drug resistance and enhance PFS, a combination approach involving TKIs and other signaling inhibitors has been employed. Notably, the findings from JO25567 research demonstrated that the inclusion of bevacizumab alongside the EGFR-TKI erlotinib resulted in a 46% reduction in the risk of disease progression compared to erlotinib alone (HR: 0.54, p = 0.015)[16]. According to the findings, the utilization of bevacizumab and erlotinib in combination has been authorized for the management of non-small cell lung cancer characterized by EGFR-sensitive mutations. These findings were further substantiated by two Phase 3 studies (NEJ026 and Artemis) [17, 18], and a recent meta-analysis also provided support for this conclusion [19]. Our research outcomes demonstrate that in real-world scenarios, the efficacy of the targeted combination of bevacizumab surpasses that of targeted combination chemotherapy and targeted drug therapy administered individually, which is in line with the findings of JO25567, NEJ026, and Artemis. In the subgroup analysis of the subforest map, it was observed that significant differences existed only when employing first-generation targeted drugs. Conversely, no statistically significant differences were observed among treatment plans involving second-generation, third-generation, or drugs of unknown generations. Consequently, we conducted a comparative analysis of the survival rates associated with the combination of bevacizumab, a first-generation targeted drug, with single first-generation and single third-generation drugs. The findings indicate that the initial generation targeted combination involving bevacizumab yields superior outcomes compared to the single third generation targeted approach. However, it is noteworthy that the current highest-level guidelines, both domestic and foreign, do not endorse this particular regimen. Consequently, we intend to closely monitor these findings in subsequent research endeavors.

The initial administration of a targeted combination of bevacizumab is not recommended by either domestic or foreign guidelines. This raises the question of whether this recommendation is due to the high occurrence of adverse events, particularly grade 3–4 adverse events. The incidence of grade 3–4 adverse events associated with the use of bevacizumab in combination therapy ranges from 54–88%, which is relatively high. Hypertension, in particular, may be a significant factor influencing the utilization of Bevacizumab. However, some studies suggest that the therapeutic toxicity is still within acceptable limits [20]. In Haruhiro Saito's phase III clinical study, which was open, randomized, and multicenter in nature, it was observed that among the erlotinib bevacizumab group consisting of 112 patients, 98 individuals (88%) experienced grade 3 or more serious adverse events. Similarly, within the erlotinib alone group comprising 114 patients, 53 individuals (46%) encountered such adverse events. The most prevalent grade 3–4 adverse event reported in both groups was rash, with an identical incidence rate. The research findings conducted by Professor Wu Yilong's research group comparing the efficacy of erlotinib in combination with bevacizumab versus erlotinib alone indicate that within the bevacizumab and erlotinib group, 10.2% (16/157) of patients experienced kidney and ureteral complications, leading to discontinuation of bevacizumab. Additionally, 22.9% of patients exhibited hypertension and other adverse events, which warrant particular attention. However, a meta-analysis of 20 phase III clinical trials revealed that bevacizumab has the potential to significantly elevate the risk of hypertension by a factor of 5.28. Moreover, the toxicity associated with hypertension appears to be contingent upon the dosage administered, with a 3.0-fold increase (95% CI: 2.2–4.2; p < 0.001) observed for a dosage of 2.5 mg/kg/week and a 7.5-fold increase (95% CI: 4.2–13.4; p < 0.001) observed for a dosage of 5.0 mg/kg/week[21]. Currently, there have been reports indicating that bevacizumab-induced hypertension is associated with various factors, such as age (≥ 60 years old), body mass index (≥ 25) [22], diabetes or elevated abdominal blood glucose levels, previous or familial history of cardiovascular disease, dyslipidemia, kidney disease, subclinical organ damage, smoking, and other factors [23]. In cases of hypertension induced by bevacizumab, it is advised to initiate antihypertensive treatment, optimize current antihypertensive therapy for improved control, or consider adjunctive pharmacotherapy. Early initiation of antihypertensive therapy has been demonstrated to effectively mitigate complications, including life-threatening encephalopathy cases [24], and prevent or attenuate hypertension during ongoing bevacizumab treatment [25, 26]. In cases where hypertension remains uncontrolled, discontinuation of bevacizumab is advised, while dose reduction is not recommended. Following cessation of the medication, blood pressure typically reverts to pretreatment levels [23]. Currently, there is no specific pharmacological intervention that offers superior control of bevacizumab-induced hypertension. Currently, the utilization of angiotensin enzyme inhibitors in conjunction with other medications is prevalent for the purpose of regulating blood pressure. Several researchers have investigated the mechanism underlying bevacizumab-induced hypertension. Presently, this understanding of the pharmacogenetics associated with bevacizumab-induced hypertension can be employed to explore approaches aimed at enhancing prevention or mitigating this adverse effect [27]. Our findings indicate that among patients lacking hypertension, the targeted combination of bevacizumab yielded superior outcomes compared to the other two groups.

In the subgroup analysis, it was observed that patients with stage IV adenocarcinoma of the lung with EGFR-sensitive mutations who were female (p = 0.05), aged ≤ 65 years (p = 0.05), had no history of hypertension (p = 0.04), no history of diabetes (p = 0.04), no history of smoking (p = 0.05), had a smoking index ≤ 200 years (p = 0.04), and had no brain metastasis (p = 0.05) could potentially benefit from targeted combined therapy with bevacizumab in terms of survival. To ascertain the potential for improved prognosis and reduced risk of adverse events among patients, it is imperative to exclude the subgroup of individuals at high risk. This can be achieved through the utilization of the initial generation targeted combination of bevacizumab. However, the substantiation of this claim necessitates the conduction of prospective, randomized controlled clinical trials.

Limitations: First, it should be noted that this study is characterized by its single-center and observational nature, which raises questions regarding the potential factors contributing to the variations in treatment plan selection. The underlying reasons for these discrepancies remain unclear, and the presence of bias in the selection process cannot be definitively ascertained. Second, it is important to acknowledge that adverse drug events, specifically hypertension, were not encompassed within the scope of this investigation. Third, there were no information after patient progression; Last, it is worth mentioning that this study did not undertake a comparative analysis of progression-free survival or assess the disease control status of the three regimens. Instead, the evaluation solely focused on overall survival after disease progression.

In the case of patients diagnosed with stage IV adenocarcinoma of the lung with EGFR-sensitive mutations, the targeted combination of bevacizumab demonstrates superior efficacy compared to targeted combination chemotherapy and single targeted therapy. Furthermore, the efficacy of first-generation targeting combined with bevacizumab surpasses that of third-generation targeting alone. It is suggested that female patients aged ≤ 65 years, without a history of hypertension or diabetes, no smoking history, a smoking index ≤ 200 years, and no brain metastasis may represent the primary group benefiting from bevacizumab targeting.

NSCLC

Non-small cell lung cancer

EGFR

epidermal growth factor receptor

TKIs

tyrosine kinase inhibitors

PFS

progression-free survival

CSCO

Chinese society of clinical oncology

NCCN

National Comprehensive Cancer Network

VEGFR2

vascular endothelial growth factor receptor 2

VEGFR

vascular endothelial growth factor

overall survival

computed tomography

MRI

magnetic resonance imaging

targeted therapy

targeted combined chemotherapy

targeted therapy combined with bevacizumab

First-TB

first generation target combined bevacizumab

First-T

first generation targeted therapy

Third-T

third generation targeted therapy

Authors' contributions

(I) Conception and design: Yongkui Yu, Wenqun Xing

(II) Administrative support: Yongkui Yu, Wenqun Xing

(III) Provision of study materials or patients:Yongkui Yu, Haomiao Li, Qi Liu, Haibo Ma, Haibo Sun,

(IV) Collection and assembly of data: Yongkui Yu, Lei Xu , Hou-nai Xie, Haomiao Li, Qi Liu, Haibo Ma, Haibo Sun

(V) Data analysis and interpretation:Yongkui Yu, Lei Xu , Hou-nai Xie, Yongfeng Chen

(VI) Manuscript writing: All authors

(VII) Final approval of manuscript: All authors

Funding

None.

Data availability

All the data used to support our results are available in this article. All the data are available from the corresponding author on reasonable request ([email protected]).

Ethics approval and consent to participate

Data were collected after obtaining written informed consent according to the protocols approved by the institutional review boards of the participating institutions under the regulations set forth in the Declaration of Helsinki.

Consent for publication

We didn’t obtain the consent from patients because it is a retrospective study.

Competing interest

The authors have no competing interest to declare.

Acknowledgements

The authors would like to thank the HOME for Researchers for language editing.

Author details

1.Department of Thoracic Surgery, The Affiliated cancer hospital of Zhengzhou University/Henan Cancer Hospital, No. 27 Dongming Road, Zhengzhou, Henan, China, 450008

2.Departments of Thoracic Surgery, Shanghai Chest Hospital , School of Medicine，Shanghai Jiao Tong University, Shanghai, China

3.Department of Thoracic Surgery, Cancer Hospital of the Chinese Academy of Medical Sciences, No. 17 Panjiayuan Nanli, Chaoyang District, Beijing, China 100021

4.Departments of Thoracic Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China

5.Department of Information Center, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, China.

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Table 1

Baseline data of the three groups of patients.
Variable	T (n = 573)	TC (n = 145)	TB (n = 104)	p
sex				0.633
Male	206(36.0%)	57(39.3%)	35(33.7%)
Female	367(64.0%)	88(60.7%)	69(66.3%)
Age(year)				0.001
≤ 65	378(66.0%)	117(80.7%)	78(75.0%)
༞65	195(34.0%)	28(19.3%)	26(25.036.0%)
Hypertension				0.942
No	443(77.3%)	114(78.6%)	81(77.9%)
Yes	130(22.7%)	31(21.4%)	23(22.1%)
Diabetes				0.413
No	522(91.1%)	137(94.5%)	95(91.3%)
Yes	51(8.9%)	8(5.5%)	9(8.7%)
History of smoking				0.471
No	397(69.3%)	106(73.1%)	77(74.0%)
Yes	176(30.7%)	39(26.9%)	27(26.0%)
Smoking index				0.879
≤ 200	486(84.8%)	122(84.1%)	87(83.7%)
200–400	6(1.0%)	3(2.1%)	1(1.0%)
≥ 400	81(14.1%)	20(13.8%)	16(15.4%)
EGFR gene mutations				0.164
19	309(53.9%)	73(50.3%)	44(42.3%)
21	222(38.7%)	62(42.8%)	54(51.9%)
unkonwn mutations	42(7.3%)	10(6.9%)	6(5.8%)
brain metastases				0.101
No	353(61.6%)	94(64.8%)	54(51.9%)
Yes	220(38.4%)	51(35.2%)	50(48.1%)
Targete drugs				< 0.001
First generation	428(74.7%)	117(80.7%)	62(59.6%)
Second generation	22(3.8%)	5(3.4%)	6(5.8%)
Third generation	63(11.0%)	13(9.0%)	27(26.0%)
unkonwn	60(10.5%)	10(6.9%)	9(8.7%)

*T: target therapy; TC: target combined chemotherapy; TB: target combined bevacizumab.

Table 2

Survival analysis of all three groups (p < 0.0001, HR = 0.667, 95% CI: 0.502–0.887).
Group	T	TC	TB
T	-	0.019	1.5e-08
TC	0.019	-	5.4e-05
TB	1.5e-08	5.4e-05	-

T: target therapy; TC: target combined chemotherapy; TB: target combined bevacizumab.

Table 3

Survival differences between the three groups of patients with exon 19 mutations (p = 0.0001, HR = 0.814, 95% CI: 0.54–1.225)
Group	T	TC	TB
T	-	0.29042	7.5e-05
TC	0.29042	-	0.00037
TB	7.5e-05	0.00037	-

T: target therapy; TC: target combined chemotherapy; TB: target combined bevacizumab.

Table 4

Survival differences between the three groups of patients with exon 21 mutations (p < 0.001, HR = 0.648, 95% CI: 0.412–1.019)
Group	T	TC	TB
T	-	0.0663	4e-05
TC	0.0663	-	0.0081
TB	4e-05	0.0081	-

T: target therapy; TC: target combined chemotherapy; TB: target combined bevacizumab.

Table 5

Survival differences between three groups of patients with unknown mutations (p = 0.291, HR = 0.228, 95% CI: 0.072–0.724)
Group	T	TC	TB
T	-	0.30	0.88
TC	0.30	-	0.30
TB	0.88	0.30	-

T: target therapy; T C: target combined chemotherapy; T B: target combined bevacizumab.

Table 6

Survival comparison of first-generation targeted combined bevacizumab versus simple-generation targeted and simple-third generation targeting.
Group	First-TB	First-T	Third-T
First-TB	-	1.1e-05	0.0014
First-T	1.1e-05	-	0.185
Third-T	0.0014	0.185	-

First-T B: first generation target combined bevacizumab; First-T: first generation targeted therapy; Third-T: third generation targeted therapy.

No competing interests reported.

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Targeted combination of Bevacizumab demonstrates superior efficacy for stage IV Adenocarcinoma of the lung with EGFR mutation: A Real World Study

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