Efficacy and safety of anlotinib plus EGFR-TKI for advanced non-small cell lung cancer with EGFR mutations: A meta-analysis of randomized controlled trials

Kanglaite (KLT) is a Chinese medicine antitumor drug independently developed in China, which has been widely used in the treatment of advanced non-small cell lung cancer (NSCLC). The purpose of this study was to systematically evaluate the efficacy and safety of KLT plus epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) in the treatment of advanced NSCLC. Up to September 1, 2022, the databases of PubMed, EMBASE, Cochrane Library, ClinicalTrials.gov, China National Knowledge Infrastructure, Chinese Biomedical Literature, China Science and Technology Journal, and Wanfang were searched, and the randomized controlled clinical trials (RCTs) of KLT plus EGFR-TKI in the treatment of advanced NSCLC were included. Two researchers independently screened the literature, extracted data, and evaluated the quality of the included literature. Revman5.4 software was used for meta-analysis. A total of 1057 patients were included in 13 RCTs. The results of meta-analysis showed that KLT plus EGFR-TKI could improve the objective response rate (ORR) (risk ratio (RR) confidence interval (CI) [RR = 1.54, 95% CI: 1.27-1.86, P < .00001]), the disease control rate (DCR) (RR = 1.23, 95% CI: 1.14-1.32, P < .00001), and quality of life (QOL) (RR = 1.79, 95% CI: 1.36-2.36, P < .0001) in patients with advanced NSCLC. The percentages of CD3+T cells (standardized mean difference [SMD = 2.37, 95% CI: 0.80-3.93, P = .003]), CD4+T cells (SMD = 1.39, 95% CI: 0.85-1.93, P < .00001), NK cells (SMD = 1.59, 95% CI: 0.88-2.30, P < .0001), and CD4+/CD8+ratio (SMD = 0.37, 95% CI: 0.19-0.55, P < .0001) were also increased. However, the results of subgroup analysis showed that in patients with EGFR mutation NSCLC, compared with EGFR-TKI alone, KLT plus EGFR-TKI did not significantly increase ORR and DCR (RR = 1.43, 95% CI: 0.88-2.32, P = .15; RR = 1.07, 95% CI: 0.96-1.20, P = .21). In terms of adverse events of drugs, the incidence of diarrhea, rash, anorexia, nausea and vomiting, liver and renal function damage of KLT plus EGFR-TKI was similar to that of EGFR-TKI alone (P > .05). KLT plus EGFR-TKI has some clinical benefits and good safety compared with EGFR-TKI alone in the treatment of advanced NSCLC. However, it seems that patients with EGFR mutations do not get significant clinical benefits, and more high-quality RCTs are needed to prove the efficacy of the combined regimen.

The Challenges of Third-Generation EGFR Tyrosine Kinase Inhibitors in the Therapy of Advanced NSCLC

Background: Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are considered as the first-line treatment for advanced EGFR mutation-positive non-small cell lung cancer (NSCLC). We aimed to analyze the efficacy of EGFR-TKIs treatment in patients with advanced NSCLC of different smoking habits. Methods: We conducted a search for meta-analyses and systematic reviews on the PubMed, MEDLINE, Embase, and the Cochrane Library to address this knowledge gap. Patients were divided into 2 groups: (1) experimental group: treated with EGFR-TKIs or EGFR-TKIs combined with chemotherapy, immunotherapy, antiangiogenesis, radiotherapy and (2) control group: treated with chemotherapy. Progressive-free survival (PFS) and total survival (OS) were adopted for evaluating the efficacy of EGFR-TKIs between experimental group and control group. Results: Eleven studies including 6760 patients were included in the meta-analysis. The results showed that smoking (including previous and current smoking) significantly reduces the PFS and OS in comparison to non-smoking group in the treatment of NSCLC with EGFR-TKIs. In addition, EGFR-TKIs combined with anti-vascular endothelial growth factor therapy can reduce the risk of disease progression in smokers. Conclusions: Our study indicated that smoking significantly reduced the PFS and OS in comparison to non-smoking group in the treatment of NSCLC with EGFR-TKIs.

BackgroundFor patients with advanced non-small-cell lung cancer (NSCLC) with EGFR mutations, the suggested course of action is epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs). Even with a high disease control rate, a majority of patients develop acquired EGFR-TKIs resistance and eventually advance. To increase the benefits of treatment, clinical trials are increasingly exploring the value of EGFR-TKIs combined with angiogenesis inhibitors as a first-line treatment in advanced NSCLC carrying EGFR mutations.MethodUsing PubMed, EMBASE and Cochrane Library, to locate published full-text articles in print or online, a thorough literature search was done from the database's inception to February 2021. Additionally, oral presentation RCTs from ESMO and ASCO were obtained. We sifted out RCTs that used EGFR-TKIs along with angiogenesis inhibitors as first-line therapy for advanced EGFR-mutant NSCLC. ORR, AEs, OS, and PFS were the endpoints. Review Manager version 5.4.1 was used for data analysis.ResultsOne thousand eight hundred twenty-one patients were involved in 9 RCTs. According to the results, combining EGFR-TKIs with angiogenesis inhibitors therapy prolonged PFS of advanced EGFR-mutation NSCLC patients on the whole [HR:0.65 (95%CI: 0.59~0.73, P<0.00001)]. No significant statistical difference was identified between the combination group and single drug group in OS(P=0.20) and ORR (P=0.11). There are more adverse effects when EGFR-TKIs are used in combination with angiogenesis inhibitors than when used alone.ConclusionThe combination of EGFR-TKIs and angiogenesis inhibitors prolonged PFS in patients with EGFR-mutant advanced NSCLC, but the OS and ORR benefit was not significant, and the risk of adverse events was higher, more pronounced with hypertension and proteinuria; PFS in subgroups suggested that the combination was associated with better PFS in the smoking, liver metastasis, and no brain metastasis groups, and the included studies suggested that the smoking group , liver metastasis group, and brain metastasis group may have a potential OS benefit.

背景与目的 晚期表皮生长因子受体（epidermal growth factor receptor, EGFR）阳性非小细胞肺癌 (non-small cell lung cancer, NSCLC）患者的一线治疗首选EGFR酪氨酸激酶抑制剂（epidermal growth factor receptor tyrosine kinase inhibitors, EGFR-TKIs）。晚期驱动基因阴性，程序性死亡配体1（programmed cell death ligand 1, PD-L1）阳性或高表达的NSCLC患者一线治疗推荐免疫检查点抑制剂（immune checkpoint inhibitors, ICIs）单药治疗或ICIs联合化疗。所以不同PD-L1表达水平的EGFR阳性晚期NSCLC患者的一线治疗策略值得进一步探究。既往众多研究提示PD-L1的表达明显受EGFR突变情况的影响，PD-L1表达很有可能与EGFR-TKIs耐药机制相关。本研究旨在分析晚期EGFR阳性NSCLC患者PD-L1表达特点及其与EGFR-TKIs疗效的关系。方法 以159例EGFR阳性初治晚期NSCLC患者（其中包含141例EGFR敏感突变患者）为研究对象，分析159例患者相关临床病理特征与PD-L1表达的关系及141例EGFR敏感突变患者EGFR-TKIs治疗疗效的的相关影响因素。结果 所纳入159例患者PD-L1表达按肿瘤细胞阳性比例分数（tumor proportion score, TPS）分类：阴性（TPS<1%）占47.2%，低表达（1%≤TPS<50%）占32.1%，高表达（TPS≥50%）占20.7%。癌细胞病理形态学分类实体为主型患者更容易出现PD-L1高表达（高表达占比52.9%，组间差异P<0.0001）。PD-L1阴性表达、低表达、高表达患者一线接受一代EGFR-TKIs治疗的中位无进展生存期分别为12.4个月、10.5个月和3.7个月，三者间差异有明显统计学意义（P<0.0001）；EGFR-TKIs治疗期间，有肺部病灶放疗史相对于无肺部病灶放疗史有更长的无进展生存期获益（中位无进展生存期：17.0个月 vs 9.3个月，P<0.0001）。结论 晚期EGFR阳性NSCLC患者PD-L1的表达水平与癌细胞病理形态学分类显著相关。PD-L1高表达NSCLC患者接受EGFR-TKIs疗效明显较差。靶向治疗期间联合肺部病灶放疗可以显著延长无进展生存期。

Objective: To investigate if concomitant gene alterations impact the therapeutic efficacy of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKI) in advanced non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) sensitive mutation. Methods: From November 2016 to December 2017, 51 patients (19 males and 32 females, age 37-85 years) with histology or cytology diagnosed,locally advanced or metastatic NSCLC from Zhongshan Hospital Fudan University were prospectively recruited in the study. All patients harboring EGFR sensitive mutation detected by a 123 lung cancer specific gene panel of next-generation sequencing(NGS) analysis were under treatment of EGFR-TKIs. Multi-factors analysis of the correlation between EGFR-TKIs efficacy and concomitant gene alterations were analyzed by multivariate Cox regression model. Results: 82% of the NSCLC patients with EGFR mutation presented concomitant gene alterations with an average number of 2.1. Patients not harboring concomitant gene alterations had a longer median progression free survival (mPFS: not reached vs 8.8 m, P=0.008). Those who had less than 2 concomitant genes had a higher objective response rate[ORR: 52% (17/33) vs 33% (6/18) , P=0.251]and better mPFS (13.8 vs 8.0 m, P=0.003). The top 3 concomitant gene alterations were TP53 gene mutation(55%, 28/51), EGFR gene amplification (26%, 13/51) and RB1 gene mutation (18%,9/51) respectively. The mPFS of EGFR-TKI treatment in patients with either one of these 3 concomitant genes was 8.0, 8.0, and 6.0 months respectively, significantly shorter than those without one of the 3 gene alterations (13.8, 13.1, and 10.8 months respectively). Multivariate Cox regression revealed that concomitant gene abnormalities (P=0.036) and accompanied by RB1 gene mutation (P=0.025) were independent risk factors for the survival benefit of EGFR-TKI in the treatment of advanced NSCLC with EGFR-sensitive mutation. Conclusions: The efficacy of EGFR-TKI decreased significantly in advanced NSCLC with EGFR-sensitive mutation who had concomitant gene abnormalities, especially accompanied by more than 2 of the 3 gene alterations (TP53 gene mutation, EGFR gene amplification or RB1 gene mutation). This study suggested that the concomitant gene alterations should be an important issue for consideration when applying a personalized combination therapy for advanced NSCLC harboring EGFR sensitive mutation.

ObjectiveThe aim of this meta-analysis was to evaluate efficacy and toxicity of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) in combination with chemotherapy (CT) compared to EGFR-TKI monotherapy as first-line treatment in advanced non-small cell lung cancer (NSCLC) harboring activating EGFR mutation.MethodsA systematic literature search of randomized controlled trials using Cochrane Library, PubMed, Embase, and Web of Science, was performed up to Jan. 7th, 2020. Hazard ratios (HRs) with 95% confidence intervals (CI) were calculated as effect values for progress-free survival (PFS) and overall survival (OS). Risk ratio (RR) and Odds ratio (OR) were calculated as effect values for objective response rate (ORR) and toxicity, respectively.ResultsA total of eight randomized trials involving 1,349 advanced NSCLC patients with sensitive EGFR mutation were included in the meta-analysis. All patients in both groups received first-generation TKI as first-line treatment. The pooled HR of PFS and OS was 0.56 (95% CI = 0.50–0.64; P <0.00001) and 0.70 (95% CI = 0.54–0.90; P = 0.005), respectively. Subgroup analysis showed significantly higher OS advantages in patients receiving doublet CT (P = 0.02) and concurrent therapy (P = 0.002). The ORR in the EGFR-TKI plus CT group was significantly higher than in the EGFR-TKI monotherapy group (RR = 1.18, 95% CI = 1.10–1.26). The combination regimen showed a higher incidence of chemotherapy-induced toxicities. Subgroup analysis indicated that doublet chemotherapy rather than single-agent chemotherapy significantly increased incidence of grade 3 or higher leukopenia, neutropenia and anemia.ConclusionsCompared with EGFR-TKI monotherapy, the combination of first-generation EGFR-TKI and CT, especially when applying concurrent delivery of platinum-based doublet chemotherapeutic drugs, significantly improve ORR and prolong PFS and OS in first-line treatment for advanced EGFR-mutated NSCLC. Although increasing incidence of chemotherapy-induced toxicities occurs in the combination group, it is well tolerated and clinically manageable.

Icotinib is the first generation of epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) independently developed in China, which has been widely used in the treatment of advanced EGFR mutation-positive nonsmall cell lung cancer (NSCLC). The purpose of this study was to systematically evaluate the efficacy and safety of icotinib in the treatment of advanced EGFR mutation-positive NSCLC and to provide evidence-based evidence for clinical rational drug use. Up to September 30, 2022, the databases of PubMed, EMBASE, Cochrane Library, ClinicalTrials.gov, China National Knowledge Infrastructure, and Wanfang were searched, and the randomized controlled trials (RCTs) of icotinib (experimental group) versus gefitinib or erlotinib (control group) in the treatment of EGFR-positive advanced NSCLC were included. Two researchers independently screened the literature, extracted data, and evaluated the quality of the included literature. Revman5.4 software was used for meta-analysis. A total of 957 patients were included in 12 studies. The results of meta-analysis showed that the objective response rate (ORR) and disease control rate (DCR) of the experimental group were better than those of the control group (relative risk (RR) = 1.29, 95% confidence interval (CI): 1.10-1.50, P = .001; RR = 1.10, 95%CI: 1.02-1.18, P = .01). There was no significant difference in progression-free survival (PFS) and overall survival between the 2 groups (P > .05). The results of stratified analysis showed that icotinib significantly improved the ORR of EGFR-positive advanced NSCLC patients compared with gefitinib (RR = 1.20, 95%CI: 1.01-1.43, P = .03), but had no significant improvement in DCR (RR = 1.08, 95%CI: 0.99-1.16, P = .07). Compared with erlotinib, icotinib significantly improved ORR and DCR (RR = 1.69, 95%CI: 1.17-2.45, P = .005; RR = 1.21, 95%CI: 1.01-1.44, P = .04). In terms of adverse events of drugs, the incidence of nausea and vomiting in the experimental group was significantly lower than that in the control group (P < .05). Icotinib is safer than gefitinib or erlotinib in the treatment of advanced EGFR-positive NSCLC and seems to bring more clinical benefits to patients. However, there is no obvious advantage in improving the survival rate of patients, and long-term follow-up clinical studies are needed to verify its efficacy.

Oncogene-addicted metastatic non-small-cell lung cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up

Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) and anti-angiogenic drugs have individually demonstrated clinical benefit in the treatment of patients with advanced non-small cell lung cancer (NSCLC). Recent studies demonstrate that the combination of anti-EGFR and anti-angiogenesis can more significantly enhance clinical benefit, and even can remit EGFR-TKIs resistance in the treatment of advanced NSCLC. According to the different kinds of anti-angiogenesis drugs, recent clinical studies mainly include the combination of anti-vascular endothelial growth factor monoclonal antibody bevacizumab plus EGFR-TKIs and multi-targeted receptor anti-angiogenic tyrosine kinase inhibitor plus EGFR-TKIs, and the former results show a more significant improvement in terms of safety and efficacy in the treatment of advanced NSCLC. Therefore, the combination of bevacizumab plus EGFR-TKIs can be used as a new treatment standard in the treatment of some patients with NSCLC. Key words: Carcinoma, non-small-cell lung; Angiogenesis inhibitors; Epidermal growth factor receptor-tyrosine kinase inhibitors

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)

Update on afatinib-based combination regimens for the treatment of EGFR mutation-positive non-small-cell lung cancer.

AB036. Comparison of the effectiveness of gefitinib, erlotinib and afatinib in epidermal growth factor receptor mutated tumors of non-small cell lung cancer

Objective To explore the efficacy,prognosis,and side effects of epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) therapy for advanced non-small cell lung cancer and lung cancer with brain metastasis.Methods Clinical datas of advanced non-small cell lung cancer who received EGFR-TKI treatment in Fujian Provincial Hospital from January 2007 to August 2012 were retrospectively analyzed.All patients received EGFR-TKI until the disease progression or intolerable toxicity.Results The objective response rate (ORR) and the disease control rate (DCR) after administration of EGFR-TKI were 34.6％ (18/52) and 75.0％ (39/52),respectively.The median progression free survival time and overall survival time were six months and 18 months,respectively.The DCR in patients with adenocarcinoma,non-smoking,and tumor size ＜5 cm was higher than that in patients with non-adenocarcinoma,smokers and tumor size ≥ 5 cm (P ＜ 0.05).Survival analysis suggested that the median progression survival in patients with tumor size ＜5 cm and stable disease was longer than that in patients with tumor size ≥ 5 cm and progression disease (P ＜ 0.05).The median survival time in non-smokers and patients of tumor size ＜ 5 cm was longer than that in smokers and patients of tumor size ≥5 cm (P ＜0.05).Among 21 cases of lung cancer with brain metastasis treated with EGFR-TKI,overall ORR and DCR of intracranial lesions were 38.1 ％ and 90.5 ％,respectively.The ORR and DCR of systemic disease were 38.1％ and 85.7％,respectively.The most common side effects were rash (25.0 ％) and pruitus (19.2 ％).Conclusions EGFR-TKI is effective and safe in the treatment of advanced non-small cell lung cancer patients.EGFR-TKI may be effective on brain metastases in lung cancer patients. Key words: Epidermal growth factor receptor-tyrosine kinase inhibitor; Non-small cell lung cancer; Efficacy; Prognosis

A small, international, closed-door conference on Novel Agents in the Treatment of Lung Cancer, held in Cambridge, Massachusetts, October 17–18, 2003, was convened to present and discuss findings from recent and ongoing trials of investigational drugs for the treatment of lung cancer. Invited