Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors Group Research Articles

Optimal sequence of LT for symptomatic BM in EGFR-mutant NSCLC: a comparative study of first-line EGFR-TKIs with/without upfront LT

BackgroundThe third-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) can penetrate blood–brain barrier and are effective for brain metastases (BMs). There is no consensus on the optimal sequence of local therapy (LT) and EGFR-TKIs for symptomatic BM patients because patients suffering neurological symptoms were not enrolled in most clinical trials.MethodsNon-small cell lung cancer (NSCLC) patients with EGFR mutation (EGFRm) and symptomatic BM receiving first-line osimertinib and aumolertinib from two medical centers were collected. All participants were allocated into the third-generation EGFR-TKIs (TKIs) group and the upfront LT (uLT) plus third-generation EGFR-TKIs (TKIs + uLT) group. Demographic data, survival outcomes, treatment failure patterns, and adverse events were evaluated between the two groups. We also conducted subgroup analyses to explore the impact of BM number on survival outcomes.Results86 patients were enrolled, 44 in the TKIs group and 42 in the TKIs + uLT group. There were no significant differences in the short-term response between the groups. TKIs + uLT was associated with significantly longer overall survival (OS) (43 vs. 28 months; hazard ratio [HR], 0.36, 95% confidence interval [CI], 0.17–0.77; p = .011). No differences in progression-free survival (PFS), intracranial PFS (iPFS), failure patterns, or safety were observed. In subgroup analyses of oligo-BM patients, TKIs + uLT could prolong OS (43 vs. 31 months; HR 0.22; 95% CI 0.05–0.92; p = .015).ConclusionsEGFRm NSCLC patients with symptomatic BM might benefit from uLT, particularly oligo-BM patients. However, larger prospective cohort studies should be carried out to confirm the responses of the TKIs + uLT scheme.

Major adverse cardiovascular events in advanced-stage lung cancer: a multicenter cohort study.

Lung cancers are common worldwide. First-line targeted therapy and chemotherapy are both standard treatments in the current guidelines. With the development of new anticancer therapy, the lifespan of patients with late-stage lung cancer has increased. Cardiovascular events can occur during cancer treatment. This observational study aimed to report the incidence of major adverse cardiovascular events (MACE) after cancer treatment using real-world data. Patients diagnosed with advanced-stage lung cancer between January 2011 and December 2017 were enrolled. Data were collected from the Chang Gung Research Database (CGRD). Retrospective cohort study. Baseline characteristics, clinical stages, pathologies, and outcomes were retrieved from the CGRD. We identified 4406 patients with advanced lung cancer, of whom 2197 received first-line epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) therapy and 2209 received first-line platinum-based chemotherapy. Most patients in the first-line EGFR-TKI group were never-smokers (74.9%), whereas those in the first-line chemotherapy group were ever-smokers (66.0%). The incidence of MACE was not significantly different between the two groups (12.0% versus 11.9%, p = 0.910). However, the incidence of ischemic stroke was higher in the first-line EGFR-TKI group than in the first-line chemotherapy group (3.9% versus 1.9%, p < 0.001). MACEs are common in patients with advanced-stage lung cancer during treatment. The incidence of MACE was similar between the first-line EGFR-TKI therapy and first-line chemotherapy groups. Although more patients in the EGFR-TKI group were female and never-smokers, the risk of ischemic stroke was higher in patients who received first-line EGFR-TKI therapy than in those who received first-line chemotherapy.

Long QT syndrome after using EGFR-TKIs in older patients with advanced non-small cell lung cancer

ABSTRACT Background Long QT syndrome (LQTS) has been reported in older patients with advanced non-small cell lung cancer (NSCLC) following the use of osimertinib, the third-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI). However, there have not been analytic epidemiology studies on this topic. We aimed to compare the risk of LQTS between osimertinib and first/second-generation EGFR-TKIs in older patients with advanced NSCLC. Research design and methods This retrospective observational study used the 2006–2019 Surveillance, Epidemiology, and End Results (SEER)-Medicare data and included older patients with advanced NSCLC who were treated with either osimertinib or first/second-generation EGFR-TKIs during 2007–2017. Inverse probability of treatment weighting (IPTW) was used to balance the two groups with propensity scores estimated based on the patients’ socioeconomic and clinical characteristics. Crude incidence rate (IR) and adjusted hazard ratio (HR) of the primary outcome, incident LQTS, were estimated. Results A total of 545 and 1,135 patients were included in the osimertinib and first/second-generation EGFR-TKI groups, which increased to 1,614 and 1,659, respectively, after IPTW. The osimertinib group had a higher IR of LQTS (2.62 per 100 person-years, 95% CI 2.03–3.38) compared to the first/second-generation EGFR-TKI group (1.33 per 100 person-years, 95% CI 0.92–1.92). After adjusting for covariates, the osimertinib group had a higher risk of LQTS than the first/second-generation EGFR-TKI group, with an HR of 1.94 (95% CI 1.23–3.08). The increased LQTS risk in the osimertinib group was even higher in females, whites and patients aged ≥ 75. Conclusions Given the elevated risk of LQTS associated with osimertinib user, close monitoring for cardiac rhythm irregularities of high-risk patients following initiation of EGFR-TKI is recommended.

Comparison of perioperative outcomes among non-small cell lung cancer patients with neoadjuvant immune checkpoint inhibitor plus chemotherapy, EGFR-TKI, and chemotherapy alone: a real-world evidence study.

BackgroundThe utilization of neoadjuvant immune checkpoint inhibitor (ICI) plus chemotherapy has increased significantly for resectable non-small cell lung cancer (NSCLC). It is still unclear whether such a treatment paradigm affects perioperative outcomes compared with other neoadjuvant treatment. We aimed to evaluate the perioperative outcomes of pulmonary resection after neoadjuvant ICI plus chemotherapy and to compare them with neoadjuvant epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKI) and neoadjuvant chemotherapy alone for resectable NSCLC.MethodsA retrospective cohort including 194 stage IB–IIIB NSCLC underwent surgical resection after neoadjuvant treatment between 2018 and 2020 were reviewed. Perioperative complications were evaluated using the Common Terminology Criteria for Adverse Events, and were compared using one-way analysis of variance for continuous variables and Pearson chi-square test.ResultsThere were 42, 54, and 98 patients in the neoadjuvant ICI plus chemotherapy, EGFR-TKI, and chemotherapy alone groups, respectively. The tumor size before neoadjuvant treatment was well balanced among the three groups (P=0.122). A shorter median surgical time was observed in the EGFR-TKI group than ICI plus chemotherapy group and chemotherapy group alone (120 vs. 150 vs. 146 min, P=0.041). Video-assisted thoracoscopic surgery was performed in 37 (88.1%), 49 (90.7%), and 57 (58.7%) patients in the three groups, respectively (P<0.001). A higher incidence of pneumonia (P=0.014) was found in the chemotherapy group. Perioperative mortality was observed in 1 patient (2.4%) in the ICI plus chemotherapy group and in 3 patients (3.1%) in the chemotherapy alone group (P=0.440). Patients in the ICI plus chemotherapy group had higher proportions of pathological complete response (40.5% vs. 11.1% vs. 6.1%, P<0.001) and downstaging of clinical N2 status (68.6% vs. 42.9% vs. 31.7%, P=0.012) than patients in EGFR-TKI group and chemotherapy alone group.ConclusionsSurgical resection for NSCLC following neoadjuvant ICI plus chemotherapy was safe and feasible, the perioperative outcomes were similar with neoadjuvant EGFR-TKI and chemotherapy alone without unexpected perioperative complications. Additional prospective studies are necessary to validate our findings.

Symptomatic Radiation Pneumonitis in NSCLC Patients Receiving EGFR-TKIs and Concurrent Once-daily Thoracic Radiotherapy: Predicting the Value of Clinical and Dose-volume Histogram Parameters.

Background and objectivesThe incidence of symptomatic radiation pneumonitis (RP) and its relationship with dose-volume histogram (DVH) parameters in non-small cell lung cancer (NSCLC) patients receiving epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) and concurrent once-daily thoracic radiotherapy (TRT) remain unclear. We aim to analyze the values of clinical factors and dose-volume histogram (DVH) parameters to predict the risk for symptomatic RP in these patients.MethodsBetween 2011 and 2019, we retrospectively analyzed and identified 85 patients who had received EGFR-TKIs and once-daily TRT simultaneously (EGFR-TKIs group) and 129 patients who had received concurrent chemoradiotherapy (CCRT group). The symptomatic RP was recorded according to the Common Terminology Criteria for Adverse Event (CTCAE) criteria (grade 2 or above). Statistical analyses were performed using SPSS 26.0.ResultsIn total, the incidences of symptomatic (grade≥2) and severe RP (grade≥3) were 43.5% (37/85) and 16.5% (14/85) in EGFR-TKIs group vs 27.1% (35/129) and 10.1% (13/129) in CCRT group respectively. After 1:1 ratio between EGFR-TKIs group and CCRT group was matched by propensity score matching, chi-square test suggested that the incidence of symptomatic RP in the MATCHED EGFR-TKIs group was higher than that in the matched CCRT group (χ2=4.469, P=0.035). In EGFR-TKIs group, univariate and multivariate analyses indicated that the percentage of ipsilateral lung volume receiving ≥30 Gy (ilV30) [odds ratio (OR): 1.163, 95%CI: 1.036-1.306, P=0.011] and the percentage of total lung volume receiving ≥20 Gy (tlV20) (OR: 1.171, 95%CI: 1.031-1.330, P=0.015), with chronic obstructive pulmonary disease (COPD) or not (OR: 0.158, 95%CI: 0.041-0.600, P=0.007), were independent predictors of symptomatic RP. Compared to patients with lower ilV30/tlV20 values (ilV30 and tlV20 < cut-off point values) and without COPD, patients with higher ilV30/tlV20 values (ilV30 and tlV20 > cut-off point values) and COPD had a significantly higher risk for developing symptomatic RP, with a hazard ratio (HR) of 1.350 (95%CI: 1.190-1.531, P < 0.001).ConclusionPatients receiving both EGFR-TKIs and once-daily TRT were more likely to develop symptomatic RP than patients receiving concurrent chemoradiotherapy. The ilV30, tlV20, and comorbidity of COPD may predict the risk of symptomatic RP among NSCLC patients receiving EGFR-TKIs and conventionally fractionated TRT concurrently.

The different overall survival between single-agent EGFR-TKI treatment and with bevacizumab in non-small cell lung cancer patients with brain metastasis

Comparison of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) monotherapy or with bevacizumab in real-world non-small cell lung cancer (NSCLC) patients was lacking. 310 patients of advanced NSCLC with common EGFR mutation receiving first-generation EGFR-TKI monotherapy or with bevacizumab were included and propensity-score matched. Progression-free survival (PFS), overall survival (OS) and secondary T790M mutation were analysed. Patients receiving EGFR-TKI and bevacizumab were significantly younger, had better performance status and with high incidence of brain metastasis (55.8%). In the propensity-score matched cohort, PFS (13.5 vs. 13.7 months; log-rank p = 0.700) was similar between the two groups. The OS (61.3 vs. 34.2 months; log-rank p = 0.010) and risk reduction of death (HR 0.42 [95% CI 0.20–0.85]; p = 0.017) were significantly improved in EGFR-TKI plus bevacizumab group. Analysis of treatment by brain metastasis status demonstrated EGFR-TKI plus bevacizumab in patients with brain metastasis was associated with significant OS benefit compared to other groups (log-rank p = 0.030) and these patients had lower early-CNS and early-systemic progressions. The secondary T790M did not significantly differ between EGFR-TKI plus bevacizumab and EGFR-TKI monotherapy groups (66.7% vs. 75.0%, p = 0.460). Forty-one (31.1%) and 31 (23.5%) patients received subsequent osimertinib and chemotherapy, respectively. The post-progression OS of osimertinib and chemotherapy were 22.1 and 44.9 months in EGFR-TKI plus bevacizumab group and were 10.0 and 14.1 months in EGFR-TKI monotherpay group, respectively. First-generation EGFR-TKI with bevacizumab improved treatment efficacy in real-world patients of NSCLC with EGFR mutation. Patients with brain metastasis received additional OS benefit from this treatment.

Efficacy and safety of first-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) combined with chemotherapy or antiangiogenic therapy as first-line treatment in patients with EGFR-mutant non-small cell lung cancer: A systematic review and meta-analysis.

We conducted a meta-analysis to synthesize the results of published randomized controlled trials conducted to evaluate the efficacy and safety of epidermal growth factor receptor - tyrosine kinase inhibitors (EGFR-TKIs) combined with chemotherapy or antiangiogenic therapy. PubMed, EMBASE, Cochrane Library and ClinicalTrials.gov databases were searched and literatures from international conferences were read to identify eligible studies. The primary endpoints were objective response rate (ORR) and progression free survival (PFS). The secondary endpoints were disease control rate (DCR), overall survival (OS) and treatment-emergent adverse events (TEAEs). 10 studies, all on first-generation EGFR-TKI combination therapy, involving 2367 patients were included. Combination therapy resulted in significant improvements in ORR (RR: 1.11, 95% CI: 1.06-1.17, P < 0.001), DCR (RR: 1.03, 95% CI: 1.01-1.05, P = 0.007), PFS (HR: 0.56, 95% CI: 0.51-0.62, P < 0.001), OS (HR: 0.74, 95% CI: 0.64-0.84, P = 0.002) over monotherapy. This improvement was more apparent in the EGFR-TKIs combination chemotherapy group, and indirect comparisons revealed that EGFR-TKIs combined with chemotherapy appeared to be superior to combined with antiangiogenic therapy in ORR (RR: 1.19, 95% CI: 1.07-1.32), DCR (RR: 1.04, 95% CI: 1.02-1.08), and OS (HR: 0.79, 95% CI: 0.66-0.96). Of additional concern is the increased incidence of TEAEs in combination therapy. As a first-line treatment for patients with EGFR-mutated advanced non-small cell lung cancer (NSCLC), first-generation EGFR-TKIs combined with chemotherapy or antiangiogenic therapy was associated with significant improvement in ORR, DCR, PFS and OS compared with monotherapy.

P52.11 Prognostic Positioning of EGFR Mutated Advanced Lung Cancer in Relation to the Treatment Modalities

The treatment of epidermal growth factor receptor (EGFR)-mutated lung cancer cases has shown remarkable development in the past two decades. However, there have been limited studies comparing prognostic effect of EGFR tyrosine kinase inhibitor (TKI) and other treatment modalities. Therefore, we set to compare the survival outcomes in patients treated with EGFR TKIs versus those treated with other treatment modalities. Patient data were collected from the Korean National Health Insurance Database, NHIS-NSC 2002-2015, which was released by the Korean National Health Insurance Service (KNHIS) in 2015. The Lung cancer group included patients (N=2003) initially diagnosed with lung cancer between January 2010 and December 2013. The main outcome was all-cause mortality. A Cox proportional hazard regression analyses was used to calculate the relative risk of mortality. Among the newly diagnosed lung cancer cases, 1004 (50.1%) were included for the analysis. A 15.1 months median survival benefit was observed in the EGFR TKI group than in the multimodality therapy group. Further, the risk of mortality was as follows: EGFR TKI treatment group (n = 142; HR: 5.29; 95% CI: 3.57-7.86) and multimodality therapy group (n = 326; HR: 7.42; 95% CI: 5.19-10.63) compared to surgery only (n = 275). Patients with advanced lung cancer harbouring EGFR mutations treated with EGFR-TKIs showed better median survival and low risk of mortality than those in the multimodality therapy group. Moreover, EGFR-TKI therapy can be considered to down-stage EGFR-mutant tumours in TNM classification.

Cost-effectiveness analysis of different sequences of osimertinib administration for epidermal growth factor receptor-mutated non-small-cell lung cancer.

Osimertinib is a third-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) that is clinically effective in patients with EGFR-mutated non-small-cell lung cancer (NSCLC). However, the use of this treatment is limited by its high cost. A cost-effectiveness analysis of different sequences of osimertinib administration in China and the United States was conducted in the present study. Markov models were established based on data from the FLAURA and AURA3 trials. First-line osimertinib was compared with both first-generation EGFR-TKIs and second-line osimertinib after the failure of first-generation EGFR-TKIs. The analysis also considered different payment modalities available in China. Additionally, one-way and probability sensitivity analyses, with a willingness-to-pay threshold (WTP) of three times the per capita gross domestic product [$27,783/quality-adjusted life year (QALY) for China and $100,000/QALY for the United States], were performed. The first-line osimertinib group displayed higher QALYs and costs than those of the first-generation EGFR-TKI group. The first generation EGFR-TKI group displayed an incremental cost-effectiveness ratio (ICER) of $212,252/QALY in China and $151,922/QALY in the United States. In addition, the ICERs were negative in the second-line osimertinib group, with higher QALYs and lower costs compared with those in the first-line osimertinib group. Furthermore, osimertinib company donation was of benefit in China, with an average cost-effectiveness of $836/QALY. The one-way sensitivity analysis highlighted the influence of utilities in different states. First-line osimertinib could be cost-effective either with higher WTP or a price reduction of 68% in China and 9% in the United States. Although first-line osimertinib therapy could have health benefits, it was not cost-effective compared with first-line first-generation EGFR-TKIs and second-line osimertinib therapy. However, paying via company donation may be a good choice in China.

Traditional Chinese Medicine Prolongs Progression-Free Survival and Enhances Therapeutic Effects in Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor (EGFR-TKI)Treated Non-Small-Cell Lung Cancer (NSCLC) Patients Harboring EGFR Mutations.

BackgroundLung cancer is the most common cause of cancer-associated deaths worldwide. This study aimed to investigate the efficacy and safety of Traditional Chinese Medicine combining EGFR-TKIs in treatment of NSCLC patients harboring EGFR mutations.Material/MethodsThis study involved 153 advanced-stage NSCLC patients harboring EGFR mutations. Patients were divided into a Control group (administered EGFR-TKI, n=61) and an Experimental group (administered Traditional Chinese Medicine combining EGFR and TKI, n=92). Progression-free survival (PFS) was evaluated for exon 19 deletion and/or 21 deletion patients. Disease control rate (DCR) was assessed to observe therapeutic effects. Adverse effects, including rashes, diarrhea, ALT/AST increase, dental ulcers, and onychia lateralis, were also evaluated.ResultsTCM combining EGFR-TKI (90.11%) demonstrated no DCR improvement compared to single EGFR-TKI (83.33%) (p>0.05). Median PFS (mPFS) of TCM combining EGFR-TKI (13 months) was significantly longer compared to that in the single EGFR-TKI group (8.8 months) (p=0.001). For 19DEL mutant NSCLC, the mPFS (11 months) in TCM combining EGFR-TKI was significantly longer compared to single EGFR-TKI (8.5 months) (p=0.007). The mPFS of L858 mutant NSCLC patients in EGFR-TKI combining CTM (14 months) was significantly longer compared to single EGFR-TKI (9.5 months) (p=0.015). TCM combining EGFR-TKI was more inclined to prolong mPFS of NSCLC with exon 21 deletion. TCM combining EGFR-TKI illustrated no additional adverse effects in NSCLC patients (p=0.956).ConclusionsApplication of Traditional Chinese Medicine prolonged progression-free survival and enhanced therapeutic effect in NSCLC patients harboring EGFR mutations receiving EGFR-TKI treatment. Meanwhile, adjunctive Chinese medicine combining EGFR-TKI in NSCLC with EGFR mutations caused no adverse effects.

Therapeutic Effect of First-line Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor (EGFR-TKI) Combined with Whole Brain Radiotherapy on Patients with EGFR Mutation-positive Lung Adenocarcinoma and Brain Metastases.

This study compared the therapeutic effect of first-line epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) with that of EGFR-TKI plus whole brain radiotherapy (WBRT) on patients with EGFR mutation-positive lung adenocarcinoma and brain metastases. A total of 139 patients with lung adenocarcinoma and brain metastases treated with first-line EGFRTKI therapy from September 2008 to December 2017 were enrolled in this study. The study endpoints were intracranial time to progression (TTP) and overall survival (OS). The effects of clinical pathological parameters and EGFR gene status on the study endpoints were compared. The results showed that the intracranial TTP was significantly longer in EGFR-TKI plus WBRT group than in EGFR-TKI group (median 30.0 vs.18.2 months, χ2=10.824, P=0.001), but no significant difference in the OS was noted between the two groups (median 48.0 vs. 41.1 months, χ2=0.012, P=0.912). Also, there was no statistically significant difference in the OS between patients treated with early and late radiotherapy (P=0.849) and between those with asymptomatic and those with symptomatic intracranial metastases (P=0.189). The OS and intracranial TTP of patients with intracranial oligometastases (≤3 metastatic sites) were not significantly different from those of patients with multiple intracranial metastases (P=0.104 and P=0.357, respectively), and exon 19 and exon 21 mutations didn't show significant effects on the OS and intracranial TTP of patients (P=0.418 and P=0.386, respectively). In conclusion, there was no statistically significant difference in the OS between the EGFR-TKI alone group and EGFR-TKI plus WBRT group. However, simultaneous use of WBRT was found to significantly prolong intracranial TTP and improve cerebral symptoms, and thus EGFR-TKI and WBRT combined may be clinically beneficial for patients with EGFR mutation-positive lung adenocarcinoma and brain metastases.

Combination of EGFR-TKIs with chemotherapy versus chemotherapy or EGFR-TKIs alone in advanced NSCLC patients with EGFR mutation.

PurposeBoth epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) and chemotherapy are widely applied for the treatment of advanced non-small-cell lung cancer (NSCLC) with EGFR mutations, and the combination of EGFR-TKIs and chemotherapy has been used for advanced NSCLC patients; however, little is known about the efficacy of the direct comparison among them.Patients and methodsThe demographic and clinical characteristics of 92 patients harboring advanced NSCLC with EGFR mutation were retrospectively reviewed. We evaluated the effects of EGFR-TKIs, chemotherapy, and EGFR-TKIs plus chemotherapy on advanced NSCLC patients with EGFR mutations, and the efficacy of combination of chemotherapy and EGFR-TKIs vs chemotherapy or EGFR-TKIs alone in advanced NSCLC patients was evaluated.ResultsThe statistical results showed that the intercalated combination of EGFR-TKIs plus chemotherapy significantly improved progression-free survival (PFS; HR, 1.76; 95% CI 1.03–3.01; P=0.036; median, 20.5 vs 16 months) compared with EGFR-TKI monotherapy, but no difference in overall survival (OS) was observed between these two groups (HR, 1.52; 95% CI 0.81–2.83; P=0.19; median, 36 vs 29 months). However, patients who received the combination of chemotherapy and EGFR-TKIs had longer PFS (HR, 2.78; 95% CI 1.57–4.93; P<0.0001; median, 20.5 vs 12 months) as well as OS (HR, 2.86; 95% CI 1.56–5.27; P=0.001; median, 36 vs 18 months) than those who received chemotherapy alone. Toxicities were mild among the three treatment groups. Rash and diarrhea were common adverse events (AEs) in the EGFR-TKI group, anemia and nausea in the chemotherapy group, and anemia and diarrhea in the combination group.ConclusionThis study demonstrated that the combination of chemotherapy with EGFR-TKIs as first-line treatment has a significant effect on PFS in patients with advanced NSCLC whose tumors harbor activating EGFR mutations. The combination treatment had more toxicity, but was clinically manageable.

Microwave ablation combined with EGFR-TKIs versus only EGFR-TKIs in advanced NSCLC patients with EGFR-sensitive mutations.

We conducted this retrospective study to investigate whether microwave ablation (MWA) of primary tumor sites plus epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) could improve survival in advanced non small cell lung cancer (NSCLC) with EGFR mutations. MWA was conducted at the primary tumor sites, followed by EGFR-TKIs in the MWA plus EGFR-TKIs group. EGFR-TKIs were administered until disease progression or intolerable toxicity. The primary endpoint was progression-free survival (PFS); secondary endpoints were overall survival (OS) and objective response rate (ORR). A total of 58 patients were recruited, including 34 in the MWA plus EGFR-TKIs group and 24 in the EGFR-TKIs group. No significant difference in ORR was observed with MWA treatment (61.8% vs. 45.8%, p = 0.230). Patients treated with MWA plus EGFR-TKIs failed to show superior survival in either PFS (13.2 months vs. 11.6 months, p = 0.640) or OS (39.8 months vs. 20.4 months, p = 0.288). MWA was not an independent prognostic factor for PFS or OS. MWA of primary tumor sites plus EGFR-TKIs demonstrated no survival advantage compared with EGFR-TKIs alone in advanced NSCLC patients with EGFR sensitive mutations. MWA should not be recommended for unselected patients with EGFR-sensitive mutations.

Primary Application of Radiofrequency Ablation after Locally Progression of EGFR-TKIs in Non-small Cell Lung Cancer

背景与目的表皮生长因子受体酪氨酸激酶抑制剂(epidermal growth factor receptor-tyrosine kinase inhibitors, EGFR-TKIs)是EGFR敏感突变非小细胞肺癌患者的主要治疗手段之一，但是部分患者在EGFR-TKIs治疗有效后出现原发灶局部进展。本文研究了射频消融在EGFR-TKIs治疗EGFR突变非小细胞肺癌后局部进展的临床应用结果。方法入组符合条件的28例非小细胞肺癌患者，肺部肿瘤经过射频消融和后续的EGFR-TKI或化疗，观察其安全性及治疗效果。结果所有患者无围手术期死亡。平均随访17.25个月。局部进展率为10.7%(3/28)，局部进展时间平均为16.6个月。平均肿瘤无进展时间为(24.55±5.36)个月(95%CI: 14.04-35.05)，平均总生存时间(overall survival, OS)为(25.57±5.45)个月(95%CI: 14.88-36.27)。射频消融后续治疗分为EGFR-TKIs组和化疗组，两组平均肿瘤无进展时间分别为(27.82±7.58)个月(95%CI: 12.97-42.68)和(17.88±3.76)个月(95%CI: 10.52-25.25)(P > 0.05)；平均OS分别为(29.42±7.68)个月(95%CI: 14.36-44.48)和18.44±3.87(95%CI: 14.89-36.27)(P > 0.05)。结论针对EGFR敏感突变的非小细胞肺癌患者，应用EGFR-TKIs治疗有效后出现原发灶局部进展，射频消融可提高局部控制率，并延长肿瘤无进展生存期和总生存期。

Clinical Studies on conformal radiotherapy combined with epidermal growth factor receptor-tyrosine kinase inhibitor in second-line treatment of non-small cell lung cancer

Purpose: To study the effect of conformal radiotherapy combined with epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) in the second-line treatment of non-small cell lung cancer (NSCLC). Methods: A total of 316 patients attending Shanghai Pulmonary Hospital affiliated to Tongji University, were divided into two groups: 106 patients were treated with conformal radiotherapy combined with EGFR-TKI (gefitinib, 250 mg/day; or erlotinib, 150 mg/day), while 210 patients were treated with EGFRTKI alone. Some factors, including adverse reactions (AR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and one-year and two-year survival rate, were evaluated. Results: No obvious difference was observed in AR between the two groups ( p > 0.05). In the combination therapy group, complete response (CR) was 5 cases, partial response (PR) 43 cases, and stable disease (SD) 47 cases, progressive disease (PD) was 11 cases, response rate (RR) was 45.3 %, and DCR 89.6 %. Median PFS in the combination therapy group and targeted therapy group was 6.5 and 5.0 months, respectively. On the other hand, median OS in the combination therapy group and targeted group was 14.1 and 12.6 months, respectively. One-year survival rate of the combination therapy group and EGFR-TKI group was 60.3 and 50.0 %, respectively, while the two-year survival rate was 26.3 and 19.0 %, respectively. Conclusion: Conformal radiotherapy combined with EGFR-TKI can be used as an effective second-line treatment for NSCLC. Keywords: Non-small cell lung cancer, Epidermal growth factor receptor tyrosine kinase inhibitor, Conformal radiotherapy, Targeted therapy, Survival rate

Factor associated with failure to administer subsequent treatment after progression in the first-line chemotherapy in EGFR-mutant non-small cell lung cancer: Okayama Lung Cancer Study Group experience

Early administration of both epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) monotherapy and cytotoxic chemotherapy is crucial for non-small cell lung cancer (NSCLC) patients harboring EGFR mutations. We investigated the effect of first-line administration of these therapies on subsequent therapy in NSCLC patients. This study enrolled 63 consecutive patients with advanced EGFR-mutant NSCLC and good performance status (PS) and who underwent first-line EGFR-TKI therapy or standard cytotoxic chemotherapy and then had progressive disease, from 2007 to 2011. The ability of each patient to receive the other therapy after first-line treatment failure was assessed. In the first-line setting, 23 and 40 patients received EGFR-TKI therapy and cytotoxic chemotherapy, respectively. At relapse, the EGFR-TKI therapy group showed more frequent PS deterioration (p = 0.042) and greater likelihood of symptomatic central nervous system (CNS) relapse (p = 0.093) compared with the cytotoxic chemotherapy group. Nine (39 %) of 23 patients initially receiving EGFR-TKI therapy could not receive standard cytotoxic therapy after progression mainly due to symptomatic CNS relapse. Only one (3 %) of 40 initially treated with cytotoxic chemotherapy failed to receive subsequent EGFR-TKI therapy (p < 0.001). Multivariate analysis revealed a correlation between the first-line therapy and the failure to switch to the other therapy after disease progression (OR 48.605, p = 0.005). In this study, patients who could not receive both EGFR-TKI therapy and cytotoxic chemotherapy in the early-line setting were included more in the first-line EGFR-TKI group, suggesting a potential risk associated with missing the timing of administration of subsequent therapy. Further investigation is warranted to detect their pretreatment clinical or molecular characteristics for development of a new treatment strategy specific for such subpopulation.

Chemotherapy and EGFR tyrosine kinase inhibitors for treatment of brain metastases from non-small-cell lung cancer: survival analysis in 210 patients

BackgroundChemotherapy and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors are controversial in the treatment of patients with brain metastases from non-small-cell lung cancer (NSCLC).MethodsWe retrospectively studied the effects of solely localized treatment or localized treatment in combination with chemotherapy and/or EGFR tyrosine kinase inhibitors on outcomes in 210 NSCLC patients with brain metastases. The effects of treatment modality, Karnofsky performance status, age, primary tumor histology, number of brain metastases, and other factors on survival time were analyzed, and the robustness of two prognostic indices, ie, recursive partitioning analysis and graded prognostic assessment, was evaluated.ResultsThe median survival time in patients with systemic medication and localized treatments was higher than in those with localized treatments alone (11 versus 3 months, P=0.000). Within the systemic medication group, median survival time was significantly longer for EGFR tyrosine kinase inhibitors than for other types of chemotherapy (12 versus 9 months, P=0.002). In the EGFR tyrosine kinase inhibitor group, median survival time for patients with EGFR gene mutation was 20 months versus 8 months for those with the wild-type EGFR gene. The median survival time with pemetrexed was significantly higher than with other chemotherapies (13 versus 7 months, P=0.006). In multivariate analysis, the prognosis was significantly correlated with treatment modality (P=0.000), Karnofsky performance status (P=0.000), number of brain metastases (P=0.001), and histologic tumor type (P=0.007). In the graded prognostic assessment model, survival curves for the subgroups showed clear separations.ConclusionNSCLC patients with brain metastasis benefited from pemetrexed and/or tyrosine kinase inhibitors along with localized treatments, and the graded prognostic assessment index is a robust model for prognostic evaluation.

A Survey of Non-Small Cell Lung Cancer Patients with Meningeal Carcinomatosis in Japan: Incidence and Medical Resource Consumption

Background: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) may be effective for patients for non-small cell lung cancer (NSCLC) with meningeal carcinomatosis (MC), but evidence is limited particularly for the economics aspects. This study aimed to estimate the incidence of MC and resource consumption for NSCLC patients with MC as an exploratory study for further pharmacoeconomic evaluation of EGFR-TKI treatment in these patients. Methods: Patients diagnosed with NSCLC in Kyoto University Hospital between January 1, 2005 and December 31, 2008 was identified using medical record data in the hospital. The cumulative incidence of MC was calculated taking into account the competing risk of death. The economic analysis adopted the payer perspective and included direct medical costs (2010 costs) from the date of diagnosis of MC until the time of death. The resource utilization data are expressed as costs per patient per month. Results: Of 376 patients diagnosed with NSCLC in the study period, 28 were diagnosed with MC up to December 31, 2009 and the cumulative incidences at 1 and 2 years after NSCLC diagnosis were 2.4% and 6.0% respectively. The drug costs per patient per month in MC patients treated with an EGFR-TKI were more than twice that in the non-EGFR-TKI group, but the total costs per patient per month were lower in the EGFR-TKI group. A comparison of sub-categories of costs showed that hospitalization accounted for the highest percentage of medical resource consumption. Conclusions: These estimates constitute a basis for cost-effectiveness analysis of EGFR-TKI treatment for NSCLC patients.

Brief report: Retrospective review of efficacy of erlotinib or gefitinib compared to docetaxel as subsequent line therapy in advanced non-small cell lung cancer (NSCLC) following failure of platinum-based chemotherapy

Randomized trials of advanced non-small cell lung cancer (NSCLC) have demonstrated the activity of docetaxel in second-line and erlotinib in the third-line setting after failure of platinum-based chemotherapy. The role of epidermal growth factor receptor tyrosine kinase inhibitors (EGFRTKI) as second-line treatment prior to docetaxel is currently the subject of ongoing trials. Here we explore the outcomes of these agents' uses in clinical practice. A retrospective review of the NSCLC database at Princess Margaret Hospital in Toronto, Canada was undertaken. Patients who have previously received docetaxel after failure of platinum-based chemotherapy were identified and a chart review was undertaken to further identify those who also received an EGFRTKI to assess their clinical benefits. Primary outcome assessed was response rate and secondary outcomes were time to progression (TTP) and overall survival (OS). Seventy-four patients received docetaxel for advanced NSCLC from 2001 to 2006, 52 (70%) as second line and 22 (30%) as third line. Twenty-two and 31 of these patients received second- and third-line EGFRTKI, respectively. In the second-line setting, the overall response rate was 10% in the EGFRTKI group and 9% in the docetaxel-treated patients. In the third-line setting, this was 20% and 5%, respectively (p-value 0.29). In both the second- and third-line setting, TTP and OS were not significantly different between the two groups. For patients with advanced NSCLC who progressed following first-line platinum-based chemotherapy, the use of an EGFRTKI in second line appears to be equivalent to docetaxel chemotherapy, and docetaxel has activity third line, post EGFRTKI therapy.

Is the Importance of Achieving Stable Disease Different between Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors and Cytotoxic Agents in the Second-Line Setting for Advanced Non-small Cell Lung Cancer?

It is controversial whether achieving stable disease leads to a survival benefit and whether the importance of achieving stable disease differs between cytotoxic agents and molecular targeted agents. To examine these questions, the authors retrospectively reviewed phase II and III studies in the second-line setting for advanced non-small cell lung cancer using epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) and cytotoxic agents separately. The authors chose 45 trials for the chemotherapy group and nine for the EGFR TKI group by searching the PubMed database. All nine trials in the EGFR TKI group concern gefitinib and erlotinib. The median survival time increased 0.0375 month with each 1% increase in stable disease rate (p = 0.039), and each 1% increase in response rate resulted in 0.0744 (p < 0.001) month of median survival time in the analysis combined with both cytotoxic agents and EGFR TKIs. Main and interaction terms for EGFR TKI treatment were not statistically significant. With respect to time to progression, only response rate showed a statistically significant relationship with survival. To obtain response seems to be more important than to achieve stable disease for both cytotoxic agents and EGFR TKIs, although achieving stable disease is still valuable. The relationship between survival and response or stable disease appears similar for cytotoxic agents and EGFR TKIs.