Advanced EGFR-mutant Non-small Cell Lung Cancer Patients Research Articles

Resistance to osimertinib in advanced EGFR-mutated NSCLC: a prospective study of molecular genotyping on tissue and liquid biopsies.

Resistance to osimertinib in advanced EGFR-mutated non-small cell lung cancer (NSCLC) constitutes a significant challenge for clinicians either in terms of molecular diagnosis and subsequent therapeutic implications. This is a prospective single-centre study with the primary objective of characterising resistance mechanisms to osimertinib in advanced EGFR-mutated NSCLC patients treated both in first- and in second-line. Next-Generation Sequencing analysis was conducted on paired tissue biopsies and plasma samples. A concordance analysis between tissue and plasma was performed. Sixty-five advanced EGFR-mutated NSCLC patients treated with osimertinib in first- (n = 56) or in second-line (n = 9) were included. We managed to perform tissue and liquid biopsies in 65.5% and 89.7% of patients who experienced osimertinib progression, respectively. Acquired resistance mechanisms were identified in 80% of 25 patients with post-progression samples, with MET amplification (n = 8), EGFR C797S (n = 3), and SCLC transformation (n = 2) the most frequently identified. The mean concordance rates between tissue and plasma for the EGFR activating mutation and for the molecular resistance mechanisms were 87.5% and 22.7%, respectively. Resistance to osimertinib demonstrated to be highly heterogeneous, with MET amplification the main mechanism. Plasma genotyping is a relevant complementary tool which might integrate tissue analysis for the study of resistance mechanisms.

Front-line therapy for brain metastases and non-brain metastases in advanced epidermal growth factor receptor-mutated non-small cell lung cancer: a network meta-analysis.

The brain is a common metastatic site in patients with non-small cell lung cancer (NSCLC), resulting in a relatively poor prognosis. Systemic therapy with epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) is recommended as the first-line treatment for EGFR-mutated, advanced NSCLC patients. However, intracranial activity varies in different drugs. Thus, brain metastasis (BM) should be considered when choosing the treatment regimens. We conducted this network meta-analysis to explore the optimal first-line therapeutic schedule for advanced EGFR-mutated NSCLC patients with different BM statuses. Randomized controlled trials focusing on EGFR-TKIs (alone or in combination) in advanced and EGFR-mutant NSCLC patients, who have not received systematic treatment, were systematically searched up to December 2021. We extracted and analyzed progression-free survival (PFS) and overall survival (OS). A network meta-analysis was performed with the Bayesian statistical model to determine the survival outcomes of all included therapy regimens using the R software. Hazard ratios (HRs) and 95% confidence intervals (CIs) were used to compare intervention measures, and overall rankings of therapies were estimated under the Bayesian framework. This analysis included 17 RCTs with 5077 patients and 12 therapies, including osimertinib + bevacizumab, aumolertinib, osimertinib, afatinib, dacomitinib, standards of care (SoC, including gefitinib, erlotinib, or icotinib), SoC + apatinib, SoC + bevacizumab, SoC + ramucirumab, SoC + pemetrexed based chemotherapy (PbCT), PbCT, and pemetrexed free chemotherapy (PfCT). For patients with BM, SoC + PbCT improved PFS compared with SoC (HR = 0.40, 95% CI: 0.17-0.95), and osimertinib + bevacizumab was most likely to rank first in PFS, with a cumulative probability of 34.5%, followed by aumolertinib, with a cumulative probability of 28.3%. For patients without BM, osimertinib + bevacizumab, osimertinib, aumolertinib, SoC + PbCT, dacomitinib, SoC + ramucirumab, SoC + bevacizumab, and afatinib showed superior efficacy compared with SoC (HR = 0.43, 95% CI: 0.20-0.90; HR = 0.46, 95% CI: 0.31-0.68; HR = 0.51, 95% CI: 0.34-0.77; HR = 0.50, 95% CI: 0.38-0.66; HR = 0.62, 95% CI: 0.43-0.89; HR = 0.64, 95% CI: 0.44-0.94; HR = 0.61, 95% CI: 0.48-0.76; HR = 0.71, 95% CI: 0.50-1.00), PbCT (HR = 0.29, 95% CI: 0.11-0.74; HR = 0.31, 95% CI: 0.15-0.62; HR = 0.34, 95% CI: 0.17-0.69; HR = 0.34, 95% CI: 0.18-0.64; HR = 0.42, 95% CI: 0.21-0.82; HR = 0.43, 95% CI: 0.22-0.87; HR = 0.41, 95% CI: 0.22-0.74; HR = 0.48, 95% CI: 0.31-0.75), and PfCT (HR = 0.14, 95% CI: 0.06-0.32; HR = 0.15, 95% CI: 0.09-0.26; HR = 0.17, 95% CI: 0.09-0.29; HR = 0.16, 95% CI: 0.10-0.26; HR = 0.21, 95% CI: 0.12-0.35; HR = 0.21, 95% CI: 0.12-0.39; HR = 0.20, 95% CI: 0.12-0.31; HR = 0.23, 95% CI: 0.16-0.34) in terms of PFS. And, SoC + apatinib showed relatively superior PFS when compared with PbCT (HR = 0.44, 95% CI: 0.22-0.92) and PfCT (HR = 0.21, 95% CI: 0.12-0.39), but similar PFS to SoC (HR = 0.65, 95% CI: 0.42-1.03). No statistical differences were observed for PFS in patients without BM between PbCT and SoC (HR = 1.49, 95% CI: 0.84-2.64), but both showed favorable PFS when compared with PfCT (PfCT vs. SoC, HR = 3.09, 95% CI: 2.06-4.55; PbCT vs. PfCT, HR = 0.14, 95% CI: 0.06-0.32). For OS, SoC + PbCT was most likely to rank first in patients with and without BM, with cumulative probabilities of 46.8%, and 37.3%, respectively. Osimertinib + bevacizumab is most likely to rank first in PFS in advanced EGFR-mutated NSCLC patients with or without BM, and SoC + PbCT is most likely to rank first in OS.

Circulating tumor DNA to guide furmonertinib monotherapy or combination therapy in advanced EGFR mutant non-small cell lung cancer (NSCLC): A randomized, open-label, multicenter study (FOCUS-C).

TPS9150 Background: Detection of EGFR ctDNA after several weeks EGFR-TKIs treatment was an effective method to identify prognosis of advanced EGFR mutant NSCLC patients. Patients with uncleared EGFR ctDNA had shorter progression-free survival (PFS) ( Mack PC et al; CCR 2022). However, whether they can benefit from EGFR-TKI combination therapy has not been reported. Furmonertinib (AST2818), a potent, orally bioavailable, highly brain penetrant, third generation EGFR-TKI with unique chemical structure designed to improve potency and specificity, showed superior efficacy compared with gefitinib as first-line therapy in EGFR mutant NSCLC along with an acceptable safety profile without new signals ( Shi, YK et al.; Lancet Respir Med 2022). We hypothesized that monitoring clearance of EGFR ctDNA in blood could rationally guide subsequent monotherapy or combination therapy with furmonertinib and will improve outcomes in patients with uncleared EGFR ctDNA. Methods: The FOCUS-C study is a multicenter, open-label, randomized study. Patients who are aged 18 years or older and have histologically confirmed, locally advanced or metastatic, stage IIIB, IIIC, or IV unresectable NSCLC with EGFR exon 19 deletions (19Del) or exon 21 Leu858Arg mutation (L858R) on tissue biopsy and plasma will be treated with furmonertinib. Eligible patients with uncleared EGFR 19Del or L858R ctDNA after 3 weeks furmonertinib treatment will be stratified according to EGFR mutation (19Del or L858R), central nervous system metastases (with or without) and detectable accompanying gene aberrances in plasma (with or without) and randomly assigned (2: 2: 1) to receive furmonertinib or furmonertinib plus chemotherapy (pemetrexed and carboplatin for 4 cycles followed by maintenance pemetrexed) or furmonertinib plus chemotherapy plus bevacizumab (pemetrexed, carboplatin and bevacizumab for 4 cycles followed by maintenance pemetrexed and bevacizumab) in 21-day cycles until disease progression, the occurrence of intolerable toxicities, withdrawal of consent, or other discontinuation reasons judged by the investigators. The primary endpoint is PFS between furmoneritnib plus chemotherapy versus furmonertinib alone. Secondary endpoints include PFS, objective response rate, duration of response, disease control rate, overall survival and safety. Several exploratory endpoints will also be evaluated based on ctDNA detection by next-generation sequencing (Genecast, Wuxi, China). The study is enrolling. 34 patients had been enrolled till 2nd Feb 2023. Clinical trial information: NCT05334277 .

Retreatment with EGFR inhibitor in non-small cell lung cancer patients previously exposed to EGFR-TKI: A systematic review and meta-analysis.

e21159 Background: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) are the standard therapy for EGFR-mutated non-small cell lung cancer (NSCLC) patients. Unfortunately, patients eventually develop resistance to EGFR-TKI and disease progression. Re-exposure after a drug-free interval may be an alternative to overcome tumor resistance. We performed a systematic review and meta-analysis to assess EGFR-TKI retreatment’s efficacy in advanced NSCLC. Methods: We systematically searched PubMed, Embase, and Cochrane databases for clinical trials and observational cohort studies evaluating EGFR-TKI retreatment in advanced NSCLC patients. We aimed to assess the objective response rate (ORR), disease control rate (DCR), and survival outcomes. Subgroup analyses were performed according to the type of EGFRmutation and the TKI drug used in retreatment. We further stratified studies to assess the efficacy of rechallenging with the same drug used initially or a different one. Heterogeneity was assessed using the Cochran Q test, and I2 statistics and random effects models were fitted. Results: We included 16 studies (7 prospective clinical trials, and 9 retrospective cohorts) with 806 patients. Most of them had adenocarcinoma (70.8%), were females (58.1%), and were non-smokers (74.5%). The most frequently TKI given as the initial treatment was gefitinib (58.1%), whereas in the rechallenge it was erlotinib (36.6%) followed by gefitinib (31.6%). In a pooled analysis of patients who were retreated with TKI, the median PFS was 4.1 months (95%CI 3.0 - 4.4), and OS was 12.6 months (95%CI 10.2 - 12.6). ORR was 16% (95%CI 10 - 22%) and DCR was documented in 63% (95%CI 0.54 - 0.72%). Patients harboring a sensitive EGFR mutation had a significantly higher DCR, compared to patients with EGFRT790M mutation, and those with unknown mutational status, (DCR: 70%, 62%, and 48%, respectively, p = 0.02). Patients rechallenged with gefitinib, erlotinib, or afatinib had a similar DCR of 60%, while patients re-exposed to osimertinib had a greater DCR of 70% (95%CI 59 - 80%), (p < 0.01). Regarding ORR, no significant difference was observed amongst the groups defined by the type of EGFR mutation (p = 0.74) or type of TKI used (p = 0.05). Rechallenge using the same versus a different TKI resulted in similar ORR and DCR. In a subgroup analysis of 102 patients who had disease control with the first TKI, 62% (95%CI 45 – 79%) achieved disease control with TKI rechallenge. Conclusions: Our meta-analysis suggests that a subgroup of advanced EGFR-mutated NSCLC patients who failed TKI treatment benefit from rechallenge with an EGFR-TKI after a TKI-free interval. Re-exposure with either the same or a different TKI was shown to be equally effective. Patients treated with osimertinib and those with EGFR-sensitive mutations have better responses to the treatment.

The Role of Neutrophil-to-Lymphocyte Ratio in Advanced EGFR-Mutant NSCLC Patients Treated with First-Line Osimertinib.

Although serum neutrophil-to-lymphocyte ratio (NLR) is correlated with the outcome of various cancer types, its role in treatment-naïve, advanced, epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) patients treated with osimertinib remains uncertain. We have the intention to use this biomarker to evaluate the outcomes in NSCLC. Advanced EGFR-mutant NSCLC patients receiving osimertinib as the first-line treatment were included. We evaluated the prognostic role of baseline NLR and explored its association with patients' characteristics. A high NLR was defined as pretreatment serum NLR ≥ 5. A total of 112 eligible patients were included. The objective response rate was 83.7%. The median progression-free survival (PFS) and overall survival (OS) were 20.5 months (95% CI 14.5-26.5) and 47.3 months (95% CI 36.7-58.2), respectively. A high NLR predicted an inferior PFS (HR 1.90 [95% CI 1.02-3.51], P = 0.042) and OS (HR 3.85 [95% CI 1.39-10.66], P = 0.009). Patients with stage IVB disease were more likely to have a high baseline NLR than those with stage IIIB-IVA (33.9% vs 15.1%, P = 0.029). Other patients' characteristics did not correlate with the baseline NLR significantly. Patients with a high NLR had significantly more metastatic organs than those with a low NLR (2.5 ± 1.3 vs 1.8 ± 0.9, P = 0.012), particularly brain, liver, and bone metastasis. There was no significant association between NLR and intrathoracic metastasis. Baseline serum NLR could act as an important prognostic marker for EGFR-mutant NSCLC patients receiving first-line osimertinib. A high NLR was associated with higher metastatic burden, more extrathoracic metastases, and therefore, a worse outcome.

Treatment outcomes of EGFR-TKI with or without locoregional brain therapy in advanced EGFR-mutant non-small cell lung cancer patients with brain metastases.

This study aimed to evaluate the treatment outcomes of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) therapy alone or in combination with locoregional brain therapy for advanced EGFR-mutant non-small cell lung cancer (NSCLC) patients with brain metastases. A retrospective study involving 72 advanced EGFR-mutant NSCLC patients with brain metastases at the Vietnam National Cancer Hospital were conducted. Patients were divided into 2 groups: EGFR-TKI (erlotinib) monotherapy and EGFR-TKI combined with locoregional therapy (γ knife surgery - GKS or whole-brain radiation therapy). Evaluation criteria included clinical and laboratory characteristics, central nervous system (CNS) progression time, progression-free survival (PFS), overall survival (OS), T790M mutation rate, and adverse events. Epidermal growth factor receptor tyrosine kinase inhibitor monotherapy patients had better performance status (PS), fewer CNS symptoms, and significantly fewer brain metastases (p < 0.05). Median PFS and OS were 11 and 25 months, respectively, in both groups. Patients with PS 0-1 had longer median PFS (15 months) than those with PS 2 (7 months) (p = 0.039). Exon 19 deletion patients in both groups had longer median OS (26 months) than those with L858R exon 21 (15 months) (p = 0.023). Patients with T790M mutation who received osimertinib after progression had longer median OS (41 months vs. 23 months, p = 0.0001). Median time to CNS progression was 13.9 months (48 patients). Longer time to CNS progression correlated with longer OS (R2 = 0.89). Epidermal growth factor receptor tyrosine kinase inhibitor therapy, with or without locoregional therapy, is effective for advanced EGFR-mutant NSCLC patients with brain metastases. Exon 19 deletion patients had better prognosis.

The effect of EGFR-TKIs on survival in advanced non-small-cell lung cancer with EGFR mutations: A real-world study.

Few large-scale studies have been published using real-world data related to overall survival (OS) improvements in advanced epidermal growth factor receptor (EGFR)-mutant lung cancer patients; therefore, little is known regarding the characteristics of patients who could benefit most from EGFR-tyrosine kinase inhibitors (TKIs). Our study aimed to assess whether EGFR-TKI treatment confers survival benefits among advanced non-small-cell lung cancer (NSCLC) patients harboring EGFR mutations in the Chinese population. A total of 6451 advanced NSCLC patients were diagnosed between January 1, 2013 and June 30, 2019 in Zhejiang Cancer Hospital. Ultimately, 2864 patients with a confirmed EGFR mutation genotype were enrolled in our study. OS was measured from the time of diagnosis of advanced NSCLC until death or last follow-up. Median follow-up for OS of advanced EGFR-mutant NSCLC patients was 28.33 months in our study. Patients who received EGFR-TKIs demonstrated better survival compared to those without EGFR-TKI treatment (mOS: 29.77 vs. 22.97 months, p < 0.0001). A total of 451 patients switched to third-generation EGFR-TKI treatment and obtained a significantly better survival than those who adopted first-line third-generation EGFR-TKIs or those who did not receive third-generation EGFR-TKIs after disease progression with first- or second-generation EGFR-TKI treatment (mOS: 38.0 vs. 32.5 vs. 28.3 months, p < 0.0001). As for EGFR genotypes, patients with exon 19 deletion showed better OS, followed by those with L858R mutation (32.4 vs. 24.83 months, p=0.0013). NGS versus PCR testing showed no statistical differences with respect to survival outcomes (mOS: 27.5 vs. 27.47 months, p=0.6745). Advanced EGFR-mutant patients treated with EGFR-TKIs obtained absolute superior survival in the Chinese population.

The efficacy and tolerability of combining pemetrexed-based chemotherapy with gefitinib in the first-line treatment of non-small cell lung cancer with mutated EGFR: A pooled analysis of randomized clinical trials.

BackgroundEpidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) monotherapy is the standard of care in treating advanced non-small cell lung cancer (NSCLC). Nevertheless, whether adding pemetrexed-based chemotherapy to EGFR-TKI targeted therapy furtherly prolongs survival outcomes and improves responses remains controversial. Therefore, we conducted this pooled analysis to compare the efficacy and tolerability between gefitinib plus pemetrexed-based chemotherapy and gefitinib alone in the first-line treatment of advanced NSCLC patients with mutated EGFR.MethodsWe systematically searched PubMed, Web of Science, Embase, and Cochrane CENTRAL on June 23, 2022. Eligible studies were registered randomized clinical trials comparing gefitinib plus pemetrexed-based chemotherapy with gefitinib alone. The primary outcomes were overall survival (OS) and progression-free survival (PFS). Objective response rate (ORR), disease control rate (DCR), and discontinuation rate (DR) were explored as secondary outcomes.ResultsEight studies within five randomized clinical trials were eligible. Gefitinib combined with pemetrexed-based chemotherapy significantly prolonged OS (hazard ratio [HR] 0.57, 95% confidence interval [CI] 0.37–0.89, p = 0.0125) and PFS (HR 0.52, 95% CI 0.39–0.70, p < 0.0001) versus gefitinib alone. In subgroup analysis, patients with EGFR exon 19 deletion and exon 21 L858R could benefit from the addition of pemetrexed-based chemotherapy to gefitinib in terms of PFS (EGFR exon 19 deletion: HR 0.50, 95% CI 0.34–0.75, p = 0.0008; EGFR exon 21 L858R: HR 0.46, 95% CI 0.26–0.82, p = 0.0079) but not OS. In addition, ORR was improved after the administration of gefitinib plus pemetrexed-based chemotherapy against gefitinib (odds ratio [OR] 1.91, 95% CI 1.44–2.55, p < 0.0001). Both strategies showed comparable DCRs (OR 1.46, 95% CI 0.94–2.26, p = 0.0952) and DRs (risk ratio [RR] 2.80, 95% CI 0.69–11.44, p = 0.1509).ConclusionCompared with gefitinib alone, combining pemetrexed-based chemotherapy with gefitinib significantly improved OS and PFS in advanced EGFR-mutant NSCLC patients with acceptable tolerability. However, the accurate sub-population who could have OS benefits requires further validation.

EP08.02-035 Clinical Utility of Liquid Biopsy After Progression to First and Second-Generation TKIs in Advanced EGFR Mutant NSCLC Patients

Liquid biopsy (LB) has increased its usefulness in selecting precise therapy during different treatment phases in advanced EGFR-mutant (EGFRm) non-small cell lung cancer (NSCLC). In addition, it has played a prognostic and predictive role in EGFRm patients. Detection of main oncogenic driver alteration on LB has been associated with worse oncological outcomes and increased disease burden. This study aims to assess survival and clinical characteristics associated with LB findings at first EGFR-TKI progression.

EP08.02-082 Treatment Patterns and Outcomes of First-line Osimertinib-treated Advanced EGFR Mutated NSCLC Patients: A Real-world Study

Based on the survival benefit seen in the FLAURA trial, first-line osimertinib has become the standard-of-care for patients with EGFR mutation in advanced non-small cell lung cancer (NSCLC). However, treatment options are limited after progression on osimertinib. We explored survival outcomes, subsequent treatment lines, and metastatic sites post-osimertinib in patients with EGFR-mutated NSCLC treated with first-line osimertinib in a real-world setting.

EP08.02-164 The Effect of Metformin on Survival Outcomes of Advanced EGFR-mutant NSCLC Patients Treated with EGFR TKIs in Thailand

EGFR tyrosine kinase inhibitor (TKI) is mainstay treatment of advanced mutant NSCLC. Mechanism of action of EGFR TKI is inhibitory effects on cell proliferation via through down regulation of AKT and MAPK signaling pathways. Metformin may have direct effect on cancer cells by the similar pathway. The synergistic effect of metformin and EGFR TKI on survival outcomes has been explored. This is the first study in Thailand aim to evaluate the progression free survival (PFS) and overall survival (OS) in advanced EGFR-mutant non-small cell lung cancer (NSCLC) patients with or without type 2 diabetes (T2DM) who were treated with EGFR TKI and metformin/ or other oral hypoglycemic agent, and EKFR TKI alone, respectively.

PD-L1 strong expressions affect the clinical outcomes of osimertinib in treatment naïve advanced EGFR-mutant non-small cell lung cancer patients

The impact of strong Programmed Death-ligand 1 (PD-L1) expression on the clinical outcomes of osimertinib in treatment naïve advanced Epidermal Growth Factor Receptor (EGFR)-mutant Non-small Cell Lung Cancer (NSCLC) patients remains uncertain. We enrolled advanced NSCLC patients who harbored sensitizing EGFR mutation and were treated first-line with osimertinib between 2017 and 2021. The PD-L1 expression level was also tested. A total of 85 patients were included. The objective response rate to osimertinib was 78.9%, with the disease control rate being 90.8%. Median Progression-free Survival (PFS) was 22.1 months, while median Overall Survival (OS) was not reached (NR). Patients with the exon 19 deletion experienced better PFS than those with the exon 21 L858R mutation (NR vs 12.4 months, aHR 0.24 (95% CI, 0.10 to 0.57); p = 0.001). Seventy-one of these 85 patients had reported on their PD-L1 expression. Patients with a PD-L1 < 50% experienced longer PFS than patients with a PD-L1 ≧50% (26.5 vs 9.7 months, aHR 0.19 (95% CI, 0.06 to 0.67); p = 0.009). Additionally, patients with a PD-L1 < 50% experienced better OS than those with a PD-L1 ≧50% (NR vs 25.4 months, aHR 0.09 (95% CI, 0.01 to 0.70); p = 0.021). Strong expressions of PD-L1 in treatment naïve advanced EGFR-mutant NSCLC patients were associated with poor prognoses in those undergoing treatment with osimertinib as first-line therapy.

Efficacy of first-line treatments in the elderly and non-elderly patients with advanced epidermal growth factor receptor mutated, non-small cell lung cancer: a network meta-analysis

ObjectiveEpidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) are the current standard of care for advanced or metastatic non-small cell lung cancer (NSCLC) patients harboring EGFR activating mutations. However, the optimal strategy for elderly NSCLC patients is still under debate. This study was designed to explore the optimal first-line regimens by comparing diverse strategies for elderly and non-elderly EGFR-mutated NSCLC patients.MethodsA systematic review was conducted to summarize all available randomized controlled trials (RCTs) from PubMed, EMBASE, Cochrane Central Register of Controlled Trials databases, and international conferences before September 30, 2020. The primary outcome was progression free survival (PFS), and the secondary outcome was overall survival (OS). A network meta-analysis (NMA) was constructed using the Bayesian statistical model to synthesize the survival outcomes of all the treatments.ResultsIn total, 12 RCTs were deemed eligible for inclusion with 3779 patients who have received 10 diverse treatments including EGFR-TKIs. Results from the Bayesian ranking suggested that osimertinib was most likely to rank the first in overall population and in elderly patients in PFS, with the cumulative probabilities of 42.20% and 31.46%, respectively. In non-elderly group (younger than 65 years old), standard of care (SoC, representing first-generation EGFR-TKIs in this NMA) + chemotherapy ranked the first (31.66%). As for OS, SoC + chemotherapy ranked first in all patients (64.33%), patients younger than 65 years old (61.98%), or older than 65 years old (34.45%).ConclusionThe regimen of osimertinib is associated with the most favorable PFS in elderly advanced EGFR-mutated NSCLC patients, while SoC + chemotherapy is the optimal strategy in PFS for non-elderly NSCLC patients harboring EGFR activating mutations, and in OS for both elderly and non-elderly EGFR-mutated advanced NSCLC patients.Trial registrationINPLASY protocol 2020100061 https://doi.org/10.37766/inplasy2020.20.0061.

Concurrent High PD-L1 Expression and CD8+ Immune Cell Infiltration Predict PD-1 Blockade Efficacy in Advanced EGFR-Mutant NSCLC Patients

ObjectivesThe effectiveness of PD-1 blockade therapy in advanced epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) is limited. We investigated whether patient characteristics, PD-L1 expression, and immune cell (IC) status in the tumor microenvironment (TME) were associated with PD-1 blockade therapy outcomes. Materials and methodsWe retrospectively reviewed patients with advanced EGFR-mutant NSCLC treated with PD-1 blockade (nivolumab or pembrolizumab) between January 2016 and March 2018. The PD-L1 expression tumor proportion score (TPS) and types and distribution of ICs (CD8, PD-1, CD204, tumoral, and stromal) in the TME were analyzed. ResultsAmong 57 EGFR-mutant NSCLC patients treated with PD-1 blockade, 39 patients had sufficient tissues for analyzing the TME. The overall response rate (ORR) of PD-1 blockade was 12.3%. Only tumoral CD8 positive (CD8+) IC status was significantly associated with the response (median tumoral CD8+ICs: 299/mm2 vs. 115/mm2, P < .01). Among the 6 patients with concurrent high PD-L1 expression (TPS: ≥ 50%)/high tumoral CD8+ ICs (≥ 205/mm2), 5 (83.3%) showed a response and a significantly longer progression-free survival (PFS) (PFS: 9.4M vs. 1.8M, P < .01). In contrast, none of the 7 patients with high PD-L1 expression/low tumoral CD8+ICs (<205/mm2) showed a response. ConclusionConcurrent high PD-L1 expression and high tumoral CD8+ ICs could predict the response and longer PFS of PD-1 blockade therapy in EGFR-mutant patients.

Afatinib Treatment Alone or with Bevacizumab in a Real-World Cohort of Non-Small Cell Lung Cancer Patients with Epidermal Growth Factor Receptor Mutation.

Simple SummaryPrevious studies of first-generation EGFR-TKI erlotinib and bevacizumab combination have demonstrated superior treatment efficacy compared to erlotinib monotherapy for advanced EGFR-mutant NSCLC patients. Whether this combination benefit can also be observed in second-generation EGFR-TKI afatinib-treated patients remains unclear. The study presented a real-world cohort of advanced NSCLC patients with EGFR mutation treated by afatinib plus bevacizumab or single-agent afatinib. After balancing the key characteristics between the two treatment groups, the result showcased a similar therapeutic efficacy of afatinib plus bevacizumab compared to afatinib monotherapy. The incidence of drug-resistant mutation was also similar between the two groups. This study provided a clinical practice-based evidence that the additional benefit of bevacizumab is likely moderate in afatinib-treated patients.Background: Treatment outcome between afatinib alone or with bevacizumab in non-small cell lung cancer (NSCLC) patient with epidermal growth factor receptor (EGFR) mutation remains insufficiently reported. Methods: A total of 405 advanced NSCLC patients with sensitizing-EGFR mutation receiving first-line single-agent afatinib or with bevacizumab were grouped and propensity score-matched. Progression-free survival (PFS), overall survival (OS) and secondary T790M mutation were analyzed. Results: In the original cohort, 367 (90.6%) patients received afatinib treatment alone and 38 (9.4%) patients received afatinib plus bevacizumab. Patients who received bevacizumab combination were significantly younger (54.6 ± 10.9 vs. 63.9 ± 11.5; p < 0.001) compared to the afatinib alone group. After propensity score matching, the afatinib alone and afatinib plus bevacizumab groups contained 118 and 34 patients, respectively. A non-significantly higher objective response was noted in the afatinib plus bevacizumab group (82.4% vs. 67.8%; p = 0.133). In the propensity score-matched cohort, a bevacizumab add-on offered no increased PFS (16.1 vs. 15.0 months; p = 0.500), risk reduction of progression (HR 0.85 [95% CI, 0.52–1.40]; p = 0.528), OS benefit (32.1 vs. 42.0 months; p = 0.700), nor risk reduction of death (HR 0.85 [95% CI, 0.42–1.74] p = 0.660) compared to the single-agent afatinib. The secondary T790M rate in afatinib plus bevacizumab and afatinib alone groups was similar (56.3% vs. 49.4%, p = 0.794). Multivariate analysis demonstrated that EGFR L858R (OR 0.51 [95% CI, 0.26–0.97]; p = 0.044), EGFR uncommon mutation (OR 0.14 [95% CI, 0.02–0.64]; p = 0.021), and PFS longer than 12 months (OR 2.71 [95% CI, 1.39–5.41]; p = 0.004) were independent predictors of secondary T790M positivity. Conclusion: Bevacizumab treatment showed moderate efficacy in real-world, afatinib-treated NSCLC patients with EGFR-sensitizing mutation.

Front-Line ICI-Based Combination Therapy Post-TKI Resistance May Improve Survival in NSCLC Patients With EGFR Mutation.

BackgroundData on the use of immune checkpoint inhibitors (ICIs) in advanced non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutation are limited. The current study aimed to assess the efficacy of ICIs in EGFR-mutant advanced NSCLC and explore the relevant influential factors.Materials and MethodsRelevant clinical data of EGFR-mutant NSCLC patients who had received ICIs were collected from multiple hospitals. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were overall survival (OS), objective response rate (ORR), and relevant influential factors.ResultsA total of 122 advanced EGFR-mutant NSCLC patients were included in the final analysis. The total cohort had an objective response rate (ORR) of 32.0%, a median progression-free survival (mPFS) of 5.0 months, and a median overall survival (mOS) of 14.4 months. Among 96 patients with common EGFR mutations (19Del, 52 patients; L858R, 44 patients), those who were administered front-line ICI exhibited better survival benefits than those who received later-line ICI after disease progression on tyrosine kinase inhibitors (TKIs) treatment (mPFS: 7.2 months vs. 3.4 months, respectively, P < 0.0001; mOS: 15.1 months vs. 8.4 months, respectively, P <0.0001). Moreover, the efficacy of ICI-based combination therapy was better than that of ICI monotherapy (mPFS: 5.0 months vs. 2.2 months, respectively, P = 0.002; mOS: 14.4 months vs. 7.0 months, respectively, P = 0.001). Multivariate analysis showed that ICI-based combination therapy and front-line ICI administration after progression on EGFR-TKI were associated with significant improvements in both PFS and OS (P < 0.05). A high PD-L1 expression (tumor proportion score, TPS≥50%) and the EGFR L858R mutation were only significantly associated with a better PFS (P <0.05). A better Eastern Cooperative Oncology Group (ECOG) status was independently associated with a favorable OS (P <0.05).ConclusionsTaken together, combination immunotherapy in front-line was associated with improvement of survival in EGFR-mutant NSCLC patients post-TKI resistance. Further prospective studies with large sample sizes are required to identify the optimal combinatorial treatment strategy.

The impact of different first-line EGFR-TKIs on the clinical outcome of sequential osimertinib treatment in advanced NSCLC with secondary T790M

The impact of different first-line epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI)s to the clinical efficacy of osimertinib in EGFR-mutant non-small-cell lung cancer (NSCLC) patients with acquired T790M was still unclear. We enrolled 733 advanced EGFR-mutant NSCLC patients with gefitinib, erlotinib or afatinib as first-line EGFR-TKIs treatment for analysis. 373 patients received re-biopsies after progressive disease to first-line EGFR-TKIs treatment, and the total positive rate of T790M was 51.7%. 151 patients who harbored T790M received osimertinib as subsequent treatment. Among them, the median progression-free survival (PFS) of first-line EGFR-TKI (PFS1) was 14.0 months, and the median PFS of osimertinib (PFS2) was 10.1 months. The median PFS1 + PFS2 was 27.5 months, and the median overall survival from first-line EGFR-TKI was 61.3 months. Concerning different first-line EGFR-TKIs, the median PFS2 was 10.9 months in the gefitinib group, 10.0 months in the erlotinib group, and 6.7 months in the afatinib group (p = 0.534). The median PFS1 + PFS2 was 27.7 months, 26.8 months and 24.0 months in the gefitinib, erlotinib, and afatinib group, respectively (p = 0.575). In conclusion, both first-generation and second-generation EGFR-TKIs sequential osimertinib treatment provided good clinical efficacy in advanced EGFR-mutant NSCLC patients with acquired T790M mutation.

Associated factors for poor response in advanced EGFR-mutated NSCLC patients under tirosine kinasa inhibitors: Peruvian real-world data.

e21214 Background: Although tirosine kinasa inhibitors (TKI) are the first line of therapy in patients with non-small cell lung cancer (NSCLC) harboring EGFR mutations, some patients do not have benefit with TKI. The aim of this study is to determinate if there are associated factors with poor response with TKI. Methods: This is an observational study of a single institution patient cohort. Clinical records of advanced NSCLC patients harboring EGFR mutations that have received TKI as first line therapy in ALIADA cancer center since january 2015 until december 2019 were evaluated. Clinical records with incomplete data were excluded. Type of EGFR mutation, type of TKI agent, BMI, neutrophil, lymphocyte, platelets, neutrophil/lymphocyte ratio (NLR) and platelet/lymphocyte ratio (PLR) were evaluated in all cases. Poor responders where defined as NSCLC patients who progressed within 3 months with erlotinib or afatinib and 6 months within osimertinib. The statistical analysis was performed with SPSS version 20 and MINITAB 14. Results: 46 patients were finally included. Mean age was 63.6 ± 11.7 years, 54.4% of patients were female and 93% had adenocarcinoma histology. Mean neutrophil, lymphocyte and platelet counts were 4.82, 1.96 and 396.07 respectively; meanwhile mean NLR was 4.85 and mean PLR 282.36. 45% of patients were overweight or obese. 65.2% of all mutations were EGFR exon 19 deletions, 19.6% were exon21 L858R substitution and 10% EGFR uncommon mutations (de novo exon20 T790 mutations and exon18 G719X substitution). 45.7% of patients received erlotinib, 37% received afatinib and 17.3% osimertinib. 61.5% of patients achieved partial response, 17.3% achieved complete response, 9.6% stable disease and 28.3% of patients were poor responders to TKI treatment. In bivariate analysis, odds ratio for poor response was more associated with uncommon mutations (OR = 8.21, IC95% = 1.94-97.18; p = 0.025) and patients with neutrophil &gt; 4.82 (OR = 1.65, IC 95% = 1.08-2.52; p = 0.020). Odds ratio for poor response decreases 95% with erlotinib (OR = 0.05, IC95% = 0.00-0.58; p = 0.016). There was no statistical association with the rest factors. In the logistic regression model, poor response to TKI are related to uncommon EGFR mutations (OR = 8.21, 95% CI = 1.3-51.99; p = 0.009) and neutrophils &gt; 4.82 (OR: 1.85, 1.13 -3.05). Conclusions: Disease progression is a phenomenon present in patients with EGFR-mutated NSCLC. According to our data, poor response is associated with uncommon EGFR mutations, TKI agent (erlotinib) and neutrophil count level. We need larger studies to validate our results.

The prognostic role of body-mass index (BMI) for advanced EGFR positive non-small cell lung cancer (NSCLC) patients treated with osimertinib.

e21078 Background: In advanced EGFR-mutated non-small cell lung cancer (NSCLC) population, osimertinib represents the standard of care both for EGFR tyrosine kinase (TK) inhibitor-naive patients and for those with EGFR-mutated NSCLC harboring the T790M mutation and progressed following prior EGFR-TK inhibitor. No clear data supports the relationship between body mass index (BMI) and osimertinib's efficacy. Methods: We conducted a single-center, retrospective study including advanced EGFR-mutated NSCLC patients treated with Osimertinib as second or subsequent lines from February 2016 to December 2020. We examined survival outcomes according to BMI among a BMI-low group ( &lt; 25 Kg/mq2) and BMI-high group (≥25 Kg/mq2). Results: A total of 37 consecutive patients received osimertinib as second- or subsequent line at our Institution. The mean age was 63.5 years (range 34-83 years), 24 (65%) patients were female, 16 (59%) were former or never smokers, and 25 (67%) had three or more metastatic sites at the start of therapy. The BMI-low group includes 25 (67%) patients and the BMI-high group 12 (33%), respectively. Globally, the median overall survival (mOS) was 29.9 mo. (95% CI, 18.2 – NR) and median progression-free survival (mPFS) was 17.5 mo. (95% CI, 15.7-33.3). The median follow-up was 32.5 mo. (IQR, 13.35-42.06). The mPFS was 21.0 mo. (95 CI, 16.8 – NR) within the BMI-low group and 16.8 mo. (95 CI, 4.4 – NR) within the BMI-high group, respectively (p = 0.03). Analogously, the mOS within the BMI-low group was 29.9 mo. (95 CI, 20.8 – NR) versus 18.2 mo. (95 CI, 11.7- NR) for the BMI-high group (p = 0.01). A BMI ≥25 Kg/mq2 constituted an independent risk factor for mortality [HR 3.99, (95 CI, 1.2 – 13.2), p 0.02] at multivariate analysis, including also age and number of metastatic sites. The BMI-high group showed a non-significant tendency to progression [HR 2.76, (95 CI, 0.9 - 8.3), p 0.06] at the same multivariate analysis. Conclusions: In our experience, a BMI ≥25 Kg/mq2 negatively influenced survival outcomes of 2nd-line osimertinib' treated NSCLC patients. More comprehensive studies are warranted to confirm these findings.

Cost-effectiveness analysis of first-line treatments for advanced epidermal growth factor receptor-mutant non-small cell lung cancer patients.

ObjectivesRecent studies showed prolonged survival for advanced epidermal growth factor receptor (EGFR)‐mutant non‐small cell lung cancer (NSCLC) patients treated with both monotherapies and combined therapies. However, high costs limit clinical applications. Thus, we conducted this cost‐effectiveness analysis to explore an optimal first‐line treatment for advanced EGFR‐mutant NSCLC patients.Materials and MethodsSurvival data were extracted from six clinical trials, including ARCHER1050 (dacomitinib vs. gefitinib); FLAURA (osimertinib vs. gefitinib/erlotinib); JO25567 and NEJ026 (bevacizumab +erlotinib vs. erlotinib); NEJ009 (gefitinib +chemotherapy vs. gefitinib); and NCT02148380 (gefitinib +chemotherapy vs. gefitinib vs. chemotherapy) trials. Cost‐related data were obtained from hospitals and published literature. The effect parameter (quality‐adjusted life year [QALY]) was the reflection of both survival and utility. Incremental cost‐effectiveness ratio (ICER), average cost‐effectiveness ratio (ACER), and net benefit were calculated, and the willingness‐to‐pay (WTP) threshold was set at $30828/QALY from the perspective of the Chinese healthcare system. Sensitivity analysis was performed to explore the stability of results.ResultsWe compared treatment groups with control groups in each trial. ICERs were $1897750.74/QALY (ARCHER1050), $416560.02/QALY (FLAURA), ‐$477607.48/QALY (JO25567), ‐$464326.66/QALY (NEJ026), ‐$277121.22/QALY (NEJ009), ‐$399360.94/QALY (gefitinib as comparison, NCT02148380), and ‐$170733.05/QALY (chemotherapy as comparison, NCT02148380). Moreover, ACER and net benefit showed that the combination of EGFR‐TKI with chemotherapy and osimertinib was of more economic benefit following first‐generation EGFR‐TKIs. Sensitivity analyses showed that the impact of utilities and monotherapy could be cost‐effective with a 50% cost reduction.ConclusionFirst‐generation EGFR‐TKI therapy remained the most cost‐effective treatment option for advanced EGFR‐mutant NSCLC patients. Our results could serve as both a reference for both clinical practice and the formulation of medical insurance reimbursement.