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

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 > 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 > 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 ( < 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.

Overall Survival Analysis of Bevacizumab Plus Erlotinib for Advanced EGFR-Mutant Metastatic NSCLC

Overall Survival Analysis of Bevacizumab Plus Erlotinib for Advanced <i>EGFR</i>-Mutant Metastatic NSCLC

Comparative analysis of first-line treatment regimens for advanced EGFR-mutant non-small cell lung cancer patients with stable brain metastases

To compare the survival outcomes of first-line treatment regimens for advanced epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) patients with stable brain metastases. We conducted a systematic review of available data from randomized controlled trials (RCTs) of first-line treatment regimens of NSCLC patients with stable brain metastases. Progression free survival (PFS) and overall survival (OS) were extracted and analysed from the RCT subgroups. A network meta-analysis was constructed using the Bayesian statistical model to synthesize the survival outcomes of all the treatments. The analysis included 6 eligible RCT subgroups with 417 patients and 7 treatment regimens osimertinib, afatinib, first-generation EGFR-TKI (gefitinib or erlotinib), erlotinib + bevacizumab, gefitinib + pemetrexed + carboplatin, gemcitabine + cisplatin, and pemetrexed + cisplatin. Of these seven treatment regimens, gefitinib + pemetrexed + carboplatin had the highest potential for favorable PFS and OS, followed by osimertinib, in the treatment of advanced EGFR-mutant NSCLC patients with stable brain metastases. None of the results met the predetermined statistical significance of P<0.05. The regimens of "Gefitinib + pemetrexed + carboplatin" and "Osimertinib" were associated with the most favorable PFS and OS compared to the other therapies in advanced EGFR-mutant NSCLC patients with stable brain metastases, although the difference between these regimens and the others was not statistically significantly different.

Genomic landscape of acquired resistance to third-generation EGFR tyrosine kinase inhibitors in EGFR T790M-mutant non-small cell lung cancer.

EGFR tyrosine kinase inhibitors (TKIs) have shifted the treatment paradigm in advanced EGFR-mutant non-small cell lung cancer (NSCLC). However, patients who are treated with TKIs inevitably develop acquired resistance by mechanisms that are not fully understood. The purpose of this study was to investigate the mechanism of acquired resistance after treatment with third-generation EGFR TKIs. Advanced EGFR-mutant NSCLC patients treated with olmutinib or osimertinib who underwent a rebiopsy before treatment or after progression were analyzed retrospectively. Targeted sequencing was performed on 113 specimens (77 pretreatment and 36 posttreatment, including 15 paired samples) obtained via tissue biopsy. A total of 98 patients were included, 53 (54%) of whom were treated with osimertinib and 45 (46%) of whom were treated with olmutinib. Of the 36 patients with posttreatment biopsies, EGFR-dependent mechanisms, including C797S and L718Q mutations, were observed in 10 (28%) patients: 29% (5/17) in the osimertinib group and 26% (5/19) in the olmutinib group. EGFR-independent mechanisms were detected in 21 patients (21/36, 58%): 65% (11/17) in the osimertinib group and 53% (10/19) in the olmutinib group. The disappearance of EGFR T790M was detected in 14 patients (39%); of these patients, 59% (10/17) were treated with osimertinib and 21% (4/19) were treated with olmutinib. Patients who lost the T790M mutation were more inclined to show EGFR-independent pathways as a secondary resistance mechanism. Resistance acquired after third-generation EGFR TKIs is associated with diverse pathways; however, treatment with osimertinib is primarily associated with a loss of EGFR T790M and the subsequent emergence of EGFR-independent resistance mechanisms.

Detection of plasma T790M mutation after the first generation EGFR-TKI resistance of non-small cell lung cancer in the real world.

BackgroundThe epidermal growth factor receptor (EGFR) gene has been identified as the driving gene of non-small cell lung cancer (NSCLC), and EGFR-tyrosine kinase inhibitor (TKI) has shown efficacy, but acquired resistance is inevitable. It has been confirmed that the secondary EGFR Thr790Met (T790M) mutation accounts for about 50% of the mechanisms of acquired resistance to EGFR-TKI. The third-generation of EGFR-TKI has significantly efficacy in advanced T790M-positive NSCLC patients. Therefore, it is necessary to detect the status of T790M in patients with acquired resistance after first generation EGFR-TKI. The objective of this study was to investigate the positive rate of plasma test T790M mutation and its relationship with different clinical characteristics, and the frequency of T790M mutation in advanced EGFR-mutant NSCLC patients with acquired resistance after firstline EGFR-TKI treatment.MethodsPatients from a single clinical center (Taizhou hospital) were recruited prospectively from September 2017 to June 2018. The eligibility criteria of the trial included the following: (I) aged 18 years or older, histologically confirmed NSCLC stage IIIB/st and EGFR mutation positive; (II) progressive disease (PD) after first generation EGFR-TKI by RECIST v1.1, with PFS>3 months; (III) no third generation TKI treatment. All patients signed informed consent, had 10 mL of blood drawn, and were evaluated for the presence of T790M gene by amplification refractory mutation system (ARMS). The study was approved by the Ethics Committee of Taizhou Hospital (ethical batch number: 201637).ResultsA total of 189 patients were included in the analysis. The overall T790M mutation rate of plasma detection was 36.51% (69/189). The positive rate of T790M mutation after the failure of first generation EGFR-TKI treatment was not correlated with the patient’s age, sex, and the type of first generation TKI drugs. However, it was related to the mutation type of EGFR in baseline and the mode of progression according to reports by Wu et al. The frequency of T790M mutation among patients with initial exon 19 deletion mutation, exon 21 L858R point mutation, and other mutations were 45.45%, 26.19% and 33.33%, respectively. The mutation rate of T790M in 19del mutant patients was higher than that of L858R mutation and other mutations (P=0.026). The frequency of T790M mutation in local progression patients was 50% after the first generation TKI was resistant to drug treatment: in gradual progression it was 26.92%, and in dramatic progression it was 38.10%. The frequency of T790M mutation of patients with local progression was significantly higher (P=0.031).ConclusionsThe patients with EGFR mutations after the first generation of EGFR-TKI-acquired resistance of NSCLC were evaluated for their plasma EGFR mutation status, and the overall T790M mutation rate of was 36.51%. The frequency of T790M mutation with initial mutation of 19 del was higher than that of L858R mutation and other mutations, and local progression was higher than that in patients with gradual progression and dramatic progression.

1417P - Analysis of circulating tumour DNA in paired plasma and sputum samples of EGFR-mutated NSCLC patients

Abstract Background Liquid biopsy is a minimally invasive strategy to detect genetic alterations in non-small cell lung cancer (NSCLC) patients. In particular, it is clinically useful for the detection of the EGFR T790M resistance mutation in advanced EGFR-mutated NSCLC patients who had progressed under treatment with an EGFR-TKI. While plasma analysis is commonly performed, sputum could be another potential source for circulating tumor DNA (ctDNA) in NSCLC, which has not yet been entirely evaluated. Methods Paired plasma and sputum samples from 23 patients with EGFR-mutated lung adenocarcinoma were analyzed for EGFR exon 19 deletions (del19), L858R, and T790M mutations by droplet digital PCR (ddPCR). All patients had histologically confirmed lung adenocarcinoma with EGFR mutations in their initial tissue biopsy at diagnosis. Results Tissue genotyping at diagnosis revealed 18 patients with EGFR del19 and 5 patients with L858R mutations. Among the 18 EGFR del19-positive patients, 8 showed concordant test results in plasma and sputum (2 positive, 6 negative), 6 had del19-positive plasma samples but del19-negative sputum samples, 4 were del19 negative in plasma and del19 positive in sputum. Among 5 L8585R-positive patients, 4 had concordant test results in plasma and sputum (3 positive, 1 negative), one patient was L858R positive in the plasma sample but L858R negative in sputum. In 10 out of 23 patients the T790M mutation was assessed in paired samples, 9 showed concordant test results in plasma and sputum (3 positive, 6 negative), one patient was T790M positive only in the sputum sample. Conclusions Our results show a high concordance between plasma and sputum for EGFR L858R and T790M mutation testing. A lower concordance was observed for EGFR del19. Thus liquid biopsy from sputum is a promising strategy that should be further evaluated. Clinical trial identification GS1-EK4/479-2017, 20.07.2017 EK-18-172-0918, 08.11.2018. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest.

Impact of next-generation sequencing on clinical outcomes in advanced EGFR-mutant lung cancer patients after resistance to osimertinib.

e20726 Background: Osimertinib is used to treat EGFR-mutant non–small-cell lung cancer (NSCLC) with acquired T790M mutation. Next-generation sequencing (NGS) is helpful to understand mechanisms of resistance to osimertinib. However, whether NGS after resistance to osimertinib has an impact on clinical outcomes of patients treated with subsequent treatments has been elusive. Methods: We retrospectively identified advanced, EGFR-mutant T790M positive NSCLC patients treated with the 2nd or further-line osimertinib from January 27th, 2015 to January 31th, 2019 at our institute. Genetic profiles and clinical outcomes were analyzed. These patients were divided into 2 groups based on NGS data after resistance to osimertinib. Progression-free survival1 (PFS1) was calculated from the start of osimertinib to progression or death. PFS2 was calculated from the start of subsequent-line treatment to progression or death. Objective response rate (ORR) of subsequent-line treatments was evaluated by RECIST1.1. Results: Among 187 patients treated with osimertinib, 66 had NGS data and 27 had no NGS data after progression. Maintained EGFR T790M was detected in 23 patients (34.8%), and loss of T790M was seen in 43 patients (65.2%). Mutations of EGFR C797S were detected in 12 patients (18.1% overall; 52.2% of those with retained T790M), 11 in cis with a maintained T790M, 1 in trans with a maintained T790M. There was no significant difference in median PFS1 between the maintained T790M group and the loss of T790M group (10.8 vs. 7.0 months, P = 0.085).The NGS group was treated with TKIs according to the results of NGS strictly (n = 36), the non-NGS group received chemotherapy or best supportive care (n = 11).There was a significant difference in median PFS2 between the NGS and non-NGS groups (5.4 vs. 2.9 months, P = 0.043). The ORR of the NGS group was significantly superior to that of the non-NGS group (16.2% vs 11.1%, P &lt; 0.001). Conclusions: NGS after resistance to osimertinib might favor clinical outcomes of advanced EGFR-mutant NSCLC patients. Further more investigations are warranted.

Comparing the efficacy of concurrent EGFR-TKI and whole-brain radiotherapy vs EGFR-TKI alone as a first-line therapy for advanced EGFR-mutated non-small-cell lung cancer with brain metastases: a retrospective cohort study.

BackgroundNon-small-cell lung cancer (NSCLC) is a global public health problem, and brain is a common metastatic site in advanced NSCLC. Currently, whole-brain radiotherapy (WBRT) remains a major treatment for brain metastases, while EGFR-tyrosine kinase inhibitor (TKI) is the standard treatment for advanced NSCLC harboring EGFR mutations, which is also effective for brain metastases. However, whether EGFR-TKIs plus radiotherapy is superior to EGFR-TKIs alone for the treatment of advanced EGFR-mutant NSCLS with brain metastases remains controversial. This study aimed to compare the efficacy of concurrent EGFR-TKIs and WBRT vs EGFR-TKI alone in a retrospective cohort of advanced EGFR-mutant NSCLS with brain metastases.Patients and methodsThe medical records of 104 treatment-naïve, advanced EGFR-mutant NSCLC patients with brain metastases were retrospectively reviewed, and there were 56 patients undergoing concurrent EGFR-TKI and WBRT, and 48 patients given EGFR-TKI alone, including 20 cases with salvage WBRT upon brain metastasis progression. The survival prognosis was compared between the two cohorts.ResultsThe baseline clinicopathologic factors were balanced between the two cohorts. After a median follow-up of 23 months, 35.6% of the study subjects survived. Concurrent EGFR-TKI and WBRT significantly improved the median intracranial PFS (iPFS) compared with EGFR-TKI alone (17.7 vs 11.0 months, P=0.015); however, no significant difference was seen in median overall survival between the two cohorts (28.1 vs 24.0 months, P=0.756). In addition, the median iPFS was found to significantly vary in the number of brain metastases (≤3 vs>3 metastases: 18.0 vs 12.5 months, P=0.044). Subgroup analysis showed that concurrent EGFR-TKI and WBRT improved median iPFS compared with EGFR-TKI alone in patients with more than three brain metastases (P=0.001); however, no significant difference was observed between the two regimens in patients with three or less brain metastases (P=0.526).ConclusionOur data demonstrate that concurrent EGFR-TKI and WBRT achieves longer iPFS than EGFR-TKI alone in advanced EGFR-mutant NSCLC with brain metastases. In advanced EGFR-mutant NSCLC with three or less brain metastases, EGFR-TKI alone may be an option as a first-line therapy.

Influence of afatinib dose on outcomes of advanced EGFR-mutant NSCLC patients with brain metastases

BackgroundAfatinib is an oral irreversible epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitor (TKI) indicated in first-line treatment of advanced EGFR-mutant (EGFRm+) non-small cell lung cancer (NSCLC). Dose dependent side effects can limit drug exposure, which may impact on extracranial and central nervous system (CNS) disease control.MethodsWe performed a retrospective study of 125 patients diagnosed with advanced EGFRm+ NSCLC treated with first-line afatinib at a tertiary Asian cancer center, exploring clinicopathological factors that may influence survival outcomes. Median progression free survival (PFS) was estimated using the Kaplan-Meier method. Comparison of PFS between subgroups of patients was done using log-rank tests and Cox proportional hazards models.ResultsOut of 125 patients, 62 (49.6%) started on 40 mg once daily (OD) afatinib, 61 (48.8%) on 30 mg OD and 1 (0.8%) on 20 mg OD. After median follow-up of 13.8 months from afatinib initiation, the observed response rate was 70.4% and median PFS 11.9 months (95% CI 10.3–19.3). 42 (33.6%) patients had baseline brain metastases (BM) and PFS of those who started on 40 mg OD (n = 17) vs. 30 mg OD (n = 25) was 13.3 months vs. 5.3 months (HR 0.39, 95% CI 0.15–0.99). BM+ patients who started on 40 mg had similar PFS to patients with no BM (13.3 months vs. 15.0 months; HR 0.79, 95% CI 0.34–1.80).ConclusionIn patients with advanced EGFRm+ NSCLC with BM+, initiating patients on afatinib 40 mg OD was associated with improved PFS compared to 30 mg OD, underscoring the potential importance of dose intensity in control of CNS disease.

Evaluation of Patients with Lung Cancer Treated with Epidermal Growth Factor Receptor–Tyrosine Kinase Inhibitor

AbstractEpidermal growth factor receptor–tyrosine kinase inhibitor (EGFR-TKI) is currently the standard therapy for EGFR-mutated non–small cell lung cancer (NSCLC). Gefitinib is the first EGFR-TKI marketed in Indonesia and has been used since 2012 in Dr. Soetomo General Hospital, a tertiary hospital in Surabaya, East Java, Indonesia. Although the drug had shown some positive results, the overall treatment outcome for Indonesian patients has not been reported yet. The aim of the study is to evaluate the progression-free survival (PFS), overall survival (OS), and subjective response of gefitinib as first-line treatment in advanced EGFR-mutated NSCLC patients in Dr. Soetomo General Hospital. This retrospective study includes all eligible patients treated from 2013 to 2016. Demographic data, performance status, tumor histopathologic types, treatment response, and adverse effects (AEs) during the treatment course were collected from patient's medical records. Objective response was based on RECIST 1.1. Quality of life was assessed using Eq. 5D questionnaire. From evaluable data of 63 patients, median PFS was 8.3 months (95% confidence interval [CI: 6.50–10.2) with median OS of 16 months (95% CI: 11.9–20.2). Eq. 5D scores were decreased in 21 (33.3%) patients, stable in 22 (34.9%), and increased in 20 (31.7%). The most common side effects were itchy skin rash in 52 (82%) patients and diarrhea in 29 (46%). Gefitinib as first-line therapy provides a good objective response and is generally well tolerated in patients with EGFR-mutated NSCLC in Dr. Soetomo General Hospital.

PD-L1 expression and its effect on clinical outcomes of EGFR-mutant NSCLC patients treated with EGFR-TKIs.

Objective:Epidermal growth factor receptor (EGFR) activation was reported to upregulate programmed death-ligand 1 (PD-L1) expression in lung cancer cells and subsequently contribute to immune escape, indicating its critical role in EGFR-driven lung tumors. This study characterized PD-L1 expression in patients with surgically resected EGFR-mutant non-small cell lung cancer (NSCLC). The effect of PD-L1 expression on clinical outcomes was also investigated in advanced EGFR-mutant NSCLC treated with EGFR-tyrosine kinase inhibitors (TKIs).Methods:In total, 73 patients with surgically resected NSCLC and EGFR mutations were identified. PD-L1 expression and CD8+ tumor-infiltrating lymphocyte (TIL) density were assessed by immunohistochemistry. A literature review of publications that assessed the predictive and prognostic value of PD-L1 expression in advanced EGFR-mutant NSCLC patients treated with EGFR-TKIs was performed.Results:Nineteen (26.0%) patients were positive for PD-L1 expression, which was significantly associated with concomitant KRAS mutation (P = 0.020) and marginally associated with higher CD8+ TILs density (P = 0.056). Positive PD-L1 expression was associated with markedly inferior overall survival (OS) in multivariate analysis (P = 0.032). The combination of PD-L1 and CD8+ TILs expression could be used to stratify the population into three groups with distinct prognoses. A meta-analysis of six publications showed that positive PD-L1 expression was not associated with OS [hazard ratio (HR) = 0.90; 95% confidence interval (CI), 0.42–1.38] or progression-free survival (HR = 1.03; 95 CI, 0.73–1.33) in advanced EGFR-mutant NSCLC patients receiving EGFR-TKIs. Conclusions:PD-L1 expression tended to correlate with CD8+ TIL expression, concomitant KRAS mutation, and poor survival in surgically resected EGFR-mutant NSCLC. PD-L1 expression was neither the predictive nor the prognostic factor in advanced EGFR-mutant NSCLC patients treated with EGFR-TKIs.

The efficacy and toxicity of afatinib in advanced EGFR-positive non-small-cell lung cancer patients after failure of first-generation tyrosine kinase inhibitors: a systematic review and meta-analysis.

The first generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), gefitinib and erlotinib, have become the standard first-line treatment for non-small-cell lung cancer (NSCLC) patients with EGFR mutation. However, there was no pooled analysis focused on the usage of the second-generation TKI, afatinib, in advanced EGFR-positive NSCLC patients after failure of first generation TKIs. Therefore, a meta-analysis was conducted to solve the above question. Electronic databases were searched for eligible literatures. ORR (objective response rate), DCR (disease controlled rate), PFS (progression-free survival), OS (overall survival) and primary grade 3/4 adverse events were pooled with the corresponding 95% confidence interval using R software. Sensitivity analyses and heterogeneity were quantitatively evaluated. A total of 545 EGFR-positive patients were available for analysis from five studies after detailed screening from 909 relevant studies. The pooled ORR and DCR of afatinib in EGFR-positive patients after failure of the first generation EGFR-TKIs were 0.12 (0.08-0.19) and 0.60 (0.53-0.68), respectively. Besides, the 6 m-PFS rate, 1 y-PFS rate and 6 m-OS rate were 0.26 (0.22-0.30), 0.08 (0.06-0.10) and 0.74 (0.56-0.86). The grade 3/4 rate of diarrhea and that of skin deformity were 0.23 (0.10-0.46) and 0.14 (0.05-0.33), respectively. Sensitivity analyses revealed similar results with lower heterogeneity. Considering the efficacy, toxicity and current availability, afatinib could be a therapeutic option for advanced EGFR mutated NSCLC patients after the failure of 1st-generation TKIs.

Osimertinib benefit inEGFR-mutant NSCLC patients withT790M-mutation detected by circulating tumour DNA

Approximately 50% of epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC) patients treated with EGFR tyrosine kinase inhibitors (TKIs) will acquire resistance by the T790M mutation. Osimertinib is the standard of care in this situation. The present study assesses the efficacy of osimertinib when T790M status is determined in circulating cell-free tumour DNA (ctDNA) from blood samples in progressing advanced EGFR-mutant NSCLC patients. ctDNA T790M mutational status was assessed by Inivata InVision™ (eTAm-Seq™) assay in 48 EGFR-mutant advanced NSCLC patients with acquired resistance to EGFR TKIs without a tissue biopsy between April 2015 and April 2016. Progressing T790M-positive NSCLC patients received osimertinib (80 mg daily). The objectives were to assess the response rate to osimertinib according to Response Evaluation Criteria in Solid Tumours (RECIST) 1.1, the progression-free survival (PFS) on osimertinib, and the percentage of T790M positive in ctDNA. The ctDNA T790M mutation was detected in 50% of NSCLC patients. Among assessable patients, osimertinib gave a partial response rate of 62.5% and a stable disease rate of 37.5%. All responses were confirmed responses. After median follow up of 8 months, median PFS by RECIST criteria was not achieved (95% CI: 4-NA), with 6- and 12-months PFS of 66.7% and 52%, respectively. ctDNA from liquid biopsy can be used as a surrogate marker for T790M in tumour tissue.

Impact of Continuing First-Line EGFR Tyrosine Kinase Inhibitor Therapy Beyond RECIST Disease Progression in Patients with Advanced EGFR-Mutated Non-Small-Cell Lung Cancer (NSCLC): Retrospective GFPC 04-13 Study.

Retrospective studies suggested a benefit of first-line tyrosine kinase inhibitor (TKI) treatment continuation after response evaluation in solid tumors (RECIST) progression in epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer (NSCLC) patients. The aim of this multicenter observational retrospective study was to assess the frequency of this practice and its impact on overall survival (OS). The analysis included advanced EGFR-mutated NSCLC patients treated with first-line TKI who experienced RECIST progression between June 2010 and July 2012. Among the 123 patients included (67 ± 12.7years, women: 69%, non smokers: 68%, PS 0-1: 87%), 40.6% continued TKI therapy after RECIST progression. There was no difference between the patients who did and did not continue TKI therapy with respect to progression-free survival (PFS1: 10.5 versus 9.5months, p = 0.4). Overall survival (OS) showed a non-significant trend in favor of continuing TKI therapy (33.0 vs. 21.2months, p = 0.054). Progressions were significantly less symptomatic in the TKI continuation group than in the discontinuation group (18% vs. 37%, p < 0.01). Univariate analysis showed a higher risk of death among patients with PS >1 (HR 4.33, 95 %CI: 2.21-8.47, p = 0.001), >1 one metastatic site (HR 1.96, 95 %CI: 1.06-3.61, p = 0.02), brain metastasis (HR 1.75, 95 %CI: 1.08-2.84, p = 0.02) at diagnosis, and a trend towards a higher risk of death in cases of TKI discontinuation after progression (HR 1.62, 95 %CI: 0.98-2.67, p = 0.056 ). In multivariate analysis only PS >1 (HR 6.27, 95 %CI: 2.97-13.25, p = 0.00001) and >1 metastatic site (HR 2.54, 95 %CI: 1.24-5.21, p = 0.02) at diagnosis remained significant. This study suggests that under certain circumstances, first-line TKI treatment continuation after RECIST progression is an acceptable option in EGFR-mutated NSCLC patients. NCT02293733.

A decade of EGFR inhibition in EGFR-mutated non small cell lung cancer (NSCLC): Old successes and future perspectives.

The discovery of Epidermal Growth Factor Receptor (EGFR) mutations in Non Small Cell Lung Cancer (NSCLC) launched the era of personalized medicine in advanced NSCLC, leading to a dramatic shift in the therapeutic landscape of this disease. After ten years from the individuation of activating mutations in the tyrosine kinase domain of the EGFR in NSCLC patients responding to the EGFR tyrosine kinase inhibitor (TKI) Gefitinib, several progresses have been done and first line treatment with EGFR TKIs is a firmly established option in advanced EGFR-mutated NSCLC patients. During the last decade, different EGFR TKIs have been developed and three inhibitors have been approved so far in these selected patients. However, despite great breakthroughs have been made, treatment of these molecularly selected patients poses novel therapeutic challenges, such as emerging of acquired resistance, brain metastases development or the need to translate these treatments in earlier clinical settings, such as adjuvant therapy. The aim of this paper is to provide a comprehensive review of the major progresses reported so far in the EGFR inhibition in this molecularly-selected subgroup of NSCLC patients, from the early successes with first generation EGFR TKIs, Erlotinib and Gefitinib, to the novel irreversible and mutant-selective inhibitors and ultimately the emerging challenges that we, in the next future, are called to deal with.