EGFR Mutation Type Research Articles

Comparison of the effectiveness of erlotinib, gefitinib, and afatinib for treatment of non-small cell lung cancer in patients with common and rare EGFR gene mutations.

Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are routinely used to treat non-small cell lung cancer (NSCLC) in patients with common activating mutations of the EGFR gene. The aim of the study was to compare the efficacies of EGFR-TKIs in patients with common (exon 19 deletions and exon 21 p.Leu858Arg) and rare EGFR mutations. A retrospective analysis of 180 NSCLC patients with common (n=167) and rare (n=13) EGFR mutations treated with erlotinib (n=98), gefitinib (n=66) and afatinib (n=16) was performed. EGFR mutations were determined using RT-PCR and the EntroGen EGFR Mutations Analysis kit. Partial and complete response (PR and CR), progression-free survival (PFS), and overall survival (OS) were analyzed. Demographic and clinical factors had no impact on PFS or OS in patients treated with EGFR-TKIs. Erlotinib, gefitinib, and afatinib showed similar efficacies based on treatment response, median PFS, and OS. The type of EGFR mutation had no impact on median OS; however, median PFS was significantly longer in patients with the exon 19 deletion compared to patients with the exon 21 p.Leu858Arg substitution and rare EGFR gene mutations (P=0.013). Patients with common EGFR mutations showed significantly longer median PFS than those with rare EGFR mutations (10 vs. 5 months; P=0.009). Erlotinib, gefitinib, and afatinib show similar efficacies in NSCLC patients with both common and rare EGFR mutations. When undergoing EGFR-TKI treatment, patients with rare EGFR mutations showed similar OS but poorer PFS. Further investigation into the associations between particular rare EGFR mutations and EGFR-TKIs treatment outcomes is required.

Most T790M mutations are present on the same EGFR allele as activating mutations in patients with non–small cell lung cancer

ObjectivesThe T790M and C797S mutations of the epidermal growth factor receptor gene (EGFR) confer resistance to first- and third-generation EGFR tyrosine kinase inhibitors (TKIs), respectively, in patients with non–small cell lung cancer (NSCLC) harboring activating mutations of EGFR. C797S has been identified in cis or in trans with T790M in tumor specimens from patients who experienced treatment failure with first- and third-generation EGFR-TKIs. The allelic relation between T790M and activating mutations of EGFR has not been well characterized, however. We have now developed a digital polymerase chain reaction (dPCR)–based method for determination of the allelic relation between two types of EGFR mutation (T790M and either C797S or an activating mutation). Materials and MethodsSeven clinical NSCLC specimens and two NSCLC cell lines harboring both an activating mutation and T790M were analyzed with this new method to identify the allelic relation between these EGFR mutations. ResultsThe median ratio of the number of alleles positive for both an activating mutation and T790M to the number of T790M-positive alleles was 97.1% (range, 90.0–100%). Confirmatory analysis by next-generation sequencing yielded a corresponding value of 96.7% (range, 89.1–99.5%). Our dPCR method thus reliably identifies the allelic relation between two EGFR mutations in a quantitative manner. ConclusionsAlmost all T790M mutations were detected in cis with activating mutations of EGFR regardless of the de novo or acquired status of T790M, with cancer cells harboring T790M and activating mutations on the same allele appearing to be selected and enriched during EGFR-TKI treatment.

Lung cancer in never-smokers – what are the differences?

Introduction: Characteristics of never-smokers with lung cancer are still not fully clarified. The aim of this study was to compare never-smokers and ever-smokers with non-small cell lung cancer (NSCLC) regarding patient and tumor characteristics.Methods: All consecutive newly NSCLC patients with known smoking status diagnosed between 2011 and 2015 were included in this retrospective cohort study. Clinical, histological, and molecular characteristics were compared between ever-smokers and never-smokers.Results: Of the 558 included patients, 125 (22.4%) were never-smokers. These patients were more likely to be female (74% vs. 7%, p < .001), older (67 vs. 66 years-old, p = .019), and have adenocarcinoma (93% vs. 65%, p < .001). Never-smokers took longer to seek medical care after the symptoms onset (3 vs. 2 months, p < .001), regardless of the symptoms, histological type, or gender (OR: 1.2 [1.4–2.0]). The metastatic pattern was different in never-smokers: pleural metastases were more frequent (OR: 2.1 [1.1–4.0]), regardless of the histological type and gender. Never-smokers had a higher prevalence of ALK translocations (26% vs. 4%, p < .001) and EGFR mutations (36% vs. 8%, p < .001). The type of EGFR mutation was also significantly different between groups.Conclusions: Never-smokers with NSCLC present distinct demographic and clinical characteristics. The characteristics of tumor also differ between never-smokers and ever-smokers, which may suggest different carcinogenic pathways.

P1.02-040 Heterogeneity of the EGFR / KRAS Gene Mutation in Multifocal Lung Adenocarcinoma and the Clinical Significance

Significant advances on EGFR-targeted therapy have allowed increasing availability of therapeutic options for non-small cell lung cancers. For multifocal lung adenocarcinoma patients in clinic, the EGFR gene mutation is generally examined only on the largest tumor or the one containing the most tumor cells, which could omit the tumors harboring the EGFR mutation and thus loss of opportunity for the tyrosine kinase inhibitors therapy. A total of 58 cases of multifocal lung adenocarcinoma, including 129 intrapulmonary tumors resected surgically, was recruited for this study. The genome DNA samples were prepared from formalin-fixed and paraffin-embedded tumor tissues. The EGFR / KRAS mutational status of each tumor was examined by Sanger’s DNA sequencing. The targeted hotspot mutations in EGFR gene included p.G719S/C/A (exon 18), p.T790M (exon 20), p.S768I (exon 20), p.L858R (exon 21), p.L861Q (exon 21) and deletions in exon 19. The hotspot mutations in KRAS gene were within codon 12 including p.G12C/V/S/R/D/A. In this group of 58 patients with multifocal lung adenocarcinoma, 38 patients were found EGFR or KRAS mutations in their tumors. Among them, the EGFR mutations were detected in 59 tumors derived from 34 cases; while the KRAS mutations were detected in 7 tumors from 5 cases. One patient (Case 30) was identified EGFR (exon 18, p.G719A) or KRAS (p.G12A or p.G12C) mutation in her 3 tumors, respectively. It is noteworthy that there were 21 (36.2%) in the 58 cases showing the mutational heterogeneity among the multiple intrapulmonary tumors derived from one individual, and that 6 tumors harbored 2 different types of EGFR mutation. However, none of the specimens investigated contained both EGFR and KRAS mutations within a same tumor. Comparing data from the present study along with the molecular pathological diagnosis records from the Department of Pathology, among the 58 cases enrolled, 30 cases accepted routine molecular pathological examination to check the EGFR / KRAS mutation, and 28 cases did not. However, 37 out of 66 tumors from the 30 cases were tested -- only 5 patients had all their tumors examined; whereas in the rest total 92 tumors unchecked, 42 EGFR sensitive mutations were identified in this study. Current finding suggests that the EGFR and KRAS mutational heterogeneity is widely existed in multifocal lung adenocarcinomas. Therefore, reliable and exhaustive examination for EGFR/KRAS mutation should be executed in the every tumor, to provide more individualized therapy choices for the patients.

MA08.05 Depth of Response to First-Line EGFR TKI Does Not Predict Survival in EGFR-Mutated NSCLC Patients

The association between depth of response to EGFR TKI and prognosis of EGFR-mutated NSCLC remains unclear. We aimed to assess the correlation between maximal tumor shrinkage and survival in patients treated with gefitinib and afatinib. Patients with advanced EGFR-mutated NSCLC enrolled in first-line gefitinib and afatinib clinical trials between 2005 and 2014 at the National Taiwan University Hospital were reviewed. Patients who had at least one measurable target lesion that shrank during treatment were included. Overall survival (OS) was defined as time from date of enrollment to death or May 30th, 2016. Correlation between tumor shrinkage and OS was analyzed by Pearson correlation coefficient and Kaplan-Meier method. The influence of high maximal tumor shrinkage (defined as ≥50% tumor shrinkage), age, gender, types of EGFR mutation, central nervous system (CNS) involvement at diagnosis, CNS as site of progression, first-line EGFR TKI (gefitinib or afatinib), and subsequent treatments (chemotherapy, third-generation TKI) on OS was evaluated by a multivariate Cox proportional hazard model. A total of 189 trial patients were screened and 91 patients were eligible for analysis (gefitinib n=42, afatinib n=49). The median maximal tumor shrinkage during first-line EGFR TKI treatment was 53% (interquartile range 30.5%). Maximal tumor shrinkage did not correlate with OS in all patients (R2=0.0225, p=0.169), and either the gefitinib (R2=0.0036, p=0.689) or afatinib (R2=0.0625, p=0.085) group (Fig.1A). High maximal tumor shrinkage also did not significantly affect OS (HR 0.86, 95% CI 0.54-1.40, p=0.564) (Fig. 1B). In multivariate analysis, CNS as site of progression (HR 2.96, 95% CI 1.39-6.29, p=0.005) and first-line afatinib (HR 0.51, 95% CI 0.29-0.91, p=0.022) were the only factors that significantly influenced OS. The depth of response to first-line gefitinib and afatinib was not predictive of OS in patients with EGFR-mutated NSCLC.

OA23.06 Overall Survival (OS) of EGFR Mutation Positive Non-Small Cell Lung Cancer Patients: Real-World Treatment Patterns of 1,660 Japanese Patients

Since the epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) was launched in Japan, the survival periods of advanced/recurrent EGFR mutation positive (EGFR m+) non-small cell lung cancer (NSCLC) patients have been getting longer. However, clinical factors which contributed to the extension of survival periods of these patients remain unclear. We investigated overall survival, prognostic factors and treatments patterns of EGFR m+ NSCLC patients in real-world clinical practice. This is a multi-center, observational, retrospective study. Histologically or cytologically diagnosed EGFR m+ NSCLC patients who were started first-line treatment from 1/1/2008 to 31/12/2012 were enrolled. The primary objective was the estimated OS. The secondary objectives were to determine prognostic factors, real-world treatment patterns. 1,660 EGFR m+ NSCLC patients were enrolled from 17 hospitals in Japan (median age 67.0 years, female 64.8%, 38.9% had smoking history, ECOG-performance status 0, 1, 2, 3, 4 were 39.5%, 41.1%, 7.1%, 4.9%, 0.7%, respectively, adenocarcinoma 95.2%, 50.1% exon 19 deletion, 66.7% at stage IV). Median estimated OS was 29.7 months. Cox regression analysis revealed age, smoking history, performance status, histological diagnosis, EGFR mutation type and clinical stage were independently associated with OS. Five year survival rate of stage IV patients was 13.8%. The median number of treatment regimens was two. EGFR-TKI and platinum-doublet chemotherapy were most frequently used as first- and second-line treatments. Real world treatment of the large data-set of 1,660 EGFR m+ NSCLC patients was retrospectively investigated. Median OS was 29.7 months and EGFR-TKIs are major components of the treatment regimens for these patients in Japan. (NCT0247520).

The association between clinical prognostic factors and epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) efficacy in advanced non-small-cell lung cancer patients: a retrospective assessment of 94 cases with EGFR mutations.

ObjectiveThis study aimed to examine the association of clinical prognostic factors with epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) efficacy in advanced non-small-cell lung cancer (NSCLC) patients.MethodsThe demographic and clinical characteristics of 94 patients with stage IV NSCLC were retrospectively reviewed, and the association between clinical factors and EGFR-TKIs efficacy was evaluated.ResultsOf the 94 stage IV NSCLC patients enrolled in this study, a 74.5% objective response rate (ORR) and 97.9% disease control rate (DCR) were observed for EGFR-TKIs treatment, and a higher ORR was seen in patients with 0 and 1 ECOG scores than those with 2 or greater scores (P = 0.049). The subjects had a median PFS of 11 months and a median OS of 31 months after EGFR-TKIs treatment. ECOG score and timing of targeted therapy were factors affecting PFS, and ECOG score, smoking status and brain metastasis were factors affecting OS. In addition, ECOG score was an independent prognostic factor for PFS in stage IV NSCLC patients, and the patients with EGFR 19del mutation had a longer PFS than those with exon 21 L855R mutation (P = 0.003), while ECOG score and brain metastasis were independent prognostic factors for OS.ConclusionsThe results of this study demonstrate that EGFR-TKI therapy results in survival benefits for EGFR-mutant advanced NSCLC patients, regardless of gender, smoking history, pathologic type, type of EGFR mutations, brain metastasis and timing of targeted therapy. ECOG score is an independent prognostic factor for PFS, and ECOG score and brain metastasis are independent prognostic factors for OS in advanced NSCLC patients.

EGFR Mutation Subtypes Influence Survival Outcomes following First-Line Gefitinib Therapy in Advanced Asian NSCLC Patients

IntroductionActivating mutations in the EGFR gene have been shown to confer sensitivity to EGFR tyrosine kinase inhibitors in patients with advanced NSCLC. However, wide interpatient variability in treatment outcomes in response to EGFR tyrosine kinase inhibitors in these patients remains unaccounted for. This study aimed to evaluate the influence of EGFR mutation types and subtypes on survival outcomes in advanced Asian patients with NSCLC receiving first-line gefitinib therapy. MethodsPatients with stage IIIB or IV NSCLC who were harboring EGFR mutations, receiving first-line gefitinib treatment, and of Asian descent (N = 383) were evaluated. Overall survival (OS) and progression-free survival (PFS) were estimated by Kaplan-Meier analysis. Log-rank tests and Cox proportional hazards models were implemented to evaluate the differences in PFS and OS. ResultsSignificant differences in PFS were observed between patients carrying EGFR mutations in exons 18, 19, 20, and 21, with patients carrying EGFR exon 19 mutations having the longest median PFS (overall p = 8.88 × 10-15). Comparison of PFS among the five different exon 19 mutation subtypes and among the two exon 19 deletion start codons did not reveal any significant differences. No significant difference was observed in OS among patients carrying EGFR mutations on different exons (overall p = 0.054); however, OS was found to be significantly different among the various subtypes of exon 19 mutations, with the 15–nucleotide deletion “non-ELREA” group having the shortest OS of 11.3 months (overall p = 0.025). ConclusionsEGFR mutation types and subtypes significantly influence survival outcomes in patients with advanced NSCLC who are receiving first-line gefitinib treatment.

O2-4-3 - Overall survival (OS) of EGFR mutation-positive non-small cell lung cancer (NSCLC): 1,660 Japanese patients (pts)

Background: Since the 1st epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) was launched in Japan, the survival of EGFR mutation positive (EGFR m+) advanced/recurrent NSCLC pts have been getting longer. However, clinical factors contributing to the longer survival remains unclear. Methods: This is a multi-center, observational, retrospective study. NSCLC pts who started first-line treatment from 2008 to 2012 were enrolled. Eligible pts were diagnosed with EGFR m+ advanced/recurrent NSCLC by tissue or cytology samples. The primary objective was an OS. The secondary objectives were to determine prognostic factors and treatment patterns. In order to explore the effects of treatment sequence on OS, “Dynamic Treatment Regimen Analysis (DTRA)” was conducted. Results: 1,660 NSCLC pts were enrolled from 17 centers in Japan: 64.8% of female, median age of 67.0, 95.2% had adenocarcinoma, 50.1% had exon 19 del, 66.7% at stage IV, and Performance Status (PS) 0 or 1 were 80.1%. Median OS was 30.8 months (M). Cox regression analysis revealed sex, age, histology, EGFR mutation type, clinical stage and PS were independently associated with OS. 3.3% of pts never received EGFR-TKI, whilst 49.8% pts never received platinum (Pt) doublet chemotherapy in his/her whole treatment. The median number of treatment regimens was 2. Most frequently used 1st line treatment category was gefitinib (58.1%), followed by Pt doublet +/- bevacizumab (30.7%). Median OS for each was 29.07 M [95% CI, 26.87 to 31.60], and 35.13 M [95% CI, 30.70 to 38.30] respectively, although there is no difference by multivariate analysis. For DTRA, survival curves were estimated for treatment sequences by 2nd line and after. Conclusion: Real world treatments of the large data-set in EGFR m+ NSCLC pts were retrospectively investigated. First generation EGFR-TKIs were major components of the treatment regimens for this population either 1st or 2nd-line therapy in Japan. (NCT0247520)

1252P - Addressing disease progression in EGFRmut+ NSCLC patients

Although EGFR-Tyrosine Kinase Inhibitors (TKIs) have improved disease management in EGFR mutation-positive NSCLC patients, all patients experience disease progression (PD) and ultimately die. In current practice, EGFR-TKIs are often continued beyond PD (RECIST1.1), however optimal management at PD remains ambiguous. We set out to study the survival differences and patient characteristics associated with continuation vs discontinuation of EGFR-TKI at PD retrospectively at a single institution: the Tom Baker Cancer Centre, AB Canada (2010-2014). EGFRmut+ NSCLC patients treated with an EGFR-TKI were retrospectively analyzed. Demographic and clinical data, EGFR mutation type, treatment-variations at PD (chemotherapy, radiation, continuation with EGFR-TKI) were collected. SPSS-v19 was used to generate Kaplan-Meier survival curves. Progression-free survival (PFS) (time from initiating EGFR-TKI to PD) and time-to-complete EGFR-TKI-cessation (time from initiating EGFR-TKI to cessation of TKI completely, if extended beyond PD), were assessed. 127 EGFRmut+ NSCLC patients received EGFR-TKIs. 106/127 (83%) developed PD (RECIST 1.1) (64.8% F/35.2% M; 95% adenocarcinoma; smoking history: 47%; ex 19 del/L858R/other: 45.7%/ 35.4%/ 18.9 %). Median PFS was 7.9 months, while median overall survival (mOS) was 17.3 months. A log-rank test showed a statistical significant difference in mOS between exon 19 deletion and L858R (22.6months vs 15.0months; 95% CI, 14.8m to 21.9m; P-value = 0.014). At PD, 54.7% continued EGFR-TKI treatment; 45.2% received other forms of treatments. Female gender, PD with solitary-lesions and younger age are associated with EGFR-TKI continuation at PD. This study confirms the difference in survival of exon 19 del vs L858R patients when treated with an EGFR-TKI. Additionally, it is common practice for oncologists to continue TKI treatment beyond PD. Further analysis, by time-to-complete EGFR-TKI cessation, will provide a more stratified base for future clinical-trials exploring treatment at EGFR-TKI-PD.

1202O - Clinical and biological characteristics of non-small cell lung cancer (NSCLC) harbouring EGFR mutation: Results of the nationwide programme of the French Cooperative Thoracic Intergroup (IFCT)

EGFR mutations are associated with variable response to EGFR-TKI depending on the types of exons, mutations or clinical characteristics. To better understand these features we reviewed all cases of EGFR mutated NSCLC collected in the Biomarkers France database (Barlesi et al, Lancet 2016). Among the 17,664 patients, 1837 (10.3%) with an EGFR mutated NSCLC were analyzed for their biological and clinical characteristics. EGFR exon 18, 19, 20 and 21 mutations were found in 102 (5.6%), 931 (50.6%), 102 (5.6%) and 702 (38.2%) patients among which 70 had never been described. Proportion of smokers was higher in exon 18 (20%) and exon 20 (19%) compared to exon 19 (11%) and 21 (11%) (p = 0.002). Personal history of cancer was related in 226 patients (19.2%), irrespective of the exons. T790M mutated patients (n = 42) were excluded for survival analysis. Median follow-up was 36.7 [36.4-37] months. Median overall survivals (OS), first-line progression-free survivals (PFS) and disease control rates (DCR) under first-line EGFR-TKI according to the type of EGFR mutation are summarized in table 1. Median OS was longer for exon 19 deletions compared to L858R mutations (26.5 vs. 21.3 months, p = 0.045). In exon 19, there was no difference in OS based on the length of the deletion. In exon 21, median OS was longer for L858R than for L861Q or other substitutions or wild-type (22.4 vs. 14.1 vs. 14.9 vs. 11.8, p = <0.0001). DCR under first-line EGFR-TKI was 82, 77 and 54.5% for common, rare and complex mutations respectively (p = 0.05). There was no difference in DCR under EGFR-TKI based on the type of mutation in exon 19 (deletions vs. delins vs. substitutions) or 21 (L858R vs. L861Q vs. others).Tabled 1Wild-typeExon 18Exon 19Exon 20Exon 21pOS, months11.8 [10.1-13.3] (n = 1270)14.2 [12.4-NR] (n = 44)27.0 [23.4-29.1] (n = 555)16.0 [8.1-19.1] (n = 50)21.3 [18.5-27.8] (n = 439)<0.001PFS first-line, months7.2 [6.3-7.9] (n = 1243)12.4 [5.8-NR] (n = 44)16.3 [13.9-18.0] (n = 560)6.4 [2.9-9.0] (n = 48)13.7 [11.6-16.1] (n = 442)<0.0001DCR (TKI), %21 (n = 14)78 (n = 9)82 (n = 235)20 (n = 5)81 (n = 201)<0.0001 Open table in a new tab Common and non-common EGFR mutations presented different clinical characteristics. Among common mutations, exon 19 mutated patients had better outcomes.

BIM deletion polymorphisms in Hispanic patients with non-small cell lung cancer carriers of EGFR mutations.

BackgroundGermline alterations in the proapoptotic protein Bcl-2-like 11 (BIM) can have a crucial role in diverse tumors. To determine the clinical utility of detecting BIM deletion polymorphisms (par4226 bp/ par363 bp) in EGFR positive non-small-cell lung cancer (NSCLC) we examined the outcomes of patients with and without BIM alterations.ResultsBIM deletion was present in 14 patients (15.7%). There were no significant differences between patients with and without BIM-del in clinical characteristics or EGFR mutation type; however, those with BIM-del had a worse overall response rate (ORR) to erlotinib (42.9% vs. 73.3% in patients without BIM-del; p=0.024) as well as a significantly shorter progression-free survival (PFS) (10.8 BIM-del+ vs. 21.7 months for patients without BIM-del; p=0.029) and overall survival (OS) (15.5 BIM-del+ vs. 34.0 months for patients without BIM-del; p=0.035). Multivariate Cox regression analysis showed that BIM-del+ was an independent indicator of shorter PFS (HR 3.0; 95%CI 1.2-7.6; p=0.01) and OS (HR 3.4; 95%CI 1.4-8.3; p=0.006).MethodsWe studied 89 NSCLC Hispanic patients with EGFR mutation who were treated with erlotinib between January 2009 and November 2014. BIM deletion polymorphisms (BIM-del) was analyzed by PCR in formalin-fixed paraffin-embedded (FFPE) tissues of tumor biopsies. We retrospectively analyzed clinical characteristics, response rate, toxicity, and outcomes among patients with and without BIM-del.ConclusionsThe incidence of BIM-del found in Hispanic patients is similar to that previously described in Asia. This alteration is associated with a poor clinical response to erlotinib and represents an independent prognostic factor for patients who had NSCLC with an EGFR mutation.

Abstract 199: Evaluation of multiple EGFR tyrosine kinase inhibitors against clinically relevant EGFR mutants using in vitro modeling

Abstract Purpose: We are able to use multiple EGFR-TKIs to treat patients with lung cancer harboring EGFR mutations. However, there is no clear guideline regarding which EGFR-TKIs should be used for which mutations. The purpose of this study is to establish an in vitro model to determine the “therapeutic window” of EGFR-TKIs against various types of EGFR mutations, including several EGFR exon 20 insertion mutations. Experimental design: We evaluated drug sensitivity and downstream signaling of human lung cancer cell lines harboring EGFR mutations (PC9, H3255, PC9-ER, BID007 and H1975) and Ba/F3 cells exogenously expressing mutated or wild type EGFR for the 1st (erlotinib), 2nd (afatinib), and 3rd (osimertinib and rociletinib) generation EGFR-TKIs using MTS assay, apoptosis assay and western blotting, simultaneously. An in vitro model of mutation specificity was created by calculating the ratio of IC50 values between mutated and wild type EGFRs. Results: The model of mutation specificity identified wide therapeutic windows of afatinib for exon 19 deletions and L858R and those of osimertinib and rociletinib for T790M positive mutations in human cell lines and Ba/F3 cells. In human cell lines and Ba/F3 cells harboring exon 19 deletions or L858R, afatinib showed the lowest IC50 and most potently inhibited the phosphorylation of EGFR, AKT, and ERK. Afatinib and 3rd generation EGFR-TKIs (osimertinib and rociletinib), effectively inhibited the cell growth and the phosphorylation of downstream signaling of EGFR in T790M positive cells. For EGFR exon 20 insertion mutations, osimertinib was potent and presented the most wide therapeutic window. Conclusion: This model will provide a preclinical rationale for proper selection of EGFR-TKIs against clinically-relevant EGFR mutations including EGFR exon 20 insertions. Citation Format: Hanako Hasegawa. Evaluation of multiple EGFR tyrosine kinase inhibitors against clinically relevant EGFR mutants using in vitro modeling. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 199.

Comprehensive profiling and quantitation of oncogenic mutations in non small-cell lung carcinoma using single molecule amplification and re-sequencing technology.

Activating and resistance mutations in the tyrosine kinase domain of several oncogenes are frequently associated with non-small cell lung carcinoma (NSCLC). In this study we assessed the frequency, type and abundance of EGFR, KRAS, BRAF, TP53 and ALK mutations in tumour specimens from 184 patients with early and late stage disease using single molecule amplification and re-sequencing technology (SMART). Based on modelling of EGFR mutations, the detection sensitivity of the SMART assay was at least 0.1%. Benchmarking EGFR mutation detection against the gold standard ARMS-PCR assay, SMART assay had a sensitivity and specificity of 98.7% and 99.0%. Amongst the 184 samples, EGFR mutations were the most prevalent (59.9%), followed by KRAS (16.9%), TP53 (12.7%), EML4-ALK fusions (6.3%) and BRAF (4.2%) mutations. The abundance and types of mutations in tumour specimens were extremely heterogeneous, involving either monoclonal (51.6%) or polyclonal (12.6%) mutation events. At the clinical level, although the spectrum of tumour mutation(s) was unique to each patient, the overall patterns in early or advanced stage disease were relatively similar. Based on these findings, we propose that personalized profiling and quantitation of clinically significant oncogenic mutations will allow better classification of patients according to tumour characteristics and provide clinicians with important ancillary information for treatment decision-making.

Effect of EGFR-TKI combined with concurrent radiotherapy in the treatment of advanced non-squamous lung cancer

Objective To evaluate the safety and curative effect of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) combined with concurrent radiotherapy in the treatment of stage IIIB or IV non-squamous lung cancer patients. Methods 64 patients with EGFR mutant type advanced non-squamous lung cancer were enrolled in this study.26 patients were treated with EGFR-TKI (single treatment group), 38 patients were treated with EGFR-TKI combined with concurrent radiotherapy (combined treatment group). The acute toxicity reaction, the objective response rate and the survival benefit of all the patients were evaluated. Results In recent curative effect, the combined treatment group showed higher objective response rate, and the ORR between the two groups had statistically significant difference(71.1% vs 46.2%, χ2=4.02, P=0.02). In the combined treatment group, the median progression free survival time was 11.5 months, and the median survival time was 26.7 months.In the single treatment group, the median progression free survival time was 10.1 months, and the median survival time was 23.4 months.The differences between the two groups were not statistically significant.The main adverse reactions were skin rash and gastrointestinal reaction, and the incidence of these adverse reactions was similar in the two groups.The rate of bone marrow depression in the combined treatment group was higher than that in the drug group, and was mainly grade 1-2, which caused no treatment-related deaths. Conclusion EGFR-TKI combined with concurrent radiotherapy is effective and safe for EGFR mutant type advanced non-squamous lung cancer patients. Key words: Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI); Intensity modulated radiation therapy(IMRT); Advanced non-squamous lung cancer/concurrent radiotherapy

EGFR mutation type and efficacy of afatinib in patients who previously treated with EGFR-TKI.

e20535Background: Recent phase III studies demonstrated that afatinib improve overall survival in NSCLC patient with common EGFR mutation as compared with 1st line chemotherapy. The different effic...

Afatinib versus gefitinib as first-line treatment of patients with EGFR mutation-positive non-small-cell lung cancer (LUX-Lung 7): a phase 2B, open-label, randomised controlled trial

The irreversible ErbB family blocker afatinib and the reversible EGFR tyrosine kinase inhibitor gefitinib are approved for first-line treatment of EGFR mutation-positive non-small-cell lung cancer (NSCLC). We aimed to compare the efficacy and safety of afatinib and gefitinib in this setting. This multicentre, international, open-label, exploratory, randomised controlled phase 2B trial (LUX-Lung 7) was done at 64 centres in 13 countries. Treatment-naive patients with stage IIIB or IV NSCLC and a common EGFR mutation (exon 19 deletion or Leu858Arg) were randomly assigned (1:1) to receive afatinib (40 mg per day) or gefitinib (250 mg per day) until disease progression, or beyond if deemed beneficial by the investigator. Randomisation, stratified by EGFR mutation type and status of brain metastases, was done centrally using a validated number generating system implemented via an interactive voice or web-based response system with a block size of four. Clinicians and patients were not masked to treatment allocation; independent review of tumour response was done in a blinded manner. Coprimary endpoints were progression-free survival by independent central review, time-to-treatment failure, and overall survival. Efficacy analyses were done in the intention-to-treat population and safety analyses were done in patients who received at least one dose of study drug. This ongoing study is registered with ClinicalTrials.gov, number NCT01466660. Between Dec 13, 2011, and Aug 8, 2013, 319 patients were randomly assigned (160 to afatinib and 159 to gefitinib). Median follow-up was 27·3 months (IQR 15·3-33·9). Progression-free survival (median 11·0 months [95% CI 10·6-12·9] with afatinib vs 10·9 months [9·1-11·5] with gefitinib; hazard ratio [HR] 0·73 [95% CI 0·57-0·95], p=0·017) and time-to-treatment failure (median 13·7 months [95% CI 11·9-15·0] with afatinib vs 11·5 months [10·1-13·1] with gefitinib; HR 0·73 [95% CI 0·58-0·92], p=0·0073) were significantly longer with afatinib than with gefitinib. Overall survival data are not mature. The most common treatment-related grade 3 or 4 adverse events were diarrhoea (20 [13%] of 160 patients given afatinib vs two [1%] of 159 given gefitinib) and rash or acne (15 [9%] patients given afatinib vs five [3%] of those given gefitinib) and liver enzyme elevations (no patients given afatinib vs 14 [9%] of those given gefitinib). Serious treatment-related adverse events occurred in 17 (11%) patients in the afatinib group and seven (4%) in the gefitinib group. Ten (6%) patients in each group discontinued treatment due to drug-related adverse events. 15 (9%) fatal adverse events occurred in the afatinib group and ten (6%) in the gefitinib group. All but one of these deaths were considered unrelated to treatment; one patient in the gefitinib group died from drug-related hepatic and renal failure. Afatinib significantly improved outcomes in treatment-naive patients with EGFR-mutated NSCLC compared with gefitinib, with a manageable tolerability profile. These data are potentially important for clinical decision making in this patient population. Boehringer Ingelheim.

Contribution of ¹⁸Fluorodeoxyglucose positron emission tomography uptake and TTF-1 expression in the evaluation of the EGFR mutation in patients with lung adenocarcinoma.

The aim of this study is to evaluate the diagnostic value of PET-CT scan for the prediction of EGFR mutation status and the contribution of TTF-1 expression to PET-CT scan. We retrospectively studied 218 cases with a diagnosis of pulmonary adenocarcinoma between 2012-2014 which underwent EGFR analysis, TTF-1 and PET-CT before treatment. The EGFR mutation was present in 28.9% (n= 63) of cases. TTF-1 positivity was 66.9% (n= 105). Standardized uptake value (SUV max) was 16.7 ± 6.8 in EGFR mutant type, 13.8 ± 7.6 in cases having no EGFR mutations. According to our evaluations, high SUVmax is positively correlated with EGFR mutation status. TTF-1 expression in multivariate analysis strengthens the accuracy of detecting an EGFR mutation. PET-CT FDG uptake may, together with TTF-1 expression, help diagnosis in lung adenocarcinoma cases when evaluating for EGFR mutation status.

Monitoring EGFR T790M with plasma DNA from lung cancer patients in a prospective observational study.

Use of plasma DNA to detect mutations has spread widely as a form of liquid biopsy. EGFR T790M has been observed in half of lung cancer patients who have acquired resistance to EGFR tyrosine kinase inhibitors (EGFR-TKI). Effectiveness of monitoring T790M via plasma DNA during treatment with EGFR-TKI has not been established as an alternative to re-biopsy. This was a prospective multicenter observational study involving non-small cell lung cancer patients carrying EGFR L858R or exon 19 deletions, treated with EGFR-TKI. The primary objective was to determine whether T790M could be detected using plasma DNA in patients with progressive disease (PD). T790M was examined using the mutation-biased PCR and quenching probe (MBP-QP) method, a sensitive, fully-automated system developed in our laboratory. Eighty-nine non-small cell lung cancer patients were enrolled from seven hospitals in Japan. Sequential examinations revealed T790M in plasma DNA among 40% of patients who developed PD. Activating mutations, such as L858R and exon 19 deletions, were detected in 40% of patients using plasma DNA, and either T790M or activating mutations were observed in 62%. Dividing into four periods (before PD, at PD, at discontinuation of EGFR-TKI and subsequently), T790M was detected in 10, 19, 24 and 27% of patients, respectively. Smokers, males, patients having exon 19 deletions and patients who developed new lesions evidenced significantly frequent presence of T790M in plasma DNA. Monitoring T790M with plasma DNA using MBP-QP reflects the clinical course of lung cancer patients treated with EGFR-TKI. Detection of T790M with plasma DNA was correlated with EGFR mutation type, exon 19 deletions and tumor progression. Re-biopsy could be performed only in 14% of PD cases, suggesting difficulty in obtaining re-biopsy specimens in practice. Monitoring T790M with plasma DNA reflects the clinical course, and is potentially useful in designing strategies for subsequent treatment.

Терапия больных немелкоклеточным раком легкого в Российской Федерации: исследование EPICLIN-Lung

The first epidemiological observational EPICLIN-Lung study in Russia is aimed at revealing the true incidence and the type of EGFR mutations in the Russian population of patients with non-small cell lung cancer (NSCLC), the connection with the main epidemiological parameters, the treatment approaches and outcomes in real clinical practice. The study was conducted in 33 oncology centers across 24 Russian regions; the study included 838 patients with histologically confirmed NSCLC. Most patients (63.2%) presented with advanced disease (stage III-IV patients) and Squamous-cell carcinoma (54.3%) and adenocarcinoma (31%) were the most prevalent histology types of NSCLC. Epidemiology of EGFR mutations in this NSCLC cohort was similar to other studies of NSCLC in Caucasian populations. EGFR mutations were identified in 10.1% of NSCLC patients included in this study, most of them were women (69.4%) and associated with adenocarcinoma histologically (58.8%) and 71.8% of these patients were never-smokers. The presence of EGFR mutations in tumor indicated the low risk for progression. The results of EPICLIN-Lung study would contribute to a better understanding of prognostic and predictive factors of NSCLC in Russian populations and that would help to choose the optimal therapy in routine clinical practice.