Advanced EGFR-mutant Lung Adenocarcinoma Research Articles

Concordance of epidermal growth factor receptor mutation detection in bodily fluids other than blood with tissue biopsy: A retrospective analysis

Background: The concept of liquid biopsy as a surrogate for tumor tissue is not only restricted to blood-derived samples but also includes other malignant bodily fluids such as cerebrospinal fluid, pleural fluid, pericardial fluid, and ascites. The application of liquid biopsy in patients with metastatic lung cancer, with disease progression on epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) treatment, is unexplored in India.Objective: We aimed to determine the presence of EGFR gene mutations in various bodily fluids of patients with EGFR-mutant progressive metastatic lung adenocarcinoma.Materials and Methods: In this retrospective study conducted at the Tata Memorial Hospital in Mumbai, India, data from 11 patients with advanced EGFR-mutant lung adenocarcinoma were analyzed. Between December 2017 and June 2018, the cell-free DNA (cfDNA) obtained from the malignant bodily fluids and plasma of 11 patients were tested for the presence of EGFR-sensitizing mutations using real-time reverse transcription-polymerase chain reaction. The status of EGFR-sensitizing mutations in plasma and other bodily fluids was compared with that of the baseline tissue biopsy. In addition, the status of the acquired T790M resistance mutation in exon 20 at disease progression was determined using plasma and other bodily fluids.Results: Of the 11 patients, at disease progression, EGFR sensitizing mutations (exon 19 deletion and exon 21 L858R insertion) could be detected in the plasma of 7 (63%) and in other bodily fluids of all the 11 (100%) patients. Thus, the concordance for EGFR-sensitizing mutation detection in the plasma and other bodily fluids with the baseline formalin-fixed paraffin-embedded tissue was 63% and 100%, respectively. In addition, the acquired T790M resistance mutation was detected in the plasma of 3 (27.3%) patients and other bodily fluids of 9 (81.8%) patients.Conclusion: The rate of detection of the T790M mutation is higher in the free DNA obtained from malignancy-involved bodily fluid supernatant as compared to the plasma cfDNA. Our results suggest that cfDNA obtained from bodily fluids other than plasma can be used for the detection of EGFR mutations and that the mutation status may be a useful predictor of the response to TKIs.

P1.01-57 Association of Initial PD-L1 Expression with T790M-Acquired Resistance in Advanced EGFR-Mutant Lung Adenocarcinoma Patients

The primary objective was to investigate the association between initial programmed cell death-ligand 1 (PD-L1) expression levels and the frequency of T790M-acquired resistance to epidermal growth factor receptor (EGFR)-tyrosine kinase Inhibitor (TKI) in patients with advanced EGFR-mutant lung adenocarcinoma. We examined patients with advanced EGFR-mutant lung adenocarcinoma whose initial PD-L1 expression levels and T790M-acquired mutation status after EGFR-TKI failure (gefitinib, erlotinib or afatinib) could be evaluated. We retrospectively investigated the patients’ characteristics and survival, as well as the association between initial PD-L1 expression levels and frequency of T790M-acquired resistance Overall, 100 patients were enrolled. Nine (9%) patients had an initial PD-L1 tumor proportion score (TPS) of ≥50%, 19(19%) had PD-L1 TPS of 1%-49%, and 72 (72%) had PD-L1 TPS of <1%. T790M-acquired mutation (T790M+) was identified in 57 (57%) patients. Initial PD-L1 expression levels were not associated with the frequency of T790M-acquired mutations in patients (p=0.822). Positive PD-L1 expression (PD-L1+) was associated with lower OS compared with negative PD-L1 expression (PD-L1-) (median overall survival [OS], 40.3 vs 74.3 months, p=0.0053). Furthermore, T790M+ was associated with longer OS compared with T790M- in total and PD-L1- population (total: median OS, 74.3 vs 41.3 months, p=0.0154, PD-L1-: median OS, 82.0 vs 41.2 months, p=0.00412), but not in PD-L1+ population (median OS, 36.2 vs 46.2 months, p=0.792). Among 57 patients with T790M-aquired mutation, 49 received osimertinib treatment. The estimated median progression-free survival rate of osimertinib was 13.2 months in PD-L1- patients (n=37) and 6.9 months in PD-L1+ patients (n=12) (p=0.224). There was no association between initial PD-L1 expression levels and the frequency of T790M-aquired mutations in patients. However, PD-L1+ expression levels in patients with treatment-naïve advanced EGFR-mutant lung adenocarcinoma predicted poorer outcomes. Intriguingly, T790M-aquired mutations were related to longer OS in PD-L1- patients, but not in PD-L1+. Thus, for patients with T790M-acquired mutant and initial PD-L1 positive lung adenocarcinoma in whom the use of osimertinib is indicated, other treatment options should be considered without hesitation if the treatment effects are not as expected.

High systemic immune-inflammation index predicts poor prognosis in advanced lung adenocarcinoma patients treated with EGFR-TKIs.

EGFR-TKIs have been widely used in the first-line treatment of NSCLC patients harboring EGFR mutations. However, the prognosis indicators are limited. In the present study, the prognostic value of systemic immune-inflammation index (SII), neutrophil to lymphocyte ratio (NLR), and platelet to lymphocyte ratio (PLR) were assessed in EGFR-Mutant lung adenocarcinoma patients treated with first-generation EGFR-TKIs. Two hundred three patients were included in this retrospective analysis. SII was calculated as platelet counts × neutrophil counts / lymphocyte counts. Receiver operating characteristic (ROC) curve was used to evaluate the optimal cut-off value for SII, NLR, and PLR. Univariate and multivariate survival analysis were performed to identify factors correlated with PFS and OS. Applying cut-offs of ≥1066.935 (SII), ≥4.40 (NLR), and ≥182.595 (PLR), higher NLR was associated with worse Eastern Cooperative Oncology Group performance status (ECOG PS) (P = .006), and higher brain metastasis rate (P = .03), higher PLR was associated with smoking history (P = .037), and worse ECOG PS (P = .001), and higher SII groups were associated with worse ECOG PS (P = .002). In univariate analysis, higher NLR (P < .001), higher PLR (P = .002), and higher SII (P < .001) were associated with worse PFS. Higher NLR (P < .001), and higher SII (P < .001) were associated with worse OS. In multivariate analysis, NLR (HR 1.736;95%CI:1.020–2.954; P = .03), PLR (HR 1.823; 95%CI:1.059–3.137; P = .04), and SII (HR2.577; 95%CI:1.677–3.958; P < .001) were independently correlated with PFS. While only SII (HR 2.802; 95%CI:1.659–4.733; P < .001) was independently correlated with OS. The present study demonstrated that SII is an independent prognostic factor for poor survival of advanced EGFR-Mutant lung adenocarcinoma patients treated with first-generation TKIs.

Adjunctive Traditional Chinese Medicine Improves Survival in Patients With Advanced Lung Adenocarcinoma Treated With First-Line Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitors (TKIs): A Nationwide, Population-Based Cohort Study.

Objectives: The clinical effect of traditional Chinese medicine (TCM) on survival in patients with advanced lung adenocarcinoma treated with first-line epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) is a major concern and requires more evidence from large-scale clinical studies. Materials and Methods: This population-based cohort study used the Taiwan National Health Insurance Research Database to enroll patients between 2006 and 2012 who had newly diagnosed locally advanced and metastatic lung adenocarcinoma treated with first-line gefitinib or erlotinib. Survival was tracked until 2013. The patients were separated into TCM users and nonusers, and Cox regression models were applied to determine the association between the use of TCM and the survival of patients. Results: A total of 1988 patients receiving first-line gefitinib or erlotinib for the treatment of EGFR-mutated advanced lung adenocarcinoma, with the exclusion of TCM users after tumor progression, were included in this cohort study. Compared with TCM nonuse, TCM use for ≥180 days was associated with a significantly decreased risk of mortality by 68% (adjusted hazard ratio [HR], 0.32 [95% CI, 0.21-0.50], P < .0001). Compared with TCM nonuse, TCM use for ≥180 days was associated with a significantly decreased risk of disease progression by 59% (adjusted HR, 0.41 [95% CI, 0.29-0.58], P < .0001). Conclusion: This cohort study suggests that adjunctive TCM therapy could improve overall survival and progression-free survival in patients with advanced lung adenocarcinoma treated with first-line TKIs. Future randomized, controlled trials are required to validate these findings.

High PD-L1 expression correlates with primary resistance to EGFR-TKIs in treatment naïve advanced EGFR-mutant lung adenocarcinoma patients

ObjectivesThe main objective was to investigate the relationship between Programmed cell Death-ligand 1 (PD-L1) expression levels and the frequency of primary resistance to Epidermal Growth Factor Receptor (EGFR)-Tyrosine Kinase Inhibitor (TKI) in treatment naïve advanced EGFR-mutant lung adenocarcinoma patients. Materials and methodsFrom 2012–2017, we enrolled advanced EGFR-mutant lung adenocarcinoma patients who displayed primary resistance to EGFR-TKI therapy, along with patients with disease control, and patients experiencing either stable disease or partial response to EGFR-TKI treatment. ResultsSixty-six patients were enrolled as the primary resistance group, while 57 patients were included as the disease control group. Fifteen-five (22.7%) patients had a PD-L1 Tumor Proportion Score (TPS) ≧50% in the primary resistance group, with only one patient (1.8%) having that score in the disease control group (P＜0.001). Twenty (30.3%) patients had a PD-L1 ≧25% in the primary resistance group, with 2 (3.5%) patients having that level in the disease control group (P＜0.001). Thirty (45.5%) patients had a PD-L1 ≧1% in the primary resistance group, with 7 (12.3%) patients at that level in the disease control group (P = 0.001). Patients with a PD-L1≧1% displayed a higher incidence of primary resistance to EGFR-TKIs than those with a PD-L1＜1% (Odds Ratio (OR), 5.95; 95% Confidence Interval (CI), 2.35–15.05; P＜0.001). The phenomenon existed still when the cutoff value was changed to both 25% (OR, 11.96; 95% CI, 2.65–53.87; P = 0.001) and 50% (OR, 16.47; 95% CI, 2.10–129.16; P = 0.008). The estimated median Progression-free Survival (PFS) rate was 7.3 months in patients with a PD-L1＜1%, 2.1 months in patients with a PD-L1≧1%, 1.8 months in patients with a PD-L1≧25%, and 1.6 months in patients with a PD-L1≧50%. ConclusionsTreatment for advanced EGFR-mutant lung adenocarcinoma patients displaying a higher PD-L1 expression level experienced a higher frequency of primary resistance to EGFR-TKIs.

Thick-wall cavity predicts worse progression-free survival in lung adenocarcinoma treated with first-line EGFR-TKIs

BackgroundCavity occurs in 5.7 to 14.9% of patients with lung adenocarcinoma (ADC). However, the impact of cavity on the therapeutic response to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) in ADC patients with EGFR mutations remains unclear. The aim of the present retrospective study was to elucidate the incidence and detailed characteristics of EGFR-mutant cavitary ADC and investigate the efficacy of EGFR-TKI treatment in this subgroup.MethodsTwo hundred seventy-six consecutive patients with advanced EGFR-mutant lung ADC treated with first-line EGFR-TKIs were enrolled. Cavitation and the thickness of cavity wall were assessed based on high-resolution computed tomography scans. Progression-free survival (PFS) was analyzed by the Kaplan-Meier plots and the log-rank test was used to calculate the significance between groups.ResultsCavity occurred in 5.4% (15/276) of patients with EGFR-mutant lung ADC and was more prevalent among male patients (66.7% vs. 33.3%, P = 0.008). Of the 15 EGFR-mutant cavitary ADC, 9 patients had exon 19 deletion (19DEL) and 6 harbored L858R mutation, 9 patients had thick-wall cavity while 6 had thin-wall cavity. Cavity had an adverse impact on the PFS of EGFR-mutant ADC treated with first-line EGFR-TKIs (noncavity versus cavity, 11.0 versus 6.5 months, hazard ratio [HR]: 0.33, 95% confidence interval [CI], 0.15–0.73, P = 0.003). The impaired effect was only observed in patients with L858R mutation (11.0 vs. 4.2 months, HR: 0.05, 95%CI, 0.01–0.27, P = 0.0003) but not in those with 19DEL (10.4 versus 9.7 months, HR: 0.73, 95%CI, 0.30–1.75, P = 0.483). All six L858R-mutant cavitary ADC patients had thick-wall cavity while thick-wall cavity was only identified in one thirds (3/9) of patients with 19DEL. Further analyses showed that patients with thick-wall cavity had worse PFS (6.0 versus 11.0 months, P = 0.013). Multivariate analysis identified cavity as an independent predictive factor for PFS (HR: 0.49, 95% CI, 0.26–0.90, P = 0.022).ConclusionCavitary ADC was associated with a worse PFS of first-line EGFR-TKI therapy, mainly in those with L858R mutation. Thick-wall cavity formation may be the main cause that contribute to the worse PFS.

1458P - Bone metastasis reduces responsiveness to EGFR-TKIs in patients with EGFR-mutated advanced lung adenocarcinoma

1458P - Bone metastasis reduces responsiveness to EGFR-TKIs in patients with EGFR-mutated advanced lung adenocarcinoma

Treatment effectiveness and tolerability of afatinib at different doses in patients with EGFR-mutated lung adenocarcinoma: How low can we go?

IntroductionAfatinib is commonly used as the first-line treatment for EGFR-mutated lung adenocarcinoma. However, dose adjustments are frequently required. This study aimed to investigate the treatment effectiveness of afatinib administered at different doses to patients with EGFR-mutated lung adenocarcinoma. MethodsTreatment-naïve patients with advanced EGFR-mutated lung adenocarcinoma who received afatinib therapy between May 2014 and September 2016 were enrolled retrospectively. Collected clinical data included age, sex, smoking history, performance status, disease stages, EGFR mutation status, initial doses of afatinib, dose adjustments, treatment responses, progression-free survival and treatment-associated adverse events. The average daily dose was calculated by dividing the summation of all doses of prescribed tablets during the treatment period by the total days of afatinib use. The patients were classified into five treatment groups based on average daily doses: 40 mg, <40 and >30 mg, 30 mg, <30 and ≥ 20 mg and <20 mg. ResultsA total of 254 patients were included. No significant differences were found among these five treatment groups with respect to response rates (69.3%, 68.3%, 70.5%, 77.8% and 66.7%, respectively, p = 0.920) and disease control rates (97.4%, 95.2%, 97.7%, 100% and 100%, respectively, p = 0.749). However, the treatment group with an average daily dose of <20 mg had a significant shorter progression-free survival as compared with the other groups (16.8, 12.4, 13.9, 17.0 and 5.3 months, respectively, p = 0.049). ConclusionsDose reduction may not affect the treatment effectiveness until the average daily dose is below 20 mg. Further prospective studies of afatinib therapy at different daily doses are warranted.

Economic analysis of osimertinib in previously untreated EGFR-mutant advanced non-small cell lung cancer in Canada

IntroductionOsimertinib improves progression-free survival in previously untreated EGFR-positive advanced non-small cell lung cancer (NSCLC) patients, with marked intracranial response rates. However, its cost-effectiveness in a publically funded health care system has not been established. We assessed the cost-effectiveness of first-line osimertinib from the public payer perspective in the Canadian health care system. MethodsA Markov model was developed to project the outcomes and direct medical costs of initial treatment with osimertinib or current standard-of-care (SoC) EGFR TKIs, gefinitib or afatinib, in patients with previously untreated EGFR-mutant advanced NSCLC. Clinical and cost input estimates were informed from the available literature. Model outcomes included costs (in 2018 Canadian dollars), life years (LYs), quality-adjusted life-years (QALYs), and the cost utility of osimertinib compared to SoC EGFR TKI, or incremental cost per QALY gained. ResultsInitial treatment with osimertinib was associated with a gain of 0.79 QALY [95% confidence interval (CI), 0.74 to 0.83] at an incremental cost of $176,394 CAD (95% CI, 176,383 to 176,405) vs. SoC EGFR TKI (incremental cost-effectiveness ratio [ICER]: $223,133/QALY gained; 95%CI, 198,144 to 252,805). Osimertinib had a 0% probability of being cost-effective at a willingness-to-pay threshold of $100,000 per QALY. Deterministic sensitivity analysis showed that the cost of osimertinib had the largest impact on ICER results. ConclusionAt the current marketed price, first-line osimertinib therapy in patients with advanced EGFR-mutant lung adenocarcinoma is not cost-effective in Canada. Reduction of osimertinib cost, for example by 25%, can significantly improve the cost-effectiveness profile.

Comparison of the effects of the three major tyrosine kinase inhibitors as first-line therapy for non-small-cell lung cancer harboring epidermal growth factor receptor mutations

IntroductionPatients with advanced lung adenocarcinoma harboring epidermal growth factor receptor (EGFR)-activating mutations have good response rate and longer progression-free survival (PFS) when treated with the tyrosine kinase inhibitors (TKI) compared with platinum-based chemotherapy. However, studies comparing the effectiveness of these drugs as first-line therapy in such patients are limited.ResultsWe analyzed 422 patients with EGFR-mutated advanced lung adenocarcinoma receiving first-line gefitinib (n = 195, 46.2%), erlotinib (n = 123, 29.1%), or afatinib (n = 104, 24.6%). The PFS of the afatinib group was longer (12.2 months) than that of the gefitinib group (9.8 months) (p = 0.035) but similar to that of the erlotinib group (11.4 months) (p = 0.38). In patients without brain metastasis (BM), subgroup analysis showed that the afatinib group had significantly longer PFS (13.1 months) than erlotinib (11.7 months) and gefitinib (9.8 months) groups (p = 0.010). Patients with exon 19 deletions in the afatinib and erlotinib groups had potentially long PFS (p = 0.073). Efficacy of afatinib was similar between the 30 mg and 40 mg arms (median PFS 16.1 months vs. 10.3 months; p = 0.923).ConclusionsAfatinib may be the optimal EGFR-TKI for advanced lung adenocarcinoma harboring EGFR-activating mutations, particularly in the absence of BM. Patients with exon 19 deletions taking afatinib had potentially long PFS. An afatinib dose of 30 and 40 mg has similar effect.MethodsWe conducted this retrospective study at a single medical center from January 2013 to March 2017 and used PFS to evaluate the effectiveness of gefitinib, erlotinib, and afatinib in patients with advanced lung adenocarcinoma harboring EGFR mutations.

Significance of neutrophil-to-lymphocyte ratio in Western advanced EGFR-mutated non-small cell lung cancer receiving a targeted therapy.

Lung cancer is one of the leading causes of cancer-related death worldwide and, although targeted therapy with tyrosine kinase inhibitors has dramatically improved the rates of response and survival in advanced EGFR-mutated adenocarcinoma, the overall outcome remains unsatisfactory. Therefore, new prognostic factors, preferably simple, inexpensive, and easy to reproduce on a large scale, are needed. We performed a retrospective analysis of our database including 63 western Caucasian patients with advanced EGFR-mutated lung adenocarcinoma and receiving gefitinib, erlotinib, or afatinib as first- or second-line therapy. Several studies demonstrated a strong link between elevated neutrophil-to-lymphocyte ratio (NLR) and poor prognosis both in early and advanced stages of non-small-cell lung cancer (NSCLC). From January 2011 to December 2015, 63 consecutive elegible patients with advanced EGFR-mutated NSCLC were included in this analysis from 5 institutions. The NLR was derived from the absolute neutrophil and the absolute lymphocyte counts of a full blood count and the cutoff value was determined according to the mean NLR level. Despite the small sample analyzed, we found that NLR has a prognostic role for progression-free survival (PFS) and overall survival (OS), reaching a statistically significant difference with a better PFS and OS in the lower NLR group. Pretreatment NLR seems to represent a reliable, simple, and easy to reproduce laboratory tool to predict outcome and response to cancer therapies in this setting of Western Caucasian patients with EGFR-mutated NSCLC.

Comparison of gefitinib as first- and second-line therapy for advanced lung adenocarcinoma patients with positive exon 21 or 19 del epidermal growth factor receptor mutation.

ObjectivesGefitinib, a tyrosine kinase inhibitor (TKI) targeting epidermal growth factor receptor (EGFR), shows excellent clinical benefit in treating advanced non-small-cell lung cancer (NSCLC). The aim of this study was to compare the efficacy and toxicity of gefitinib as first-line therapy and second-line therapy for advanced lung adenocarcinoma patients with positive exon 21 (L858R) or exon 19 deletion of EGFR mutation.MethodsWe retrospectively analyzed the clinical data of 60 EGFR-mutated advanced lung adenocarcinoma patients from July 2011 to November 2015 who have received oral gefitinib 250 mg once daily. Gefitinib was taken until disease progression, intolerable toxicity or death.ResultsAfter a median follow-up of 792 days, one death had occurred. Among the 59 patients who survived, 17 patients progressed. Overall, the median progression-free survival (mPFS) was 10 months (95% confidence interval [CI]: 7.53–12.46 months, p<0.05). The response rate (RR) and disease control rate (DCR) were 33.33% and 71.66%, respectively. However, there was longer mPFS in the first line-therapy than that in the second-line therapy: in the first-line gefitinib therapy, mPFS was 12 months among 41 patients (95% CI: 9.58–14.41 months, p<0.05), and in the second-line therapy, mPFS was 7 months among 19 patients (95% CI: 1.31–12.68 months, p<0.05). Furthermore, in subgroup analyses examining different EGFR mutation types, we noted that mPFS was significantly longer for patients with exon 19 deletion than for those with positive exon 21in both the first-line therapy and second-line therapy.ConclusionPatients with advance lung adenocarcinoma who were selected by positive exon 21 or 19 deletion mutations had significantly longer mPFS in the first-line therapy than that in the second-line therapy when treated with gefitinib. EGFR mutation types may influence the response to gefitinib therapy.

Clonal History and Genetic Predictors of Transformation Into Small-Cell Carcinomas From Lung Adenocarcinomas.

Purpose Histologic transformation of EGFR mutant lung adenocarcinoma (LADC) into small-cell lung cancer (SCLC) has been described as one of the major resistant mechanisms for epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). However, the molecular pathogenesis is still unclear. Methods We investigated 21 patients with advanced EGFR-mutant LADCs that were transformed into EGFR TKI-resistant SCLCs. Among them, whole genome sequencing was applied for nine tumors acquired at various time points from four patients to reconstruct their clonal evolutionary history and to detect genetic predictors for small-cell transformation. The findings were validated by immunohistochemistry in 210 lung cancer tissues. Results We identified that EGFR TKI-resistant LADCs and SCLCs share a common clonal origin and undergo branched evolutionary trajectories. The clonal divergence of SCLC ancestors from the LADC cells occurred before the first EGFR TKI treatments, and the complete inactivation of both RB1 and TP53 were observed from the early LADC stages in sequenced tumors. We extended the findings by immunohistochemistry in the early-stage LADC tissues of 75 patients treated with EGFR TKIs; inactivation of both Rb and p53 was strikingly more frequent in the small-cell-transformed group than in the nontransformed group (82% v 3%; odds ratio, 131; 95% CI, 19.9 to 859). Among patients registered in a predefined cohort (n = 65), an EGFR mutant LADC that harbored completely inactivated Rb and p53 had a 43× greater risk of small-cell transformation (relative risk, 42.8; 95% CI, 5.88 to 311). Branch-specific mutational signature analysis revealed that apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like (APOBEC)-induced hypermutation was frequent in the branches toward small-cell transformation. Conclusion EGFR TKI-resistant SCLCs are branched out early from the LADC clones that harbor completely inactivated RB1 and TP53. The evaluation of RB1 and TP53 status in EGFR TKI-treated LADCs is informative in predicting small-cell transformation.

Phase III study of gefitinib or pemetrexed with carboplatin in EGFR-mutated advanced lung adenocarcinoma

ObjectiveOral tyrosine kinase inhibitor has been shown to prolong progression-free survival (PFS) in epidermal growthfactor receptor (EGFR) mutation positive adenocarcinoma; however, the comparator arm has not included the current standard adenocarcinoma regimen (pemetrexed carboplatin induction followed by maintenance pemetrexed) and patients from Indian subcontinent. Hence, this study was carried out in Indian patients to compare gefitinib with the above-mentioned chemotherapy regimen.MethodsThis was an open-labelled, randomised, parallel group study comparing gefitinib (250 mg orally daily) with pemetrexed (500 mg/m2) and carboplatin (area under the curve 5) doublet intravenous induction chemotherapy regimen followed by maintenance pemetrexed (500 mg/m2) in patients with EGFR-activating mutation-positive stage IIIB or stage IV adenocarcinoma lung in the first-line setting. The primary endpoint for the study was PFS. 260 patients were required to demonstrate a 50% improvement in PFS of gefitinib over chemotherapy, with 80% power and 5% type 1 error. With an expected 5% dropout rate, the sample size was 290 patients.ResultsThe median PFS in gefitinib arm was 8.4 months (95% CI 6.3 to 10.5 months) compared with 5.6 months (95% CI 4.2 to 7.0 months) in pemetrexed–carboplatin arm (HR: 95% CI 0.513 to 0.851; p −0.001). The impact of gefitinib on PFS was seen across all subgroups.There was no statistically significant difference in overall survival between the two arms. Haematologicalgrade3–4toxicities likeanaemia,neutropaenia and thrombocytopaenia were common in the pemetrexed–carboplatin arm while grade3–4 acneiform rash and diarrhoeawere common in the gefitinib arm.ConclusionThe study confirms the superiority of gefitinib in prolonging PFS against the most active chemotherapy regimen of pemetrexed–carboplatin followed by maintenance pemetrexed in EGFR-mutated lung adenocarcinoma. The median PFS in Indian patients in gefitinib arm is similar to that reported in east Asians and Caucasians.

PUB062 Risk Factors of Brain Metastasis during the Course of EGFR-TKIs Therapy for Patients with EGFR-Mutated Advanced Lung Adenocarcinoma

Brain metastasis (BM) remains a therapeutically challenging issue, which often predicts poor prognosis. Moreover, there are still some patients developing BM during the course of EGFR-TKIs therapy, although EGFR-TKIs are effective for EGFR-mutated NSCLC patients with BM. Therefore, controversial value of prophylactic cranial irradiation (PCI) in NSCLC in terms of survival benefit prompted us to explore the possible risk factors for BM during the course of EGFR-TKIs therapy from EGFR-mutated advanced lung adenocarcinoma and identify the potential population most likely to benefit from PCI. We retrospectively reviewed the records of 134 patients with EGFR-TKIs therapy from EGFR-mutated advanced lung adenocarcinoma between 2008 and 2012. Among them, 78 patients (58.2 %) were confirmed to have EGFR exon 19 point mutations, while 56 patients (41.8%) had EGFR exon 21 point mutations. The cumulative incidence of BM was calculated by the Kaplan–Meier method and differences between the groups were analyzed using the log-rank test. Multivariate Cox regression analysis was used to assess the independent risk factors of BM. Thirty-four patients (34/134, 25.4%) developed BM during the course of EGFR-TKIs therapy. Multivariate analysis indicated that age ≤ 53 years (HR: 2.751, 95% CI: 1.326-5.707; p = 0.007), serum carcinoembryonic antigen (CEA) ≥ 23 ng/mL (HR: 3.197, 95% CI: 1.512-6.758; p = 0.002) and EGFR exon 21 point mutations (HR: 2.769, 95 % CI: 1.355-5.659; p= 0.005) were the independent high-risk factors for developing BM, which could offer important insights into the individualized treatment. Patients, with age ≤ 53 years, CEA ≥ 23 ng/mL and exon 21 point mutations from EGFR-mutated advanced lung adenocarcinoma, are at the highest risk for developing BM during the course of EGFR-TKIs therapy, and are most likely to benefit from PCI. Additionally, further studies are warranted to validate our findings.

Risk factors of brain metastasis during the course of EGFR-TKIs therapy for patients with EGFR-mutated advanced lung adenocarcinoma

Controversial value of prophylactic cranial irradiation (PCI) in NSCLC in terms of survival benefit prompted us to explore the possible risk factors for brain metastasis (BM) during the course of EGFR-TKIs therapy from EGFR-mutated advanced lung adenocarcinoma and identify the potential population most likely to benefit from PCI, because BM remains a therapeutically challenging issue. We retrospectively reviewed the records of 134 patients with EGFR-mutated advanced lung adenocarcinoma between 2008 and 2012. The cumulative incidence of BM was calculated by the Kaplan-Meier method, and Multivariate Cox regression analysis was used to assess the independent risk factors for BM. Thirty-four patients (34/134, 25.4%) developed BM during the course of EGFR-TKIs therapy. Moreover, the Multivariate analysis indicated that age ≤ 53 years (HR: 2.751, 95 % CI: 1.326-5.707; p = 0.007), serum carcinoembryonic antigen (CEA) ≥ 23 ng/mL (HR: 3.197, 95 % CI: 1.512-6.758; p = 0.002) and EGFR exon 21 point mutations (HR: 2.769, 95 % CI: 1.355-5.659; p= 0.005) were the independent high-risk factors for developing BM, which could offer important insights into the individualized treatment. Further studies are warranted to validate our findings.

Circulating tumor DNA sequencing to reveal the genomic complexity of advanced EGFR-mutant lung adenocarcinoma.

e23079Background: Lung adenocarcinoma (LUAD)patients (pts)whose tumors harbor activating EGFR mutations (mt) respond initially to EGFR TKIs but responses are typically incomplete and acquired resis...

Afatinib plus Cetuximab Delays Resistance Compared to Single-Agent Erlotinib or Afatinib in Mouse Models of TKI-Naïve EGFR L858R-Induced Lung Adenocarcinoma.

The EGFR tyrosine kinase inhibitors (TKIs), erlotinib and afatinib, have transformed the treatment of advanced EGFR-mutant lung adenocarcinoma. However, almost all patients who respond develop acquired resistance on average approximately 1 year after starting therapy. Resistance is commonly due to a secondary mutation in EGFR (EGFR(T790M)). We previously found that the combination of the EGFR TKI afatinib and the EGFR antibody cetuximab could overcome EGFR(T790M)-mediated resistance in preclinical models. This combination has shown a 29% response rate in a clinical trial in patients with acquired resistance to first-generation TKIs. An outstanding question is whether this regimen is beneficial when used as first-line therapy. Using mouse models of EGFR-mutant lung cancer, we tested whether the combination of afatinib plus cetuximab delivered upfront to mice with TKI-naïve EGFR(L858R)-induced lung adenocarcinomas delayed tumor relapse and drug-resistance compared with single-agent TKIs. Afatinib plus cetuximab markedly delayed the time to relapse and incidence of drug-resistant tumors, which occurred in only 63.6% of the mice, in contrast to erlotinib or afatinib treatment where 100% of mice developed resistance. Mechanisms of tumor escape observed in afatinib plus cetuximab resistant tumors include the EGFR(T790M) mutation and Kras mutations. Experiments in cell lines and xenografts confirmed that the afatinib plus cetuximab combination does not suppress the emergence of EGFR(T790M). These results highlight the potential of afatinib plus cetuximab as an effective treatment strategy for patients with TKI-naïve EGFR-mutant lung cancer and indicate that clinical trial development in this area is warranted.

Detection of sensitizing and resistance EGFR mutations from circulating tumor DNA (ctDNA) in blood using multiplexed next-generation sequencing in patients with advanced EGFR-mutant lung adenocarcinoma.

8093 Background: Analysis of tumor biopsies obtained after the development of acquired resistance (AR) to EGFR tyrosine kinase inhibitors can contribute to the understanding of resistance mechanisms, but requires an invasive procedure and only provides data on a single site of disease at one timepoint. We developed a next-generation sequencing method that employs novel error-suppression techniques to measure tumor-specific mutations in plasma at levels as low as 1 variant in 5,000. Here we report on the detection of sensitizing EGFR mutations and the emergence of the T790M resistance mutation in ctDNA and in tumor specimens. Methods: We collected plasma samples from patients (pts) with advanced EGFR-mutant lung adenocarcinoma. When feasible, serial plasma samples were collected during treatment and repeat tumor biopsies were performed at AR. Plasma was analyzed using error-suppressed deep sequencing to quantify point-mutations and insertions/deletions in multiple genes that are commonly mutated in lung cancer, including EGFR. Results: Plasma samples were obtained from 52 pts with known activating EGFR mutations. Thirty-two pts had serial samples, allowing monitoring of mutant DNA levels and detection of the emergence of new mutations in the plasma. Of the 31 pts who had a repeat biopsy, the T790M mutation was found in 15 (48%) in the tumor at AR. Data for the ctDNA and repeat tumor biopsy results for the first 5 pts tested in this cohort are presented in the Table. Conclusions: Detection of EGFR sensitizing and resistance mutations in ctDNA from the plasma using multiplexed next generation sequencing is feasible and shows a high concordance with results from tumor biopsy. This novel method using plasma may allow for earlier identification of resistance in pts treated with targeted therapy without the need for invasive biopsies. Pt # Source of DNA Sensitizing EGFR mutation EGFR T790M resistance mutation Exon 19 del L858R 1 Lymph node - + - Plasma - + - 2 Lymph node + - + Plasma + - + 3 Pleural fluid + - + Plasma + - + 4 Neck mass - + - Plasma - + - 5 Liver mass + - + Plasma + - -

Salvage Therapy beyond Targeted Therapy in Lung Adenocarcinoma

Targeted therapy in lung adenocarcinoma has evolved rapidly over the last few years, especially in the application of epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs). Although many patients with advanced EGFR-mutated or ALK-rearranged lung adenocarcinoma do benefit from treatment with a specific TKI, the duration of disease control is notoriously short. Different patterns of disease progression have been recognized that may require distinct treatment approaches. Isolated progressive disease in the central nervous system requires additional local therapy (radiotherapy or surgery) and an exploratory pulsatile regimen of TKI. Oligoprogressive disease at extracranial sites, representing resistant tumor clones in isolated lesions, requires local ablative therapy (radiotherapy or surgery) and continuation of the existing TKI. Multifocal progressive disease is a key therapeutic challenge to overcome because of widespread acquired resistance due to heterogeneous mechanisms. It is now known that EGFR TKI-acquired resistance is mostly (50-60%) due to a single resistance mutation in exon 20 (T790M) and occasionally (5-10%) due to c-MET amplification. On the contrary, the acquired resistance mechanisms to ALK TKI appear more diverse. Specific therapeutic strategies are being developed to overcome various acquired resistance mechanisms and may further improve the overall prognosis of advanced lung adenocarcinoma with actionable driver mutations.