Mutation-positive Lung Adenocarcinoma Research Articles

Abstract 5343: Mutational signatures in EGFR sensitizing mutation positive lung adenocarcinoma

Abstract Lung cancer has high mutational burden, which is featured by smoking signature. However, lung cancer with EGFR mutations is common in nonsmokers and women, which suggests that mutational stresses other than smoking are involved. We analyzed repeated deep sequencing data of EGFR sensitizing mutation positive lung adenocarcinoma tissue to identify characteristic mutational signatures, proposed by Alexandrov et al. Targeted next-generation sequencing was performed using Ion AmpliSeq Custom Panel of 0.6 Mb size containing 70 major genes including EGFR in 69 cases harboring sensitizing EGFR mutation. Publicly available data from EGFR sensitizing mutation were extracted from GDC data portal. Mutational signature was analyzed using maftools package. EGFR-TKI domain analysis revealed 53 mutations. C> T mutation was found in 26.4%, but C> T transition at CpG site that suggests aging effect was found in 2%, and C> T or C> G mutation in TCW motif reflecting APOBEC activity were found in 1.4%. C> A transversion corresponding to Signature 4 was also found in only one case, suggesting that the possibility of EGFR mutation by smoking effect is very low. The T> C substitution in ApT, indicating signature 5, was detected in 4%. The EGFR-TKI sensitizing mutation (E19del, L858R) has lower frequency of co-mutation while other EGFR-TKI domain mutations were frequently associated with multiple co-mutations. T>G substitution, indicating signature 28 and commonly found in Korean gastric cancer, was found in 39.1%. When the mutational signatures of a total 70 genes were analyzed, the C> T mutation was the most commonly detected (73.1%) and similarity with signature 5 was highest. These findings suggest that the mutational signature of EGFR sensitizing mutant lung cancer, which is frequent in Far East Asia, may be different from that of Western data. Additional data and analysis will be updated until the annual meeting. Citation Format: Eun Young Kim, Arum Kim, Yoon Soo Chang. Mutational signatures in EGFR sensitizing mutation positive lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5343.

Erlotinib as single agent first line treatment in locally advanced or metastatic activating EGFR mutation-positive lung adenocarcinoma (CEETAC): an open-label, non-randomized, multicenter, phase IV clinical trial

BackgroundErlotinib is approved for the first line treatment of epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer. Since the number of prospective studies in Caucasian patients treated in routine clinical setting is limited we conducted a multicenter, phase IV clinical trial to determine the efficacy and safety of erlotinib and to demonstrate the feasibility of the validated standardized companion diagnostic method of EGFR mutation detection.Methods651 chemonaive, cytologically or histologically verified advanced stage lung adenocarcinoma patients from Hungary, Turkey and Latvia were screened for exon19 microdeletions and exon21 L858R EGFR mutations using the companion diagnostic EGFR test. EGFR mutation-positive, locally advanced or metastatic lung adenocarcinoma patients received as first line treatment erlotinib at 150 mg/day. The primary endpoint was progression-free survival (PFS).Results62 EGFR mutation-positive patients (9.5% of screened) were included in the safety/intent-to-treat cohort. Median PFS was 12.8 months (95%CI, 9.9–15.8), objective response rate and one-year survival was 66.1% and 82.5%, respectively. Most frequent treatment related adverse events were diarrhoea and rash. Eastern Oncology Cooperative Group Performance Status (ECOG PS), smoking status and M1a/M1b disease stage were significant prognosticators of PFS (p = 0.017, p = 0.045 and p = 0.002, respectively). There was no significant difference in PFS between the subgroups stratified by gender, age or exon19 vs exon21 mutation.ConclusionsOur study confirmed the efficacy and safety of first line erlotinib monotherapy in Caucasian patients with locally advanced or metastatic lung adenocarcinoma carrying activating EGFR mutations based on the screening with the approved companion diagnostic procedure.Trial registrationClinicalTrials.gov Identifier: NCT01609543.

Prognostic factors of afatinib as a first-line therapy for advanced EGFR mutation-positive lung adenocarcinoma: a real-world, large cohort study.

Lung cancer remains the primary cause of cancer-related mortality worldwide. Several treatment modalities are available for lung cancer, including surgery, radiation, and chemotherapy. Among the chemotherapeutics available, afatinib has been shown to be effective for those with epidermal growth factor receptor (EGFR) mutation-positive lung adenocarcinoma. Herein, we analyzed the factors affecting the prognosis of patients who received afatinib as a first-line therapy for advanced EGFR mutation-positive lung adenocarcinoma in the real-world setting. Patients who received afatinib as a first-line therapy and were reimbursed by the National Health Insurance were recruited in this study. Data on patient characteristics and treatment courses were collected. In total, 259 patients were enrolled (median follow-up, 22.0 months). Of them, 82 (31.7%) were identified to have brain metastases at baseline, which were associated with poor Eastern Cooperative Oncology Group performance status, high incidence of central nervous system progression, and short overall survival. However, the results of our analysis showed that overall survival was not affected by reductions in the afatinib dosage or any upfront local treatments for brain tumors. Multivariate analyses showed that brain metastases at diagnosis and treatment response to afatinib are two important prognostic factors for the overall survival of patients with EGFR mutation-positive lung adenocarcinoma.

Transition Rate from EGFR-TKI to Cytotoxic Chemotherapy Patients with EGFR Mutation-positive Lung Adenocarcinoma.

The transition rate from first-line epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) to cytotoxic chemotherapy (Ct) is poor. The prognosis according to treatment sequence and the reasons patients could not shift from first-line EGFR-TKIs to Ct were herein analyzed. Overall, 159 epidermal growth factor receptor mutation-positive adenocarcinoma patients were enrolled in this study. The median survival times of EGFR-TKIs combined with Ct and EGFR-TKIs were 59.8 months and 22.5 months, respectively (p<0.001) and of patients who received EGFR-TKIs first and Ct first were 38.8 months and 66.4 months, respectively (p=0.016). The main reasons patients could not make the transition to Ct was worsening of performance status and patient's preference. EGFR-TKIs and Ct lead to a good prognosis in EGFR mutation-positive adenocarcinoma patients. It is necessary to consider the timing when changing the treatment strategy before treatment options are limited.

Cytomorphological features as predictors of epidermal growth factor receptor mutation status in lung adenocarcinoma.

Background:Epidermal growth factor receptor mutation-positive (EGFR-p) lung adenocarcinomas are sensitive to tyrosine kinase inhibitors. Although histopathological subtype is an independent predictor of mutation status, there is a paucity of data on the cytomorphological features correlating with the EGFR mutation status. Therefore, the aim of this study was to determine whether certain cytomorphological features correlate with EGFR mutation in lung adenocarcinoma.Materials and Methods:A retrospective analysis of 48 lung adenocarcinoma cases diagnosed on fine needle aspiration cytology with known EGFR mutation status was conducted. All cytology smears with cellblock sections were reviewed. The cytomorphological features including tumor pattern, stromal features, nuclear and cytoplasmic features, and tumor grade were evaluated. Clinicoradiological features such as age, sex, smoking, tumor size, clinical stage, metastases, and presence of mass, nodule, lymphadenopathy, pleural effusion, and clinical outcome were also assessed.Results:Of 48 cases, 19 were EGFR-p and 29 were negative. EGFR-p cases showed a positive and significant correlation with flat monolayered sheets and acini, mild nuclear atypia, fine chromatin and smooth nuclear margins and these tumors were well differentiated. EGFR-negative tumors were moderate to poorly differentiated with predominance of solid clusters, moderate to marked nuclear atypia, with irregular nuclear margins and coarse chromatin. Clinically, female sex, nonsmoking status, smaller tumor size, and good clinical outcome correlated with EGFR-p status.Conclusion:Certain cytomorphological features correlate with and may suggest EGFR mutation status in advanced lung adenocarcinoma in an appropriate clinical context.

Overcoming erlotinib resistance in EGFR mutation-positive lung adenocarcinomas through repression of phosphoglycerate dehydrogenase.

How to improve the efficacy and reverse the resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), such as erlotinib, remains a major challenge in the targeted therapy of lung adenocarcinoma with EGFR-activating mutation. Phosphoglycerate dehydrogenase (PHGDH) is the key enzyme of de novo serine biosynthesis over-expressed in various types of cancer including lung cancer. Elevated PHGDH expression is correlated with a worse overall survival in clinical lung adenocarcinoma patients. Here we investigated the role of PHGDH in lung adenocarcinoma with the acquisition of resistance to erlotinib.Methods: The necessary genes required for the acquired erlotinib resistance in lung adenocarcinoma cells were screened out by RNA-Seq analysis. Then the protein and mRNA levels of PHGDH were confirmed by immunoblotting and qRT-PCR in the erlotinib resistant cells. The effects of PHGDH inhibition or overexpression on erlotinib resistance were examined using cell culture and tumor xenograft mouse models respectively. To explore mechanism, the ROS level and DNA damage marker, γH2AX, were tested by DCFH-DA staining and immunofluorescence after PHGDH inhibition.Results: We found that PHGDH level was significantly increased in the lung adenocarcinoma PC9ER4 and HCC827ER9 cells that acquired resistance to erlotinib. Perturbation of PHGDH by siPHGDH transfection or NCT-503, a small molecular PHGDH inhibitor, synergistically augmented the tumoricidal effect and restored sensitivity to erlotinib in cell lines and xenografts. Over-expression of PHGDH caused xenografts resistant to erlotinib. Furthermore, multiple DNA damage repair pathways related genes were changed by PHGDH depletion specifically in erlotinib resistant cells. ROS stress and DNA damage marker γH2AX were enhanced by siPHGDH and NCT-503, which was reversed by NAC.Conclusion: Our study indicated that PHGDH inhibition has potential therapeutic value in lung adenocarcinoma with the acquired resistance to EGFR-TKIs.

Overcoming erlotinib resistance in EGFR mutation-positive lung adenocarcinomas through repression of phosphoglycerate dehydrogenase

Overcoming erlotinib resistance in EGFR mutation-positive lung adenocarcinomas through repression of phosphoglycerate dehydrogenase

PD-L1 expression according to the EGFR status in primary lung adenocarcinoma

ObjectivesIt was reported that programmed cell death-ligand 1 (PD-L1) expression is associated with smoking and wild-type epidermal growth factor receptor (EGFR) in lung adenocarcinoma. However, the association between PD-L1 expression and EGFR mutation site in EGFR mutation-positive lung adenocarcinoma is unclear. Materials and methodsWe retrospectively examined the relationship between PD-L1 expression and EGFR status in 441 surgically resected primary lung adenocarcinomas. Membrane PD-L1 expression on tumor cells was evaluated by immunohistochemical analysis using a PD-L1 antibody (clone SP142) and defined by tumor proportion scores (TPSs) of 0%, 1–4%, 5–49%, and ≥50%, respectively. ResultsTwo hundred and eighteen (49.4%) patients had wild-type EGFR, and 223 (50.6%) had mutant EGFR—98 (44.0%) with exon 19 deletion, 116 (52.0%) with exon 21 L858R point mutation, and nine (4.0%) with another EGFR mutation. Overall, Fisher’s exact test showed that PD-L1 positivity was associated with wild-type EGFR, and there was only one case with PD-L1 TPS ≥50% among the cases with mutant EGFR. The analysis of cases with mutant EGFR indicated no significant association between EGFR mutation site and PD-L1 expression. However, the prevalence of PD-L1 TPS 5–49% was higher among patients with EGFR exon 19 deletion than with EGFR exon 21 L858R point mutation. ConclusionsPD-L1 expression was significantly associated with wild-type EGFR, and PD-L1 TPS ≥50% seldom overlaps with presence of driver oncogene EGFR. There was no significant difference in PD-L1 expression among the EGFR mutation sites

429P - Afatinib in the first line therapy of EGFR mutation positive adenocarcinoma of lung: Single institute experience

Background: Afatinib provide progression-free survival benefit compared to platinum-based chemotherapy in patients with non-small cell lung cancer harboring epidermal growth factor receptor-activating mutation. Therefore, we conducted this retrospective study to note the efficacy of afatinib as first-line treatment in patients with EGFR-mutated non-small cell lung cancer. Methods: We conducted this retrospective study at a single medical center in Taiwan from June 01, 2014 to December 31, 2016. We used the Kaplan-Meier method to estimate survival. Results: Total 56 patients diagnosed with stage IIIb and IV non-small cell lung cancer in the study period. The median duration of follow-up for progression-free survival was 11 months. The median progression-free survival was 20.6 months. Progression-free survival was significantly longer in the patients who had L858R mutation, good performance status, and adverse effect of afatinib had better PFS. Age, gender, smoking status, decreased dosage of afatinib would not comprised the efficancy. Conclusions: Afatinib had significant benefits in progression-free survival in non-small smallcell lung cancers harboring EGFR-activating mutations. Patients who had L858R mutation, performance status of ECOG PS 0∼1, and adverse events had better survival. Legal entity responsible for the study: This is a study without legal entity responsible for the governance, coordination and running of the study. Funding: None Disclosure: All authors have declared no conflicts of interest.

P3.03-011 A Report of BRAF V600E Positive Lung Adenocarcinoma Patient Who Respond Well to Pemetrexed

BRAF mutations is one of the important driver oncogene in non-small cell lung cancer (NSCLC), and are known to give the patients worse prognosis as same as KRAS mutations. However, we experienced that a patient with BRAF V600E positive lung adenocarcinoma was responsive to pemetrexed treatment. The patient has been followed for over 7 years without recurrence and metastasis. Here, we introduce a pemetrexed well respond patient with BRAF mutation positive lung adenocarcinoma. Clinical presentation, radiological features, histopathologic findings and genetic findings of the patient are reported. A 64 years-old never smoker female who complained bloody sputum visited our hospital. Chest X ray examination showed protrusion of the right first aortic arches. Transbronchial lung biopsy was performed and primary lung adenocarcinoma was diagnosed. Brain metastasis was suspected by magnetic resonance imaging. The patient was initially given combined chemotherapy with CDDP+VNR and Radiation therapy (60Gy). But after six months, tumor progression was found. Therapeutic agent was changed to 600mg single pemetrexed as outpatient chemotherapy for 14 months. Computed tomography showed reduction of tumor mass. Then, the patient has been still followed without any anti-cancer treatment. It passed for 7 years after diagnosis. The oncogenic driver mutations of the present patient were investigated in another study. Immunohistochemistry and DNA sequencing analysis showed the existence of BRAF mutation V600E in the present case. BRAF mutation in NSCLC was reported not associated with enhanced chemosensitivity. However, pemetrexed was effective to the present BRAF V600E positive lung adenocarcinoma patient.

Real-world experience of afatinib as a first-line therapy for advanced EGFR mutation-positive lung adenocarcinoma.

We evaluated the real-world efficacy and side effects of afatinib as a first-line therapy for advanced EGFR mutation-positive lung adenocarcinoma. The medical records of patients receiving afatinib as a first-line therapy after National Health Insurance reimbursement between May 2014 and January 2016 were reviewed, and information on patient characteristics and treatment courses were collected consecutively. Rebiopsy tissue was collected for EGFR mutation and MET amplification analyses. MET amplification was detected by fluorescence in situ hybridization and immunohistochemistry. In total, 140 patients were enrolled (median follow-up, 18.0 months). No significant differences in side effects, treatment responses, progression-free survival, or brain metastasis control were observed between patients receiving 40 mg versus < 40 mg of afatinib during the first 6 months. Patients with significant pretreatment weight loss (> 10.0% in 6 months) had a shorter median progression-free survival. Patients with brain metastases had a poorer Eastern Cooperative Oncology Group performance status and were associated with a shorter median progression-free survival. Nine patients (32.1%) had a p.T790M mutation and only 1 patient gained MET amplifications after disease progression. Afatinib is effective as a first-line therapy for advanced EGFR mutation-positive lung adenocarcinoma. Afatinib dosage does not affect clinical efficacy and drug-related side effects.

Acquired Resistance to Erlotinib in EGFR Mutation-Positive Lung Adenocarcinoma among Hispanics (CLICaP).

Lung cancer harboring epidermal growth factor receptor (EGFR) mutations and treated with EGFR tyrosine kinase inhibitors (TKIs) all eventually develop acquired resistance to the treatment, with half of the patients developing EGFR T790M resistance mutations. The purpose of this study was to assess histological and clinical characteristics and survival outcomes in Hispanic EGFR mutated lung cancer patients after disease progression. EGFR mutation-positive lung cancer patients (n=34) with acquired resistance to the EGFR-TKI erlotinib were identified from 2011 to 2015. Post-progression tumor specimens were collected for molecular analysis. Post-progression interventions, response to treatment, and survival were assessed and compared among all patients and those with and without T790M mutations. Mean age was 59.4±13.9years, 65% were never-smokers, and 53% had a performance status 0-1. All patients received erlotinib as first-line treatment. Identified mutations included: 60% DelE19 (Del746-750) and 40% L858R. First-line erlotinib overall response rate (ORR) was 61.8% and progression free survival (PFS) was 16.8months (95% CI: 13.7-19.9). Acquired resistance mutations identified were T790M mutation (47.1%); PI3K mutations (14.7%); EGFR amplification (14.7%); KRAS mutation (5.9%); MET amplification (8.8%); HER2 alterations (5.9%, deletions/insertions in e20); and SCLC transformation (2.9%). Of patients, 79.4% received treatment after progression. ORR for post-erlotinib treatment was 47.1% (CR 2/PR 14) and median PFS was 8.3months (95% CI: 2.2-36.6). Median overall survival (OS) from treatment initiation was 32.9months (95% CI: 30.4-35.3), and only the use of post-progression therapy affected OS in a multivariate analysis (p=0.05). Hispanic patients with acquired resistance to erlotinib continued to be sensitive to other treatments after progression. The proportion of T790M+ patients appears to be similar to that previously reported in Caucasians.

Feasibility and outcome of repeat biopsy upon progression on tyrosine kinase inhibitors in patients with EGFR mutation positive adenocarcinoma of lung-an Indian tertiary cancer centre experience.

e20628 Background: A repeat biopsy at the time of progression is important to evaluate the mechanism of resistance to tyrosine kinase inhibitors (TKIs) in EGFR mutation positive adenocarcinoma (ADC) of lung and dictates decisions for further therapy. Being an invasive procedure, a rebiopsy is not always possible and presents various hindrances. Methods: Between January 2012 and November 2016, EGFR mutation positive ADC of Lung treated with TKIs were evaluated for and offered a repeat biopsy at the time of progression on TKI. Feasibility of rebiopsy was done by a team of experienced interventional radiologists. Proportion of patients undergoing a rebiopsy, reason for inability to undergo a rebiopsy, histopathology findings including any small cell transformation and adequacy of tissue for further molecular testing were assessed. Results:154 patients were offered a repeat biopsy out of which 119 patients (77.3%) underwent a repeat biopsy. There was no evidence of malignancy in 17.6% (21/119) patients on the rebiopsy specimen and tumor was inadequate for molecular testing in 9 out of 98 patients (9.2%) in whom malignancy was detected on the repeat biopsy specimen. Small cell transformation was seen in 3.3% (4/119) patients who underwent a repeat biopsy. Amongst the 34 patients who could not undergo rebiopsy, patient unwillingness for the procedure was the most common reason, accounting for 47% cases (16/34) followed by a technically difficult biopsy as per judgement of the interventional radiology team in 32.3% (11/34). 5 out of 34 patients were not subjected to a rebiopsy a poor performance status and 3 patients were not subjected to rebiopsy as per treating clinician’s discretion. Thus, out of 154 patients, adequate tissue was not available for molecular testing in 41.5% patients who progressed on TKI due to various reason as elaborated above. Molecular testing is planned on the remaining biopsy specimens. Conclusions: Conventional invasive rebiopsy upon progression on TKIs fails to collect adequate tissue for molecular testing in almost 40% cases due to various reasons making liquid biopsy a very important tool in this setting.

Abstract B25: Association of variations in HLA-class II and other loci with susceptibility to EGFR-mutated lung adenocarcinoma

Abstract Background: Lung adenocarcinoma (LADC) driven by somatic EGFR mutations is more prevalent in East Asians (30-50%) than in European/Americans (10-20%). Understanding the genetic factors underlying such LADC is required to elucidate disease etiology and to identify effective methods of prevention. Methods: We investigate genetic factors underlying the risk of this disease by conducting a genome-wide association study, followed by two validation studies, in 3,173 Japanese patients with EGFR mutation-positive lung adenocarcinoma and 15,158 controls. Results: Four loci, 5p15.33 (TERT), 6p21.3 (BTNL2, HLA-class II), 3q28 (TP63) and 17q24.2 (BPTF), previously shown to be strongly associated with overall lung adenocarcinoma risk in East Asians, were re-discovered as loci associated with a higher susceptibility to EGFR mutation-positive. Citation Format: Kouya Shiraishi, Yukinori Okada, Atsushi Takahashi, Yoichiro Kamatani, Kyota Ashikawa, Yukihide Momozawa, Hideo Kunitoh, Shingo Matsumoto, Atsushi Takano, Kimihiro Shimizu, Akiteru Goto, Koji Tsuta, Shun-ichi Watanabe, Yuichiro Ohe, Yukio Watanabe, Yasishi Goto, Hiroshi Nokihara, Koh Furuta, Akihiko Yoshida, Koichi Goto, Tomoyuki Hishida, Masahiro Tsuboi, Katsuya Tsuchihara, Yohei Miyagi, Haruhiko Nakamura, Tomoyuki Yokose, Katsuya Tanaka, Toshiteru Nagashima, Yoichi Ohtaki, Daichi Maeda, Kazuhiro Imai, Yoshihiro Minamiya, Hiromi Sakamoto, Akira Saito, Yoko Shimada, Kuniko Sunami, Motonobu Saito, Teruhiko Yoshida, Jun Yokota, Fumihiko Matsuda, Keitaro Matsuo, Yataro Daigo, Michiaki Kubo, Takashi Kohno. Association of variations in HLA-class II and other loci with susceptibility to EGFR-mutated lung adenocarcinoma. [abstract]. In: Proceedings of the AACR Special Conference: Improving Cancer Risk Prediction for Prevention and Early Detection; Nov 16-19, 2016; Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2017;26(5 Suppl):Abstract nr B25.

CD200-positive cancer associated fibroblasts augment the sensitivity of Epidermal Growth Factor Receptor mutation-positive lung adenocarcinomas to EGFR Tyrosine kinase inhibitors

Cancer associated fibroblasts (CAFs) play important roles in the chemotherapeutic process, especially through influencing the resistance of tumor cells to molecular targeted therapy. Here we report the existence of a special subpopulation of patient-specific-CAFs that augment the sensitivity of EGFR gene mutation-positive lung cancer to the EGFR-tyrosine kinase inhibitor (EGFR-TKI), gefitinib. When cocultured with EGFR mutation positive lung cancer cells, these CAFs increased the apoptic effect of gefitinib on cancer cells, whereas, in the absence of gefitinib, they did not affect cancer cell viability. The assay using different single cell-derived clones demonstrated that the aforementioned sensitizing ability is clone-specific. Microarray analysis revealed that CD200 was expressed at much higher levels in this CAFs. Knocking down of CD200 expression deprived CAFs of their sensitizing potential, suggesting that CD200 is the functional molecule responsible for the effect. Immunohistochemical analysis of samples from patients receiving postoperative gefitinib treatment revealed that the individuals whose resected lung adenocarcinomas contained CD200-positive CAFs tended to have longer progression free survival of gefitinib when they recurred after surgery. These results suggest that CD200-positive CAFs can augment the sensitivity to EGFR-TKIs and may possess far reaching applications in the therapeutic use of EGFR-TKIs.

OA10.02 Association of Variations in HLA-Class II and Other Loci with Susceptibility to EGFR-Mutated Lung Adenocarcinoma

Lung adenocarcinoma (LADC) driven by somatic EGFR mutations is more prevalent in East Asians (30-50%) than in European/Americans (10-20%). Understanding the genetic factors underlying such LADC is required to elucidate disease etiology and to identify effective methods of prevention. We investigate genetic factors underlying the risk of this disease by conducting a genome-wide association study, followed by two validation studies, in 3,173 Japanese patients with EGFR mutation-positive lung adenocarcinoma and 15,158 controls. Four loci, 5p15.33 (TERT), 6p21.3 (BTNL2, HLA-class II), 3q28 (TP63) and 17q24.2 (BPTF), previously shown to be strongly associated with overall lung adenocarcinoma risk in East Asians, were re-discovered as loci associated with a higher susceptibility to EGFR mutation-positive lung adenocarcinoma. In addition, two additional loci, HLA-class II at 6p21.32 and 6p21.1 (FOXP4) were newly identified as loci associated with EGFR mutation-positive lung adenocarcinoma (Shiraishi et al., Nature Communications, 2016, in press). This study indicates that multiple genetic factors, including an immunologic one, underlie the risk of lung adenocarcinomas with EGFR mutations.

P3.02b-068 Outcomes of Patients with Advanced EGFR Mutation Positive Adenocarcinoma of Lung Treated with Gefitinib in Northern Ireland 2010-2016: Topic: EGFR Clinical

P3.02b-068 Outcomes of Patients with Advanced EGFR Mutation Positive Adenocarcinoma of Lung Treated with Gefitinib in Northern Ireland 2010-2016: Topic: EGFR Clinical

EGFR mutation detection in circulating cell-free DNA of lung adenocarcinoma patients: analysis of LUX-Lung 3 and 6

Background:In the Phase III LUX-Lung 3/6 (LL3/LL6) trials in epidermal growth factor receptor (EGFR) mutation-positive lung adenocarcinoma patients, we evaluated feasibility of EGFR mutation detection using circulating cell-free DNA (cfDNA) and prognostic and predictive utility of cfDNA positivity (cfDNA+).Methods:Paired tumour and blood samples were prospectively collected from randomised patients. Mutations were detected using cfDNA from serum (LL3) or plasma (LL6) by a validated allele-specific quantitative real-time PCR kit.Results:EGFR mutation detection rates in cfDNA were 28.6% (serum) and 60.5% (plasma). Mutation detection in blood was associated with advanced disease characteristics, including higher performance score, number of metastatic sites and bone/liver metastases, and poorer prognosis. In patients with common EGFR mutations, afatinib improved progression-free survival vs chemotherapy in cfDNA+ (LL3: HR, 0.35; P=0.0009; LL6: HR, 0.25; P<0.0001) and cfDNA− (LL3: HR, 0.46; P<0.0001; LL6: HR, 0.12; P<0.0001) cohorts. A trend towards overall survival benefit with afatinib was observed in cfDNA+ patients.Conclusions:Plasma cfDNA is a promising alternative to biopsy for EGFR testing. Detectable mutation in blood was associated with more advanced disease and poorer prognosis. Afatinib improved outcomes in EGFR mutation-positive patients regardless of blood mutation status.

Effect of dose adjustment on the safety and efficacy of afatinib for EGFR mutation-positive lung adenocarcinoma: post hoc analyses of the randomized LUX-Lung 3 and 6 trials

Afatinib 40 mg/day is approved for first-line treatment of EGFR mutation-positive non-small-cell lung cancer (NSCLC). In the case of drug-related grade ≥3 or selected prolonged grade 2 adverse events (AEs), the dose can be reduced by 10 mg decrements to a minimum of 20 mg. Here, we evaluate the influence of afatinib dose reduction on AEs, pharmacokinetics and progression-free survival (PFS) in the phase III LUX-Lung 3 and 6 (LL3/6) trials. Treatment-naïve patients with advanced EGFR mutation-positive NSCLC in LL3 (global) and LL6 (China, Thailand, South Korea) were randomized to afatinib or chemotherapy. All afatinib-treated patients (LL3, n = 229; LL6, n = 239) were included in the post hoc analyses. Incidence and severity of common AEs before and after afatinib dose reduction were assessed. Afatinib plasma concentrations were compared in patients who reduced to 30 mg versus those remaining at 40 mg. PFS was compared between patients who dose reduced within the first 6 months of treatment and those who did not. Dose reductions occurred in 53.3% (122/229) and 28.0% (67/239) of patients in LL3 and LL6, respectively; most (86.1% and 82.1%) within the first 6 months of treatment. Dose reduction led to decreases in the incidence of drug-related AEs, and was more likely in patients with higher afatinib plasma concentrations. On day 43, patients who dose reduced to 30 mg (n = 59) had geometric mean afatinib plasma concentrations of 23.3 ng/ml, versus 22.8 ng/ml in patients who remained on 40 mg (n = 284). The median PFS was similar in patients who dose reduced during the first 6 months versus those who did not {LL3: 11.3 versus 11.0 months [hazard ratio (HR) 1.25]; LL6: 12.3 versus 11.0 months (HR 1.00)}. Tolerability-guided dose adjustment is an effective measure to reduce afatinib-related AEs without affecting therapeutic efficacy. Clinicaltrials.gov identifiers: NCT00949650 and NCT0112393.

Comparing the Clinical Efficacy of TKI Alone With TKI Plus Concomitant WBRT for EGFR Mutation–Positive Lung Adenocarcinoma Patients With Brain Metastases: A Retrospective Study

Comparing the Clinical Efficacy of TKI Alone With TKI Plus Concomitant WBRT for EGFR Mutation–Positive Lung Adenocarcinoma Patients With Brain Metastases: A Retrospective Study