P3.01-037 Understanding Mechanisms of Resistance to Osimertinib by Circulating Tumor DNA Genotyping in Advanced Non-Small-Cell Lung Cancer

S2214 with inoperable/recurrent EGFRm+ NSCLC received afatinib at the approved dose (20e50 mg/day) and were observed following treatment initiation for 52 weeks/until premature discontinuation. Data were included for all patients who received afatinib during the investigational period of this study, thus minimizing patient selection bias. The incidence/severity of adverse drug reactions (ADRs)/serious ADRs (sADRs) was the primary endpoint. Other endpoints included effectiveness (objective response rate [ORR]) and the incidence/severity of ADRs of special interest (diarrhea, rash/acne, nail effects [NEs] and interstitial lung disease [ILD]). Result: As of February 2017, 1,602 patients were included in the analysis (59% female, 81% aged <75 years, 86% ECOG PS 0e1, 83% BMI <25 kg/m2). 97% of patients had adenocarcinoma, and 64%/26% had EGFR Del19/L858R mutations. 70% had
1 line of prior chemotherapy; 48%/30% had prior gefitinib/ erlotinib. Afatinib starting dose was 40 mg in 77% of patients. 95% had ADRs (36% grade
3). The most frequently reported ADRs (all grade/ grade 3e4) were diarrhea (78%/15%), rash/acne (59%/6%), stomatitis (31%/4%), and NEs (38%/4%). ILD (all grade/grade 3e4/grade 5) occurred in 4%/2%/1% of patients. Median (range) time to initial onset was 5.0 (1e316) days for diarrhea, 11.0 (1e406) days for rash/ acne, 9.0 (1e327) days for stomatitis, 38.0 (1e526) days for NEs, and 35.5 (3e329) days for ILD. Four patients (<1%) had creatinine elevation following grade
3 diarrhea. Dose reductions/permanent discontinuations occurred in 8%/7% of patients following diarrhea, 6%/4% following rash/acne, 3%/2% following stomatitis, 5%/2% following NEs, and <1%/4% following ILD. 33% of patients experienced sADRs. ADR frequency was associated with starting dose (96%/ 91% with 40/<40 mg afatinib), but was not unfavorably impacted by age, ECOG PS, number of prior chemotherapies, or previous EGFR TKIs. ORR with afatinib was higher in EGFR TKI-naïve patients than those who had previously been treated with EGFR TKIs (68% versus 21%). Conclusion: Consistent with previous studies, afatinib was effective in inoperable/recurrent EGFRm+ NSCLC, particularly as first-line targeted treatment (ORR w70%). ADRs were predictable and generally manageable. ADR frequency was not notably affected by age, ECOG PS or number of previous therapies. In clinical practice, patients should be closely monitored and ADRs, particularly diarrhea and ILD, treated early to prevent sADRs.

P3.01-036 A Phase IIIb Open-Label, Single-Arm Study of Afatinib in EGFR TKI-Naïve Patients with EGFRm+ NSCLC: An Interim Analysis Y. Wu,1 H. Tu,2 J. Feng,3 M. Shi,3 J. Zhao,4 Y. Wang,4 J. Chang,5 J. Wang,5 Y. Cheng,6 J. Zhu,6 E. Tan,7 K. Li,8 Y. Zhang,9 V. Lee,10 C. Yang,11 W. Su,12 C.L. Lam,10 B. Srinivasa,13 S. Rajappa,14 C. Ho,15 K.C. Lam,16 Y. Hu,17 S.A. Bondarde,18 X. Liu,19 J. Fan,20 D. Kuo,21 Y. Wang,21 K. Pang,22 C. Zhou23 1/, 2Guangdong Lung Cancer Institute, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou/CN, 3Jiangsu Provincial Tumor Hospital, Nanjing, Jiangsu/CN, 4Beijing Cancer Hospital, Beijing/CN, 5Fudan University Shanghai Cancer Center, Shanghai/CN, 6Division of Thoracic Oncology, Jilin Province Cancer Hospital, Changchun/CN, 7Department of Medical Oncology, National Cancer Center, Singapore/SG, 8Tianjin Medical University Cancer Institute and Hospital, Tianjin/CN, 9First Zhejiang Cancer Hospital, Hangzhou/CN, 10Department of Clinical Oncology, the University of Hong Kong, Queen Mary Hospital, Hong Kong/HK, 11ChangGung Memorial Hospital, Linkou, Taipei/TW, 12National Cheng Kung University Hospital, Tainan/TW, 13Hcg Hospital, Bangalore/IN, 14 Basavatarakam Indo American Cancer Hospital & Research Institute, Hyderabad/IN, 15Tri-Service General Hospital, Taipei/TW, 16Prince of Wales Hospital, Shatin, New Territories/HK, 17Department of Oncology, Chinese PLA General Hospital, Beijing/CN, 18Shatabdi Super Speciality

Journal of Thoracic Oncology

Vol. 12 No. 11S2

Hospital, Mumbai Naka, Nashik, Maharashtra/IN, 19307th Hospital of PLA, Beijing/CN, 20Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield/CT/US, 21Boehringer Ingelheim (China) Investment Co., Ltd, Shanghai/CN, 22Boehringer Ingelheim Singapore Pte Ltd, Singapore/SG, 23 Shanghai Pulmonary Hospital, Tongji University, Shanghai/CN Background: In the Phase III LUX-Lung (LL) 3 and LL6 trials, first-line afatinib significantly improved PFS vs platinum-doublet chemotherapy in patients with EGFRm+ NSCLC (independent review; LL3: 11.1 vs 6.9 months, HR¼0.58; p¼0.001; LL6: 11.0 vs 5.6 months, HR¼0.28; p<0.0001). In the Phase IIb LL7 trial, afatinib significantly improved PFS and TTF vs gefitinib in patients with EGFRm+ NSCLC harboring common EGFR mutations (PFS, independent review: 11.0 vs 10.9 months, HR¼0.73; p¼0.017; TTF: 13.7 vs 11.5 months, HR¼0.73, p¼0.0073). Here we report interim analysis results of a large Phase IIIb study of afatinib in a broad population of EGFR TKI-naïve patients with EGFRm+ NSCLC. Method: In this Phase IIIb trial with a similar setting to ‘real-world’ practice, EGFR TKI-naïve patients with locally advanced/ metastatic EGFRm+ NSCLC were recruited from centers in China, Hong Kong, India, Singapore and Taiwan and received afatinib 40mg/day until investigator-assessed progression or lack of tolerability. Primary endpoint: number of patients with serious adverse events (SAEs). Secondary endpoints included: number of patients with afatinib-related AEs; time to symptomatic progression (TTSP). Other assessments included PFS (investigator review). Result: At data cut-off (13 Feb 2017) 479 patients were treated with afatinib (median age: 59.0 years; female: 52.4%; common [(Del19 and/or L858R) with or without uncommon]/uncommon only EGFR mutations: 86.0%/14.0%; ECOG PS 0/ 1: 19.8%/78.1%; brain metastases: 19.2%; 0/1/
2 lines of prior chemotherapy: 59.7%/30.1%/10.2%. 24.8% of patients required dose reductions to 30mg; 6.1% had further reductions to 20mg. Median (range) treatment time was 9.7 months (0.2e38.6). SAEs were reported in 115 (24.0%) patients and afatinib-related SAEs in 29 (6.1%) patients. Grade
3 afatinib-related AEs occurred in 122 (25.5%) patients; diarrhea (n¼50; 10.4%) and rash/acne (n¼38; 7.9%) were the most common (
5%). 18 (3.8%) patients discontinued treatment due to afatinib-related AEs. Median TTSP (15.3 months [95% CI: 13.4e17.5]) was 3 months longer than PFS (12.1 months [10.8e13.7]), suggesting afatinib may be continued beyond progression, and both were longer in patients with common (with/without uncommon) vs uncommon only EGFR mutations (PFS: 12.6 vs 9.1; TTSP: 15.8 vs 10.0 months). Conclusion: The safety data of afatinib from this interim analysis of a large-scale population of EGFR TKI-naïve EGFRm+ NSCLC patients are consistent with LL3/6/7 and confirm that most afatinibrelated AEs are manageable and result in few treatment discontinuations. Afatinib also demonstrated encouraging efficacy in patients with common and uncommon EGFR mutations. Data from larger patient populations will be evaluated in further analyzes of this trial. Keywords: afatinib, EGFR, NSCLC

P3.01-037 Understanding Mechanisms of Resistance to Osimertinib by Circulating Tumor DNA Genotyping in Advanced Non-Small-Cell Lung Cancer Y. Du,1 W. Zang,2 G. Wang,3 Y. Sang,2 F. Gai,2 L. Li,2 Y. Yu,2 G. Cheng,2 P. Yu,2 G. Sun1 1The First Affiliated Hospital of Medical University of Anhui, Anhui/CN, 2Novogene Co., Ltd., Beijing/CN, 3 Huangshan People’s Hospital of Anhui Province, Anhui/CN Background: Epidermal growth factor receptor (EGFR) T790M mutation is the most common mechanism for resistance to first- and secondgeneration EGFR tyrosine kinase inhibitors (TKI). Osimertinib has been demonstrated to overcome EGFR T790M non-small cell lung cancer (NSCLC). However, most of these patients eventually developed

November 2017 resistance after 10 months. Here we performed a comprehensive next generation sequencing (NGS) using circulating tumor DNA (ctDNA) to study resistance mechanisms in patients with advanced NSCLC who had developed resistance to osimertinib, and to provide potential opportunities for treatment. Method: 10 advanced NSCLC patients were enrolled in this study after progression from first-generation EGFR-TKI treatment. Patients received osimertinib with 80mg daily, the response rate and progression-free survival (PFS) was assessed during treatment. 10ml peripheral blood was collected from patients after progression from osimertinib, and ctDNA genotyping was performed by next-generation sequence (NGS). Result: There were 3 patients received gefitinib and 7 patients received erlotinib before osimertinib therapy. All patients confirmed a partial response (PR) on osimertinib, the median PFS was 13.3 months. The initial gene mutation patterns before osimertinib therapy could be classified into two groups: L858R/ Exon 19 Deletion (19Del) +T790M, and L858R/19Del+T790M unknown or wild-type. However, after progression from osimertinib, mutation patterns varied from groups. In the L858R/19Del+T790M group, two of six patients detected with L858R/19Del+T790M+C797S, two patients with L858R (+T790M) +HER2 amplification, and two patients with only 19Del+T790M; In the L858R/19Del+T790M unknown or wild-type group, there was only one patient detected with L858R/19Del+C797S mutation, the other three patients detected with only L858R mutation. For the C797S-mutated patients, it showed that T790M and C797S mutation presented in the same allele (cis) in two patients, while in both trans and cis in one patient. Other EGFR mutations were also detected, such as A750P, L792F, E709K, A1013V, L718V, and EGFR amplification. Conclusion: Genotyping of ctDNA in osimertinib resistant patients showed that the resistance might be related to specific gene mutation, e.g., EGFR C797S and HER2 amplification. Our findings provide insight that resistance to osimertinib might be different between T790M-mutated patients and T790M wilt-type patients. Combination therapy of osimertinib with other agents may be candidate to overcome the acquired mutation. Keywords: ctDNA, NSCLC, EGFR-TKI

P3.01-038 Impact on OS and PFS of 2nd and 3rd Generation TKI in EGFR Mt+ and ALK+ Patients: Results of the NOWEL Network J. Roeper,1 M. Netchaeva,1 A. Lueers,1 C. Hallas,2 M. Falk,2 M. Tiemann,2 N. Neemann,3 L. Heukamp,3 C. Wesseler,4 G. Wiest,4 S. Sackmann,5 D. Ukena,5 F. Griesinger1 1Depatment of Hematology and Oncology, Pius Hospital Oldenburg/university of Oldenburg, Oldenburg/DE, 2Hph Hematopathology Hamburg, Hamburg/DE, 3Neo New Oncology, Cologne/DE, 4Asklepios Klinikum Harburg, Hamburg/DE, 5 Klinikum Bremen-Ost, Bremen/DE Background: EGFR TKI treatment is standard of care in patients with metastasized NSCLC carrying an activating EGFR mutation. Targeted therapies achieve a higher ORR, OS, PFS and a better quality of life than chemotherapy. With the advent of 2nd and 3rd generation TKÍs effective in 1st generation TKI resistant tumors, we wanted to study the impact of these drugs on the outcome of patients in a real life setting in 3 lung cancer centers. Method: 1473 patients from three cancer centers diagnosed with non-squamous cell NSCLC stage IV (UICC 7) were examined. Methods for the mutation testing was performed according to the German Oncopedia guidelines using either Sanger Sequencing or COBAS® or Next Generation Sequencing. Result: 964/1473 (65%) consecutive patients with non-squamous cell NSCLC were studied for the presence of tumor mutations. The EGFR mutation rate was 16% (147/943), and the ALK-translocation rate 4% (26/695). Median OS in EGFR mt+ patients was 27 months (n¼147) compared to 11 months

Abstracts

S2215

(n¼796) in patients with EGFR WT (p<0.000). Median OS in EGFR mt+ patients depending on the center was 27 (n¼95) vs. 28 (n¼38) vs. 16 (n¼14) months respectively (center 1 vs. center 2 vs. center 3). Median OS in ALK mt+ patients was 24 months (n¼19) in center 1 and 11 months (n¼5) in center 2 (p<0.025). The ORR in the CR/PR group was 54.2% for patients treated with chemotherapy and 77% for patients treated with TKI on 1st line therapy. The chance to reach a CR/PR is 2.83 higher for patients on TKI than for patients on chemotherapy (p<0.02). The use of 3rd generation TKI Osimertinib (n¼19) lead to a significantly higher OS (n¼19, median OS 67 months) than the use of only 1st and 2nd generation TKI (n¼119, median OS 23 months, p<0.000). The hazard ratio for patients treated without Osimertinib was 4.66 [95% CI 2.006-10.81] (p<0.000). Patients treated with 3rd gen TKI had significantly longer PFS (11 months, n¼7) than patients treated without (5 months, n¼20) (p<0.037). Similarly, use of 2nd and 3rd generation ALKi impacted significantly on median OS: Crizotinib alone (n¼8) 17 months, Crizotinib followed by Ceritinib and/or Brigatinib/Alectinib (n¼12) median OS not reached and 3 months for other therapies (n¼6) (p<0.000). Conclusion: Small differences in OS were observed, depending on the treatment centers, but the use of multiple EGFR and ALK-I impacted highly significantly on the outcome of patients with EGFR and ALK-alterations in a real life setting. Keywords: 3rd generation TKI, advanced NSCLC, EGFR

P3.01-039 Sequential Afatinib-Osimertinib Therapy in EGFR Mutation-Positive (EGFRm+) NSCLC: Analysis of Time on Treatment and OS K. Park,1 E. Tan,2 K. O’Byrne,3 L. Zhang,4 M. Boyer,5 T. Mok,6 V. Hirsh,7 J.C. Yang,8 M. Schuler,9 N. Yamamoto,10 L. Sequist,11 Y. Wu,12 C. Zhou,13 E. Ehrnrooth,14 A. Märten,15 W. Tang,15 L. Paz-Ares16 1Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul/KR, 2Department of Medical Oncology, National Cancer Center, Singapore/SG, 3Department of Oncology, Princess Alexandra Hospital and Queensland University of Technology, Brisbane, QLD/AU, 4Cancer Center of Sun Yat-Sen University, Guangzhou/CN, 5Department of Oncology, Chris O’Brien Lifehouse, Camperdown, NSW/AU, 6Department of Clinical Oncology, the Chinese University of Hong Kong, Hong Kong/CN, 7Department of Oncology, McGill University Health Center, Montreal/CA, 8Department of Oncology, National Taiwan University Hospital and National Taiwan University Cancer Center, Taipei/TW, 9West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen/DE, 10Wakayama Medical University, Wakayama/JP, 11Massachusetts General Hospital and Harvard Medical School, Boston, MA/US, 12Guangdong Lung Cancer Institute, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou/CN, 13Medical Oncology, Shanghai Pulmonary Hospital, Tongji University, Shanghai/CN, 14Boehringer Ingelheim, Danmark A/s/DK, 15Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, CT/US, 16Hospital Universitario Doce de Octubre and Cnio, Madrid/ES Background: Acquired resistance to EGFR TKIs necessitates further treatment for patients with EGFRm+ NSCLC. In the LUX-Lung 7 (LL7) trial, afatinib significantly improved PFS, TTF and ORR vs gefitinib. Particularly encouraging OS was observed across both treatment arms in patients who received a subsequent third-generation EGFR TKI (afatinib vs gefitinib, median: not reached vs 48.3 months). Osimertinib has demonstrated activity against tumors harboring the T790M mutation; this mutation is known to be the main mechanism of acquired resistance to afatinib. Here, we assess the outcomes of first-line afatinib followed by subsequent osimertinib treatment, in patients with EGFRm+ NSCLC. Method: Patients with common (Del19/L858R) EGFR