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Background: The OPTIMAL study was the first study to compare efficacy and tolerability of the epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) erlotinib, versus standard chemotherapy in first-line treatment of patients with EGFR mutation-positive advanced non-small-cell lung cancer (NSCLC). Findings from final overall survival (OS) analysis and assessment of post-study treatment impact are presented. Patients and methods: Of 165 randomised patients, 82 received erlotinib and 72 gemcitabine plus carboplatin. Final OS analyses were conducted when 70% of deaths had occurred in the intent-to-treat population. Subgroup OS was analysed by Cox proportional hazards model and included randomisation stratification factors and post-study treatments. Results: Median OS was similar between the erlotinib (22.8 months) and chemotherapy (27.2 months) arms with no significant between-group differences in the overall population [hazard ratio (HR), 1.19; 95% confidence interval (CI) 0.83- 1.71; P = 0.2663], the exon 19 deletion subpopulation (HR, 1.52; 95% CI 0.91-2.52; P = 0.1037) or the exon 21 L858 mutation subpopulation (HR, 0.92; 95% CI 0.55-1.54; P = 0.7392). More patients in the erlotinib arm versus the chemotherapy arm did not receive any post-study treatment (36.6% versus 22.2%). Patients who received sequential combination of EGFR-TKI and chemotherapy had significantly improved OS compared with those who received EGFR-TKI or chemotherapy only (29.7 versus 20.7 or 11.2 months, respectively; P < 0.0001). OS was significantly shorter in patients who did not receive post-study treatments compared with those who received subsequent treatments in both arms. Conclusion: The significant OS benefit observed in patients treated with EGFR-TKI emphasises its contribution to improving survival of EGFR mutant NSCLC patients, suggesting that erlotinib should be considered standard first-line treatment of EGFR mutant patients and EGFR-TKI treatment following first-line therapy also brings significant benefits to those patients. [ABSTRACT FROM AUTHOR]

Background: The phase III, randomized, open-label ENSURE study (NCT01342965) evaluated first-line erlotinib versus gemcitabine/cisplatin (GP) in patients from China, Malaysia and the Philippines with epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer (NSCLC). Patients and methods: Patients ≥18 years old with histologically/cytologically confirmed stage IIIB/IV EGFR mutation-positive NSCLC and Eastern Cooperative Oncology Group performance status 0-2 were randomized 1:1 to receive erlotinib (oral; 150 mg once daily until progression/unacceptable toxicity) or GP [G 1250 mg/m² i.v. days 1 and 8 (3-weekly cycle); P 75 mg/m² i.v. day 1, (3-weekly cycle) for up to four cycles]. Primary end point: investigator-assessed progression-free survival (PFS). Other end points include objective response rate (ORR), overall survival (OS), and safety. Results: A total of 217 patients were randomized: 110 to erlotinib and 107 to GP. Investigator-assessed median PFS was 11.0 months versus 5.5 months, erlotinib versus GP, respectively [hazard ratio (HR), 0.34, 95% confidence interval (CI) 0.22-0.51; log-rank P < 0.0001]. Independent Review Committee-assessed median PFS was consistent (HR, 0.42). Median OS was 26.3 versus 25.5 months, erlotinib versus GP, respectively (HR, 0.91, 95% CI 0.63-1.31; log-rank P = .607). ORR was 62.7% for erlotinib and 33.6% for GP. Treatment-related serious adverse events (AEs) occurred in 2.7% versus 10.6% of erlotinib and GP patients, respectively. The most common grade ≥3 AEs were rash (6.4%) with erlotinib, and neutropenia (25.0%), leukopenia (14.4%), and anemia (12.5%) with GP. Conclusion: These analyses demonstrate that first-line erlotinib provides a statistically significant improvement in PFS versus GP in Asian patients with EGFR mutation-positive NSCLC (NCT01342965). [ABSTRACT FROM AUTHOR]

Background In AURA3 (NCT02151981), osimertinib, a 3rd-generation EGFR-TKI, significantly prolonged progressionfree survival (PFS) and improved response rate vs plt-pem in pts with centrally confirmed EGFR T790M advanced NSCLC and progression on a prior EGFR-TKI. Here we report mature OS data. Methods Adult pts were randomised 2:1 to receive oral osimertinib (80 mg once daily) or intravenous pem (500 mg per m2 of body surface area) + carboplatin (target area under the curve 5)/cisplatin (75 mg per m2), every 3 weeks, ≤6 cycles. Treatment beyond progression (RECIST 1.1) was allowed if clinical benefit continued. Pts receiving plt-pem could cross over to osimertinib on disease progression. Asymptomatic CNS metastases were allowed. Primary endpoint was investigator-assessed PFS. OS and safety are reported as secondary endpoints. Data cut-off (DCO): 15 March 2019. Results In total, 419 pts were randomised (osimertinib, n = 279; plt-pem, n = 140); 99 pts (71%) crossed over to osimertinib from plt-pem. At DCO, 188 pts (67%) in the osimertinib arm vs 93 pts (66%) in the plt-pem arm had died, including 66/99 (67%) crossover pts; median OS 26.8 mo (95% confidence interval [CI] 23.5, 31.5) vs 22.5 mo (95% CI 20.2, 28.8) respectively, hazard ratio (HR) 0.87 (95% CI 0.67, 1.12; p = 0.277); survival rate at 24 mo was 55% vs 43% and at 36 mo was 37% vs 30%. Time to first subsequent treatment showed a large, clinically meaningful numerical advantage towards osimertinib, HR 0.21 (95% CI 0.16, 0.28; p < 0.001); time to second subsequent treatment, HR 0.87 (95% CI 0.69, 1.11; p = 0.263). In both arms, 99% pts had any adverse event (AE). Any AE grade ≥3 causally related to study treatment was 9% vs 34% for osimertinib and plt-pem respectively. Most common AEs were diarrhoea, 44% (grade ≥3, 1%), and nausea, 49% (grade ≥3, 4%), with osimertinib and plt-pem respectively. Conclusions A numerical advantage in OS was observed for pts receiving osimertinib vs plt-pem, with the majority of pts in the plt-pem arm having crossed over to osimertinib. The safety profile of osimertinib remains consistent with previous findings. Clinical trial identification NCT02151981. Editorial acknowledgement Laura Crocker, BMedSci, of iMed Comms, an Ashfield Company, who provided medical writing support funded by AstraZeneca. Legal entity responsible for the study AstraZeneca. Funding AstraZeneca. Disclosure Y-L. Wu: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Roche; Honoraria (self): Eli Lilly; Honoraria (self): Pfizer; Honoraria (self): MSD; Honoraria (self): Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy: Boehringer Ingelheim. T.S.K. Mok: Honoraria (self): ACEA Pharma, Alpha Biopharma Co. Ltd. Amgen, Amoy Diagnostics Co. LTD. AstraZeneca (before 1/1/19), Bayer, BI, Blueprint Medicines Corporation, BMS, Celgene, CStone Pharmaceuticals, Eli Lilly, Fishawack Facilitate Ltd, Hengrui Therapeutics Inc. Ignyt; Advisory / Consultancy: ACEA Pharma, Alpha Biopharma Co. Ltd. Amgen, Amoy Diagnostics Co. LTD. AstraZeneca (before 1/1/19), Bayer, BI, Blueprint Medicines Corporation, BMS, Celgene, Cirina, CStone Pharmaceuticals, Eli Lilly, Fishawack Facilitate Ltd, geneDecode Co. Ltd. (un; Leadership role: AstraZeneca PLC, Hutchison Chi-Med; Research grant / Funding (institution): AstraZeneca, BMS, Clovis Oncology, MSD, Novartis, Pfizer, Roche, SFJ, XCovery; Shareholder / Stockholder / Stock options: Shareholder: Hutchison Chi-Med, Sanomics Ltd. Stock option: Clearbridge Biomedics (now Biolidics Ltd.), Loxo-Oncology, OrigiMed Co. Ltd. Virtus Medical Group; Full / Part-time employment: The Chinese University of Hong Kong; Officer / Board of Directors: Remunerated: AstraZeneca PLC, Hutchison Chi-Med Non-remunerated: American Society of Clinical Oncology (ASCO) Asian Thoracic Oncology Research Group (ATORG) Chinese Lung Cancer Research Foundation Limited (CLCRF) Chinese Society of Clinical Oncology (CS. J-Y. Han: Honoraria (self): Roche, AstraZeneca, Bristol-Myers Squibb, MSD, Takeda; Advisory / Consultancy: AstraZeneca, Bristol-Myers Squibb, MSD, Takeda, Pfizer, Novartis, Lilly; Research grant / Funding (self): Roche, Pfizer, Ono Pharmaceutical, Takeda. M-J. Ahn: Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca, Merck, Sharp & Dohme, Ono Pharmaceutical, Lilly, Roche; Advisory / Consultancy: Alpha Pharmaceutical, Takeda. S.S. Ramalingam: Honoraria (self), Advisory / Consultancy: AstraZeneca, Amgen, Bristol-Myers Squibb, Merck, Roche/Genentech, Loxo, Nektar, Tesaro; Research grant / Funding (institution): AstraZeneca, Amgen, Bristol-Myers Squibb, Merck, Tesaro, Advaxis, Takeda. S-W. Kim: Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca. F.A. Shepherd: Advisory / Consultancy, Research grant / Funding (institution), Shareholder / Stockholder / Stock options: AstraZeneca. J. Laskin: Research grant / Funding (institution): AstraZeneca, Roche, Boehringer Ingelheim, Pfizer; Honoraria (self): AstraZeneca, Roche, Pfizer. H. Akamatsu: Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Honoraria (institution): Chugai; Honoraria (self), Honoraria (institution), Advisory / Consultancy: Pfizer; Honoraria (self), Honoraria (institution): Boehringer Ingelheim. W-C. Su: Travel / Accommodation / Expenses: Bristol-Myers Squibb; Travel / Accommodation / Expenses: Boehringer Ingelheim. T. John: Advisory / Consultancy: Roche, Bristol-Myers Squibb, Merck, Ignyta, AstraZeneca, Takeda, Boehringer Ingelheim, Pfizer. M. Sebastian: Honoraria (self), Honoraria (institution), Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca, Roche, Novartis; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Pfizer, Boehringer Ingelheim, Celgene, Takeda, Bristol-Myers Squibb, MSD; Honoraria (self), Advisory / Consultancy: Lilly. H. Mann: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. M. Miranda: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. G. Laus: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. Y. Rukazenkov: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. V. Papadimitrakopoulou: Honoraria (self): F Hoffman-La Roche; Advisory / Consultancy: Nektar Therapeutics, AstraZeneca Pharmaceuticals, Arrys Therapeutics, Merck&Co, LOXO Oncology, Araxes Pharma, F.Hoffman-LaRoche Ltd, Janssen Research Foundation, Bristol-Myers Squibb, Clovis Oncology, Eli Lilly &Co, Novartis Pharmaceuticals Corp. Takeda ; Research grant / Funding (institution): Eli Lilly &Co, Novartis, Merck, AstraZeneca Pharmaceuticals, F Hoffman-La Roche, Nektar Therapeutics, Janssen, Bristol-Myers Squibb, Checkmate, Incyte. All other authors have declared no conflicts of interest. [ABSTRACT FROM AUTHOR]

Background Meta-analyses were conducted to characterize patterns of mutation incidence in non small-cell lung cancer (NSCLC). Design Nine genes with the most complete published mutation coincidence data were evaluated. One meta-analysis generated a ‘mutMap’ to visually represent mutation coincidence by ethnicity (Western/Asian) and histology (adenocarcinoma [ADC] or squamous cell carcinoma). Another meta-analysis evaluated incidence of individual mutations. Extended analyses explored incidence of EGFR and KRAS mutations by ethnicity, histology, and smoking status. Results Genes evaluated were TP53, EGFR, KRAS, LKB1, EML4-ALK, PTEN, BRAF, PIK3CA, and ErbB2. The mutMap highlighted mutation coincidences occurring in ≥5% of patients, including TP53 with KRAS or EGFR mutations in patients with ADC, and TP53 with LKB1 mutation in Western patients. TP53 was the most frequently mutated gene overall. Frequencies of TP53, EGFR, KRAS, LKB1, PTEN, and BRAF mutations were influenced by histology and/or ethnicity. Although EGFR mutations were most frequent in patients with ADC and never/light smokers from Asia, and KRAS mutations were most frequent in patients with ADC and ever/heavy smokers from Western countries, both were detected outside these subgroups. Conclusions Potential molecular pathology segments of NSCLC were identified. Further studies of mutations in NSCLC are warranted to facilitate more specific diagnoses and guide treatment. [ABSTRACT FROM PUBLISHER]

In AURA3 (NCT02151981), osimertinib, a third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI), significantly prolonged progression-free survival and improved response in patients with EGFR T790M advanced non-small-cell lung cancer (NSCLC) and progression on prior EGFR-TKI treatment. We report the final AURA3 overall survival (OS) analysis. Adult patients were randomized 2 : 1 to osimertinib (80 mg orally, once daily) or pemetrexed plus carboplatin/cisplatin (platinum–pemetrexed) intravenously, every 3 weeks (≤6 cycles). Patients could crossover to osimertinib on progression confirmed by blinded independent central review. OS and safety were secondary end points. A total of 279 patients were randomly assigned to receive osimertinib and 140 to platinum–pemetrexed (136 received treatment). At data cut-off (DCO; 15 March 2019), 188 patients (67%) receiving osimertinib versus 93 (66%) receiving platinum–pemetrexed had died. The hazard ratio (HR) for OS was 0.87 [95% confidence interval (CI) 0.67–1.12; P = 0.277]; the median OS was 26.8 months (95% CI 23.5–31.5) versus 22.5 months (95% CI 20.2–28.8) for osimertinib and platinum–pemetrexed, respectively. The estimated 24- and 36-month survival was 55% versus 43% and 37% versus 30%, respectively. After crossover adjustment, there was an HR of 0.54 (95% CI 0.18–1.6). Time to first subsequent therapy or death showed a clinically meaningful advantage toward osimertinib (HR 0.21, 95% CI 0.16–0.28; P < 0.001). At DCO, 99/136 (73%) patients in the platinum–pemetrexed arm had crossed over to osimertinib, 66/99 (67%) of whom had died. The most common adverse events possibly related to study treatment were diarrhea (32%; grade ≥3, 1%) and rash (grouped term; 32%; grade ≥3, <1%) in the osimertinib arm, versus nausea (47%; grade ≥3, 3%) in the platinum–pemetrexed arm. In patients with T790M advanced NSCLC, no statistically significant benefit in OS was observed for osimertinib versus platinum–pemetrexed, which possibly reflects the high crossover rate of patients from platinum–pemetrexed to osimertinib. ClinicalTrials.gov NCT02151981 ; https://clinicaltrials.gov/ct2/show/NCT02151981. • Median OS with osimertinib was 26.8 months versus 22.5 months with platinum–pemetrexed (HR 0.87, 95% CI 0.67–1.12; P = 0.277). • The lack of a significant survival benefit could reflect high percentage (73%) of platinum–pemetrexed to osimertinib crossover. • Analysis of OS adjusted for crossover showed an HR of 0.54 (95% CI 0.18–1.60). • Among patients receiving subsequent anticancer therapy, platinum chemotherapy was the most common after osimertinib (65%). • Grade ≥3 (possibly treatment-related) adverse events were observed less frequently with osimertinib (9% versus 34% with platinum–pemetrexed). [ABSTRACT FROM AUTHOR]

Background Previous studies have proved that EGFR exon 20 insertion (EGFRex20ins) mutation present in about 1.8% of non-small cell lung cancer (NSCLC). 22% of EGFRex20ins are co-occurring with EGFR amplification. The aim of this study is to investigate the clinical characteristics and efficacy in Chinese NSCLC patients harboring EGFRex20ins and EGFR amplification. Methods A total of 1483 patients with advanced NSCLC were screened. All variants of EGFRex20ins and other oncogenic drivers were identified by next-generation sequencing (NGS). Results EGFRex20ins were found in 2.2% of patients and a total of 38 patients were included in clinical characteristics analysis. Various EGFRex20ins were identified, most commonly V769_D770dup (26.3%) and D770_N771dup (23.7%). Interestingly, co-occurring EGFR amplification was found in 39.5% of patients (15/38). In patients with EGFR amplification, the median age was 58 years (range, 38 to 75 years), and 66.7% were female. Most of them were never-smokers (86.7%) and had adenocarcinoma (93.3%). These clinical characteristics were not significantly different from those without EGFR amplification (P > 0.05). Except for patients with EGFR-sensitive mutations, a total of 25 patients who had used EGFR-tyrosine kinase inhibitors (TKIs) were included in the survival analysis. Although there were no statistically differences in two group, a tendency of prolonged median progression-free survival (mPFS) in patients without EGFR amplification was found (80.5 versus 30.0 days, P = 0.175). Conclusions EGFR amplification often co-occur with EGFRex20ins in Chinese NSCLC, and the ratio is higher than previous studies in Caucasian. Although there was no difference in clinical characteristics and efficacy between patients with and without EGFR amplification, a tendency of prolonged mPFS in patients without EGFR amplification was found. Future prospectively large-sample-size studies are needed to evaluate this finding. Legal entity responsible for the study Guangdong Lung Cancer Institute. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest. [ABSTRACT FROM AUTHOR]

CTONG0806, a multicenter phase II randomized trial, is the first trial to show significant improvement in PFS and an improved OS trend with pemetrexed compared with gefitinib as second-line setting treatment for EGFR wild-type advanced non-squamous NSCLC. ARMS should be recommended as standard testing method for EGFR mutation.Background CTONG0806 assessed the efficacy of pemetrexed versus gefitinib as second-line treatment in advanced nonsquamous nonsmall-cell lung cancer (NSCLC) harboring wild-type epidermal growth factor receptor (EGFR). Patients and methods Patients with locally advanced or metastatic nonsquamous NSCLC harboring wild-type EGFR, detected by direct sequencing, and previously treated with platinum-based chemotherapy were randomized to receive gefitinib (250 mg/day) orally or pemetrexed (500 mg/m2) i.v. on day 1 of a 21-day cycle until disease progression or unacceptable toxicity. The primary end point was progression-free survival (PFS). The Independent Review Committee (IRC) evaluated all pictorial data. Results From February 2009 to August 2012, 161 patients were enrolled, and 157 were assessable (81 in the gefitinib arm, 76 in the pemetrexed arm). Baseline characteristics were balanced between the two arms. The median PFSs were 4.8 versus 1.6 months in the pemetrexed and gefitinib arms, respectively [hazard ratio (HR) 0.54, 95% confidence interval (CI) 0.40–0.75, P < 0.001] as confirmed by IRC evaluation (5.6versus 1.7 months, HR 0.53, 95% CI 0.38–0.75, P < 0.001). The median overall survival (OS) showed a trend of superiority in the pemetrexed arm (12.4 versus 9.6 months, HR 0.72, 95% CI 0.49–1.04, P = 0.077). Quality-of-life assessment showed no marked difference between the arms. No unexpected adverse events were found. Of 108 patients with sufficient DNA samples, EGFR mutation status was re-tested by Scorpion amplification refractory mutation system (ARMS); 32 (29.6%) tested positive (19 in the pemetrexed arm, 13 in the gefitinib arm; median PFS: 8.1 versus 7.0 months, HR 0.94, 95% CI 0.43–2.08, P = 0.877). Conclusions CTONG0806 is the first trial to show significant improvement in PFS and an improved OS trend with pemetrexed compared with gefitinib as second-line setting treatment of EGFR wild-type advanced nonsquamous NSCLC. ARMS is superior to direct sequencing in excluding false-negative patients. ClinicalTrials.gov Identifier NCT00891579. [ABSTRACT FROM AUTHOR]

Background The OPTIMAL study found that erlotinib improved progression-free survival (PFS) versus standard chemotherapy in Chinese patients with advanced EGFR mutation-positive non-small-cell lung cancer (NSCLC). This report describes the quality of life (QoL) and updated PFS analyses from this study. Patients and methods Chinese patients ≥18 years with histologically confirmed stage IIIB or IV NSCLC and a confirmed activating mutation of EGFR (exon 19 deletion or exon 21 L858R point mutation) received erlotinib (150 mg/day; n = 82) or gemcitabine–carboplatin (n = 72). The primary efficacy end point was PFS; QoL was assessed using the Functional Assessment of Cancer Therapy-Lung (FACT-L) questionnaire, Trial Outcome Index (TOI) and Lung Cancer Subscale (LCS). Results Patients receiving erlotinib experienced clinically relevant improvements in QoL compared with the chemotherapy group in total FACT-L, TOI and LCS (P < 0.0001 for all scales). Erlotinib scored better than chemotherapy for all FACT-L subscales from baseline to cycles 2 and 4 (non-significant). In the updated analysis, PFS was significantly longer for erlotinib than chemotherapy (median PFS 13.7 versus 4.6 months; HR = 0.164, 95% CI = 0.105–0.256; P < 0.0001), which was similar to the previously reported primary analysis. Conclusion Erlotinib improves QoL compared with standard chemotherapy in the first-line treatment of patients with EGFR mutation-positive advanced NSCLC. [ABSTRACT FROM AUTHOR]

Background The ongoing phase III ARCHER 1050 study (NCT01774721) compared dacomitinib (daco) with gefitinib (gef) as first-line therapy for pts with advanced epidermal growth factor receptor-positive (EGFR+) non-small cell lung cancer (NSCLC). Progression-free survival, duration of response, and OS significantly improved with daco vs gef. The improvement in OS was previously reported after median follow-up of 31.3 months (mo) with 220 (48.7%) total deaths. Here, final OS results are reported after a median follow-up of 47.9 mo in ARCHER 1050 to evaluate the persistence of OS improvement with daco. Methods Pts with newly diagnosed EGFR+ NSCLC were randomized 1:1 to daco or gef. Randomization was stratified by race and EGFR mutation type. Results Over a median follow-up of 47.9 mo as of 13 May 2019, 285 deaths occurred (133 [58.6%] in the daco arm [n = 227] and 152 [67.6%] in the gef arm [n = 225]). OS was still significantly improved with daco vs gef (stratified hazard ratio [HR], 0.748; 95% confidence interval [CI], 0.591–0.947; 2-sided P = 0.0155). Median OS (95% CI) with daco was 34.1 mo (29.5–39.8) vs 27.0 mo (24.4–31.6) with gef. OS30 was 56.4% with daco and 45.7% with gef. Median OS, unstratified HR, and P values for interaction are also reported by race and EGFR mutation type (Table). Dose reductions occurred in 154 (67.8%) pts receiving daco; median OS (95% CI) in pts with and without dose reductions was 42.5 (36.7–not estimable [NE]) and 20.7 (15.4–25.6) mo, respectively. In pts reduced to a lowest daco dose of 30 mg (n = 89) and 15 mg (n = 65), median OS was 36.7 mo (28.8–44.7) and NE (40.1 mo–NE), respectively. Conclusions With extended follow-up (median 47.9 mo), daco continues to improve OS over gef in pts with advanced EGFR+ NSCLC; the same trend was observed in most subgroups defined by race and EGFR status. The benefit of OS was maintained in patients who received dose reductions. Table: LBA19 Overall survival by demographics (ITT population)   Events/N (%)   Median a (month)   HR (95% CI) (Unstratified)  P b   Daco  Gef  Daco  Gef  Overall  133/227 (58.6)  152/225 (67.6)  34.1  27.0  0.775 (0.614–0.978)    Race per CRF Asian Mainland Chinese Japanese other East Asian Non-Asian  95/170 (55.9) 69/114 (60.5) 22/40 (55.0) 4/16 (25.0) 38/57 (66.7)  115/176 (65.3) 87/117 (74.4) 22/41 (53.7) 6/18 (33.3) 37/49 (75.5)  37.7 32.5 42.2 NE 29.5  29.1 24.9 44.8 NE 20.6  0.759 (0.578–0.996) 0.687 (0.501–0.943) 0.985 (0.546–1.780) 0.787 (0.222–2.791) 0.758 (0.480–1.196)  0.9886 c   EGFR at randomization Exon 19 deletion Exon 21 L858R substitution mutation  73/134 (54.5) 60/93 (64.5)  82/133 (61.7) 70/92 (76.1)  36.7 32.5  30.8 23.2  0.847 (0.618, 1.161) 0.665 (0.470, 0.941)  0.3292    Events/N (%)   Median a (month)   HR (95% CI) (Unstratified)  P b   Daco  Gef  Daco  Gef  Overall  133/227 (58.6)  152/225 (67.6)  34.1  27.0  0.775 (0.614–0.978)    Race per CRF Asian Mainland Chinese Japanese other East Asian Non-Asian  95/170 (55.9) 69/114 (60.5) 22/40 (55.0) 4/16 (25.0) 38/57 (66.7)  115/176 (65.3) 87/117 (74.4) 22/41 (53.7) 6/18 (33.3) 37/49 (75.5)  37.7 32.5 42.2 NE 29.5  29.1 24.9 44.8 NE 20.6  0.759 (0.578–0.996) 0.687 (0.501–0.943) 0.985 (0.546–1.780) 0.787 (0.222–2.791) 0.758 (0.480–1.196)  0.9886 c   EGFR at randomization Exon 19 deletion Exon 21 L858R substitution mutation  73/134 (54.5) 60/93 (64.5)  82/133 (61.7) 70/92 (76.1)  36.7 32.5  30.8 23.2  0.847 (0.618, 1.161) 0.665 (0.470, 0.941)  0.3292  a Kaplan-Meier estimate; b P interaction; c P for interaction of treatment by Asian vs non-Asian CI, confidence interval; CRF, case report form; daco, dacomitinib; ECOG PS, Eastern Cooperative Oncology Group Performance Status; EGFR, epidermal growth factor receptor; gef, gefitinib; HR, Hazard ratio; ITT, intention-to-treat, NE, not estimable. Table: LBA19 Overall survival by demographics (ITT population)   Events/N (%)   Median a (month)   HR (95% CI) (Unstratified)  P b   Daco  Gef  Daco  Gef  Overall  133/227 (58.6)  152/225 (67.6)  34.1  27.0  0.775 (0.614–0.978)    Race per CRF Asian Mainland Chinese Japanese other East Asian Non-Asian  95/170 (55.9) 69/114 (60.5) 22/40 (55.0) 4/16 (25.0) 38/57 (66.7)  115/176 (65.3) 87/117 (74.4) 22/41 (53.7) 6/18 (33.3) 37/49 (75.5)  37.7 32.5 42.2 NE 29.5  29.1 24.9 44.8 NE 20.6  0.759 (0.578–0.996) 0.687 (0.501–0.943) 0.985 (0.546–1.780) 0.787 (0.222–2.791) 0.758 (0.480–1.196)  0.9886 c   EGFR at randomization Exon 19 deletion Exon 21 L858R substitution mutation  73/134 (54.5) 60/93 (64.5)  82/133 (61.7) 70/92 (76.1)  36.7 32.5  30.8 23.2  0.847 (0.618, 1.161) 0.665 (0.470, 0.941)  0.3292    Events/N (%)   Median a (month)   HR (95% CI) (Unstratified)  P b   Daco  Gef  Daco  Gef  Overall  133/227 (58.6)  152/225 (67.6)  34.1  27.0  0.775 (0.614–0.978)    Race per CRF Asian Mainland Chinese Japanese other East Asian Non-Asian  95/170 (55.9) 69/114 (60.5) 22/40 (55.0) 4/16 (25.0) 38/57 (66.7)  115/176 (65.3) 87/117 (74.4) 22/41 (53.7) 6/18 (33.3) 37/49 (75.5)  37.7 32.5 42.2 NE 29.5  29.1 24.9 44.8 NE 20.6  0.759 (0.578–0.996) 0.687 (0.501–0.943) 0.985 (0.546–1.780) 0.787 (0.222–2.791) 0.758 (0.480–1.196)  0.9886 c   EGFR at randomization Exon 19 deletion Exon 21 L858R substitution mutation  73/134 (54.5) 60/93 (64.5)  82/133 (61.7) 70/92 (76.1)  36.7 32.5  30.8 23.2  0.847 (0.618, 1.161) 0.665 (0.470, 0.941)  0.3292  a Kaplan-Meier estimate; b P interaction; c P for interaction of treatment by Asian vs non-Asian CI, confidence interval; CRF, case report form; daco, dacomitinib; ECOG PS, Eastern Cooperative Oncology Group Performance Status; EGFR, epidermal growth factor receptor; gef, gefitinib; HR, Hazard ratio; ITT, intention-to-treat, NE, not estimable. Clinical trial identification NCT01774721. Editorial acknowledgement Jessica Yuan (inScience Communications, Springer Healthcare, New York, NY, USA). Legal entity responsible for the study Pfizer Inc. Funding Pfizer Inc. and SFJ Pharmaceuticals® Disclosure T.S.K. Mok: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: ACEA Pharma; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Alpha Biopharma Co. Ltd.; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Amgen; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Amoy Diagnostics Co. Ltd.; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, before 1/1/19: AstraZeneca ; Honoraria (self), Advisory / Consultancy: Bayer; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: BI; Honoraria (self), Advisory / Consultancy: Blueprint Medicines Corporation; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): BMS; Honoraria (self), Advisory / Consultancy: Celgene; Honoraria (self), Advisory / Consultancy: CStone Pharmaceuticals; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Eli Lilly; Honoraria (self), Advisory / Consultancy: Fishawack Facilitate Ltd; Honoraria (self), Advisory / Consultancy: Hengrui Therapeutics Inc.; Honoraria (self), Advisory / Consultancy: Ignyta, Inc.; Honoraria (self), Advisory / Consultancy, Sept 2019: Incyte Corporation; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: InMed Medical Communication; Honoraria (self), Advisory / Consultancy, Jun 2019: Iqvia; Honoraria (self), Advisory / Consultancy: Janssen; Honoraria (self), Advisory / Consultancy: Loxo-Oncology; Honoraria (self), Advisory / Consultancy: Merck Serono; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): MSD; Honoraria (self), Advisory / Consultancy: MoreHealth; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Novartis; Honoraria (self), Advisory / Consultancy: OncoGenex Pharmaceuticals, Inc.; Honoraria (self), Advisory / Consultancy: OrigiMed; Honoraria (self), Advisory / Consultancy: PeerVoice; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Pfizer; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: PrIME Oncology; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche/Genentech; Honoraria (self), Advisory / Consultancy: Sanofi-Aventis R&D; Honoraria (self), Advisory / Consultancy: SFJ Pharmaceutical Ltd.; Honoraria (self), Advisory / Consultancy: Takeda Pharmaceuticals HK Ltd.; Honoraria (self), Advisory / Consultancy: Vertex Pharmaceuticals; Honoraria (self), Advisory / Consultancy: Yuhan Corporation; Advisory / Consultancy: Cirina; Advisory / Consultancy, uncompensated: GeneDecode Co. Ltd.; Speaker Bureau / Expert testimony: Taiho; Speaker Bureau / Expert testimony: Takeda Oncology; Leadership role, Officer / Board of Directors, Remunerated: AstraZeneca PLC; Leadership role, Officer / Board of Directors, Remunerated: Hutchison Chi-Med; Leadership role, Officer / Board of Directors, Non-remunerated: American Society of Clinical Oncology; Leadership role, Officer / Board of Directors, Non-remunerated: Asian Thoracic Oncology Research Group ; Leadership role, Officer / Board of Directors, Non-remunerated: Chinese Lung Cancer Research Foundation Limited; Leadership role, Officer / Board of Directors, Non-remunerated: Chinese Society of Clinical Oncology; Leadership role, Officer / Board of Directors, Non-remunerated: Hong Kong Cancer Fund; Leadership role, Officer / Board of Directors, Non-remunerated: Hong Kong Cancer Therapy Society ; Leadership role, Officer / Board of Directors, term ended on 30/4/19: International Association for the Study of Lung Cancer ; Research grant / Funding (institution): Clovis Oncology; Research grant / Funding (institution): Roche; Research grant / Funding (institution): SFJ; Research grant / Funding (institution): XCovery; Shareholder / Stockholder / Stock options, Shareholder: Hutchison Chi-Med; Shareholder / Stockholder / Stock options, Shareholder: Sanomics Ltd.; Shareholder / Stockholder / Stock options, now Biolidics Ltd.; Stock option: Clearbridge Biomedics; Shareholder / Stockholder / Stock options, Stock option: Loxo-Oncology; Shareholder / Stockholder / Stock options, Stock option: OrigiMed Co. Ltd.; Shareholder / Stockholder / Stock options, Stock option: Virtus Medical Group; Research grant / Funding (institution): AstraZeneca. K.H. Lee: Advisory / Consultancy: MSD; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: BMS. K. Nakagawa: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Astellas Pharma Inc.; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Takeda Pharmaceutical Co. Ltd; Honoraria (self), Research grant / Funding (institution): AstraZeneca K.K.; Honoraria (self), Research grant / Funding (institution): Chugai Pharmaceutical Co. Ltd.; Honoraria (self), Research grant / Funding (institution): MSD K.K.; Honoraria (self), Research grant / Funding (institution): Eli Lilly Japan K.K.; Honoraria (self), Research grant / Funding (institution): Ono Pharmaceutical Co. Ltd.; Honoraria (self), Research grant / Funding (institution): Nippon Boehringer Ingelheim Co. Ltd.; Honoraria (self), Research grant / Funding (institution): Daiichi Sankyo Co. Ltd.; Honoraria (self), Research grant / Funding (institution): Novartis Pharma K.K.; Honoraria (self), Research grant / Funding (institution): Taiho Pharmaceutical Co. Ltd.; Honoraria (self), Research grant / Funding (institution): Pfizer Japan Inc.; Honoraria (self), Research grant / Funding (institution): Bristol-Myers Squibb Company; Honoraria (self): Nikkei Business Publications, Inc.; Honoraria (self): Kyorin Pharmaceutical Co. Ltd.; Honoraria (self): Medicus Shuppan, Publishers Co. Ltd.; Honoraria (self): CareNet, Inc; Honoraria (self): Thermo Fisher Scientific K.K.; Honoraria (self): Nichi-Iko Pharmaceutical Co. Ltd.; Honoraria (self): Nanzando Co. Ltd; Honoraria (self): Hisamitsu Pharmaceutical Co. Inc; Honoraria (self): Medical Review Co. Ltd.; Honoraria (self): Yodosha Co. Ltd; Honoraria (self): Yomiuri Telecasting Corporation; Research grant / Funding (institution): Icon Japan K.K.; Research grant / Funding (institution): Quintiles Inc.; Research grant / Funding (institution): CMIC Shift Zero K.K.; Research grant / Funding (institution): Eisai Co. Ltd.; Research grant / Funding (institution): Parexel International Corp.; Research grant / Funding (institution): Kissei Pharmaceutical Co. Ltd.; Research grant / Funding (institution): Iqvia; Research grant / Funding (institution): Kyowa Hakko Kirin Co. Ltd; Research grant / Funding (institution): EPS Corporation; Research grant / Funding (institution): SymBio Pharmaceuticals Limited; Research grant / Funding (institution): Bayer Yakuhin, Ltd; Research grant / Funding (institution): Merck Serono Co. Ltd.; Research grant / Funding (institution): A2 Healthcare Corp.; Research grant / Funding (institution): AbbVie Inc.. S. Niho: Honoraria (self), Research grant / Funding (institution): AstraZeneca; Honoraria (self), Research grant / Funding (institution): Pfizer; Honoraria (self): Chugai; Honoraria (self): Taiho; Honoraria (self), Research grant / Funding (institution): MSD; Honoraria (self): Bristol-Myers Squibb; Honoraria (self), Research grant / Funding (institution): Eli Lilly; Honoraria (self): Novartis; Honoraria (self): Boehringer Ingelheim; Research grant / Funding (institution): Merck Serono. R. Linke: Full / Part-time employment: SFJ Pharmaceuticals®. M.R. Migliorino: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: AstraZeneca; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: MSD; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: BI; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: BMS; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Pfizer; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Roche. A. Pluzanski: Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca; Advisory / Consultancy, Speaker Bureau / Expert testimony: Boehringer Ingelheim; Advisory / Consultancy, Speaker Bureau / Expert testimony: Bristol-Myers Squibb; Advisory / Consultancy, Speaker Bureau / Expert testimony: Merck Sharp & Dohme; Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche. K. Noonan: Shareholder / Stockholder / Stock options, Full / Part-time employment: Pfizer. Y. Tang: Full / Part-time employment: Pfizer Inc. K.D. Wilner: Shareholder / Stockholder / Stock options, Full / Part-time employment: Pfizer Inc. Y. Wu: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Roche; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Boehringer Ingelheim; Honoraria (self): Eli Lilly; Honoraria (self): Pfizer; Honoraria (self): MSD; Honoraria (self): BMS. [ABSTRACT FROM AUTHOR]

Background MET amplification (METamp) is a resistance mechanism to EGFR tyrosine kinase inhibitors (TKIs) occurring via over activation of downstream signaling pathways such as PI3K and MAPK. METamp occurs in ≈10% of patients receiving erlotinib, gefitinib, afatinib, or icotinib, and is the most common resistance mechanism to osimertinib in phase III trials, occurring in ≈19% of patients. Tepotinib, an oral once daily potent and selective MET inhibitor, is associated with improved survival in combination with gefitinib in patients with EGFR-mutant MET-amplified NSCLC with EGFR TKI resistance compared with standard chemotherapy in the INSIGHT study (NCT01982955): investigator-reported progression free survival (PFS) was 21.2 vs 4.2 months (HR 0.13; 90% CI 0.04, 0.43) and overall survival, (OS) was 37.3 vs. 13.1 months (HR 0.08; 90% CI 0.01, 0.51). Trial design INSIGHT 2 (NCT03940703) is a global single-arm, open-label, phase II trial of tepotinib in patients with advanced (stage IIIB/IV) NSCLC with resistance to 1st–3rd generation EGFR TKIs driven by METamp. Eligibility criteria include patients aged ≥18 years with advanced EGFR-mutant NSCLC and known T790M status, having acquired resistance to EGFR TKIs, and are METamp positive by plasma 'liquid' biopsy, with an ECOG PS of 0 or 1 and normal organ function. Prior immunotherapy is permitted but prior MET pathway-targeted therapy is not. Tepotinib (500 mg orally once daily) in combination with osimertinib (80 mg once daily) will be administered until disease progression, unacceptable toxicity, or withdrawal of consent. An initial safety run-in will comprise 6 patients (endpoint; dose-limiting toxicities); anticipated full enrollment is 90 patients. The primary endpoint is objective response rate (ORR) by independent review committee (RECIST v1.1). Secondary objectives include investigator-assessed ORR, duration of response, disease control, PFS, OS, pharmacokinetics, health-related quality of life, tolerability, and safety (NCI-CTCAE v5.0). Recruitment is ongoing and approximately 80 study sites in 17 countries in Europe, Asia, and North America are expected to participate in this study. Clinical trial identification NCT03940703. Legal entity responsible for the study Merck Healthcare KGaA. Funding Merck Healthcare KGaA. Disclosure J.C-H. Yang: Honoraria (self), Advisory / Consultancy: Boehringer Ingelheim; Honoraria (self), Advisory / Consultancy: Eli Lilly; Honoraria (self), Advisory / Consultancy: Bayer; Honoraria (self), Advisory / Consultancy: Roche/Genentech/Chugai; Honoraria (self), Advisory / Consultancy: MSD; Honoraria (self), Advisory / Consultancy: Merck Serono; Honoraria (self), Advisory / Consultancy: Pfizer; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: Celgene; Honoraria (self), Advisory / Consultancy: Merrimack; Honoraria (self), Advisory / Consultancy: Yuhan Pharmaceuticals; Honoraria (self), Advisory / Consultancy: BMS; Honoraria (self), Advisory / Consultancy: Ono Pharmaceutical; Honoraria (self), Advisory / Consultancy: Daiichi Sankyo ; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: Takeda Oncology; Honoraria (self), Advisory / Consultancy: Blueprint Medicines; Honoraria (self), Advisory / Consultancy: Hansoh Pharmaceuticals. B. Ellers-Lenz: Full / Part-time employment: Merck Healthcare KGaA. J. Straub: Full / Part-time employment: Merck Healthcare KGaA. A. Johne: Full / Part-time employment: Merck Healthcare KGaA. Y-L. Wu: Honoraria (self), Advisory / Consultancy: AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution): Boehringer Ingelheim; Advisory / Consultancy: Merck; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Roche; Honoraria (self): Eli Lilly; Honoraria (self): Pfizer; Honoraria (self): Pierre Fabre; Honoraria (self): Sanofi. [ABSTRACT FROM AUTHOR]

Background In the registrational trials, afatinib (afa) was active against NSCLC tumors harboring common and uncommon EGFR mutations, including G719X, L861Q and S768I,1 and is approved in this setting. Here, we assess 1st-line afa in pts with uncommon EGFR mutations treated in a 'real-world' setting in the largest analysis of its kind to date. Methods Retrospective pooled analysis of three 'real-world' studies: an expanded-access program in Korea (1200.193); an Asian phase IIIB trial (1200.66); a global phase IIIB trial (mainly Europe; 1200.55). Pts had EGFR mutation-positive (EGFRm+) NSCLC, were EGFR TKI-naïve, and received afa 40 mg/day. Dose reduction was permitted (minimum 20 mg/day). Endpoints included time to symptomatic progression (TTSP), investigator-assessed PFS and ORR. Results Overall, 1108 pts were treated with afa: median age, 61 yrs; female, 58%; ECOG PS of 0/1/2, 26%/70%/4%; asymptomatic brain metastases, 19%; 1st-line afatinib, 69%. 198 (18%) had tumors harboring at least one uncommon mutation (exon 20 insertions [Ins20]: n = 70; T790M: n = 20; G719X: n = 41; L861Q: n = 47; S768I: n = 20; other: n = 25. Of note, 35% of pts had Ins20 mutations, a heterogeneous group generally resistant to EGFR TKIs). Median TTSP, PFS and ORR were 8.3 mos (95% CI 7.2–11.0), 7.4 mos (95% CI 6.0–9.0) and 37% respectively. Median duration of response was 10.2 mos (95% CI 8.4–12.9). In those pts with uncommon mutations and brain metastases, median TTSP and PFS were 7.6 mos (95% CI 4.6–10.1) and 7.4 mos (95% CI 4.6–9.1). Clinical activity in pts with uncommon mutations was greatest against tumors harboring G719X, L861Q or S768I. Some pts with Ins20 or T790M mutations appeared to benefit from treatment. Survival data in specific mutation subgroups will be presented. Conclusions In this 'real-world' analysis, nearly 20% of pts with EGFRm+ NSCLC harbored uncommon EGFR mutations. Afa was active in a broad range of these pts, including some with Ins20 mutations. 1. Yang, JC. et al. Lancet Oncol 2015;16:830–8. Table: 503P   EGFR mutation type   Common   Uncommon   Del19  L858R  T790M  Ins20  T790M + Ins 20  G719X, L861Q, S768I and Other  n  531  378  15  65  5  113  Median TTSP, mos (95% CI)  17.2 (15.5, 19.3)  14.5 (13.1, 16.5)  8.2 (2.7, 13.4)  5.9 (3.8, 8.2)  1.5 (0.1, 13.0)  11.0 (9.0, 16.4)  Median PFS, mos (95% CI)  14.5 (13.8, 15.9)  12.6 (11.1, 13.8)  7.1 (2.0, 9.0)  5.6 (3.9, 7.4)  1.5 (0.1, 9.1)  9.2 (7.3, 12.1)  ORR, %  64  52  20  23  20  49  Median DOR, mos (95% CI)  14.1 (12.6, 16.2)  12.5 (11.1, 14.9)  12.5 (1.1, 12.5)  10.1 (3.7, 21.2)  8.3 (NE, NE)  10.2 (8.3, 15.5)    EGFR mutation type   Common   Uncommon   Del19  L858R  T790M  Ins20  T790M + Ins 20  G719X, L861Q, S768I and Other  n  531  378  15  65  5  113  Median TTSP, mos (95% CI)  17.2 (15.5, 19.3)  14.5 (13.1, 16.5)  8.2 (2.7, 13.4)  5.9 (3.8, 8.2)  1.5 (0.1, 13.0)  11.0 (9.0, 16.4)  Median PFS, mos (95% CI)  14.5 (13.8, 15.9)  12.6 (11.1, 13.8)  7.1 (2.0, 9.0)  5.6 (3.9, 7.4)  1.5 (0.1, 9.1)  9.2 (7.3, 12.1)  ORR, %  64  52  20  23  20  49  Median DOR, mos (95% CI)  14.1 (12.6, 16.2)  12.5 (11.1, 14.9)  12.5 (1.1, 12.5)  10.1 (3.7, 21.2)  8.3 (NE, NE)  10.2 (8.3, 15.5)  Table: 503P   EGFR mutation type   Common   Uncommon   Del19  L858R  T790M  Ins20  T790M + Ins 20  G719X, L861Q, S768I and Other  n  531  378  15  65  5  113  Median TTSP, mos (95% CI)  17.2 (15.5, 19.3)  14.5 (13.1, 16.5)  8.2 (2.7, 13.4)  5.9 (3.8, 8.2)  1.5 (0.1, 13.0)  11.0 (9.0, 16.4)  Median PFS, mos (95% CI)  14.5 (13.8, 15.9)  12.6 (11.1, 13.8)  7.1 (2.0, 9.0)  5.6 (3.9, 7.4)  1.5 (0.1, 9.1)  9.2 (7.3, 12.1)  ORR, %  64  52  20  23  20  49  Median DOR, mos (95% CI)  14.1 (12.6, 16.2)  12.5 (11.1, 14.9)  12.5 (1.1, 12.5)  10.1 (3.7, 21.2)  8.3 (NE, NE)  10.2 (8.3, 15.5)    EGFR mutation type   Common   Uncommon   Del19  L858R  T790M  Ins20  T790M + Ins 20  G719X, L861Q, S768I and Other  n  531  378  15  65  5  113  Median TTSP, mos (95% CI)  17.2 (15.5, 19.3)  14.5 (13.1, 16.5)  8.2 (2.7, 13.4)  5.9 (3.8, 8.2)  1.5 (0.1, 13.0)  11.0 (9.0, 16.4)  Median PFS, mos (95% CI)  14.5 (13.8, 15.9)  12.6 (11.1, 13.8)  7.1 (2.0, 9.0)  5.6 (3.9, 7.4)  1.5 (0.1, 9.1)  9.2 (7.3, 12.1)  ORR, %  64  52  20  23  20  49  Median DOR, mos (95% CI)  14.1 (12.6, 16.2)  12.5 (11.1, 14.9)  12.5 (1.1, 12.5)  10.1 (3.7, 21.2)  8.3 (NE, NE)  10.2 (8.3, 15.5)  Clinical trial identification NCT01931306; NCT01953913; NCT01853826. Editorial acknowledgement Lynn Pritchard of GeoMed, an Ashfield company, part of UDG Healthcare plc. Legal entity responsible for the study Boehringer Ingelheim. Funding Boehringer Ingelheim. Disclosure F. De Marinis: Honoraria (self): Roche; Honoraria (self): AstraZeneca; Advisory / Consultancy: Takeda; Research grant / Funding (institution): Boehringer Ingelheim. V. Lee: Honoraria (self), Advisory / Consultancy: Pfizer; Honoraria (self): Eli Lilly; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: Merck Sharp & Dohme. L. Clementi: Full / Part-time employment: Boehringer Ingelheim. W. Tang: Full / Part-time employment: Boehringer Ingelheim. D.C-L. Huang: Full / Part-time employment: Boehringer Ingelheim. A. Cseh: Full / Part-time employment: Boehringer Ingelheim. K. Park: Advisory / Consultancy: AMGEN; Advisory / Consultancy: Astellas; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): AstraZeneca; Advisory / Consultancy: BluePrint; Advisory / Consultancy: BMS; Advisory / Consultancy, Speaker Bureau / Expert testimony: Boehringer Ingelheim; Advisory / Consultancy: Eli Lilly; Advisory / Consultancy: Hanmi; Advisory / Consultancy: KHK; Advisory / Consultancy: Loxo; Advisory / Consultancy: Merch KGaA; Advisory / Consultancy, Research grant / Funding (self): MSD; Advisory / Consultancy: ONO; Advisory / Consultancy: Roche. C. Zhou: Honoraria (self): BI; Honoraria (self): Roche; Honoraria (self): Sanofi; Honoraria (self): Hengrui; Honoraria (self): Qilu; Honoraria (self): MSD. Y-L. Wu: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Honoraria (self): Roche; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Boehringer Ingelheim; Honoraria (self): Pfizer; Honoraria (self): Eli Lilly; Honoraria (self): MDS; Honoraria (self): BMS. All other authors have declared no conflicts of interest. [ABSTRACT FROM AUTHOR]

Background In the LUX-Lung (LL) 3 and 6 trials, first-line afatinib significantly improved PFS vs chemotherapy in pts with EGFRm+ NSCLC and baseline brain mets (HR, 0.50; P = 0.03).1 In LL7, similar PFS improvement with afatinib vs gefitinib was observed in pts with, and without, brain metastases (HR, 0.76 and 0.74; Pint=0.93).2 Competing risk analysis of LL3/6 demonstrated low risk of de novo CNS progression in pts treated with afatinib (6%).3 Here, we assess afatinib in pts with brain metastases treated in a 'real-world' setting. Methods Retrospective pooled analysis of three 'real-world' studies: a multi-center expanded-access program in Korea (1200.193); an Asian phase IIIB trial (1200.66); a global phase IIIB trial (mainly Europe; 1200.55). All three studies recruited EGFR TKI-naïve pts with EGFRm+ NSCLC who received afatinib 40 mg/day, including pts with asymptomatic brain metastases. Dose reduction was permitted (minimum 20 mg/day). Endpoints included investigator-assessed progression-free survival (PFS), time to symptomatic progression (TTSP) and objective response rate (ORR). Results A total of 1108 pts were treated with afatinib. Baseline characteristics were: median age, 61 yrs; female, 58%; ECOG PS of 0/1/2, 26%/70%/4%; uncommon EGFR mutations: 18%; first-line afatinib, 69%. In total, 213 pts had brain metastases. Median PFS and TTSP in these pts were 10.6 months (95% CI 9.1–12.8) and 13.7 months (95% CI 11.0–14.8), respectively. When restricted to pts harboring common EGFR mutations, median PFS and TTSP were 11.7 months (95% CI 10.1–13.8) and 14.4 months (95% CI 12.9–16.4), respectively. ORR was 57% (59% in pts with common EGFR mutations); median duration of response was 11.1 months (95% CI 8.3–12.3). Conclusions Consistent with clinical trial data, afatinib is active in pts with EGFRm+ NSCLC and brain metastases treated in a real-world setting in Asian and Caucasian pts. 1. Schuler, M. et al. J Thorac Oncol 2016;11:380–90 2. Park, K. et al. Lancet Oncol 2016;17:577–89 3. Girard, N. Future Oncol. 2018;14:1117–32. Clinical trial identification NCT01931306; NCT01953913; NCT01853826. Editorial acknowledgement Lynn Pritchard of GeoMed, an Ashfield company, part of UDG Healthcare plc. Legal entity responsible for the study Boehringer Ingelheim. Funding Boehringer Ingelheim. Disclosure F. de Marinis: Honoraria (self): Roche; Honoraria (self): AstraZeneca; Advisory / Consultancy: Takeda; Research grant / Funding (institution): Boehringer Ingelheim. V. Lee: Honoraria (self), Advisory / Consultancy: Pfizer; Honoraria (self): Eli Lilly; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: Merck Sharp & Dohme. L. Clementi: Full / Part-time employment: Boehringer Ingelheim. W. Tang: Full / Part-time employment: Boehringer Ingelheim. D.C-L. Huang: Full / Part-time employment: Boehringer Ingelheim. A. Cseh: Full / Part-time employment: Boehringer Ingelheim. K. Park: Advisory / Consultancy: AMGEN; Advisory / Consultancy: Astellas; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): AstraZeneca; Advisory / Consultancy: BluePrint; Advisory / Consultancy: BMS; Advisory / Consultancy, Speaker Bureau / Expert testimony: Boehringer Ingelheim; Advisory / Consultancy: Eli Lilly; Advisory / Consultancy: Hanmi; Advisory / Consultancy: KHK; Advisory / Consultancy: Loxo; Advisory / Consultancy: Merch KGaA; Advisory / Consultancy, Research grant / Funding (self): MSD; Advisory / Consultancy: ONO; Advisory / Consultancy: Roche. C. Zhou: Honoraria (self): BI; Honoraria (self): Roche; Honoraria (self): Sanofi; Honoraria (self): Hengrui; Honoraria (self): Qilu; Honoraria (self): MSD. Y-L. Wu: Honoraria (self), Advisory / Consultancy: AZ; Advisory / Consultancy, Research grant / Funding (self): Roche; Honoraria (self), Advisory / Consultancy: BMS; Full / Part-time employment: Guangdong Provincial People's Hospital, China; Honoraria (self): Eli Lilly; Honoraria (self): Pfizer; Honoraria (self), Research grant / Funding (self): BI. All other authors have declared no conflicts of interest. [ABSTRACT FROM AUTHOR]

Background In patients with EGFR-mutant NSCLC, MET amplification (METamp) is a resistance mechanism to EGFR tyrosine kinase inhibitors (TKI). In the randomized phase Ib/II INSIGHT study (NCT01982955) that halted full enrolment due to low recruitment, tepotinib (TEP), a potent, selective MET TKI, plus gefitinib (GEF) improved progression-free survival (PFS) and objective response rate (ORR) vs chemotherapy (CTx) in patients with EGFR-mutant NSCLC and resistance to 1st-line EGFR TKIs due to METamp (≥6-month follow-up). We now present long-term survival outcomes (≥18-month follow-up) for this predefined analysis. Methods Patients were randomized to TEP 500 mg + GEF 250 mg orally once daily (until progressive disease, intolerable toxicity or other withdrawal) or platinum + pemetrexed IV (≤6 x 21-day cycles). METamp was defined as GCN ≥5 and/or MET/CEP7 ratio ≥2. Primary endpoint was investigator-assessed (INV) PFS. Secondary endpoints included overall survival (OS), ORR, PFS by independent review (IRC), safety. Results From 04/24/15 to 06/12/17, 55 patients enrolled in the INSIGHT study and 19 were METamp (TEP+GEF 12; CTx 7); this predefined subgroup is analysed here. Median GCN was 8.8 (range 4.8–29.5); 18 patients had GCN ≥5, 13 had MET/CEP7 ratio ≥2. At data cutoff (12/12/18), median treatment duration (weeks [range]) for TEP+GEF was 49 (4.6–110.9; 3 patients still ongoing for ≥24 months), pemetrexed was 18.0 (5.9–60.4), cisplatin 12.0 (6.6–25.1) or carboplatin 12.8 (5.9–19.7), all CTx patients discontinued. TEP+GEF compared with CTx improved PFS (INV mPFS 21.2 vs 4.2 months, HR [90% CI] 0.13 [0.04, 0.43]; IRC mPFS 19.3 vs 5.5 months; 0.18 [0.06, 0.61]) and OS (mOS 37.3 vs 13.1 months, 0.08 [0.01, 0.51]), as well as ORR (INV 66.7 v 42.9%; OR 2.67 [0.37, 19.56]; IRC 75.0 vs 42.9%; OR 4.00 [0.51, 31.38]). Grade ≥3 treatment-related AEs in METamp patients (≥15% in either arm, TEP+GEF vs CTx) were amylase or lipase increased (both 33.3% vs 0%), anemia, neutrophil or WBC count decreased (all 0 vs 28.6%). Conclusions TEP+GEF improved survival of patients with EGFR TKI-resistant NSCLC due to METamp. TEP + osmertinib is currently being investigated in patients with METamp, EGFR-mutant NSCLC with acquired EGFR TKI resistance (NCT03940703). Clinical trial identification NCT01982955. Editorial acknowledgement Medical writing assistance was provided by Lisa Jolly, Bioscript, Macclesfield, UK, and funded by Merck KGaA, Darmstadt, Germany. Legal entity responsible for the study Merck KGaA, Darmstadt, Germany. Funding Merck KGaA, Darmstadt, Germany. Disclosure K. Park: Advisory / Consultancy: AstraZeneca, Boehringer Ingelheim, Clovis; Elli Lilly; Hanmi; ONO; Roche; Novartis. R.A. Soo: Honoraria (self): BMS, Celgene, Ignyta, Lilly, Merck, Novartis, Pfizer, Roche, Taiho, Takeda, Yuhan; Honoraria (self), Research grant / Funding (institution): AstraZeneca; Honoraria (self), Research grant / Funding (institution): Boehringer Ingelheim. R. Bruns: Full / Part-time employment: Merck KGaA. J. Straub: Full / Part-time employment: Merck KGaA. A. Johne: Full / Part-time employment: Merck KGaA. J. Scheele: Full / Part-time employment: Merck KGaA. J.C-H. Yang: Honoraria (self), Advisory / Consultancy: Boehringer Ingelheim, Eli Lilly, Bayer, Roche/Genentech/Chugai, MSD, Merck Serono, Pfizer, Novartis, Celgene, Merrimack, Yuhan Pharmaceuticals, BMS, Ono pharmaceutical, Daiichi Sankyo and AstraZeneca, Takeda Oncology, Blueprint Medicines, Hansoh Pharmaceu. Y-L. Wu: Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Roche; Advisory / Consultancy, Research grant / Funding (institution): Boehringer Ingelheim ; Advisory / Consultancy: Merck; Honoraria (self): Eli Lilly, Pierre Fabre, Pfizer, Sanofi. All other authors have declared no conflicts of interest. [ABSTRACT FROM AUTHOR]

Background In the ongoing phase 3 comparison of dacomitinib (daco) and gefitinib (gef) (ARCHER 1050; NCT01774721) as first-line therapy for EGFR-mutation-positive (EGFR+) advanced NSCLC, daco was associated with significant improvement in progression free survival (PFS) and overall survival (OS). Here we present results for the subset of Asian patients (pts). Methods Eligible pts with newly diagnosed stage IIIB/IV or recurrent EGFR+ advanced NSCLC were randomized (1:1) to oral daco 45 mg once daily or gef 250 mg. Randomization was stratified by race and EGFR mutation (exon 19 del/exon 21 L858R) status. The primary efficacy endpoint was PFS by blinded independent radiologic central review (BIRC). Secondary endpoints were OS, objective response rate (ORR) and duration of response (DOR) by BIRC, and safety. Results Of 346 Asian pts, 170 were randomized to daco treatment and 176 to gef. Demographics and baseline characteristics of the groups were well balanced. At the July 29, 2016 data cutoff, the hazard ratio for PFS was 0.510 (95% confidence interval [CI] 0.392, 0.664), favoring daco (2-sided p value < 0.0001). Median PFS was 16.5 months (95% CI 12.9, 18.4) for daco and 9.3 months for gef (95% CI 9.2, 11.0). OS, ORR and DOR are shown in the table. Treatment-related adverse events (TRAEs) occurring in ≥ 50% of daco-treated pts were diarrhea (88.2%), paronychia (64.7%), and dermatitis acneiform (56.5%). In the gef arm, diarrhea (52.3%) was the only TRAE that occurred in ≥ 50% of pts. The daco dose was reduced in 67.6% of pts associated with adverse events (AEs); gef dose was reduced to every other day dosing in 9.7% of pts associated with AEs. Conclusions First-line daco was associated with significant prolongation of PFS compared with gef in Asian pts with EGFR+ advanced NSCLC. Daco treatment showed improved OS, ORR, and DOR compared to gef treatment. The AE profile for daco and gef in Asian pts was consistent with the overall ARCHER 1050 study. Table: 480P Key secondary endpoints   Dacomitinib N = 170  Gefitinib N = 176  Median overall survival, months (95% CI) a   34.2 (30.1, NE  29.1 (25.2,NE)  Objective response rate, % (95% CI)  77.1 (70.0, 83.1)  72.7 (65.5, 79.2)  ---Patients with complete response (n, %)  9 (5.3)  4 (2.3)  ---Patients with partial response (n, %)  122 (71.8)  124 (70.5)  Median duration of response, months (95% CI)  16.6 (13.8, 30.4)  8.3 (8.1, 10.2)    Dacomitinib N = 170  Gefitinib N = 176  Median overall survival, months (95% CI) a   34.2 (30.1, NE  29.1 (25.2,NE)  Objective response rate, % (95% CI)  77.1 (70.0, 83.1)  72.7 (65.5, 79.2)  ---Patients with complete response (n, %)  9 (5.3)  4 (2.3)  ---Patients with partial response (n, %)  122 (71.8)  124 (70.5)  Median duration of response, months (95% CI)  16.6 (13.8, 30.4)  8.3 (8.1, 10.2)  CI, confidence interval; N/n;number of patients; NE; not estimable. a Feb 17, 2017 was the data cutoff for final OS analysis. Table: 480P Key secondary endpoints   Dacomitinib N = 170  Gefitinib N = 176  Median overall survival, months (95% CI) a   34.2 (30.1, NE  29.1 (25.2,NE)  Objective response rate, % (95% CI)  77.1 (70.0, 83.1)  72.7 (65.5, 79.2)  ---Patients with complete response (n, %)  9 (5.3)  4 (2.3)  ---Patients with partial response (n, %)  122 (71.8)  124 (70.5)  Median duration of response, months (95% CI)  16.6 (13.8, 30.4)  8.3 (8.1, 10.2)    Dacomitinib N = 170  Gefitinib N = 176  Median overall survival, months (95% CI) a   34.2 (30.1, NE  29.1 (25.2,NE)  Objective response rate, % (95% CI)  77.1 (70.0, 83.1)  72.7 (65.5, 79.2)  ---Patients with complete response (n, %)  9 (5.3)  4 (2.3)  ---Patients with partial response (n, %)  122 (71.8)  124 (70.5)  Median duration of response, months (95% CI)  16.6 (13.8, 30.4)  8.3 (8.1, 10.2)  CI, confidence interval; N/n;number of patients; NE; not estimable. a Feb 17, 2017 was the data cutoff for final OS analysis. Clinical trial identification NCT01774721. Editorial acknowledgement Medical writing support was provided by Michelle Daniels (inScience Communications, Springer Healthcare, Philadelphia, PA, USA). Legal entity responsible for the study Pfizer Inc. Funding Pfizer Inc. Disclosure T.S.K. Mok: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: ACEA Pharma; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Alpha Biopharma Co. Ltd.; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Amgen; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Amoy Diagnostics Co. LTD.; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, before 1/1/19: AstraZeneca; Honoraria (self), Advisory / Consultancy: Bayer; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: BI; Honoraria (self), Advisory / Consultancy: Blueprint Medicines Corporation; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): BMS; Honoraria (self), Advisory / Consultancy: Celgene; Honoraria (self), Advisory / Consultancy: CStone Pharmaceuticals; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Eli Lilly; Honoraria (self), Advisory / Consultancy: Fishawack Facilitate Ltd; Honoraria (self), Advisory / Consultancy: Hengrui Therapeutics Inc.; Honoraria (self), Advisory / Consultancy: Ignyta, Inc.; Honoraria (self), Advisory / Consultancy, Sept 2019: Incyte Corporation; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: InMed Medical Communication; Honoraria (self), Advisory / Consultancy, Jun 2019: IQVIA; Honoraria (self), Advisory / Consultancy: Janssen; Honoraria (self), Advisory / Consultancy: Loxo-Oncology; Honoraria (self), Advisory / Consultancy: Merck Serono; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): MSD; Honoraria (self), Advisory / Consultancy: MoreHealth; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Novartis; Honoraria (self), Advisory / Consultancy: OncoGenex Pharmaceuticals, Inc.; Honoraria (self), Advisory / Consultancy: OrigiMed; Honoraria (self), Advisory / Consultancy: PeerVoice; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Pfizer; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: PrIME Oncology; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche/Genentech; Honoraria (self), Advisory / Consultancy: Sanofi-Aventis R&D; Honoraria (self), Advisory / Consultancy: SFJ Pharmaceutical Ltd.; Honoraria (self), Advisory / Consultancy: Takeda Pharmaceuticals HK Ltd.; Honoraria (self), Advisory / Consultancy: Vertex Pharmaceuticals; Honoraria (self), Advisory / Consultancy: Yuhan Corporation; Advisory / Consultancy: Cirina; Advisory / Consultancy, uncompensated: geneDecode Co. Ltd.; Speaker Bureau / Expert testimony: Taiho; Speaker Bureau / Expert testimony: Takeda Oncology; Leadership role, Officer / Board of Directors, Remunerated: AstraZeneca PLC; Leadership role, Officer / Board of Directors, Remunerated: Hutchison Chi-Med; Leadership role, Officer / Board of Directors, Non-remunerated: American Society of Clinical Oncology; Leadership role, Officer / Board of Directors, Non-remunerated: Asian Thoracic Oncology Research Group; Leadership role, Officer / Board of Directors, Non-remunerated: Chinese Lung Cancer Research Foundation Limited; Leadership role, Officer / Board of Directors, Non-remunerated: Chinese Society of Clinical Oncology; Leadership role, Officer / Board of Directors, Non-remunerated: Hong Kong Cancer Fund; Leadership role, Officer / Board of Directors, Non-remunerated: Hong Kong Cancer Therapy Society; Leadership role, Officer / Board of Directors, term ended on 30/4/19: International Association for the Study of Lung Cancer ; Research grant / Funding (institution): Clovis Oncology; Research grant / Funding (institution): Roche; Research grant / Funding (institution): SFJ; Research grant / Funding (institution): XCovery; Shareholder / Stockholder / Stock options, Shareholder: Hutchison Chi-Med; Shareholder / Stockholder / Stock options, Shareholder: Sanomics Ltd.; Shareholder / Stockholder / Stock options, now Biolidics Ltd.; Stock option: Clearbridge Biomedics; Shareholder / Stockholder / Stock options, Stock option: Loxo-Oncology; Shareholder / Stockholder / Stock options, Stock option: OrigiMed Co. Ltd.; Shareholder / Stockholder / Stock options, Stock option: Virtus Medical Group; Research grant / Funding (institution): AstraZeneca. K.H. Lee: Advisory / Consultancy: MSD; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: BMS. K. Nakagawa: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Astellas Pharma Inc.; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Takeda Pharmaceutical Co. Ltd; Honoraria (self), Research grant / Funding (institution): AstraZeneca K.K.; Honoraria (self), Research grant / Funding (institution): Chugai Pharmaceutical Co.Ltd.; Honoraria (self), Research grant / Funding (institution): MSD K.K.; Honoraria (self), Research grant / Funding (institution): Eli Lilly Japan K.K.; Honoraria (self), Research grant / Funding (institution): Ono Pharmaceutical Co. Ltd.; Honoraria (self), Research grant / Funding (institution): Nippon Boehringer Ingelheim Co. Ltd.; Honoraria (self), Research grant / Funding (institution): Daiichi Sankyo Co. Ltd.; Honoraria (self), Research grant / Funding (institution): Novartis Pharma K.K.; Honoraria (self), Research grant / Funding (institution): Taiho Pharmaceutical Co. Ltd.; Honoraria (self), Research grant / Funding (institution): Pfizer Japan Inc.; Honoraria (self), Research grant / Funding (institution): Bristol-Myers Squibb; Honoraria (self): Nikkei Business Publications, Inc.; Honoraria (self): Kyorin Pharmaceutical Co. Ltd.; Honoraria (self): Medicus Shuppan, Publishers Co. Ltd.; Honoraria (self): CareNet, Inc.; Honoraria (self): Thermo Fisher Scientific K.K.; Honoraria (self): Nichi-Iko Pharmaceutical Co. Ltd.; Honoraria (self): Nanzando Co. Ltd; Honoraria (self): Hisamitsu Pharmaceutical Co. Inc; Honoraria (self): Medical Review Co. Ltd.; Honoraria (self): Yodosha Co. Ltd; Honoraria (self): Yomiuri Telecasting Corporation; Research grant / Funding (institution): ICON Japan K.K.; Research grant / Funding (institution): Quintiles Inc.; Research grant / Funding (institution): CMIC Shift Zero K.K.; Research grant / Funding (institution): Eisai Co. Ltd.; Research grant / Funding (institution): Parexel International Corp.; Research grant / Funding (institution): Kissei Pharmaceutical Co. Ltd.; Research grant / Funding (institution): IQVIA; Research grant / Funding (institution): Kyowa Hakko Kirin Co. Ltd; Research grant / Funding (institution): EPS Corporation; Research grant / Funding (institution): SymBio Pharmaceuticals Limited; Research grant / Funding (institution): Bayer Yakuhin, Ltd; Research grant / Funding (institution): Merck Serono Co. Ltd.; Research grant / Funding (institution): A2 Healthcare Corp.; Research grant / Funding (institution): AbbVie Inc.. S. Niho: Honoraria (self), Research grant / Funding (institution): AstraZeneca; Honoraria (self), Research grant / Funding (institution): Pfizer; Honoraria (self): Chugai; Honoraria (self): Taiho; Honoraria (self), Research grant / Funding (institution): MSD; Honoraria (self): Bristol-Myers Squibb; Honoraria (self), Research grant / Funding (institution): Eli Lilly; Honoraria (self): Novartis; Honoraria (self): Boehringer Ingelheim; Research grant / Funding (institution): Merck Serono. R. Linke: Full / Part-time employment: SFJ Pharmaceuticals®. C.H. Wong: Shareholder / Stockholder / Stock options, Full / Part-time employment: Pfizer. Y. Tang: Full / Part-time employment: Pfizer Inc. M. Singh: Shareholder / Stockholder / Stock options, Full / Part-time employment: Pfizer. K.D. Wilner: Shareholder / Stockholder / Stock options, Full / Part-time employment: Pfizer Inc. Y-L. Wu: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Roche; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Boehringer Ingelheim; Honoraria (self): Eli Lilly; Honoraria (self): Pfizer; Honoraria (self): MSD; Honoraria (self): BMS. All other authors have declared no conflicts of interest. [ABSTRACT FROM AUTHOR]

Background Afatinib has demonstrated efficacy and safety in pts with EGFRm+ NSCLC. We report a biomarker analysis of EGFR TKI-naïve pts with EGFRm+ NSCLC treated with afatinib in a Phase IIIb study. The analysis explored the effect of tumor mutation status on patient outcomes. Methods Pts with EGFR TKI-naïve locally advanced/metastatic EGFRm+ NSCLC received 40 mg/day afatinib. Primary endpoint was incidence of serious adverse events (SAEs). Secondary endpoints included drug-related AEs (DRAEs). Progression-free survival (PFS) was a further endpoint. For biomarker analysis, DNA was extracted from peripheral blood samples and analyzed using an amplification refractory mutation system. Samples taken at baseline and regular intervals were analyzed for EGFR mutations; specified non-EGFR mutations were identified at baseline. Results This analysis included 64 Chinese pts (female 70%; mean age 57 years; EGFR mutations: L858R 50%; Del19 42%). All pts had ≥1 DRAE, most commonly (all grades/≥3) diarrhea (98/14%) and rash/acne (grouped term; 81/8%). 15 pts (23%) had ≥1 SAE; 6 (9.4%) had drug-related SAEs. 58 pts (90.6%) showed disease control; including 39 (60.9%) with an objective response. At baseline, 19/42 pts analyzed (45%) had additional non-EGFR mutations; 17 progressed, 2 died. Median PFS was 8 months (mo), vs 12 mo for pts with EGFR-only mutations (HR 1.72; 95% CI 0.88, 3.36; p = 0.1054). At Visit 3, EGFR mutation status of 33/40 pts (83%) changed from positive to negative; 28 progressed, 5 died. Median PFS was 11 mo vs 6 mo for pts who remained EGFRm + (HR 1.25; 95% CI 0.47, 3.30; p = 0.6556). Conclusions In this analysis, there were no unexpected safety findings. There was no significant difference in PFS between pts with additional non-EGFR mutations vs those with EGFR-only mutations. Median PFS was almost twice as long in pts who became EGFR-mutation negative compared with those who remained EGFRm + (non-significant). This analysis suggests afatinib has clinical benefit for pts regardless of type of initial EGFR mutation. Clinical trial identification NCT01953913. Editorial acknowledgement Medical writing assistance, supported financially by Boehringer Ingelheim, was provided by Beth de Klerk of GeoMed, an Ashfield company, part of UDG Healthcare plc. The authors acknowledge Nick Xue, of Boehringer Ingelheim (China) Investment Co. and Agnieszka Cseh, of Boehringer Ingelheim RCV GmbH & Co. KG, for their support in the development of this abstract. Legal entity responsible for the study Boehringer Ingelheim. Funding Boehringer Ingelheim. Disclosure S. Meng: Full / Part-time employment: Boehringer Ingelheim. Y. Tian: Full / Part-time employment: Boehringer Ingelheim. D.C-L. Huang: Full / Part-time employment: Boehringer Ingelheim. Y-L. Wu: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Honoraria (self): Roche; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Boehringer Ingelheim; Honoraria (self): Pfizer; Honoraria (self): Eli Lilly; Honoraria (self): MDS; Honoraria (self): BMS. All other authors have declared no conflicts of interest. [ABSTRACT FROM AUTHOR]

Background Patient-derived cancer organoid (PDOs) models have proven with powerful research value and significant clinical application prospects. However, we still know little about organoid models of non-small cell lung cancer (NSCLC). This study aims to characterize the consistency of genomic variations between the primary tumours and PDOs, and to explore utility of PDOs as preclinical models to predict the treatment response for the precision medicine. Methods Tumour samples were collected for organoid culture. Primary tumour and PDO samples were analysed by whole exon sequencing (WES). C-MET overexpression of tissue was test by immunohistochemistry. Antineoplastic drugs were tested by the PDOs. Cell viability was measured by Cell Titer Glo assay 7-10 days after drug treatment. Heatmap of log IC50 values were calculated from drug response analyses of PDOs by applying nonlinear regression (curve fit). Results A total of 7 patients (pts) (I-III stage) were enrolled. 7 paired surgical tumour and PDOs were analysed, respectively. Comparison of gene mutations of top 20 ranked genes related with lung cancer, the concordance were over 80% between tumour and PDOs in 5 pts. The concordances of the other 2 pts were less than 50%. Both tissues and PDOs harbored driver mutations in 4 pts (2 EGFR L858R, 1 EGFR EX20 ins and 1 KRAS G12C). Drug screen was carried out by using 26 antineoplastic drugs in the 7 PDOs in vitro. Of the 2 PDOs with EGFR L858R, one displayed the most significant response to Gefitinib, the other showed resistance to Gefitinib but significant response to Osimertinib, whose matched tissue showed c-MET overexpression indicating a mechanism of resistant to Gefitinib. The PDO with EGFR EX20 ins also indicated resistance to Gefitinib but significant response to Osimertinib in accordance with public articles. Conclusions Patient-derived lung cancer organoids could provide us a practical model system for studying NSCLC and predict treatment response for personal precision medicine. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest. [ABSTRACT FROM AUTHOR]