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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-naive, 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. 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) 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. 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.

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-naive 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.

Background First-line afatinib significantly improved progression-free survival (PFS) in pts with EGFRm+ NSCLC compared with chemotherapy in LUX-Lung (LL) 3 and 6, and with gefitinib in LL7. However, in clinical practice, some EGFRm+ pts still receive chemotherapy as a first-line therapy. We report a combined analysis of data from two large, prospective, open-label, single-arm Phase IIIb studies of afatinib in pts with EGFR TKI-naive NSCLC treated in a setting similar to real-world practice. Methods EGFR TKI-naive pts with locally advanced/metastatic EGFRm+ NSCLC received 40 mg/day afatinib until progressive disease or lack of tolerability. Dose reduction to minimum 20 mg/day was permitted. Pts were enrolled across 8 European countries, Russia, Israel and Australia (study 1), and China, Hong Kong, India, Singapore and Taiwan (study 2). Time to symptomatic progression (TTSP), PFS, objective response and safety were analysed using interim (study 1; data cut-off 30 April 2018) and final (study 2; data cut-off 6 July 2018) data. Results A total of 1020 pts were treated: female: 59%; Asian/White: 54%/46%; median age: 61 years; ECOG PS 0/1/2: 26%/69%/5%; common/uncommon EGFR mutations: 82%/18%; treatment line 1/2/≥3: 69%/23%/8%; brain metastases: 18%. Median TTSP was 14.6 months (95% CI: 13.8–15.8); median PFS was 12.9 months (95% CI: 11.6–13.7). Objective response (OR) rate was 52.7%; median duration of OR was 12.9 months (95% CI: 11.7–13.8). Adverse events (AEs; any grade/grade ≥3) occurred in 1012/556 pts (99.2%/54.5%). Drug-related AEs (DRAEs; any grade/grade ≥3) occurred in 990/361 pts (97.1%/35.4%); most frequently (grade ≥3) diarrhoea (13.3%) and rash (9.2%). DRAEs leading to treatment discontinuation were reported in 54 pts (5.3%). AEs leading to dose reduction occurred in 412 patients (40.4%). Serious AEs occurred in 366 pts (35.9%). Conclusions In this combined analysis, safety data for afatinib were consistent with results from LL3, 6 and 7. Efficacy data were encouraging, with a median TTSP of 14.6 months. This analysis, which includes pts treated in later lines, and pts with ECOG PS 2, brain metastases, or uncommon mutations, suggests that afatinib has clinical benefit for pts in the real-world clinical setting. Clinical trial identification NCT01853826 and NCT01953913. Editorial acknowledgement Beth de Klerk, of GeoMed, an Ashfield company, part of UDG Healthcare plc.; supported financially by Boehringer Ingelheim. Legal entity responsible for the study Boehringer Ingelheim. Funding Boehringer Ingelheim. Disclosure F. de Marinis: Honoraria (self), Advisory / Consultancy: Roche; Advisory / Consultancy: Takeda; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (institution), Research grant / Funding (self): Merck Sharp and Dohme; Research grant / Funding (self): Boehringer Ingelheim. A. Poltoratskiy: Advisory / Consultancy, Speaker Bureau / Expert testimony: GCP.center Russia. V. Lee: Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: Eli Lilly; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: Pfizer; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: Merck Sharp and Dohme. D.M. Kowalski: Advisory / Consultancy: Boehringer Ingelheim. A. Passaro: Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Merck Sharp and Dohme; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: Roche; Advisory / Consultancy: Dako. L. Clementi: Full / Part-time employment: Boehringer Ingelheim Italia SpA. W. Tang: Full / Part-time employment: Boehringer Ingelheim. D.C. Huang: Full / Part-time employment: Boehringer Ingelheim (Taiwan Limited). A. Cseh: Full / Part-time employment: Boehringer Ingelheim; Shareholder / Stockholder / Stock options, Husband: Mylan. C. Zhou: Honoraria (self): Boehringer Ingelheim; Honoraria (self): Roche; Honoraria (self): Sanofi; Honoraria (self): Hengrui; Honoraria (self): Qilu; Honoraria (self): Merck Sharp and Dohme. Y. Wu: Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Roche; Honoraria (self), Advisory / Consultancy: Bristol-Myers Squibb; Full / Part-time employment: Guangdong Provincial People’s Hospital, China; Honoraria (self): Eli Lilly; Honoraria (self): Pfizer; Honoraria (self), Research grant / Funding (self): Boehringer Ingelheim. All other authors have declared no conflicts of interest.

Introduction Bevacizumab and cetuximab both improve treatment efficacy when given with chemotherapy for metastatic colorectal carcinoma (mCRC) in both first- and second-line setting. Cetuximab has enhanced efficacy in Kras wild-type tumor. However, inferior outcomes were reported in two phase III randomised controlled trials for the concurrent use of bevacizumab and cetuximab with chemotherapy. There is an urgent need to define the optimal sequence of use of these two agents. With regard to the pre-clinical data that increased VEGF expression is associated with acquired resistance to anti-EGFR antibody, we performed a retrospective analysis on the outcomes of patients who received bevacizumab-containing regimens after cetuximab failure in Kras wild-type mCRC. Methods From January 2006 to December 2011, patients who received bevacizumab-containing regimens for mCRC in our institution were reviewed. Patients were eligible for further analysis if all the following criteria were met: [1] Kras wild-type mCRC, [2] received chemotherapy and cetuximab as immediate prior treatment, [3] received chemotherapy and bevacizumab as the index line of treatment and [4] had imaging for response evaluation. Outcome measures included median progression-free survival (mPFS) and objective response rate (ORR). Targeted adverse events were recorded in accordance with the two prospective observational cohort studies, the BRiTE and BEAT study. Adverse events include gastrointestinal perforation [perforation, intra-abdominal abscess, and fistula], arterial thromboembolic events (ATE) [myocardial infarction, cerebrovascular accident, transient ischemic attack, and unstable angina], postoperative bleeding or wound-healing complications (POWHC), grade 3/4 bleeding, and hypertension requiring additional anti-hypertensive. Results Fifty patients received bevacizumab-containing regimens were reviewed and 18 of them met all the criteria for further analysis. The median age was 56.5 and 10 patients had metastasis in multiple organs. After a median follow up of 12.1 months, the mPFS for the whole group of patients was 26.3 weeks (95% CI 19.5 – 33.0 weeks) with an ORR of 38.9%. For the 8 patients who received bevacizumab-containing regimens at second line, 1 complete response and 3 partial responses were observed, giving an ORR of 50%. The mPFS was 27.4 weeks (95% CI 2.0-52.8 weeks). For the 10 patients treated at third line, 3 PRs were observed, giving an ORR of 30%. The mPFS was 23.9 weeks (95% CI 19.7 – 28.1 weeks). Regarding previous exposure to oxaliplatin, irinotecan and 5FU, patients who exposed to only two of these agents, compared with those who exposed to all three agents, were more likely to respond to bevacizumab-containing regimen after cetuximab failure (Odds ratio 5.0, 95% CI 0.44-56.6). 2 patients (11.1%) had hypertension that required additional anti-hypertensive and 1 patient died of bowel perforation. The event of bowel perforation was unlikely attributed to bevacizumab since the event occurred 78 days after the last dose of bevacizumab while the patient was receiving hypofractionated palliative radiotherapy to the pelvis. There was no case of ATE, POWHC and grade 3/4 bleeding. Conclusion In patients with Kras wild-type mCRC, bevacizumab-containing regimens after cetuximab failure have promising activity and manageable toxicity. Further study is needed to compare switching to bevacizumab versus cetuximab beyond progression in this specific cohort of patients.

Introduction A previous retrospective study revealed that oxaliplatin could induce splenic enlargement which in turn was associated with thrombocytopenia in patients with early stage colorectal cancer. However it has not still been known whether cetuximab aggravates or alleviates such effects in patients with metastatic colorectal cancer. We performed a retrospective study to investigate the effect of addition of cetuximab to oxaliplatin-based regimen as 1st line palliative chemotherapy on liver and spleen size and its association with thrombocytopenia in patients with metastatic colorectal cancer. Methods Ninety two consecutive patients with metastatic colorectal cancer, recruited from January 2008 to December 2011, received either oxaliplatin-based chemotherapy (XELOX or FOLFOX4, n=57) and the same regimen with cetuximab (n=35) as 1st line palliative chemotherapy for their metastatic colorectal cancer. Contrast-enhanced computed tomography (CT) scan was performed at baseline and after chemotherapy +/- cetuximab at regular intervals. The volumes of the residual liver after excluding liver metastases if present and spleen at baseline and after oxaliplatin-based chemotherapy +/- cetuximab were determined by contouring these organs in Eclipse Treatment Planning System version 8.9. Changes in volume of liver and spleen in all patients and subgroups stratified according to the use of cetuximab were compared by paired and independent sampled t-tests respectively. Binary logistic regression was performed for any factors predictive of thrombocytopenia defined as Results Both liver (mean increase 4.2%, p=0.029) and spleen (mean increase 36.4%, p=0.000) enlarged in all patients after the use of oxaliplatin-based chemotherapy +/- cetuximab. Use of cetuximab in addition to oxaliplatin did not aggravate or protect the liver (mean decrease 0.56% for chemotherapy alone group vs mean increase 4.71% for cetuximab group, p=0.374) or spleen (mean increase 41.0% for chemotherapy alone group vs mean increase 31.9% for cetuximab group, p=0.338) from further change in size. Cumulative dose of cetuximab correlated with platelet count (Pearson's correlation coefficient r=0.503, p=0.020) and it was also associated with thrombocytopenia (relative risk: 4.563, p=0.033). However the risk of grade 3 or above (CTCAE version 4.0) thrombocytopenia was similar between those who received cetuximab and those who did not. Conclusion Oxaliplatin-based chemotherapy was confirmed to increase liver and spleen size in patients with metastatic colorectal cancer. Addition of cetuximab to oxaliplatin-based chemotherapy did not cause further hepatic or splenic enlargement but was associated with an increased chance of mild degree of thrombocytopenia.