tipiracil in metastatic colorectal cancer: An updated multicentre real-world analysis on efficacy, safety and predictive factors

abstracts

Funding (self): MSD.K.K.; Research grant / Funding (self): Sumitomo Dainippon Pharma Co., Ltd.; Research grant / Funding (self): Chugai Pharmaceutical Co., Ltd.; Research grant / Funding (self): Sanofi K.K.; Research grant / Funding (self): Daiichi Sankyo Company, Limited; Research grant / Funding (self): PAREXEL International Inc.; Research grant / Funding (self): Ono Pharmaceutical Co., Ltd. H. Taniguchi: Research grant / Funding (self): Takeda; Research grant / Funding (self): Daiichi Sankyo; Research grant / Funding (self): Sysmex; Honoraria (self): Chugai; Honoraria (self): Taiho; Honoraria (self): Eli Lilly. All other authors have declared no conflicts of interest.

600P

Trifluridine/tipiracil in metastatic colorectal cancer: An updated multicentre real-world analysis on efficacy, safety and predictive factors

C. Stavraka1, A. Pouptsis1, A. Synowiec2, V. Aggelis2, L. Satterthwaite3, S. Khan4, M. Chauhan4, C.E. Holden5, S. Young5, C. Karampera1, M. Martinou6, T. Mills-Baldock6, M. Baxter7, B.K. Eccles5, T.J. Iveson3, K-K. Shiu8, M.E. Hill2, S. Abdel-Raouf6, A. Thomas9, P.J. Ross1 1 Medical Oncology, Guy’s and St. Thomas’ NHS Foundation Trust, London, UK, 2Medical Oncology, Maidstone and Tunbridge Wells NHS Trust, Maidstone, UK, 3Medical Oncology, Southampton General Hospital Southampton University Hospitals NHS Trust, Southampton, UK, 4Medical Oncology, Leicester Royal Infirmary, Leicester, UK, 5 Oncology, Poole Hospital NHS Foundation Trust, Poole, UK, 6Oncology, Queen’s Hospital, Essex, UK, 7Medical Oncology, Beatson West of Scotland Cancer Centre, Glasgow, UK, 8Oncology, University College London Hospital, London, UK, 9Leicester Cancer Research Centre, University of Leicester, Leicester, UK Background: The orally administered combination trifluridine and tipiracil hydrochloride (TAS-102) has been approved as third line treatment in metastatic colorectal cancer, demonstrating survival benefit and acceptable toxicity profile in the phase III RECOURSE study. Methods: We performed an updated multicentre retrospective observational study of patients with metastatic colorectal cancer, receiving TAS-102 as third line treatment between 2016 and 2019 in 8 cancer centers across the UK. Medical records were reviewed for clinicopathological characteristics, treatment, survival and toxicity outcomes. Prognostic and predictive factors were identified with uni-and multivariate regression analyses. Results: A total of 236 patients were included. Median age was 69 years (31-89). All patients had received at least 2 lines of fluoropyrimidine-based chemotherapy doublet with oxaliplatin or irinotecan. About 10% of patients had ECOG > 2. Median duration of TAS-102 treatment was 3 months (0.2-25.9), with an ORR of 2.1% and disease control rate of 21.6%. Median OS was 7.6 months (95%CI 6.5-8.6) and median PFS 3.3 months (95%CI 3.01-3.57). A dose reduction was required in 27% of patients, while 7.6% discontinued treatment due to toxicity. Neutropenia was present in 53%, (>G3 34%) with 4.6% cases of neutropaenic fever. Thrombocytopenia was less frequent 11% (>G3 1.6%). Fatigue was reported in 67.3% (G3 9%), nausea 30% (G3 3.3%) and diarrhoea 24.5% (G3 2%). Baseline Neutrophil to Lymphocyte ratio (NLR) <5 and CEA <200 had favourable prognostic (HR: 0.52 and 0.39, p < 0.001) and predictive value

v226 | Gastrointestinal Tumours, Colorectal

(OR: 4.1 and 6.7, p < 0.05). Development of G3 neutropenia predicted treatment response (OR: 0.32, p < 0.001). Following TAS-102 treatment 41% were referred for Phase I trial or rechallenged with chemotherapy. Conclusions: These results are consistent with the efficacy and toxicity outcomes from RECOURSE study. However, lower disease control rates and higher rates of dose reductions are seen in the real-world population. Pre-treatment NLR and CEA could serve as potential markers for patient selection. Prospective validation is needed. Legal entity responsible for the study: The authors. Funding: Has not received any funding. Disclosure: C. Stavraka: Travel / Accommodation / Expenses: Servier; Travel / Accommodation / Expenses: Amgen. V. Aggelis: Travel / Accommodation / Expenses: Amgen. T.J. Iveson: Advisory / Consultancy: Servier; Advisory / Consultancy: Roche; Advisory / Consultancy: Pierre Fabre; Advisory / Consultancy: Bristol-Myers Squibb. K. Shiu: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Amgen; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: BMS; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Guardant Health; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Merck KGaA; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: MSD; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Sirtex; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Servier. M.E. Hill: Honoraria (self), Travel / Accommodation / Expenses: Amgen; Honoraria (self), Travel / Accommodation / Expenses: Servier; Honoraria (self), Travel / Accommodation / Expenses: Merck; Honoraria (self), Travel / Accommodation / Expenses: Roche. P.J. Ross: Research grant / Funding (self): Sanofi; Honoraria (self), Travel / Accommodation / Expenses: Servier; Honoraria (self), Travel / Accommodation / Expenses: BMS; Honoraria (self), Travel / Accommodation / Expenses: Bayer; Honoraria (self): Sirtex; Honoraria (self): Celgene; Honoraria (self): Pierre Fabre. All other authors have declared no conflicts of interest.

601P

Correlation between p53 expression and clinical outcome in RAS/BRAF wild type metastatic colorectal cancer patients receiving later-line irinotecan-cetuximab

E. Lai1, M. Schirripa2, M. Puzzoni1, F. Loupakis2, P. Ziranu1, A. Pretta3, R. Giampieri4, S. Mariani1, N. Liscia3, P. Soro1, V. Pusceddu1, G. Astara1, V. Impera3, S. Camera3, F. Musio1, A. Zaniboni5, M. Fassan6, S. Lonardi7, V. Zagonel8, M. Scartozzi1 1 Medical Oncology Unit, University Hospital and University of Cagliari, Cagliari, Italy, Monserrato, Italy, 2Medical Oncology Unit 1, Department of Clinical and Experimental Oncology, Istituto Oncologico Veneto IRCCS, Padua, Italy, 3Medical Oncology Unit, Sapienza University of Rome - University Hospital and University of Cagliari, Cagliari, a Italy, Monserrato, Italy, 4Medical Oncology Unit, University Hospital and Universit Politecnica delle Marche, Ancona, Italy, 5Medical Oncology, Casa di Cura 6 Poliambulanza, Brescia, Italy, Department of Medicine and Surgical Pathology and Cytopathology Unit, University Hospital of Padua, Padua, Italy, 7Unit of Medical Oncology 1, Department of Clinical and Experimental Oncology, Veneto Institute of Oncology, Istituto Oncologico Veneto - IRCSS, Padua, Italy, 8Department of Oncology, Oncology 1, Veneto Institute of Oncology, IOV – IRCCS, Padua, Italy Background: Preclinical and clinical data support that p53 might modulate the EGFR activity and as a consequence it might influence response/resistance to anti-EGFR monoclonal antibodies. However, the association between p53 status and clinical outcome has not been clarified yet. In our study we evaluated the role of p53 expression in RAS/BRAF wild type (WT) metastatic colorectal (mCRC) patients (pts) receiving irinotecan-cetuximab by using a validation cohort. Methods: p53 immunohistochemical expression was retrospectively analysed in tumour samples of RAS/BRAF WT mCRC pts treated with second-third line irinotecan-cetuximab. Our aim was to evaluate the correlation between p53 expression and OS, PFS and RR. Statistical analysis was performed with the MedCalc package. Survival distribution was assessed by the Kaplan-Meyer method and comparison of survival curves was performed with log-rank test. Results: Globally 120 RAS/BRAF WT mCRC pts were included in our analysis, 88 in the exploratory cohort and 32 in the validation cohort. 36/88 and 14/32 pts had p53 normal expression, whereas 52/88 and 18/32 showed p53 overexpression. In the exploratory cohort, RR was 61.1% in pts with p53 normal expression versus (vs) 3.8% in pts overexpressing p53 (p < 0.0001); median OS (mOS) was 18 months in pts with normal p53 (95% CI 17-20) vs 8 months (95% CI 5.9-9; p < 0.0001) and median PFS (mPFS) was 8 months in pts with p53 normal status (95% CI 6.98-8.10) vs 3 months in pts with abnormal p53 (95% CI 2.90-3.63; p < 0.0001). These results were confirmed in the validation cohort: RR was 56.2% in pts with normal p53 and 43.7% in pts with abnormal p53 (p ¼ 0.4830); mOS was 30.1 months in pts with p53 normal status (95% CI 22.4253.31) vs 13.4 months in pts with p53 overexpression (95% CI 12.04-24.84; p ¼ 0.03) and mPFS was 9.8 months in pts with normal p53 (95% CI 7.51-12.55) vs 7.9 months in pts with abnormal p53 (95% CI 5.32-8.21; p ¼ 0.02). Conclusions: In our study p53 normal expression was associated with better outcome in RAS/BRAF WT mCRC pts receiving irinotecan-cetuximab, as confirmed by the validation cohort. Further prospective studies are needed to validate the role of p53 in these pts and to investigate its cross-talk with EGFR. Legal entity responsible for the study: Mario Scartozzi. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.

Volume 30 | Supplement 5 | October 2019

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Background: Patients (pts) who underwent a curative resection for solitary colorectal liver metastasis (CRLM) have a relatively favorable prognosis. Clinical impact of BRAF V600E mutations in those pts remains unclear. Methods: Consecutive pts who had undergone initial hepatectomy for histologically confirmed solitary CRLM were included. Tumor RAS (KRAS/NRAS)/BRAF V600E mutation tests were centrally performed by a PCR method. The association between BRAF V600E mutation and survival outcome in pts with resectable solitary CRLM was retrospectively investigated. Results: From Jan 2005 to Dec 2017, 218 pts were included with a median follow-up of 52 months (m). BRAF mutant (mBRAF) was observed in 5 (2.3%) pts, while mRAS was in 92 (42.2%) pts and RAS/BRAF wild-type (wRAS/BRAF) was in 121 (55.5%) pts. mBRAF was associated with a higher serum CA19-9 level at pre-hepatectomy (p ¼ 0.03). Median longest diameter for solitary CRLM were similar among three cohorts (19 mm vs. 25 mm vs. 27 mm, p ¼ 0.21). However, all the mBRAF pts experienced early recurrence within 9 m. In the univariate analysis, mBRAF was associated with a worse survival in terms of both recurrence-free survival (RFS) with the hazard ratio (HR) of 8.68 for mBRAF vs. wRAS/BRAF (mBRAF vs. mRAS vs. wRAS/BRAF; median, 4.8 m vs. 17.1 m vs. not reached, p < 0.001: 3-year RFS rate, 0% vs 39.6% vs 56.2%, p < 0.001) and overall survival (OS) with the HR of 20.8 for mBRAF vs. wRAS/ BRAF (mBRAF vs. mRAS vs. wRAS/BRAF; median, 14.4 m vs. not reached vs. not reached, p < 0.001: 3-year OS rate, 20.0% vs 78.9% vs 94.9%, p < 0.001). In the multivariate analysis, mBRAF was strongly associated with a worse survival and had the highest HR among all the indicators in terms of both RFS (HR: 5.0, 95% CI: 1.8–13.8, p < 0.001) and OS (HR: 15.4, 95% CI: 5.2–45.5, p < 0.001). Conclusions: Among resectable solitary CRLM pts, mBRAF was rare (2.3%). However, given that all the mBRAF pts experienced early recurrence and the striking value of HRs in the univariate and multivariate analyses on both RFS and OS, mBRAF itself may become the most relevant indicator beyond known clinicopathological indicators in pts with resectable solitary CRLM. A novel treatment strategy for these patients is warranted. Clinical trial identification: UMIN000034557. Legal entity responsible for the study: The authors. Funding: The National Cancer Center Research Development Fund, Japan (Research number: 30-A-8, Principal investigator: Shinichiro Takahashi). Disclosure: T. Yoshino: Research grant / Funding (self): Novartis Pharma K.K.; Research grant /

Annals of Oncology