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439 Background: Standard first-line treatment for advanced biliary tract cancer (BTC) with gemcitabine plus cisplatin confers only modest benefits (objective response rate [ORR], 26%; Valle et al. N Engl J Med 2010;362:1273-1281) and patient prognosis is poor. Therefore, new first-line strategies are urgently required. Human epidermal growth factor receptor (HER) tyrosine kinases are commonly overexpressed in BTC. Varlitinib is a reversible small molecule pan-HER inhibitor. Methods: This was a multicentre, phase 1B/2 study in patients with advanced BTC who had not received prior systemic therapy. Using a modified 3+3+3 escalation design in phase 1B, patients received oral varlitinib twice daily (BID) every day (starting dose 200 mg BID) plus gemcitabine/cisplatin on Days 1 and 8 in a 3-week cycle. The primary objective was to determine the maximum tolerated dose (MTD) and safety profile of varlitinib in combination with gemcitabine plus cisplatin. Patients were evaluable for MTD if they had varlitinib treatment compliance of ≥80% and received 2 doses of chemotherapy in Cycle 1, or if they experienced a dose-limiting toxicity (DLT) in Cycle 1. Preliminary efficacy was a secondary objective. Results: Overall, 23 patients were enrolled in Korea (3 sites), Singapore (1 site), and Taiwan (1 site). Patient characteristics at baseline: male, 52%; median (range) age, 66 (47-82) years; ECOG PS, 0 (43%)/ 1 (57%); primary tumor site, intrahepatic bile duct (43%)/ extrahepatic bile duct (22%)/ gallbladder (22%)/ ampulla of Vater (13%). In total, 11 and 12 patients were included in the varlitinib 200 mg and 300 mg cohorts, of whom 9 and 7 were evaluable for MTD, respectively. DLTs were observed in 2 patients in the 200 mg cohort. Prior to study termination, the 300 mg dose was being assessed with 1 patient experiencing a DLT. In the overall population (n = 23), 36% of patients in the 200 mg cohort and 67% in the 300 mg cohort had at least one grade ≥3 treatment-related adverse event. Grade ≥3 treatment-related investigations abnormalities and blood and lymphatic system disorders were reported in 27% and 18% of patients in the 200 mg cohort, and 25% and 25% of those in the 300 mg cohort, respectively. Among all 23 patients, 8 had a partial response and 12 had stable disease for ≥12 weeks, giving an ORR of 35% and a disease control rate of 87%. The median (Q1-Q3) duration of objective response was 4.0 (2.8-11.0) months. At the time of analysis, 17 patients had progression events and 6 were censored. The median (Q1-Q3) progression-free survival was 6.8 (5.1-10.7) months. Conclusions: Varlitinib combined with gemcitabine plus cisplatin was well tolerated and associated with preliminary anti-tumor activity in patients with treatment-naïve advanced BTC. Clinical trial information: NCT02992340.

4603 Background: In locally advanced or metastatic biliary tract cancer (BTC), second-line chemotherapy is challenging after progression from first-line gemcitabine/cisplatin, although mFOLFOX has been proven to be superior to active symptom control in ABC-06 trial. Irinotecan is an active drug in other gastrointestinal cancers. This study evaluated whether mFOLFIRI was superior to mFOLFOX in second-line treatment of BTC. Methods: Patients diagnosed with BTC with disease progression after prior gemcitabine/cisplatin were randomized (1:1) to either mFOLFOX (oxaliplatin 100mg/m2 over 2 hours, leucovorin 100mg/m2 over 2 hours, 5-fluorouracil 2400mg/m2 over 46 hours, every 2 weeks) or mFOLFIRI (irinotecan 150mg/m2 over 2 hours, leucovorin 100mg/m2 over 2 hours, 5-fluorouracil 2400mg/m2 over 46 hours). Randomization was stratified by tumor location (intrahepatic vs extrahepatic vs gallbladder vs ampulla of vater) and ECOG performance status (0, 1 vs 2). Primary end-point was overall survival (OS) rate at 6 months. Results: In total, 120 patients were enrolled and 114 patients were treated (mFOLFOX:57, mFOLFIRI:57). Median age was 63 years old. Most patients had ECOG 0/1 (89.5%). Tumor location was intrahepatic in 47 patients (41.2%), extrahepatic in 27 (23.7%), gallbladder in 35 (30.7%) and ampulla of vater in 5 (4.4%). At the median follow-up duration of 10.7 months (95% CI, 8.2-13.2), 6-month OS rate was 58.1% in mFOLFOX and 46.0% in mFOLFIRI. Of 102 evaluable patients (mFOLFOX:51, mFOFIRI:51), objective response rate and disease control rate were 5.9% (95% CI, 0-12.4) and 64.7% (95% CI, 51.6-77.8) in mFOLFOX and 3.9% (95% CI, 0-9.2) and 58.8% (95% CI, 45.3-72.3) in mFOLFIRI. Median progression-free survival was 2.8 months (95% CI, 2.3-3.3) in mFOLFOX and 2.1 months (95% CI, 1.3-2.9) in mFOLFIRI (p = 0.682). Median OS was 6.6 months (95% CI, 5.6-7.6) in mFOLFOX and 5.9 months (95% CI, 4.3-7.5) in mFOLFIRI (p = 0.887). The most common grade 3/4 adverse events were neutropenia (26.3%) and AST/ALT elevation (15.8%) in mFOLFOX and neutropenia (24.6%) and anemia (17.5%) in mFOLFIRI. Peripheral neuropathy (36.8%) and thrombocytopenia (35.1%) in mFOLFOX and vomiting (19.3%) and cholangitis (10.5%) in mFOLFIRI occurred more frequently. No chemotherapy-related deaths were reported. Conclusions: In second-line treatment of BTC, mFOLFIRI was tolerable But, mFOLFIRI was not superior to mFOLFOX. Adverse events were different between two groups. Clinical trial information: NCT03464968 .

319 Background: BTC is a rapidly progressing cancer with limited response to chemotherapy. First line therapy (gem/cis) was defined in the ABC-02 study (Valle et al), where a 26% response was seen. HER family receptors are overexpressed and may be involved in tumour proliferation and survival in BTC. Varlitinib, a reversible tyrosine kinase inhibitor of EGFR, HER2, and HER4, shows potent activity as monotherapy in preclinical BTC models and clinical activity in BTC patients (pts) in phase (ph) 1 trials. We conducted a ph Ib/2 study of varlitinib plus gem/cis in BTC to understand the safety profile and determine the maximum tolerated dose (MTD) of the combination. Methods: A modified 3+3+3 escalation design was used in Ph1b, with 2 varlitinib dose levels (200 and 300 mg BID) plus gem/cis on Day 1 and 8 in a 3 week cycle. The primary objectives are to determine the MTD and to characterize the safety profile. Secondary objectives are to assess the preliminary efficacy and to evaluate the pharmacokinetics of varlitinib and any circulating metabolites. Results: As of 10 Sep 2018, 21 pts were enrolled (11 in 200 mg cohort and 10 in 300 mg cohort, with 9 and 4 evaluable for MTD, respectively). Dose limiting toxicities (DLTs) were observed in 3 pts (1 G3 unconjugated hyperbilirubinemia and 1 G3 ALT transaminitis/G4 AST transaminitis in 200 mg cohort; 1 G4 thrombocytopenia/G3 febrile neutropenia/G3 AST elevation in 300 mg cohort). In 19 pts who were on varlitinib ≥ 1 month, 7 had partial response and 10 achieved stable disease (all > 12 weeks), giving the overall response rate of 37% and the disease control rate of 89%. The median PFS for the 200 mg cohort was 248 days and was not reached for the 300 mg cohort. The most common (≥ 30%) all-grade adverse events (AEs) regardless of causality were thrombocytopenia (62%), neutropenia (52%), anorexia (38%), nausea (38%), diarrhoea (38%), and anaemia (33%); the most common (≥ 15%) grade ≥ 3 AEs were neutropenia (48%), thrombocytopenia (33%), and anaemia (19%). Conclusions: Varlitinib plus gem/cis was well tolerated in the 200 mg cohort; the 300 mg cohort is ongoing. Preliminary anti-tumour activity was observed. Data will be updated at the time of presentation. Clinical trial information: NCT02992340.

515 Background: Oxaliplatin-based regimens are standard treatments for patients with colorectal (CRC) and advanced gastric cancer (AGC). However, the use of oxaliplatin sometimes results in hepatic sinusoidal obstruction syndrome (SOS). The aim of the study was to evaluate the utility of non-invasive liver fibrosis indices for monitoring oxaliplatin-induced hepatic SOS. We have reported a preliminary data in ASCO Annual Meeting 2014. Methods: From February 2004 to April 2014, patients with CRC or AGC who received oxaliplatin-based chemotherapy were studied. Possibility of SOS development was evaluated before and after the oxaliplatin exposure with splenic volume index (SVI). Four different non-invasive liver fibrosis indices were used for risk analysis: age-platelet index (API), AST to platelet ratio index (APRI), platelet to spleen ratio (PSR), Fibrosis-4 score (FIB-4). A prospective observation with serial elastrography is also ongoing. Results: A total of 275 patients were eligible for evaluation: 200 patients had CRC, and 75 patients had AGC. Using a cutoff of SVI increase ≥ 0.3, 113 patients (41.1%) were positive for hepatic SOS. Changes of indices were significantly correlated with SVI increase. Adjusted odds ratios for those indices were as follows: API = 1.16 (95% Confidential Interval [CI], 1.01 - 1.32; P = 0.032); APRI = 2.45 (95% CI, 1.30 - 4.63; P = 0.006); PSR = 0.69 (95% CI, 0.59 - 0.80; P < 0.001); FIB-4 = 1.37 (95% CI, 1.16 - 1.63; P < 0.001). Optimal cutoff-value with statistical significance were calculated and suggested. A total of 20 patients have been enrolled into the prospective observation until now. Comparison of elastographic changes and the indices in these patients will be presented. Conclusions: Changes of non-invasive liver fibrosis indices showed good correlation with SVI increase during oxaliplatin-based chemotherapy. These indices might be useful markers for monitoring of oxaliplatin-induced hepatic SOS. Serial monitoring of hepatic elastography could also be used for non-invasive monitoring of hepatic SOS.

9617 Background: Even though oxaliplatin (OXA) could induce hepatic sinusoidal obstruction syndrome (SOS), OXA-based regimes are still standard treatment for patients with colorectal (CRC) and advanced gastric cancer (AGC). The aim of the study was to evaluate the utility of non-invasive liver fibrosis index (NIFI) for monitoring OXA-induced hepatic SOS. Methods: From February 2004 to December 2013 patients with CRC or AGC who received OXA-based chemotherapy (CTx) were identified in the institutional electronic patient database. Liver fibrosis were evaluated before and after the OXA exposure with splenic volume index (SVI) and 4 different NIFIs: age-platelet index (API), AST to platelet ratio index (APRI), platelet to spleen ratio (PSR), Fibrosis-4 score (FIB-4). Adjusted odd ratio (aOR) with 95% confidence intervals (CI) were analyzed to evaluate risk after matching age, body mass index, cancer type, stage, previous chemotherapy cycle. Results: A total of 288 patients (pts) were eligible for evaluation: ...

7566 Background: Other than in-frame deletional mutation (MT) in exon 19 and Leu858Arg point MT in EGFR gene, there are many rare and complex MT. The purpose of this study was to investigate was to clarify the clinical significance of rare and complex MT, and the efficacy of EGFR TKI in these patients. Methods: Rare MTs were defined any MT other than deletional MT in exon 19, Leu858Arg in exon 21, and Thr790Met in exon 20. Complex MT was defined two different EGFR MTs co-occurring within the single tumor sample. We have analyzed consecutive database of NSCLC patients who were treated with either gefitinib or erlotinib at Seoul National University Hospital between Jan. 2002 and Dec. 2011. For analysis of EGFR MT, coding sequences from exon 18 to 21 were amplified by nested PCR and subjected to direct sequencing methods. Results: Among the 1,159 TKI treated patients, 301 patients had EGFR MT (177 patients (58.8%) with del-19, 104 patients (34.6%) with Leu858Arg, and 20 patients (6.6%) with rare MT). Twenty-three (7.6%) patients have complex MT, and 55 (18.3%) patients have Gln787Gln polymorphism particularly associated with Leu858Arg MT. Identified rare MT were follows; exon 18: Leu692Phe, Glu707Lys, Glu709Gly, Lys714Asn, Gly7Ala, Thr725Thr, exon 19: Ala755Asp Lys737Thr, exon 20: Val786Met, exon21: Ala871Gly, Gly873Gln, Leu833Val, Val834Leu, Arg836Cys, Pro848Leu, Ala859Thr, Leu861Gln. When categorizing 3 groups (group A: classic MT alone, group B: complex MT with classic + rare MT, group C: rare MT alone or complex MT with rare MTs), response rate (RR) to TKI was different between each groups (RR= 78.7% in group A vs. 69.2% in group B vs. 38.5% in group C, respectively, P < 0.001). Progression-free survival (PFS) was also poorer in rare MT (median PFS: 12.1 mo vs. 7.6 mo vs. 2.1 mo, respectively, P= 0.020,). Gln787Gln polymorphism of exon 21 was not associated with RR or PFS (P= 0.101, P= 146, respectively) Conclusions: In this large case series, NSCLC patients who harboring rare MT other than del-19 and Leu858Arg, does not seems response to EGFR TKI. However, complex MT with the classical MT showed similar treatment efficacy toward EGFR TKI with that of classical MT alone.

626 Background: Systemic chemotherapy is still mainstay of treatment of metastatic colorectal cancer (mCRC), while the role of palliative resection is not convincing. We intended to find out the role of palliative resection in mCRC. Methods: A total of 1,015 patients were diagnosed with mCRC at Seoul National University Hospital between 2000 and 2009. Except 169 patients who received curative metastectomy of liver and/or lung, 847 patients were retrospectively analyzed. Results: Out of 847 patients, 556 (65.6%) had metastasis at the time of diagnosis and 291 (34.4%) had recurrence after surgery. The median age was 61 (range, 16-88) and 491 (58.0%) were male. The median number of metastatic site was 1 (range, 1-6) and 738 (87.1%) had limited metastasis (number of metastatic site ≤2). The liver was most frequently involved site (451, 53.2%). Surgery was done in 527 (62.2%). One hundred three patients received resection of both primary and metastatic sites (group 1), while 347 and 78 received resection of primary (group 2) and metastatic sties (group 3), respectively. R0 resection was done in 95 patients (G1: 53, G3: 42), while R1/2 was done 431 in patients (G1: 56, G2: 336, G3:39). Of 95 patients with R0 resection, 93 (97.8%) had limited metastasis (number of metastatic organ ≤2) in the peritoneum, lymph nodes, liver, or lung. The median overall survival (OS) was 19.0 months (95% CI, 17.8-20.1) and resected patients had prolonged median OS compared with patients never resected (21.3 vs 14.1 months, p < 0.001). In multivariate analysis, R0 resection was associated with superior OS compared to R2 resection (51.3 vs 18.7 months; HR, 3.0; 95% CI, 1.86 to 4.85, P Conclusions: Palliative resection with curative intent and chemotherapy confer long-term survival on subsets of mCRC with limited metastasis.