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548 Background: Biliary tract cancers (BTCs) include gallbladder cancer (GBC), intrahepatic cholangiocarcinoma (IHCC), extrahepatic cholangiocarcinoma (EHCC), and ampulla of Vater cancer (AV). Although it was previously reported that there were differences in clinical features individually, the reported data were limited to data from some subgroup analyses of recent randomized controlled trials. JCOG1113 (UMIN000010667) showed the non-inferiority of gemcitabine plus S-1 to gemcitabine plus cisplatin in terms of overall survival (OS) in patients (pts) with advanced BTCs. We aimed to compare clinical features among the primary sites of BTCs using JCOG1113 data. Methods: Among the 354 pts enrolled in JCOG1113, 352 pts were included in this analysis except for 2 pts without BTCs. We compared the patient characteristics and treatment outcomes, such as OS, progression-free survival (PFS), and objective response rate (ORR), among the four primary sites. Results: Of the 352 pts, 137 pts (38.9%), 94 pts (26.7%), 108 pts (30.7%) and 13 pts (3.7%) had GBC, IHCC, EHCC, and AV, respectively. GBC was more common in females (58.4%) than males, in contrast to the other primary sites. The percentage of pts with metastatic disease for GBC was the highest (78.1%) and involved multiple metastatic organs (41.6%), in contrast with the other primary sites. The median OS for GBC, IHCC, EHCC and AV were 12.6 months (reference), 15.7 months (hazard ratio [HR]; 0.749, 95% confidence interval [CI], 0.559-1.005), 16.3 months (0.704, 0.532-0.934) and 11.5 months (1.148, 0.633-2.080), respectively. The median PFS for GBC, IHCC, EHCC and AV were 5.7 months (reference), 6.2 months (0.843, 0.644-1.104), 8.7 months (0.636, 0.489-0.826) and 4.1 months (1.506, 0.851-2.665), respectively. The ORRs for GBC, IHCC, EHCC and AV were 34.4%, 28.9%, 34.4%, and 0.0%, respectively. Conclusions: Except for AV which included a few patients in this trial, GBC showed a poorer prognosis compared with the other primary sites. Furthermore, it was more likely to include metastatic disease and multiple metastases, and this is likely one of the causes of the poorer prognosis. [Table: see text]

732 Background: S-1, an oral fluoropyrimidine derivative, is standard adjuvant therapy in Japanese patients with resected biliary tract cancer (BTC), based on the results of JCOG1202, a phase III trial evaluating adjuvant S-1 following curative resection for BTC compared to surgery alone. The efficacy of 5-FU-based therapy is related to the expression of enzymes involved in 5-FU metabolic pathways, such as thymidylate synthase (TS), thymidine phosphorylase (TP), orotate phosphoribosyltransferase (OPRT) and dihydropyrimidine dehydrogenase (DPD). The aim of this study was to evaluate the impact of messenger RNA (mRNA) levels of the four 5-FU metabolic pathway genes on the outcomes of patients enrolled in JCOG1202. Methods: Tumor cell RNA was isolated from formalin-fixed paraffin-embedded primary BTC specimens resected in 264 of 440 randomized patients in JCOG1202. The four 5-FU metabolic pathway genes were measured in 183 patients (surgery alone: n = 94; adjuvant S-1: n = 89) who were randomly divided to training (n = 96) or validation set (n = 87). The endpoints of interest were the predictive values of the four genes for the efficacy of adjuvant S-1 on overall survival and relapse-free survival (RFS), and we here report the results regarding RFS. Cut-off levels for mRNA expression were selected in the training set which minimized the bootstrap p-values (2,000 samples) of an interaction term of treatment (surgery alone or S-1) and mRNA expression in a Cox regression model. Results: There were no obvious differences in each mRNA level and clinical characteristics between surgery alone and adjuvant S-1 groups. RFS tended to be better with adjuvant S-1 (hazard ratio [HR] = 0.790, [95% confidence interval: 0.524-1.192]) compared to surgery alone, which was maintained in the low DPD population (HR = 0.440 [0.216-0.898] in training set and 0.748 [0.334-1.675] in validation set), in the low TP population (HR = 0.709 [0.388-1.296] and 0.602 [0.287-1.262]), and in the high OPRT population (HR = 0.520 [0.152-1.779] and 0.609 [0.161-2.304]). Conclusions: The efficacy of adjuvant S-1 on RFS was representative in BTC patients with intratumoral gene expressions of low DPD, low TP, and high OPRT, which was disappeared in the population with high DPD, high TP, and low OPRT. These biomarkers might be useful to predict therapeutic benefits with S-1 containing chemotherapy for BTC.

682 Background: Pancreatic cancer and especially late-line chemotherapy often negatively impact patient quality of life (QoL). However, QoL outside of the date of hospital visits has not been adequately evaluated. This study assessed QoL at home in patients receiving chemotherapy using electronic patient-reported outcomes (ePRO). Methods: This multicenter prospective observational study was conducted in 29 Japanese centers. Pathologically confirmed unresectable pancreatic cancer patients who were going to receive a second cycle of second-line chemotherapy, liposomal irinotecan plus fluorouracil/leucovorin (nal-IRI+FF), gemcitabine plus nab-paclitaxel (GEM+nab-PTX), or gemcitabine alone (GEM) at the outpatient department were included. QoL was assessed by electronic instruments on days 1, 2, 4, 6, 8, and 11 of each administration during two consecutive cycles (second and third cycles). The primary outcome was the index value of EuroQol 5-dimensions 5-levels (EQ-5D-5L). Secondary outcomes were the status of the European Organization for Research and Treatment of Cancer (EORTC)-QLQ-C30 and Patient-Reported Outcome Common Terminology Criteria for Adverse Events (PRO-CTCAE). Results: A total of 90 patients, 56 receiving nal-IRI+FF, 27 receiving GEM+nab-PTX, and 7 receiving GEM, were eligible for this study. The patients who responded to at least the first questionnaire and received nal-IRI+FF (n = 46) or GEM+nab-PTX (n = 16) were selected for analysis. In the nal-IRI+FF group, the mean index value of EQ-5D-5L on day 1 of the second cycle was 0.803±0.142, declined up to day 6 (0.678±0.247), and had recovered by day 1 of the third cycle (0.776±0.197). Similar trends were observed in the third cycle; the nadir of the mean index value was 0.723±0.182 on day eight and had recovered by day 15 (0.782±0.159). On the other hand, in the GEM+nab-PTX group, the nadir of the mean index value in the second cycle was on day 6 of the third administration (0.751±0.184) and had not fully recovered by day 1 of the third cycle (0.789±0.182). For global health status according to EORTC-QLQ-C30, a similar trend to EQ-5D-5L was observed in both groups. According to the results of the PRO-CTCAE, pain (40.4%), diarrhea (36.5%), abdominal pain (30.8%), fatigue (28.8%), and anorexia (28.8%) were frequent severe or very severe adverse events in the nal-IRI+FF group. In comparison, diarrhea (29.2%) and anorexia (25.0%) were frequent severe or very severe adverse events in the GEM+nab-PTX group. Conclusions: QoL assessed by ePRO outside the date of hospital visits revealed the pattern or details of QoL transition. Further study is needed so that these trends can be taken into account in the management of chemotherapy. Clinical trial information: UMIN000044245 .

494 Background: LAT1 is a transporter ( SLC7A5) of L-type amino acid. Overexpression in cancer cells supports aggressive proliferation. High expression of LAT1 in tumor specimens has been identified as a predictor of poor prognosis in patients with various cancer types, including BTC. The efficacy and safety of nanvuranlat (JPH203), a first-in-class, single agent that selectively inhibits LAT1, was evaluated in patients with pretreated, advanced, refractory BTC in a placebo-controlled randomized trial. Methods: Patients with four different subtypes of advanced BTC were enrolled: intrahepatic (IHC), extrahepatic (EHC), gallbladder (GBC) and ampulla of Vater (AVC). All were refractory to or intolerant of standard chemotherapy and other investigational medicines. Patients were pre-classified as non-rapid acetylators via N-acetyltransferase 2 ( NAT2), to maximize efficacy/safety by minimizing the metabolism of nanvuranlat. The primary endpoint was progression-free survival (PFS), assessed by blinded independent center review (BICR), using RECIST 1.1. Results: At data cut-off (February 28, 2022), 211 BTC patients were consented at 14 centers in Japan. Using NAT2 testing for classification, a total of 106 patients were randomized (2:1) to nanvuranlat (n = 70) or placebo (n = 36). Nanvuranlat met its primary endpoint and demonstrated a statistically significant improvement in PFS by BICR in comparison with the placebo group (Hazard Ratio = 0.557; 95% CI, 0.3435 – 0.9029; one-sided p = 0.0164). The disease control rate (DCR) in the nanvuranlat group was approximately 25% (average = 24.6%) across all BTC subtypes, while it was 11.4% in the placebo group. Grade 3 adverse events were reported in 30.0% for nanvuranlat vs 22.9% for placebo. Treatment-related adverse event rates were respectively 41.4% and 57.1% in the nanvuranlat and placebo groups. No patient had adverse events leading to nanvuranlat treatment discontinuation, dose reduction, or death. Conclusions: The study met the primary endpoint. LAT1 inhibitor monotherapy with nanvuranlat demonstrated useful clinical efficacy in patients with four different subtypes of pre-treated, advanced, refractory BTC. Safe and highly tolerated profile was also documented. Clinical trial information: UMIN000034080 .

425 Background: Blocking immune checkpoint (IC) pathways, particularly mediated by PD1 and PDL1, has attracted great attention as a promising strategy for treating gastrointestinal cancer. However, the clinical responses are low in many cases, and thus a new treatment strategy and its biomarker are urgently needed for improving the clinical outcome. Blocking other IC molecules, including LAG3, has been evaluated in many clinical trials, while the therapeutic efficacy and the predictive biomarkers remains to be determined due to the same issues as anti-PD1/PDL1 therapy. Methods: We analyzed soluble LAG3 (sLAG3) in sera by ELISA, and LAG3+ cells by flow cytometry, using fresh peripheral blood (PB) obtained from 91 patients with advanced gastric cancer (AGC) before and about one month after nivolumab monotherapy (2 courses) in the WJOG10417GTR study, according to the protocol approved by the IRB (August 2018 - November 2020). Progression-free survival (PFS) and overall survival (OS) were compared between high/low groups divided by the cutoff value determined by visually assessing the continuous trend and change point of log hazard ratios obtained by applying penalized splines to each molecular marker. This study was supported by ONO PHARMACEUTICAL CO., LTD. and Bristol Myers Squibb. Results: Posttreatment values were significantly more associated with patients’ prognosis rather than baseline values, and the sLAG3-high group showed significantly shorter PFS/OS as compared to the low group divided by the median: median PFS (mPFS) 51.5 vs 95.5 days (HR = 2.04, P = 0.002), and median OS (mOS) 188 vs 393 days (HR = 1.81, P = 0.032). Patients with high levels of LAG3+ PBCs after treatment showed worse prognosis as compared to those with low levels divided by the cutoff values: a CD3+CD4+LAG3+ T-cell subset, mPFS 43 vs 72 days (HR = 2.23, P = 0.015) and mOS 178 vs 282 days (HR = 1.56, P = 0.249); a CD3+CD8+LAG3+ T-cell subset, mPFS 57 vs 69 days (HR = 1.89, P = 0.012) and mOS 228 vs 303 days (HR = 1.40, P = 0.233); and a CD56+LAG3+ NK subset, mPFS 57 vs 88 days (HR = 2.15, P = 0.003) and mOS 217 vs 409 days (HR = 1.88, P = 0.031). Patients with sLAG3-high/CD56+LAG3+ NK-high levels showed markedly worse prognosis than those with low/low levels (mPFS-HR = 10.55, P < 0.001; and mOS-HR = 4.59, P < 0.001). Conclusions: Patients with posttreatment high levels of sLAG3 and LAG3+ cells in PB showed poor prognosis of AGC patients after the nivolumab therapy, suggesting that these are useful predictive biomarkers. LAG3 may be a promising target in immunotherapy for AGC. Clinical trial information: UMIN000032686 .

4006 Background: BTCs have an aggressive tumor biology with limited treatment options. With a HER2-positivity rate of 5–20% in BTCs, case series and small clinical trials have shown signs of activity for HER2 blockade in these pts. T-DXd is an antibody-drug conjugate composed of a humanized monoclonal anti-HER2 antibody, a cleavable linker, and a topoisomerase I inhibitor. The HERB trial is an investigator-initiated, multicenter, single-arm phase 2 trial of T-DXd in pts with HER2-expressing BTCs. Methods: Centrally confirmed HER2-expressing (HER2-positive: IHC3+ or IHC2+/ISH+, and HER2-low-expressing [HER2-low]: IHC/ISH status of 0/+, 1+/-, 1+/+, or 2+/-) pts with BTCs who were refractory or intolerant to gemcitabine containing regimen received 5.4 mg/kg of T-DXd every 3 weeks. The primary endpoint was the confirmed objective response rate (ORR) in HER2-positive pts by independent central review. The sample size of 22 had 80% power with one-sided alpha error of 5%; threshold ORR, 15%; and expected ORR, 40%. The ORR, disease control rate (DCR), progression-free survival (PFS), overall survival (OS) in HER2-positive/-low pts, and incidence of treatment-emergent adverse events (TEAEs) were assessed as secondary endpoints. Results: A total of 32 pts, 24 with HER2-positive and 8 with HER2-low BTCs, received T-DXd. Twenty-two pts with HER2-positive, excluding 2 ineligible pts, were identified for primary efficacy analysis. Among the 22 pts, IHC3+ and IHC2+/ISH+ were 45.5% and 54.5%, primary sites: gallbladder/extrahepatic/intrahepatic/Vater were 11/6/3/2, median number of prior regimens was 2 (range, 1–4). The confirmed ORR in HER2-positive pts was 36.4% (8/22; 2 CR and 6 PR; 90% CI, 19.6–56.1), indicating statistically significant improvement in ORR (P = 0.01). The DCR, median (m) PFS, mOS were 81.8% (95% CI, 59.7–94.8), 4.4 months (mo) (95% CI, 2.8–8.3), 7.1 mo (95% CI, 4.7–14.6), respectively. In addition, encouraging efficacy were seen even in HER2-low pts; ORR, DCR, mPFS, and mOS were 12.5% (1/8; 1 PR; 95% CI, 0.3–52.7), 75.0% (95% CI, 34.9–96.8), 4.2 mo (95% CI, 1.3–6.2), and 8.9 mo (95% CI, 3.0–12.8), respectively. In the safety analysis set (n = 32), TEAEs of > = grade (G) 3 occurred in 81.3% (26/32); the common TEAEs were anemia (53.1%), neutropenia (31.3%), and leukopenia (31.3%). TEAEs leading to drug discontinuation occurred in 8 pts (25.0%). Eight pts (25.0%) had interstitial lung disease (ILD; G1/G2/G3/G5 were 3/1/2/2) not adjudicated by an independent committee. Conclusions: T-DXd showed promising activity in pts with HER2-expressing BTCs. Although the safety profile was generally consistent with other T-DXd studies, ILD, an important identified risk of T-DXd, requires more careful monitoring and intervention. These results support further exploration of T-DXd in this patient population. Clinical trial information: JMA-IIA00423.

TPS627 Background: Pancreatic cancer is one of the most dismal cancers with few effective drugs. Both FOLFIRINOX (FFX) and gemcitabine plus nab-paclitaxel (GnP) showed superiority in overall survival (OS) to gemcitabine in phase III studies and became the standard of care for first-line chemotherapy. However, to date, there is no prospective randomized controlled studies comparing FFX and GnP. In addition, the original FFX has the problems of high toxicity and complicated administration, and we have been developing modified FFX with dose reduction of irinotecan and without bolus fluorouracil and S-IROX, which replaces continuous intravenous fluorouracil with orally administered fluoropyrimidine of S-1. The modified FFX showed median OS of 11.2months [95% confidence interval (CI), 9.0-not calculated] as good as the original FFX in a phase II study, and the S-IROX showed a high objective response rate (ORR) of 57.1% (95% CI, 34.0–78.2%) in a phase I study. This phase II/III study aims to confirm the superiority of modified FFX and S-IROX to GnP in metastatic or recurrent pancreatic cancer. Methods: The main eligibility criteria are metastatic or recurrent pancreatic cancer, histologically diagnosed as adenocarcinoma or adenosquamous carcinoma, no prior chemotherapy for pancreatic cancer, Eastern Cooperative Oncology Group Performance Status 0 or 1, and age 20-75 years old. Enrolled patients are randomized 1:1:1 to GnP, modified FFX, or S-IROX. GnP is consisted of nab-paclitaxel (125 mg/m2) and gemcitabine (1000 mg/m2) on days 1, 8, and 15, every 4 weeks, modified FFX is consisted of oxaliplatin (85 mg/m2), irinotecan (150 mg/m2), l-leucovorin (200 mg/m2), and fluorouracil (2400 mg/m2, 46-hour continuous infusion), every 2 weeks, and S-IROX is consisted of oxaliplatin (85 mg/m2), irinotecan (150 mg/m2) and S-1 (80 mg/m2, days 1-7), every 2 weeks. All regimens are administered until disease progression or unacceptable toxicity. The primary endpoint of the phase II part is the ORR to S-IROX with the null hypothesis of a threshold ORR of less than 20%, which decide whether to proceed to the phase III part in three arms or two arms (GnP and modified FFX). The primary endpoint of the phase III part is OS, and secondary endpoints are progression-free survival, ORR, incidence of adverse events (AEs) and serious AEs, and dose intensity. We calculated a sample of 732 patients to maintain 80% power at a one-sided alpha error of 2.5% in each comparison, and the hazard ratios of modified FFX and S-IROX versus GnP were estimated at 0.73 each. The study started patient accrual in April 2019 and 349 patients have been enrolled as of September 2021. Clinical trial registry: jRCTs031190009. Clinical trial information: jRCTs031190009.

280 Background: Combination of ramucirumab (RAM) + weekly paclitaxel (PTX) is recommended as a standard second-line therapy for unresectable or recurrent gastric cancer (GC). A recent phase II trial evaluating nab-PTX and RAM combination showed that nab-PTX+RAM is promising efficacy and tolerability as well as PTX+RAM. In subgroup analysis of another phase III trial (ABSOLUTE) comparing different nab-PTX scheduling with PTX, weekly nab-PTX was especially effective for the patients with peritoneal dissemination compared to PTX without RAM combination. Therefore, we hypothesized that nab-PTX+RAM would be more effective than PTX+RAM for patients with peritoneal dissemination. Methods: The P-SELECT trial (WJOG10617G) is an open-label randomized phase II study evaluating the safety and efficacy of PTX+RAM and nab-PTX+RAM in GC patients with peritoneal metastasis. Key eligibility criteria were: 1) histologically proven adenocarcinoma, 2) unresectable or recurrent gastric cancer, 3) peritoneal dissemination, 4) intolerance or refractory to first-line therapy including fluoropyrimidines, 5) PS 0–2. Peritoneal dissemination was confirmed by either contrast enema/enterography, CT scan, clinical signs, or operative findings (including exploratory laparoscopy). The primary endpoint was overall survival (OS), and the secondary endpoints were progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), ascites control rate, safety, and neuropathy-specific quality of life. 105 subjects were required to maintain the power of ≥70% expecting the hazard ratio (HR) of 0.90 in OS. The study was conducted in 58 centers of the West Japan Oncology Group. Results: A total of 105 patients (median age 67; M:F 66:39) were randomized (53 patients in PTX+RAM and 52 in nab-PTX+RAM). Moderate and massive amount of ascites was observed in 39.0% of patients. Median OS was 8.1 months in PTX+RAM and 7.2 months in nab-PTX+RAM (HR 1.04, 95% confidence interval [CI] 0.67–1.61, P = 0.63). Median PFS was 5.1 months in PTX+RAM and 3.9 months in nab-PTX+RAM (HR 1.04, 95% CI 0.69–1.56, P = 0.89). The ORR and DCR for PTX+RAM and nab-PTX+RAM were 20.7% vs. 20.0% (P = 0.99) and 77.4% vs. 63.5% (P = 0.15), respectively. The ascites control rate was 86.1% in PTX+RAM and 70.3% in nab-PTX+RAM (P = 0.07). The incidence of grade 3/4 neuropathy was higher in nab-PTX+RAM (7.5% vs 17.6%, P = 0.14), whereas there was no difference in neuropathy-specific quality of life between the two groups. The incidence of febrile neutropenia was higher in PTX+RAM (11.3% vs 5.9%, P = 0.49). Conclusions: The potential difference in efficacies between nab-PTX+RAM and PTX+RAM was not shown in advanced gastric cancer with peritoneal dissemination. The results of the pre-planned translational research will be available soon. Clinical trial information: jRCTs031180022.

301 Background: JCOG1113 is a randomized phase III trial to confirm the non-inferiority of gemcitabine (GEM) plus S-1 (GS) compared with GEM plus cisplatin (GC) regarding overall survival (OS) in patients with advanced biliary tract cancer (BTC). Although the non-inferiority of GS to GC was demonstrated, the difference in the nature of tumor shrinkage effects between GC and GS is not clear. Early tumor shrinkage (ETS) and depth of response (DpR) are considered as on-treatment markers that reflect the anti-tumor effect to chemotherapy and have been reported to be associated with survival in metastatic colorectal cancer. However, there are few studies assessing ETS or DpR in advanced BTC. Therefore, we evaluated the association between ETS, DpR, and clinical outcomes in JCOG1113. Methods: We conducted an exploratory analysis of JCOG1113, which included chemotherapy-naïve patients with recurrent or unresectable BTC. ETS was defined as tumor reduction in the sum of the longest diameters of the target lesions at week 6 when compared with that at baseline. DpR was defined as the maximum tumor shrinkage observed until 12 weeks from enrollment. Survival curves were estimated using the Kaplan–Meier method. Progression-free survival (PFS) and OS for ETS and DpR were estimated from week 6 and 12 (landmarks) after enrollment, respectively. Multivariable analyses for PFS and OS, adjusted for baseline factors, were performed using a stratified Cox regression model. Results: Of the 354 registered patients in JCOG1113, 277 patients in the ETS group and 230 patients in the DpR group were included in this study. Seventy-seven patients (27.8%) achieved ETS ≥ 20% (ETS high group) and 52 patients (22.6%) achieved DpR ≥ 40% (DpR high group). The proportion of ETS high group (GC, 25.4%; GS, 30.4%) and DpR high group (GC, 21.2%; GS, 24.1%) was similar between the arms. The patient characteristics of ETS high group were not different between GC and GS. The hazard ratio (HR) of the ETS high group compared with the ETS low group for PFS and OS was 0.76 (95% confidence interval [CI] 0.58–1.00) and 0.80 (95% CI 0.60–1.07), respectively. The impact of ETS was higher in GC (HR 0.64, 95% CI 0.43–0.95) than GS (HR 0.88, 95% CI 0.60–1.28) in PFS. The HR of DpR high group compared with DpR low group for PFS and OS was 0.75 (95% CI 0.55–1.03) and 0.79 (95% CI 0.57–1.09), respectively. The impact of DpR was higher in GC (HR 0.63, 95% CI 0.40–0.998) than GS (HR 0.88, 95% CI 0.57–1.37) in PFS. ETS and DpR were significantly associated with both PFS and OS in the multivariable analyses. Conclusions: ETS and DpR may be useful as on-treatment markers associated with PFS and OS in patients with advanced BTC, especially in those treated with GC. Clinical trial information: UMIN000010667.

TPS4654 Background: Biliary tract cancer (BTC) is one of the most lethal cancers with limited treatment options. Early clinical trials showed a hint of activity of HER2 blockade for HER2 positive BTC, the prevalence of which was reported to be from 5% to 20%. Trastuzumab deruxtecan (DS-8201) is an antibody-drug conjugate composed of an anti-HER2 antibody, cleavable terapeptide-based linker, and a topoisomerase I inhibitor, which showed durable response in HER2 positive breast cancer as well as in a wide spectrum of cancer subtypes in a phase I study. In addition, preclinical research demonstrated the effectiveness of trastuzumab deruxtecan for HER2 positive BTC patient derived xenograft model. This phase II study is being conducted to evaluate the efficacy and safety of trastuzumab deruxtecan for HER2 positive BTC. Methods: The main inclusion criteria are unresectable or recurrent BTC, histologically diagnosed as adenocarcinoma or adenosquamous carcinoma, confirmed HER2-expressing status by central pathological examination, refractory or intolerant to treatment including gemcitabine, and adequate organ function. Patients are registered and receive 5.4 mg/kg trastuzumab deruxtecan every 3 weeks until disease progression or unacceptable toxicities. Primary endpoint is the overall response rate (ORR) in HER2 positive (defined as IHC3+, or IHC2+/ISH+; ISH+ defined as HER2/ CEP17 ≥2.0) patients by central imaging review. The ORR in all HER2-expressing patients (including HER2 low expressing defined as IHC/ISH status of 0/+, 1+/-, 1+/+, or 2+/-), progression-free survival, overall survival, and incidence of adverse events are assessed as secondary endpoints. Thirty-two patients will be enrolled, including 24 with HER2 positive BTC as primary cohort and 8 with HER2 low expressing BTC. The study has 80% power for primary endpoint in HER2 positive BTC patients, with one-sided alpha error of 5%; threshold ORR of 15% and expected ORR of 40%. Pharmacokinetics and circulating tumor DNA analyses serially are performed. The study was initiated in May 2019 with enrollment ongoing. A total of 15 patients were enrolled as of January 2020. Funding: Japan Agency for Medical Research and Development, and Daiichi Sankyo. Clinical trial information: JMA-IIA00423 .

647 Background: Pancreatic adenosquamous carcinoma (PASC) is a rare variant of pancreatic ductal adenocarcinoma (PDAC). Although unresectable or recurrent PASC is usually treated by systemic chemotherapy, there are few reports which show the efficacy of chemotherapy. The aim of this study was to evaluate the efficacy of chemotherapy for patients (pts) with unresectable or recurrent PASC. Methods: We collected data retrospectively from 24 Japanese institutions. The selection criteria were as follows: 1) histologically or cytologically proven PASC (non-surgical specimens were eligible if squamous cell carcinoma (SCC) was detected), 2) unresectable or recurrent disease treated with 1st line chemotherapy between April 2001 and December 2017. Results: This study included 138 pts with median age of 66 years (range: 36-85). About 60% of pts were diagnosed with biopsy and only SCC was detected in 13.0% of pts. Median overall survival (mOS) was 6.7 months (M), median progression free survival (mPFS) was 2.8 M, and the 1-year survival rate (1YSR) was 26.7%. For the 102 metastatic or distal recurrent pts with PS of 0-1, patient characteristics were as follows: ≥76 years old, 9 (8.8%); PS of 0, 39 (38.2%); number of metastatic sites ≥2, 25 (24.5%). The treatment efficacies (The objective response rates(%)/mPFS(M)/mOS(M)/1YSR(%)) of the 5 major regimens were Gemcitabine(GEM) (n=45, 4.4%/2.2M/4.8M/28.1%), GEM+nab-PTX (n=24, 29.2%/2.9M/7.6M/23.1%), GEM+S-1 (n=9, 11.1%/5.1M/9.9M/25.4%), FOLFIRINOX (n=7, 14.3%/2.5M/7.5M/14.3%), and S-1 (n=7; 28.6%/2.6M/5.0M/28.6%), respectively. One patient with liver metastasis underwent conversion surgery after GEM+nab-PTX and achieved long survival. CRP ≥3.0mg/dl, CA19-9 ≥1000 U/ml, residual primary site, and monotherapy had a significant correlation with poor survival in multivariate analysis. Conclusions: Although combination chemotherapy regimens such as FOLFIRINOX and GEM+nab-PTX are now available, the prognosis of metastatic PASC remains poor. Development of more effective treatment options is required.

306 Background: This phase 1 study evaluated the safety and efficacy of the immune checkpoint inhibitor nivolumab (monotherapy or combined with chemotherapy) in Japanese patients with biliary tract cancer (BTC). Methods: In the monotherapy cohort (N = 30), patients with unresectable/recurrent BTC refractory or intolerant to gemcitabine-based treatment regimens received nivolumab monotherapy (240 mg, 2-week intervals). In the combined therapy cohort (N = 30), chemonaïve patients with unresectable/recurrent BTC received nivolumab (240 mg, 2-week intervals) plus cisplatin-gemcitabine chemotherapy. The primary objective was tolerability and safety. Secondary efficacy endpoints included overall survival (OS), progression-free survival (PFS) and objective response rate (ORR) (central assessment). Results: The most frequently reported nivolumab-related adverse events were decreased appetite (5/30, 17%), malaise (4/30, 13%), and pruritus (4/30, 13%) in the monotherapy cohort, and malaise (8/30, 27%) and decreased appetite (7/30, 23%) in the combined therapy cohort. Median duration of follow-up for efficacy (Table) was 5.1 months (mo; monotherapy cohort) and 8.2 mo (combined therapy cohort). In the monotherapy cohort, median OS and median PFS were longer in patients with programmed death-ligand 1 (PD-L1) ≥ 1% (including the patient who responded) than in those with PD-L1 < 1% (Table). In the combined therapy cohort, the ORR was higher, but median OS and median PFS were lower, in patients with PD-L1 ≥ 1% than in those with PD-L1 < 1% (Table). Conclusions: Nivolumab was well tolerated, with a manageable safety profile and signs of clinical activity, in this phase 1 study in patients with unresectable/recurrent BTC. PD-L1 expression status may predict clinical activity of nivolumab in advanced BTC. Clinical trial information: JapicCTI-153098. [Table: see text]

2519Background: The uptake of amino acids is essential for cancer growth. The L-type amino acid transporter 1 (LAT1) is overexpressed in various cancers, and the LAT1-mediated uptake of plasma-free...

419 Background: Uptake of amino acids is essential for cancer growth. L-type amino acid transporter-1 (LAT-1) is overexpressed in various cancers, and uptake of LAT-1 substrate amino acids is known to have a critical role in cancer growth. JPH203 is a novel, selective, LAT-1 inhibitor. A first-in-human phase I study of JPH203 was designed to determine the safety, maximum-tolerated dose (MTD) and recommended dose. This study included evaluation of the anti-tumor effect, pharmacokinetics, and pharmacodynamics of JPH203 and analyzed plasma free amino acids. Methods: JPH203 was administered intravenously for 7 days followed by 21 days’ rest at planned doses ranging from 12 to 110 mg/m2 in patients with advanced solid tumors refractory to standard therapy. Before starting this schedule, we confirmed safety of a single dose of JPH203. Dose-limiting toxicity was evaluated during the first cycle, using a 3+3 design. Results: 17 patients were enrolled from January 2015 to August 2016. One patient was discontinued after a single dose of JPH203 because of tumor progression. Dosage was escalated up to 85 mg/m2. Grade 3 liver dysfunction occurred in 1 of 6 patients at 60 mg/m2 and in the first patient at 85 mg/m2. Therefore, it was determined that MTD was 60 mg/m2. Common treatment-related adverse events were increased ALT/AST, malaise, nausea, hypertension and fever of Grade 1 or 2. Partial response was achieved in a patient with biliary tract cancer (BTC) who continued JPH203 for two years without progression. Disease control (PR+SD) was observed in 3 of 5 patients with BTC and 2 of 6 with colorectal cancer. LAT-1 substrate amino acids and branched chain amino acids including LAT-1 substrate amino acids were higher in patients with BTC than in those with other cancers. All patients with disease control had a body mass index more than the median of 20.5 kg/m2. In exploratory analysis, longer survival was achieved in patients with high inhibition of uptake of LAT-1 substrate amino acids, compared with patients with low inhibition of uptake. Conclusions: JPH203 was well tolerated, resulting in promise against BTC. This phase I study suggested that LAT-1 could be targeted in treatment for advanced BTC, because LAT-1 substrate amino acids in plasma tended to remain high. Clinical trial information: UMIN000016546.

3573Background: We initiated a nationwide screening project in Japan to detect rare cancer-related genome alterations in CRC (GI-SCREEN 2013-01-CRC) or non-CRC GI cancer and to facilitate the enrol...

407 Background: In Japan, indication of FOLFIRINOX for unresectable and recurrent pancreatic cancer was approved in 2013. Because clinical data of FOLFIRINOX in Japanese patients based on only one exploratory trial is limited, this observational study was conducted to survey practical use of FOLFIRINOX and to evaluate incidences of adverse events in Japanese patients. Methods: The subjects were patients with unresectable or recurrent pancreatic cancer who received FOLFIRINOX therapy during one year from Dec. 20, 2013 (approval date of this study). All the subjects were registered and their clinical data were sent to the data center. In this preliminary report, we analyzed patients’ characteristics related to serious adverse event (SAE). This study was approved by the IRB in each institution. Results: Four hundred patients (pts) were registered from 27 institutions in Japan. Median age was 63 years (range 27-80). Sixty-four percent (n = 254) had no prior treatment and 254 pts (60%) had distant metastatic lesions. The UGT1A1 genotype was wild-type in 56.8% of the subjects, heterozygous (*1/*6, *1/*28) in 39.3%, and homozygous (*6/*6, *6/*28, *28/*28) in 3.9%. One hundred forty-one SAEs in 115 pts (28.8％) were reported until Aug. 10, 2015. Most common SAEs were febrile neutropenia (n = 26), neutrophil count decreased (n = 26), anorexia (n = 21) and biliary tract infection (n = 18). Of these 141 events, five events were results in death. The proportion of patients who met the inclusion criteria (as follows: ECOG PS of 0 or 1; age 20-75 years; adequate hematological, liver and renal functions) used in the phase II trial of FOLFIRINOX for Japanese patients was significantly lower in the subjects with SAEs than those without SAE (60.5% vs. 72.4%, p = 0.023). Four of the 5 pts who resulted in death did not fulfill the inclusion criteria; C-reactive protein in 4, platelet count in 1 and hemoglobin in 1. Conclusions: This is a first report to evaluate the safety profile of FOLFIRINOX in Japanese pancreatic cancer patients. These data highlight the importance of patient selection for FOLFIRINOX. The final safety and efficacy results of this study will be reported at the coming meeting. Clinical trial information: UMIN000014658.

2544 Background: TAS-114 is a first-in-class oral deoxyuridine triphosphatase inhibitor, which acts as a modulator of the pyrimidine nucleotide metabolic pathway. We are conducting a first combinat...