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4527 Background: Nivolumab (Nivo) demonstrated survival benefit in previously treated gastric cancer (GC) patients (pts), with a response rate (RR) of 11% and a disease control rate (DCR) of 40% (Kang YK, et al. Lancet 2017). There are few real-world data of Nivo and its predictive markers are needed in GC. It has been demonstrated that some tumors grow rapidly after Nivo treatment, but the proportion is uncertain. Methods: DELIVER trial was a prospective, multicenter, observational/translational study which assessed pts with advanced GC treated with Nivo alone and ECOG Performance Status (PS) 0-2 (UMIN000030850). The aims were to evaluate the efficacy and safety of Nivo in real world, and to discover novel host-related immune-biomarkers (gut microbiome, genetic polymorphism, gene expression, and metabolome) using fecal and blood samples which were collected before and after Nivo treatment. The RR, DCR, progression-free survival, overall survival, and tumor growth rate (TGR) were estimated as the efficacy. The response was evaluated by first imaging based on RECIST version 1.1. The TGR was calculated as a percentage increase in tumor volume during 1 month (Champiat et al. Clin Cancer Res 2017). Results: A total of 501 pts was enrolled in this study from Mar 2018 to Aug 2019, and 487 pts were evaluable for analysis (median age 70-y, 71% male, ECOG PS0/1/2 42%/44%/14%, tub/por/sig 45%/41%/5%, 21% HER2-pos, 42% pts with ascites). The DCR was 39.2% (95%CI 34.9-43.7) in evaluable pts. In 282 pts with measurable lesions, the RR was 6.7% (95%CI 4.1-10.3) and DCR was 36.5%. Sub-analysis by patient background indicated that DCR was 41% for PS0, 42% for PS1, and 24% for PS2. In addition, the DCR was lower in pts with ascites compared to those without ascites (28.6% vs. 47.0%, p= 0.005). The TGR decreased after introduction of Nivo in 124 (56.6%) of 219 evaluable pts for TGR; however, 20.5% pts were identified as experiencing hyper-progressive disease (HPD) which was defined as a ≥2-fold increase of the TGR before and after Nivo. When defining HPD as a ≥2-fold increase of tumor growth kinetics ratio and 50% increase of tumor burden, 9.6% pts experienced it. Conclusions: The real-word data of the large observational trial showed a comparable DCR to that of clinical trial in advanced GC treated with Nivo. This trial revealed the tumor behavior and some pts who experienced rapid tumor growth after Nivo treatment in clinical practice; biomarkers for HPD and the definition should be established. Clinical trial information: UMIN000030850 .

113 Background: BBP has been recognized as one of the standard 2nd-line treatment strategy for pts with mCRC based on the ML18147 trial. However, this trial excluded pts with disease progression < 3 months in the 1st-line BEV-containing chemotherapy. Methods: The subjects were mCRC pts who received the 2nd-line chemotherapy after experiencing disease progression < 100 days in the 1st-line BEV-containing chemotherapy between Apr 2010 and Dec 2016. This multi-institutional retrospective study compared the efficacy and safety between the 2nd-line chemotherapy with BEV (BBP) and without BEV (non-BBP), adjusting ECOG PS, WBC, ALP, number of metastatic sites, RAS status, and sidedness using Cox proportional hazard model. Results: 61 pts were evaluated. Patients' backgrounds were numerically different between BBP (n = 36) and non-BBP (n = 25), such as PS (0-1/2≤/unknown: 89/8/3 and 56/40/4%) and RASstatus (wild/mutant/unknown: 28/56/16 and 76/16/8%). There were no significant differences in age (median: 59 and 57), sex (male/female: 53/47 and 32/68%), tumor location (right/left: 44/56 and 40/60%), disease status (stage IV/recurrence: 67/33 and 84/16%), number of metastatic sites (1/2≤: 33/67 and 20/80%), the 1st-line regimens (oxaliplatin-based/irinotecan-based: 83/17 and 96/4%) between two arms. The 2nd-line chemotherapy regimens with EGFR antibody-containing/cytotoxic alone were 64/36% in non-BBP, respectively. The response rates were 5.9 and 8.7% in BBP and non-BBP. Median PFS were 3.7 and 2.8 months (HR 0.83, 95%CI 0.49-1.41, p = 0.486; adjusted HR 0.97, 95%CI 0.48-1.96, p = 0.932), respectively. The proportions of pts who received subsequent chemotherapy were 58 and 32% (p = 0.068). Median OS were 7.6 and 5.4 months (HR 0.70, 95%CI 0.41-1.19, p = 0.193; adjusted HR 0.65, 95%CI 0.34-1.25, p = 0.195). Common grade 3-4 adverse events (AEs) were neutropenia (11/24%) and anemia (3/16%), and other AEs were similar between two arms. Conclusions: The 2nd-line chemotherapy for pts with early progression in the 1st-line BEV-containing chemotherapy showed poor outcomes regardless of strategy.

121 Background: We have conducted the multicenter, phase Ib/II study to assess the activity and safety of biweekly Trifluridine/tipiracil (FTD/TPI) plus bevacizumab (BEV) combination for pts with metastatic colorectal cancer (mCRC) who were refractory or intolerant to standard therapies, and the primary endpoint of investigator assessed progression-free survival rate at 16 weeks (16w-PFS) was met [Kotaka M, ASCO-GI 2018]. We show longer follow-up data from this prospective study. Methods: Patients with unresectable mCRC; refractory or intolerant to standard chemotherapies were enrolled. Phase Ib part is designed to determine the recommended phase II dose (RP2D), and the treatment was determined as biweekly FTD/TPI (70mg/m2/day on day 1-5, every 2 weeks) with BEV (5mg/kg, every 2 weeks). The primary endpoint in phase II part was a 16w-PFS with a hypothesis of 15% considered unacceptable and 38.7% deemed promising. Given a one-sided α of 0.025 and statistical power of 90%, a minimum of 40 pts were required for phase II part. This trial registered in University Hospital Medical Information Network, number UMIN000029198. Results: From October 2017 to January 2018, totally 46 pts were enrolled. Nine patients (20.5 %) received regorafenib before enrollment. Of the 44 eligible pts, 16w-PFS rate was 40.9 %. With a median follow up of 15.36 months (range, 2.79-16.93), median PFS was 4.29 months (95% CI: 2.54 to 5.83), median TTF was 4.16 months (95% CI: 2.39 to 5.82), and median OS was 10.86 months (95% CI:8.32 to 13.68), respectively. Disease control rate was 59.1 % (95%CI: 43.3 to 73.7 %). Patients received the study treatment for a median of 6.5 cycles (range, 1 to 24). The median relative dose intensity of FTD/TPI and BEV was 80.9% (range: 44.0 to 100%), 81.5% (range: 50.0 to 100%), respectively. Common grade 3 or higher adverse events were hypertension (40.9%), neutropenia (11.4 %) and leucopenia (11.4 %). Conclusions: An update analysis confirmed that biweekly FTD/TPI plus BEV showed promising anti-tumor effect with acceptable less toxicities, and might be one of the treatment options for patients with heavily treated mCRC. Clinical trial information: UMIN000029198.

201 Background: The WJOG 6210G trial demonstrated a similar efficacy between Pani and Bev arms at 2nd-line setting in pts with KRAS exon2 wild-type mCRC (Shitara K, et al, Cancer Sci 2016). The exploratory analyses of clinical trials evaluating 1st-line chemotherapy for mCRC have shown significant associations of ETS and DpR with prognosis; however, there is few data in 2nd-line treatment. We investigated whether ETS and DpR are associated with clinical outcomes in mCRC pts treated with 2nd-line treatment using the data of WJOG 6210G trial. Methods: ETS was defined as tumor reduction of 20% at week 8 compared to baseline in the sum of longest diameters of target lesions according to the RECIST criteria. DpR was defined as the percentage of maximum tumor shrinkage of target lesions. Fisher’s exact test and t-test were used to compare ETS and DpR between Pani and Bev arms. A Cox regression model was used to evaluate associations between ETS and progression-free survival (PFS), and overall survival (OS). The association of DpR with PFS and OS was analyzed using Spearman’s rank correlation coefficient. Results: Eighty-seven pts were evaluable for ETS and DpR (Pani, n = 41; Bev, n = 46) among 121 pts enrolled in the WJOG6210G. Pts in the Pani arm had a higher ETS rate (39.0 % vs. 8.7 %, p < 0.001) and greater DpR [median: 23.7 % (range: -49.0 to 100) vs. 0 % (range: -40.7 to 61.5), p < 0.001] than pts in the Bev arm. Pts with ETS achieved longer PFS [median: 10.5 vs. 5.4 m, HR: 0.40 (95% CI: 0.20-0.80), p = 0.009] and OS [median: 22.3 vs. 14.5 m, HR: 0.49 (95% CI: 0.23-0.98), p = 0.044] than pts without ETS in the Pani arm. Similarly, the Bev arm pts with ETS had longer PFS [median: 17.1 vs. 5.6 m, HR: 0.078 (95% CI: 0.004-0.38), p = 0.0002] and OS [median: 30.9 vs. 13.2 m, HR: 0.35 (95% CI: 0.083-0.99), p = 0.048]. There were moderately linear correlations of DpR with PFS and OS in both Pani (PFS: r = 0.75, p < 0.001; OS: r = 0.60, p < 0.001) and Bev arms (PFS: r = 0.68, p < 0.001; OS: r = 0.44, p = 0.002). Conclusions: ETS and DpR were significantly associated with PFS and OS in mCRC pts treated with 2nd-line FOLFIRI in combination with Pani or Bev. Clinical trial information: UMIN000031621.

431 Background: FGFR2 and HER2 proteins are well-known molecular targets for cancer therapy, and there are emerging attractive protein-targeted agents such as second generation antibody-drug conjugates. However, there are still limited information about the expression status of FGFR2 and HER2 in gastrointestinal cancer and their relationship to patient background with cancer. In this study, expression status of FGFR2 and HER2 in advanced/metastatic gastric cancer (GC) and colorectal cancer (CRC) were prospectively analyzed in clinical setting. Moreover, eligible patients for the clinical trials of DS-1123 or DS-8201, which are FGFR2- or HER2-targeting anti-cancer agent respectively, were screened. Methods: Patients with advanced/metastatic GC, gastroesophageal junctional cancer (GEJ), and CRC were enrolled. Expression status of FGFR2 and HER2 were prospectively analyzed by IHC and/or FISH. Results: A total of 565 patients (GC; 160, GEJ; 16, CRC; 389) have been enrolled in this study from November 2016 to June 2018. FGFR2 expression (IHC 1+~3+) was observed in 24%, 44%, and 3% of GC, GEJ, and CRC respectively. HER2 expression (IHC 2+, 3+) was observed in 24%, 44%, and 17% of GC, GEJ, and CRC respectively. Expression levels of FGFR2 and HER2 seemed to be not correlated with each other in all 3 types of cancer. Distributions of expression level of FGFR2 or HER2 were slightly different among the histological types in GC. In CRC, distribution of HER2 expression level was also slightly different among the histological types and HER2 expression level was higher in KRAS/NRAS wild type compared to KRAS/NRAS mutant. There was no association between HER2 expression level and primary tumor sites in patients with CRC. Slight concordance of HER2 expression was observed between IHC and FISH in CRC. A total of 7 patients have been enrolled in clinical trials of DS-1123 or DS-8201 through this study based on the analysis findings. Conclusions: This study showed insights into the expression status of FGFR2 and HER2 in GC and CRC as a large-scale prospective analysis. Seven patients who had no standard therapy could access exploratory new drug based on targetable agents through this study. Clinical trial information: 163380.

661 Background: Gemcitabine plus nab-paclitaxel (GnP) and FOLFIRINOX (FFX) have been established as standard first-line combination chemotherapy (CTx) for patients with metastatic pancreatic cancer (MPC). However, the efficacy of second-line CTx and the significance of combination CTx in clinical practice are unclear. We therefore investigated the efficacy of second-line CTx in patients with MPC. Methods: Data were collected from CTx-naive MPC patients treated with first-line combination CTx at 14 hospitals in the Kyushu area of Japan from December 2013 to June 2018. The median overall survival (mOS) from second-line treatment was compared between patients who received second-line CTx (CT group) and those who received best supportive care (BSC group). Furthermore, in the CT group, the mOS was compared between the patients who received combination CTx and those who received mono-CTx. To control potential bias in the selection of second-line treatment, we also conducted a propensity score-adjusted analysis. Results: A total of 255 patients received GnP or FFX as first-line CTx. Of these, there were 156 (61%) in the CT group and 77 (30%) in the BSC group. The number of patients who received FFX/GnP as first-line CTx was 79 (51%)/77 (49%) in the CT group and 15 (20%)/62 (80%) in the BSC group, respectively (P < 0.01). The mOS in the CT group was significantly longer than that in the BSC group (5.2 vs. 2.7 months; hazard ratio [HR] 0.42; 95% confidence interval [CI] 0.31-0.57; p < 0.01 and 5.2 vs. 2.6 months; adjusted HR 0.39; 95% CI 0.28-0.55; p < 0.01). In the CT group, 89 (57%) patients received combination CTx, and 67 (43%) received mono-CTx. There was no significant difference in the mOS between the combination CTx and mono-CTx patients (5.5 vs. 4.4 months; HR 0.88; 95% CI 0.62-1.26; p = 0.88 and 5.6 vs. 4.4 months; adjusted HR 0.85; 95% CI 0.56-1.30; p = 0.47). Conclusions: Among patients with MPC receiving second-line treatment, the CT group had a significantly longer mOS than the BSC group, but combination CTx conferred no improvement in the survival duration compared with mono-CTx.

226 Background: The WJOG 6210G trial demonstrated a similar efficacy between FOLFIRI plus Bev and FOLFIRI plus panitumumab (Pani) at 2nd-line treatment in pts with KRAS exon2 wild-type mCRC (Shitara K, et al, Cancer Sci 2016). Recently, angiogenesis biomarker studies of clinical trials have identified VEGF-D as a potential predictor for angiogenesis inhibitors in mCRC. We evaluated whether VEGF-D level are associated with clinical outcomes in the WJOG 6210G trial. Methods: Plasma samples which were collected at pre-treatment were analyzed. VEGF-D level in plasma was measured by means of magnetic bead panel (G & G SCIENCE CO., LTD.). The correlations of VEGF-D level with progression-free survival (PFS) and overall survival (OS) were evaluated by cox regression analyses. Results: Ninety-nine pts were evaluable for VEGF-D level (Bev, n = 51; Pani, n = 48) among 121 pts enrolled in the WJOG6210G. The median VEGF-D level was 441 pg/ml (range 60-1570). VEGF-D level was not affected by the period from last administration of 1st-line Bev to start of 2nd-line treatment. When the median VEGF-D level was adopted as cut-off value, pts with high VEGF-D achieved a shorter PFS and OS than pts with low VEGF-D in the Bev arm [HR: 0.58 (95%CI 0.32-1.07), p = 0.08; HR: 0.62 (95%CI 0.34-1.11), p = 0.10]. In pts with high VEGF-D, the Bev arm tended to have a shorter OS and PFS compared to Pani arm [median: 12.4 m vs. 17.5 m, HR: 1.58 (95%CI 0.87-2.88); median: 4.7 m vs. 5.5 m, HR: 1.31 (95%CI 0.72-2.40)]; whereas, comparable OS and PFS in pts with low VEGF-D [median: 18.9 m vs. 16.5 m, HR: 1.08 (95%CI 0.59-2.01); median: 5.9 m vs. 7.2 m, HR: 1.10 (95%CI 0.62-1.99)]. OS was stratified by VEGF-D level quartile, then OS of Bev arm in each quartile was compared with that of Pani arm (Table). Clinical trial information: UMIN000031621. Conclusions: Our study suggests clinically meaningful association between VEGF-D level and clinical outcomes in mCRC pts treated with 2nd-line FOLFIRI plus Bev. [Table: see text]

105 Background: In the recent years, primary tumor location (PTL) is considered as an important prognostic and predictive factor in first-line treatment of mCRC. Although regorafenib (REG) and trifluridine/tipiracil (TFTD) have been available recently, the prognostic value of PTL in later-line with these agents is not well understood. TFTD improved survival regardless of PTL in the RECOURSE trial, while REG did not show survival benefit in the patients (pts) with rectal cancer in the CORRECT trial. Methods: We retrospectively evaluated pts with mCRC who were registered in a multicenter observational study (the REGOTAS study). The main inclusion criteria were ECOG PS of 0–2, refractory or intolerant to fluoropyrimidines, oxaliplatin, irinotecan, and anti-VEGF and anti-EGFR therapy (if KRAS wild type), and no prior use of REG and TFTD. The impact of PTL on overall survival (OS) were evaluated using Cox proportional hazards models based on baseline characteristics and propensity score matching. Results: A total of 550 pts (223 pts in the REG group, 327 pts in the TFTD group; 122 pts in the right-sided, 428 pts in the left-sided) were included in this study. Although the right-sided pts was significantly shorter OS compared with the left-sided pts by univariate analysis (hazard ratio [HR] 0.79, 95% confidence interval [CI] 0.63-0.99, P = 0.04), multivariate analysis revealed that PTL was not an independent prognostic factor (HR 0.88, 95% CI 0.69-1.1, P = 0.26). The similar results were obtained in each treatment group. In subgroup analysis according to PTL, OS were comparable between REG and TFTD groups regardless of PTL (HR 0.93, 95% CI 0.62-1.39 in the right-sided; HR 1.08, 95% CI 0.83-1.39 in the left-sided [excluding rectum]; and HR 1.01, 95% CI 0.62-1.62 in the rectal cancer pts). These results were similar in sensitivity analysis using propensity score-matching. Conclusions: In the present study, PTL is not a prognostic factor in patient with mCRC treated with either REG or TFTD as later-line. No difference in OS was observed between REG and TFTD groups irrespective of PTL.

Dose modification of chemotherapy for metastatic colorectal cancer (MCRC) is often needed, especially in second-line and later-line treatments due to adverse events of previous treatment and poor patient condition. No study has focused on ramucirumab plus modified dose of FOLFIRI for MCRC, and whether low relative dose intensity (RDI) affects treatment efficacy has not been clarified. MCRC patients who received ramucirumab plus FOLFIRI, which consisted of 150 mg/m2 of irinotecan, at six institutions were retrospectively analyzed. A total of 43 patients were assessed. Median age was 63 years, and 22 patients (51%) were women. Twenty-six patients (60%) were given ramucirumab plus FOLFIRI as second-line therapy, and 17 (40%) as third or later-line. The median relative dose intensity (RDI) of irinotecan was 60.6%, which is lower than that in the pivotal phase 3 study (RAISE), and other agents showed the same trend. Median progression-free survival was 4.8 [95% confidence interval (CI) 3.2–5.7] months for all patients, 5.4 (95% CI 3.5–7.2) months for second-line patients, and 2.8 (95% CI 1.6–5.8) months for third or later-line patients. Median overall survival was 17.3 (95% CI 11.5–22.4) months for all patients. Patients with irinotecan RDI less than 60% showed similar treatment efficacy. Hematological toxicities of grade 3 or worse were observed in 21 patients, but all were manageable. Low RDI did not compromise the treatment efficacy of ramucirumab plus modified FOLFIRI for MCRC patients.

Background Nuclear protein in testis (NUT) carcinoma (NC) is a rare epithelial malignancy characterized by rearrangement of the NUT gene on chromosome 15. If NC is not suspected, it is often diagnosed as other malignancies. We present the case of NC of the nasal cavity that responded to a chemotherapy regimen for Ewing’s sarcoma family of tumors (ESFT). Case presentation A 49-year-old male presented with epistaxis and pain in the left eye. The patient had a tumor in the left nasal cavity at initial visit and it was biopsied. Firstly, the man was diagnosed with ESFT based on a histopathological examination. The tumor markedly responded to standard cytotoxic chemotherapy for ESFT with distant metastasis. After the start of therapy, a chromosomal analysis revealed an atypical translocation in ESFT and additional immunostaining was positive for anti-NUT antibody. Ultimately, the patient was definitively diagnosed with NC. He received multidisciplinary therapy and symptoms were temporarily relieved. However, he died 9 months after the diagnosis of NC. Conclusions When a pathologically undifferentiated tumor is evident along the midline of the body, NC must be included in the differential diagnosis, and immunohistochemical staining or genetic testing/chromosomal analysis needs to be performed.

Purpose: Combination therapy of fosaprepitant, dexamethasone (DEX) and a serotonin (5-HT3) receptor antagonist is a standard antiemetic prophylaxis for patients receiving highly emetogenic chemotherapy (HEC). However, the appropriate dose of DEX has not been established in Japan. This study determined the efficacy and safety of triplet antiemetic prophylaxis in Japanese patients receiving HEC when administered the same doses of DEX as those given in a previous international phase 3 study on this drug. Methods: To assess the efficacy and safety of a sufficient dose of DEX (12 mg on day 1, 8 mg on day 2, 16 mg on days 3 and 4) in combination with intravenous fosaprepitant and granisetron, we prospectively examined patients receiving HEC including cisplatin (≥50 mg/m2). The primary endpoint was to determine the percentage of patients who had achieved a complete response (CR), which was defined as no vomiting and no rescue therapy during the entire treatment course. Results: Between February 2013 and January 2015, 44 patients were enrolled with a median age of 65 years (range, 30–75). There were 34 males (77.3%) in the study. Most of the patients had upper gastrointestinal cancers. The CR rate during the treatment course was 70% (95% confidence interval [CI]: 55%–83%) in the overall phase and 91% (95% CI: 78%–97%) in the acute phase and 70% (95% CI: 55%–83%) in the delayed phase. Appreciable severe toxicities related to the antiemetic therapy were not observed. Conclusions: These results suggest that a sufficient dose of DEX in combination with fosaprepitant and granisetron is optimal as an antiemetic prophylaxis for Japanese patients receiving HEC.

Peripheral sensory neuropathy (PSN) and thrombocytopenia are the main dose-limiting toxicities of oxaliplatin for the treatment of advanced gastric cancer (AGC). Because the risk factors for those toxicities in practice have not been clarified, we conducted this prospective study. AGC patients who received oxaliplatin-based therapy at any of seven institutions participating in the Kyushu Medical Oncology Group were assessed after we obtained written informed consent. A total of 60 patients including 39 males and 21 females were examined. The median age was 66 years. The numbers of patients receiving oxaliplatin as the first, second, or third and later lines of therapy were 39, 16, and 5, respectively. An initial dose of 130, 100, or

FOLFOXIRI plus bevacizumab is considered a standard initial therapy for metastatic colorectal cancer (mCRC). However, few prospective trials have evaluated triplet therapy plus bevacizumab in patients with RAS mutant mCRC. Patients with an age of 20 to 75 years, and unresectable, measurable tumors harboring RAS mutation were given first-line treatment with bevacizumab (5 mg/kg on day 1) plus modified-FOLFOXIRI (irinotecan 150 mg/m2, oxaliplatin 85 mg/m2, levofolinate 200 mg/m2, and fluorouracil 2400 mg/m2 as a 46-h continuous infusion on day 1, repeated every 2 weeks). The primary endpoint was the objective response rate (ORR) as evaluated by an external review board. Progression-free survival (PFS), overall survival, early tumor shrinkage (ETS), depth of response (DpR), and safety were secondary endpoints. Among 64 patients who were enrolled between October 2014 and August 2016, 62 were evaluable for efficacy (right-sided tumors in 27%). ORR and disease control rate were 75.8% (95% confidence interval [CI] 65.1-86.5) and 96.8%, respectively. ETS was 73.8%, and median DpR was 49.2%. Median PFS was 11.5 (95% CI 9.5-14.0) months as of the cut-off date of September 2017. Adverse events of grade 3 or 4 were neutropenia (54%), hypertension (32%), diarrhea (13%), anorexia (11%), peripheral neuropathy (2%), and febrile neutropenia (5%). In conclusion, this prospective trial demonstrated for the first time that FOLFOXIRI plus bevacizumab is an active first-line treatment for patients with RAS mutant mCRC. Modified-FOLFOXIRI plus bevacizumab might become an alternative regimen of triplet chemotherapy for mCRC in Japan.

Background Elderly patients often cannot tolerate the usual combination of two cytotoxic agents. Recently, bevacizumab plus trifluridine/tipiracil (FTD/TPI) was shown to be a good candidate regimen for vulnerable patients. We aimed to assess the efficacy and safety of bevacizumab plus FTD/TPI in elderly patients with metastatic colorectal cancer. Methods Patients aged 70 years or older, with previously untreated unresectable, metastatic colorectal cancer, who were not deemed to be candidates for oxaliplatin-based or irinotecan-based chemotherapy regimens, were included in this trial. The treatment consisted of FTD/TPI (35 mg/m2, twice daily on Days 1–5 and Days 8–12) with bevacizumab (5mg/kg intravenously on Day 1 and 15), administrated every 4 weeks until disease progression. The primary endpoint was progression-free survival (PFS). Based on a previous report, we estimated the expected PFS as 9 months and the lower limit of interest as 5 months. As this research was designed to have a statistical power of 80% and one-sided type I error of 0.10, we calculated that 32 patients were required and planned enrolling 35 patients. The secondary endpoints were response rate (ORR), overall survival (OS), and adverse events (AEs). Results Between 2017 January and 2018 March, 39 patients (17 male; 22 female), with a median age of 77.5 years (range: 70–88), ECOG performance status 0 (79.5%) or 1 (20.5%), and RAS WT/MT/Unknown 23.1/41.0/35.9% were enrolled. The median PFS was 8.0 months (80% CI 6.7–11.2), and the median OS was not reached. The best response was 40.5% (15/37; 95% CI: 24.8–57.9), and the disease control rate was 86.5% (32/37; 95% CI: 71.2–95.5). The most frequently occurring grade 3 or 4 AEs were neutropenia (71.8%), leucopenia (48.7%), hypertension (20.5%), anemia (17.9%), anorexia (12.8%), febrile neutropenia (10.3%), and fatigue (10.3%). No treatment-related deaths occurred. Conclusions In this Phase 2 KSCC 1602 trial of bevacizumab plus FTD/TPI, the primary endpoint of PFS was achieved. This combination therapy showed favorable survival outcomes with an acceptable safety profile for elderly patients with previously untreated metastatic colorectal cancer. Clinical trial identification UMIN000025241. Legal entity responsible for the study Kyushu Study group of Clinical Cancer. Funding Taho Pharmaceutical. Disclosure A. Makiyama: Advisory / Consultancy, Speaker Bureau / Expert testimony: Eli Lily Pharmaceutical; Speaker Bureau / Expert testimony: Chugai Pharmaceutical; Speaker Bureau / Expert testimony: Taiho Pharmaceutical; Speaker Bureau / Expert testimony: Takeda Pharmaceutical. M. Kotaka: Honoraria (self): Yakult Honsya; Honoraria (self): Chugai pharmaceutical. H. Baba: Research grant / Funding (institution): Taiho pharmaceutical; Research grant / Funding (institution): Chugai pharmaceutical. M. Mori: Research grant / Funding (institution): Taiho Pharmaceutical Co, Ltd. All other authors have declared no conflicts of interest.

Extrapulmonary neuroendocrine carcinomas (EPNEC) are rarely observed and are associated with poor outcomes. Based on the clinicopathological similarity, treatment used for small cell lung carcinoma has also been employed for EPNEC, but the response to such therapy has not been well examined. The goal of this study was to investigate amrubicin (AMR) monotherapy as a salvage therapy for EPNEC arising from digestive organs.Patients with EPNEC of the digestive organs who had prior platinum-based chemotherapy and were subsequently treated with AMR between July 2005 and December 2013 at any one of four institutions were retrospectively examined to characterize the safety and efficacy of AMR.Thirteen patients (ten males, three females; median age 64 years) were examined. Primary cancer sites included stomach (n = 6), rectum (n = 3), esophagus (n = 2), liver (n = 1) and pancreas (n = 1). Prior irinotecan- and etoposide-containing chemotherapies were used in ten and six patients, respectively. Median initial dose of AMR was 40 mg/m(2)/day for three consecutive days, and median of treatment cycles was 4 (range 1-9). The objective response rate (ORR) was 38.5%. Median progression-free survival (PFS) and overall survival (OS) were 107 (range 22-275) and 215 days (range 71-535), respectively. Common severe adverse events (grade 3/4) were neutropenia (84.6%) and febrile neutropenia (30.8%). Patient with longer platinum-free interval (90 days) exhibited longer PFS and OS than those with shorter platinum-free interval (190 vs. 63 days and 348 vs. 145 days, respectively).AMR showed evidence of clinical activity and safety when used for the treatment of EPNEC. It might be especially useful for populations with sensitive relapse.

Background: Regorafenib is an oral multikinase inhibitor with a proven survival benefit for metastatic colorectal cancer patients. The KSCC1402/HGCSG1402 study investigated the prophylactic effect of oral dexamethasone (DEX) on regorafenib-related fatigue and/or malaise. Patients and Methods: Patients who progressed after standard chemotherapy were randomized 1: 1 to a DEX group (2 mg/day; days 1–28) with regorafenib or a placebo group with regorafenib. The primary endpoint was the incidence of fatigue and/or malaise, based on version 4.0 of the National Cancer Institute’s CTCAE (Common Terminology Criteria for Adverse Events). One of the secondary endpoints was the in­cidence of fatigue and/or malaise based on the CTCAE assessed by patient-reported outcome (PRO). Results: The incidence of any grade of fatigue and/or malaise assessed by the investigators was 58.8% in the DEX group and 61.1% in the placebo group (p = 0.8101), and that assessed by PRO was 47.2 and 58.3%, respectively (p = 0.3450). The incidence of grade ≥2 fatigue and/or malaise, as assessed by the investigators, was 19.4% for the DEX group and 38.9% for the placebo group (p = 0.0695), and that assessed by PRO was 27.8 and 52.8%, respectively (p = 0.0306). Conclusion: Our results suggest that prophylactic oral DEX is clinically effective in improving regorafenib-related fatigue and/or malaise.

Background/aim Readministration of anti-epidermal growth factor receptor (EGFR) antibody for metastatic colorectal cancer (mCRC) after disease progression remains to be determined. Patients and methods Readministration of anti-EGFR antibody in mCRC patients previously refractory to anti-EGFR antibody was prospectively observed. Results A total of thirteen patients with a median age of 60-years old and an Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1, were enrolled. The median number of previous chemotherapies was 3 (range 2-5). Prior anti-EGFR antibody in combination with cytotoxic drugs was administered in 12 patients. Anti-EGFR antibody readministration regimens were cetuximab/panitumumab plus capecitabine/S-1 (seven patients), panitumumab plus FOLFOX (three patients), cetuximab plus irinotecan (two patients), and panitumumab monotherapy (one patient). Seven patients showed stable disease following readministration and six patients showed progressive disease. The median overall survival (OS) following readministration was 228 days and the median PFS was 102 days. Patients with intervals longer than 90 days between anti-EGFR therapies exhibited more favorable survival than those with intervals shorter than 90 days. Switching of anti-EGFR antibody between treatments was observed to contribute survival. Conclusion Anti-EGFR antibody readministration could show a modest survival benefit in mCRC patients, with the length of therapy interval and switching of antibody being important contributory factors.

Patients with advanced gastric cancer (AGC) are often treated with irinotecan monotherapy as salvage-line therapy. However, the survival benefit of this therapy remains to be elucidated. Medical records of AGC patients who were treated with irinotecan monotherapy as salvage-line treatment in six institutions from 2007 to 2014 were reviewed. A total of 146 patients had prior fluoropyrimidine and taxane therapies, and 75.3% had prior platinum therapy. The median age was 66 (range 27–81) years, and 102 males (69.9%) were included. Performance status (PS) was 0/1/2/3 in 53/70/19/4 patients. Eighty-nine patients (61.0%) had two or more metastatic sites. Irinotecan monotherapy as 3rd-/4th-line therapy was performed in 135/11 (92.5%/7.5%). The median number of administrations was 4 (range 1–62). Forty-six patients (31.5%) required initial dose reduction at the physician’s discretion. The overall response rate was 6.8%, and the disease control rate was 43.1%. The median PFS was 3.19 months [95% confidence interval (CI) 2.30–4.08 months], and the median OS was 6.61 months (95% CI 5.94–7.28 months). Grade 3/4 adverse events were hematological toxicity (46 patients, 31.5%) and non-hematological toxicity (50 patients, 34.2%). Hospitalization due to adverse events was required in 31 patients (21.2%). Patients with relative dose intensity (RDI) less than 80% showed similar survival to those with RDI 80% or higher. Irinotecan monotherapy was relatively safely performed as salvage-line treatment for AGC in Japanese clinical practice. Careful patient selection and intensive modification of the dose of irinotecan might possibly be associated with favorable survival.

Standard therapy for advanced small bowel adenocarcinoma (SBA) has not yet been established. The present study assessed the efficacy and safety of chemotherapy (CT) in association with molecular targeting approaches for SBA. The histories of 33 advanced SBA patients from six different institutions in Japan, who received CT from 2008 to 2016, were retrospectively examined for background, clinical course and outcome. Median patient age was 65 years (range 39–83). Primary tumor was located in the duodenum in 21 patients (67%), the ampulla of Vater in three patients (9%), the jejunum in seven patients (21%) and the ileum in one patient (3%). Histologically, well-to-moderately and poorly differentiated adenocarcinoma were identified in 20 (61%) and nine (27%) patients, respectively. Thirteen patients received a single CT regimen, seven patients received two types of CT regimen, and 13 patients received three or more CT regimens. As first-line CT, modified FOLFOX6, capecitabine plus oxaliplatin, and S-1 plus cisplatin were employed in 13, 1, and 4 patients, respectively. The response rate (RR) and median progression-free survival (PFS) were 25% and 6.0 months, respectively. Median overall survival (OS) was 13.0 months. Nine out of the 33 patients received bevacizumab-containing CT and three received cetuximab-containing CT. Median OS of bevacizumab-containing CT patients was 21.9 months. No unexpected serious adverse events were observed. The analysis indicates that combination CT for advanced SBA is associated with modest efficacy and safety, and bevacizumab-containing CT may contribute to favorable outcome in these patients.

Background Significant efficacy of oxaliplatin-based chemotherapy has been demonstrated for advanced gastric cancer (AGC). However, the appropriate dose of oxaliplatin, and the efficacy and toxicity of administration of oxaliplatin subsequent to cisplatin therapy still remain unclear. Patients and methods In total, 55 patients with AGC that were scheduled to receive oxaliplatin-based chemotherapy were prospectively examined. Results The median age was 67 years and oxaliplatin was administered to 39 (71%) patients as first-line and in 16 (29%) patients as second-line therapy. An initial dose of 130 or 100 mg/m2 of oxaliplatin was administered to 11 and 36 patients, respectively. The overall response rates (ORR) and median progression free survival (mPFS) were 86 and 33%, and 7.2 and 7.8 months, respectively. Compared to 100 mg/m2, the relative dose intensity was significantly lower and severe toxicity tended to increase with oxaliplatin at 130 mg/m2 A total of 10 patients (18%) had a prior cisplatin-based therapy. The ORR of the patients pretreated with cisplatin was 14% and the mPFS was 6.1 months. Conclusion An initial oxaliplatin dose of 130 mg/m2 resulted in a good response, but tended to increase the risk of toxicity. Subsequent oxaliplatin-based therapy after cisplatin exhibited modest efficacy, especially in cases with cisplatin intolerance.

Background GEM plus nab-PTX (GnP) and FOLFIRINOX (FFX) have been shown to improve overall survival for advanced pancreatic cancer patients. However, clinical utility of C-reactive protein/albumin ratio (CAR) as prognostic factor for the patients treated with GnP or FFX remains unclear. We conducted the exploratory analysis to elucidate prognostic impact of CAR using a multicenter retrospective study (the NAPOLEON study) cohort which examined the efficacy and safety of GnP and FFX in clinical practice. Methods Between December 2013 to March 2017, 255 patients with unresectable advanced or recurrent pancreatic cancer who received GnP or FFX as 1st-line chemotherapy at 14 centers participating in the NAPOLEON study were examined. Patient characteristics at the start of 1st and 2nd line chemotherapy including age, gender, ECOG performance status, primary tumor site, disease status, metastatic site, underwent biliary drainage or not, treatment regimen at 1st line chemotherapy, LDH and CAR were analyzed to investigate correlation with prognosis by Cox regression model. The cut-off value of CAR adopted 0.54 based on a previous study. Patients were divided into groups according to CAR level less than 0.54 (CAR-low) and 0.54 or greater (CAR-high). Results Cox regression analysis of OS identified underwent biliary drainage (HR: 1.76, 95%CI: 1.19–2.61), CAR-high (HR: 1.52, 95%CI: 1.05–2.21), and higher LDH level (HR: 2.10, 95%CI: 1.36–3.22) as significant factors at the start of 1st-line chemotherapy. Similarly, Cox regression analysis of OS identified a poor PS (HR: 1.62, 95%CI: 1.07–2.47), a high level of CA19-9 (HR: 2.14, 95%CI: 1.07–4.29) and CAR-high (HR: 2.15, 95%CI: 1.32–3.49) as significant factors at the start of 2nd-line chemotherapy. Eighty-six of 140 patients (82.7%) with CAR-high at the start of 1st-line chemotherapy still remained CAR-high at the start of 2nd-line chemotherapy. Conclusions CAR may be useful prognostic factor at the start of both 1st and 2nd-line treatment. Almost all the patients with CAR-high before 1st line treatment still remained CAR-high after 1st line treatment. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest.

Background FOLFOXIRI plus bevacizumab (bev) is one of preferred 1st-line regimens for RAS mutant metastatic colorectal cancer (mCRC); however, the original dosage is slightly toxic for Japanese patients (pts) due to frequent febrile neutropenia. We have reported that modified (m)-FOLFOXIRI (IRI 150mg/m2, OHP 85mg/m2, levofolinate 200mg/m2, and 5-FU 2400mg/m2 for 46-h continuous, up to 12 cycles followed by maintenance with 5-FU/levofolinate) plus bev has good objective response rate (ORR) of 76% as well as tolerability in Japanese pts with RAS mutant mCRC [Satake H, et al. Oncotarget 2018]. However, the follow-up time was short; therefore, clinical data was immature. Methods The primary endpoint was ORR. Progression-free survival (PFS), overall survival (OS), early tumor shrinkage (ETS), depth of response (DpR), and safety were secondary endpoints. The tumor shrinkage was evaluated every 8 weeks by the external review board. Pre-planned updated analysis was performed in January 2019. Results 62 pts (median 62.5-y old, 92% PS0, 90%/10% for KRAS/NRAS mutations, 27% right-side) were evaluable for efficacy and 63 pts for toxicity. The median cycle of treatment was 15 (range 1-46). Two pts still continued the protocol treatment and 40 (67%) pts received 2nd-line chemotherapy (triplet-regimen 28%, IRI-regimen+bev 23%, FOLFIRI+ramucirumab 15%, FOLFIRI+aflibercept 3%, OHP-regimen 10%, 5-FU+bev 10%, FTD/TPI 10%). Fourteen (23%) pts underwent surgery after protocol treatment. Median PFS was 11.9 (95%CI 9.5-14.0) months, median OS was 31.2 (95%CI 25.8-37.6), ETS was 73.8%, and median DpR was 49.2% (-28.7-100). Sub-analyses in each tumor side showed that ETS, DpR, median OS were 77.3%, 49.6%, 34.0 months in the left-side and 64.7%, 40.2%, 26.2 months in the right-side. No new adverse events were observed. Conclusions Updated analysis of the JACCRO CC-11 trial shows that m-FOLFOXIRI plus bev is a clinically useful regimen as a good option for RAS mutant mCRC.

Background Nivolumab (Nivo) demonstrated survival benefit in previously treated gastric cancer (GC) patients (pts), with a response rate (RR) of 11% and a disease control rate (DCR) of 40% (Kang YK, et al. Lancet 2017). There are few real-world data of Nivo and its predictive markers are needed in GC. It has been demonstrated that the efficacy of anti-PD-1-based immunotherapy was associated with composition of gut microbiome in various types of cancers. Methods This observational/translational study (UMIN000030850) has been enrolling pts with advanced GC treated with Nivo alone and ECOG PS 0-2, up to 500 pts from March 2018. The aims are to evaluate the efficacy and safety of Nivo in real world, and to discover novel immune-related biomarkers (gut microbiome, genetic polymorphism, gene expression, and metabolome in plasma) using fecal and blood samples which are collected before and after treatment. Candidate factors will be explored in first 200 pts and then validated in last 300 pts. Pre-planned interim analysis was performed to evaluate response and biomarkers in first 200 pts. We report the response evaluated by first imaging based on RECIST version 1.1. Results In 198 evaluable pts (median age 70-y, 75% male, ECOG PS0/1/2 47%/39%/14%, 20% HER2-pos, tub/por/sig 47%/38%/6%), DCR was 34.8%. In 124 pts with measurable lesions, RR was 5.6% (95%CI 2.3-11.3): 7 PR, 34 SD, and 78 PD, and DCR was 33.1% (95%CI 24.9-42.1). Tumor growth rate (TGR) was calculated as a percentage increase in tumor volume during 1 month [Champiat et al. Clin Cancer Res 2017] in 105 evaluable pts. The TGR decreased after introduction of Nivo in 58.4% pts; however, 26 (24.8%) pts were identified as experiencing hyperprogressive disease which was defined as a ≥ 2-fold increase of the TGR before and after Nivo. Sub-analysis by patient background indicated that DCR was 38% for PS0, 35% for PS1, and 22% for PS2. In addition, the DCR was lower in pts with factors of signet-ring cell, peritoneal metastasis, or ascites. There was no difference in the DCR according to HER2 status or neutrophil-lymphocyte ratio. Conclusions This interim analysis of the observational trial showed real-world data of Nivo treatment in terms of response for advanced GC for the first time. Clinical trial identification UMIN000030850. Legal entity responsible for the study Japan Clinical Cancer Research Organization. Funding Ono pharmaceutical Co. Ltd. and Bristol-Myers Squibb. Disclosure Y. Sunakawa: Honoraria (self): Bristol-Myers Squibb; Honoraria (self), Research grant / Funding (institution): Taiho Pharmaceutical Co. Ltd.; Honoraria (self), Research grant / Funding (institution): Chugai Pharmaceutical Co. Ltd.; Honoraria (self), Research grant / Funding (institution): Yakult Honsha Co. Ltd.; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Takeda Pharmaceutical Co. Ltd.; Honoraria (self), Research grant / Funding (institution): Merck Serono; Honoraria (self): Bayer Yakuhin Ltd.; Honoraria (self), Research grant / Funding (institution): Sanofi K.K.; Honoraria (self), Research grant / Funding (institution): Eli Lilly Japan; Research grant / Funding (institution): Daiichi Sankyo Pharma; Research grant / Funding (institution): MSD K.K.; Research grant / Funding (institution): Dainippon Sumitomo Pharm Co. Ltd.; Research grant / Funding (institution): Solasia Pharma K.K. M. Takahashi: Speaker Bureau / Expert testimony: Taiho Pharmaceutical Co. Ltd.; Speaker Bureau / Expert testimony: Eli Lilly and Company; Travel / Accommodation / Expenses: Takeda Pharmaceutical Co. Ltd. A. Makiyama: Advisory / Consultancy, Speaker Bureau / Expert testimony: Eli Lily Pharmaceutical; Speaker Bureau / Expert testimony: Chugai Pharmaceutical Co. Ltd.; Speaker Bureau / Expert testimony: Takeda Pharmaceutical Co. Ltd.; Speaker Bureau / Expert testimony: Taiho Pharmaceutical Co. Ltd. H. Yasui: Honoraria (self): Yakult Honsha; Honoraria (self): Chugai Pharmaceutical Co. Ltd.; Honoraria (self): Taiho Pharmaceutical Co. Ltd.; Research grant / Funding (institution): Ono Pharmaceutical Co. Ltd.; Research grant / Funding (institution): MSD; Research grant / Funding (institution): Daiichi Sankyo company. H. Kawakami: Honoraria (self), Advisory / Consultancy: Bristol-Myers Squibb Co. Ltd.; Honoraria (self), Advisory / Consultancy: Eli Lilly Japan K.K.; Honoraria (self), Advisory / Consultancy: MSD K.K.; Honoraria (self), Advisory / Consultancy: Ono Pharmaceutical Co. Ltd.; Honoraria (self), Advisory / Consultancy: Taiho Pharmaceutical Co. Ltd.; Honoraria (self): AstraZeneca K.K.; Honoraria (self): Bayer yakuhin Ltd.; Honoraria (self): Chugai Pharmaceutical Co. Ltd.; Honoraria (self), Research grant / Funding (self): Daiichi Sankyo Co. Ltd.; Honoraria (self): Takeda Pharmaceutical Co. Ltd.; Research grant / Funding (self): Eisai Co. Ltd.; Research grant / Funding (self): Dainippon Sumitomo Pharmaceutical Co. Ltd. T.E. Nakajima: Honoraria (self): Nippon Kayaku Pharmaceutical Co. Ltd.; Honoraria (self): Teijin Pharmaceutical Co. Ltd.; Honoraria (self), Research grant / Funding (institution): MSD K.K; Honoraria (self): Celltrion Healthcare; Honoraria (self), Research grant / Funding (self), Research grant / Funding (institution): Eli Lilly Japan; Honoraria (self): Bristol-Myers Squibb Co. Ltd.; Honoraria (self): Ono Pharmaceutical Co. Ltd.; Honoraria (self), Research grant / Funding (self), Research grant / Funding (institution): Merck Serono; Honoraria (self), Research grant / Funding (self), Research grant / Funding (institution): Taiho Pharmaceutical Co. Ltd.; Honoraria (self): Bayer yakuhin Ltd.; Honoraria (self), Research grant / Funding (self), Research grant / Funding (institution): Takeda Pharmaceutical Co. Ltd.; Honoraria (self), Research grant / Funding (self), Research grant / Funding (institution): Chugai Pharmaceutical Co. Ltd.; Honoraria (self), Research grant / Funding (self), Research grant / Funding (institution): Sanofi K.K.; Honoraria (self): Sawai Pharmaceutical Co. Ltd.; Research grant / Funding (self), Research grant / Funding (institution): Daiichi Sankyo Pharmaceutical Co. Ltd.; Research grant / Funding (institution): Dainippon Sumitomo Pharm Co. Ltd.; Research grant / Funding (institution): Solasia Pharma K.K. K. Muro: Honoraria (self): Ono Pharmaceutical Co. Ltd.; Honoraria (self): Eli Lilly Japan K.K.; Honoraria (self): Bristol-Myers Squibb Co. Ltd.; Honoraria (self): Taiho Pharmaceutical Co. Ltd.; Honoraria (self): Chugai Pharmaceutical Co. Ltd.; Honoraria (self): Takeda Pharmaceutical Co. Ltd.; Honoraria (self): Bayer yakuhin Ltd.; Honoraria (self), Research grant / Funding (self): Sanofi K.K.; Research grant / Funding (self): MSD K.K.; Research grant / Funding (self): Daiichi Sankyo Pharmaceutical Co. Ltd.; Research grant / Funding (self): Shionogi & Co. Ltd.; Research grant / Funding (self): Kyowa Hakko Kirin Pharmaceutical Co. Ltd.; Research grant / Funding (self): Gilead Sciences; Research grant / Funding (self): Pfizer; Research grant / Funding (self): Merck Serono. R. Matoba: Shareholder / Stockholder / Stock options, Officer / Board of Directors: DNA Chip Research Inc. W. Ichikawa: Honoraria (institution), Speaker Bureau / Expert testimony: Taiho Pharmaceutical Co. Ltd.; Honoraria (institution): Takeda Pharmaceutical Co. Ltd; Honoraria (institution): Shionogi Pharmaceutical Co. Ltd.; Honoraria (institution): Ono Pharmaceutical Co. Ltd.; Honoraria (institution), Speaker Bureau / Expert testimony: Merck Serono; Honoraria (institution), Speaker Bureau / Expert testimony: Chugai Pharmaceutical Co. Ltd. M. Fujii: Travel / Accommodation / Expenses: Taiho Pharmaceutical Co. Ltd.; Travel / Accommodation / Expenses: Japan Clinical Cancer Research Organization. All other authors have declared no conflicts of interest.

Background Combination treatment of FTD/TPI plus BEV in the C-TASK FORCE showed a promising activity in pts with mCRC refractory or intolerant to standard chemotherapies; however, due to the small sample size, it remains unclear if this combination works in the same way; RAS wild-type or mutant. We investigated the efficacy and safety of this combination in separate cohorts of RAS wild-type and mutant. Methods mCRC pts refractory or intolerant to prior treatments with fluoropyrimidines, irinotecan, oxaliplatin, an angiogenesis inhibitor, and an anti-EGFR antibody if RAS wild-type, and without FTD/TPI and regorafenib. Pts received FTD/TPI (35 mg/m2, twice daily, days 1 to 5 and 8 to 12) and BEV (5mg/kg, day1 and 15) every four weeks. The primary endpoint was disease control rate (DCR). A threshold and expected value of the DCR in each wild-type and mutant were set as 44% and 65%, respectively. Assuming a one-sided significance level of 5.0%, each target sample size was estimated to be 49 to achieve a power of 90%. Results From Jan to Sep 2018, 102 pts were enrolled, and 98 pts fulfilled the eligibility (49 pts in each). Baseline characteristics of RAS wild-type vs. mutant were follows; median age, 65 vs. 64 years: male, 51% vs. 59%: ECOG PS 0, 69% vs. 59%: left-sided primary, 84% vs. 67%: number of metastasis of > 2, 71% vs. 74%: median time from diagnosis of metastasis, 32.9 vs 21.2 months. The DCR in RAS wild-type was 65.3% (90% CI: 52.6-76.5%, p = 0.0022), while that in RAS mutant was 55.1% (90% CI: 42.4-67.3%, p = 0.0780). There was not a statistically significant difference in DCR between RAS wild-type and mutant after adjustment of baseline characteristics (adjusted odds ratio=0.48, 90% CI: 0.21-1.10, p = 0.1435). Partial response was observed only in three pts with RAS wild-type. There were neither unexpected safety signals nor treatment related death. Conclusions FTD/TPI plus BEV showed a promising activity with an acceptable safety profile for previously treated mCRC harboring either RAS wild-type or mutant. Survival outcome will be presented at the meeting. Legal entity responsible for the study Japanese Fondation for Multidisciplinary Treatment of Cancer (JFMC). Funding Japanese Fondation for Multidisciplinary Treatment of Cancer (JFMC). Disclosure M. Nakamura: Honoraria (self): Taiho Yakuhin; Honoraria (self): Daiichi Sankyo; Honoraria (self): Chugai Seiyaku; Honoraria (self): Merck. A. Makiyama: Advisory / Consultancy: Eli Lily Pharm; Speaker Bureau / Expert testimony: Chugai Pharm; Speaker Bureau / Expert testimony: Eli Lily Pharm; Speaker Bureau / Expert testimony: Taiho Pharm; Speaker Bureau / Expert testimony: Takeda Pharm. K. Oba: Honoraria (self): Chugai Pharm; Honoraria (self): Novartis Pharm; Honoraria (self): Takeda Pharm; Honoraria (self): BMS; Honoraria (self): Pfizer; Honoraria (self): Tsumura Pharm. T. Yoshino: Research grant / Funding (self): Novartis Pharma; Research grant / Funding (self): MSD; Research grant / Funding (self): Sumitomo Dainippon Pharma; Research grant / Funding (self): Chugai Pharmaceutical; Research grant / Funding (self): Sanofi; Research grant / Funding (self): Daiichi Sankyo Company; Research grant / Funding (self): Parexel; Research grant / Funding (self): Ono Pharmaceutical. K. Yoshida: Research grant / Funding (self): Chugai Pharma; Research grant / Funding (self): Lilly; Research grant / Funding (self): MSD; Research grant / Funding (self): Ono Pharma; Honoraria (self): EA Pharma; Honoraria (self): Johnson & Johnson; Honoraria (self): SBI Pharma; Honoraria (self): Olympus; Honoraria (self): Covidien; Honoraria (self): Sanofi; Honoraria (self): TERUMO; Honoraria (self): Novartis; Honoraria (self): Pfizer; Honoraria (self): Tsumura; Honoraria (self): Asahi Kasei; Honoraria (self): Pharma International Osaka; Honoraria (self): Daiichi Sankyo; Honoraria (self): Chugai; Honoraria (self): Lilly; Honoraria (self): Takeda; Honoraria (self): Yakult Honsha. K. Yamazaki: Speaker Bureau / Expert testimony: Taiho; Speaker Bureau / Expert testimony: Chugai. E. Oki: Speaker Bureau / Expert testimony: Taiho Pharm; Speaker Bureau / Expert testimony: Chugai Pharm. T. Takahashi: Speaker Bureau / Expert testimony: Taiho Pharm; Speaker Bureau / Expert testimony: Chugai Pharm. All other authors have declared no conflicts of interest.

Background Gemcitabine plus nab-paclitaxel (GnP) and FOLFIRINOX (FFX) are both considered as standard chemotherapy for patients with metastatic pancreatic cancer (mPC). However, there are no prospective clinical trials that directly compare these two therapies. We investigate and compare them to support the treatment selection for mPC. Methods: We retrospectively analyzed the patients with mPC who had received GnP or FFX as first-line chemotherapy at 14 institutions in Kyushu. In this study, patient characteristics and clinical outcomes; overall survival (OS), progression-free survival (PFS), overall response rate (ORR), disease control rate (DCR) and adverse events (AEs) were compared. Results: A total of 211 pts were included; GnP 119 pts (73 males and 46 females) and FFX 92 pts (55 males and 37 females). The median age of the FFX group was younger than that of GnP (GnP 68 vs. FFX 61 years). There was neither significant difference in the OS (median: 10.2 vs. 11.1 months, HR 0.98, 95%CI 0.72-1.34, p = 0.91) nor the PFS (median: 5.5 vs. 5.7 months, HR 1.05, 95%CI 0.79-1.40, p = 0.75) between the GnP and FFX group, respectively. Moreover, neither significant difference in the ORR (29% vs. 27%, p = 0.72) nor the DCR (81% vs. 79%, p = 0.25) was seen. There were no significant differences in grade 3/4 neutropenia (55% vs. 58%) and febrile neutropenia (10% vs. 13%). Grade 3/4 peripheral sensory neuropathy (12% vs. 3%) and fatigue (4% vs. 0%) were more frequent with GnP. All grades of rash and alopecia were more frequent with GnP. Otherwise, grade 3/4 anorexia (6% vs. 20%), diarrhea (0% vs. 11%) and nausea (3% vs. 11%) were more with FFX. 64% of the patients with FFX received GnP as second-line, but the rate of patients with FFX followed by GnP was only 10%. Conclusions: There was no significant difference in the effectiveness between GnP and FFX statistically. We need to select the appropriate treatment for each patient, considering that the toxicity profiles differ.

Background The IDEA collaboration, a prospective pooled analysis of four concurrently conducted randomized phase III trials (SCOT, TOSCA, ACHIEVE-2, and HORG) for pts with high-risk stage II CC investigating duration of adj oxaliplatin-based therapy, were presented at ASCO 2019. The results of ACHIEVE-2 trial, the only investigation in Asia, are presented here. Methods ACHIEVE-2 was an open-label, multicenter trial randomizing pts with high-risk stage II CC (T4, inadequate nodal harvest, poorly differentiated, obstruction, perforation or vascular invasion) to receive 3 months (m) or 6m of mFOLFOX6/CAPOX after curative surgery. Choice of regimen was declared before randomization by a site investigator. Primary endpoint was disease-free survival (DFS). No formal hypothesis testing for non-inferiority (NI) was planned in this trial. Results Between Feb 2014 and Jan 2017, 525 pts were randomized. The primary analysis included 514 randomized pts of which 82 had mFOLFOX6 (16.0%) and 432 had CAPOX (84.0%). High-risk features included 35.8% of T4, 12.8% of inadequate nodal harvest, 11.5% of poorly differentiated, 19.3% of obstruction, 6.4% of perforation and 87.5% of vascular invasion. There was significantly less grade 3-5 toxicity with 3m treatment (p = 0.0003). Grade 2 or higher neurotoxicity in 3m was significantly lower than that in 6m (16.5% vs. 42.9%, p Conclusions Shorter duration significantly decreased overall toxicities including neurotoxicity. Our results need to be interpreted within the IDEA combined analysis as well as in terms of the reproducibility of results across all trials. Clinical trial identification UMIN000013036. Legal entity responsible for the study The authors. Funding Japanese Foundation for Multidisciplinary Treatment of Cancer under the contract with Yakult Honsha. Disclosure T. Yoshino: Research grant / Funding (institution): Novartis Pharma K.K; Research grant / Funding (institution): MSD.K.K.; Research grant / Funding (institution): Sumitomo Dainippon Pharma Co., Ltd.; Research grant / Funding (institution): Chugai Pharmaceutical Co., Ltd.; Research grant / Funding (institution): Sanofi K.K.; Research grant / Funding (institution): Daiichi Sankyo Company, Limited; Research grant / Funding (institution): Parexel International Inc.; Research grant / Funding (institution): Ono Pharmaceutical Co., Ltd. T. Yamanaka: Honoraria (self), Research grant / Funding (institution): Chugai; Honoraria (self), Research grant / Funding (institution): Takeda; Honoraria (self), Research grant / Funding (institution): Taiho; Honoraria (self), Research grant / Funding (institution): Boehringer-Ingelheim; Honoraria (self), Research grant / Funding (institution): Bayer; Honoraria (self): Pfizer; Advisory / Consultancy: Gilead Sciences; Advisory / Consultancy, Research grant / Funding (institution): Daiichi-Sankyo; Advisory / Consultancy: Sysmex; Advisory / Consultancy: Huya Biosciences; Research grant / Funding (institution): Ono; Research grant / Funding (institution): Merck Serono; Research grant / Funding (institution): Astellas; Research grant / Funding (institution): Eli Lilly. M. Kotaka: Honoraria (self): Yakult Honsha; Honoraria (self): Chugai pharmaceutical. M. Gamoh: Honoraria (self): Taiho; Honoraria (self): Bayer; Honoraria (self): Novartis; Honoraria (self): Ono; Honoraria (self): Shionogi; Honoraria (self): Sanofi; Honoraria (self): Asahikasei; Honoraria (self): Chugai; Honoraria (self): Takeda; Honoraria (self): Daiichisankyo; Honoraria (self): Merck; Honoraria (self): Nipponkayaku; Honoraria (self): Eli Lilly Japan. A. Makiyama: Advisory / Consultancy, Speaker Bureau / Expert testimony: Eli Lily Pharmaceutical; Speaker Bureau / Expert testimony: Chugai; Speaker Bureau / Expert testimony: Taiho; Speaker Bureau / Expert testimony: Takeda. K. Shitara: Advisory / Consultancy, Research grant / Funding (institution): Astellas Pharma; Advisory / Consultancy, Research grant / Funding (institution): Lilly; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: Takeda; Advisory / Consultancy: Pfizer; Advisory / Consultancy, Research grant / Funding (institution): Ono; Advisory / Consultancy, Research grant / Funding (institution): MSD; Research grant / Funding (institution): Dainippon Sumitomo Pharma; Research grant / Funding (institution): Daiichi Sankyo; Research grant / Funding (institution): Taiho; Research grant / Funding (institution): Chugai; Research grant / Funding (institution): Medi Science; Honoraria (self): Novartis; Honoraria (self): AbbVie; Honoraria (self): Yakult. K. Yamazaki: Speaker Bureau / Expert testimony: Chugai; Speaker Bureau / Expert testimony: Yakult. A. Ohtsu: Honoraria (self), Research grant / Funding (institution): BMS; Honoraria (self): Chugai; Honoraria (self): Taiho; Honoraria (self): Ono; Honoraria (self): Eisai. Y. Maehara: Research grant / Funding (institution): Yakult; Research grant / Funding (institution): Chugai. All other authors have declared no conflicts of interest.

Background Ramucirumab (RAM) conferred survival benefit in patients with advanced gastric cancer (AGC) in the RAINBOW trial (HR 0.807, 95% CI: 0.678-0.962, p = 0.017). However, in the Japanese subpopulation, adding RAM showed modest overall survival (OS) benefit compared with patients in Western country (HR 0.88 vs. 0.73). The objective of this retrospective study was to clarify additional benefit of RAM in clinical practice for Japanese patients. Method We reviewed medical records of AGC patients who were treated with Paclitaxel (PTX) or PTX+RAM between Jan 2014 and Dec 2016 as second-line treatment in 9 Japanese institutions, excluding patients with prior use of taxane or RAM. Result A total of 154 patients were included (63 in PTX and 91 in PTX+RAM). Patient characteristics of PTX vs. PTX+RAM groups were: age (median) 64 vs. 64, male 67% vs. 75%, PS (0/1/2) 27/63/10% vs. 30/67/3%, disease status (metastatic/recurrent) 75/25% vs. 63/37%, histology (intestinal/diffuse/other) 24/57/19% vs. 31/44/25%, number of metastatic sites (0-2/≥3) 75/25% vs. 70/30%, ascites (+/-) 54/46% vs. 50/50%, and platinum combined with fluoropyrimidine in the first line (oxaliplatin/cisplatin) 16/84% vs. 37/63%. The median OS in the PTX vs. PTX+RAM groups were 7.0 vs. 9.3 months (HR 0.73, 95% CI: 0.52-1.04, p = 0.083). The median PFS were 3.2 vs. 4.1 months (HR 0.66, 95% CI: 0.47-0.93, p = 0.016). Among 39/55 patients who had measurable lesions, response rate and disease control rate were 18% vs. 35% and 56% vs. 76%, respectively. The proportion of patients receiving subsequent treatment was 57% in PTX group and 59% in PTX+RAM group. Grade 3 or more adverse events were observed more frequently in PTX+RAM group, including neutropenia (55% vs. 21%) and leucopenia (31% vs. 19%) than PTX group. Conclusion Although this study was retrospective investigation with small sample size, adding RAM to PTX conferred clinically meaningful efficacy and safety in clinical practice for Japanese patients.

Background According to the results of the randomized phase III study, G-SOX, the combination of S-1 and oxaliplatin (SOX) is as effective as the combination of S-1 and cisplatin for the treatment of HER2-negative advanced gastric cancer (AGC), and also has a favorable safety profile. In this trial, the dose of oxaliplatin tested was 100 mg/m2; however, the dose of 130 mg/m2 is covered by insurance in Japan, based on the results of the pivotal global study. Therefore, the efficacy and safety of the SOX regimen with oxaliplatin 130 mg/m2 (SOX130) remains to be elucidated. In this study, we conducted the final analysis of the survival outcomes in a phase II trial to assess the efficacy and safety of SOX130 in HER2-negative AGC. Methods Patients with HER2-negative AGC or recurrent gastric cancer received 80 mg/m2 S-1 per day orally on days 1-14, and 130 mg/m2 oxaliplatin intravenously, on day 1 of each 21-day cycle, until criteria for treatment withdrawal were fulfilled. The primary endpoint was the response rate (RR), and the secondary endpoints were progression-free survival (PFS) and overall survival (OS). Adverse events (AE) were recorded according to CTCAE version 4.0. Results In this study, 71 patients were enrolled from June 2015 to November 2016, but 8 patients were excluded owing to ineligibility. Therefore, the efficacy and safety analyses were finally conducted among 63 patients. The confirmed RR, assessed by an independent review committee, was 46.0% (95% confidence interval [CI]: 34.3-58.2), and the disease control rate was 77.8% (95% CI: 66.1-86.3). The median PFS and OS were 4.9 months (95% CI: 4.2-7.1) and 14.8 months (95% CI: 11.1-18.9), respectively. The incidence rates of grade 3 or 4 AE were as follows: neutropenia, 9.5%; thrombocytopenia, 11.1%; anemia, 6.3%; sensory neuropathy, 12.7%; anorexia, 19.0%; and diarrhea, 6.3%. Conclusions SOX130 showed favorable survival outcomes and an acceptable safety profile in the treatment of HER2-negative AGC.

Background Irinotecan have been well known to correlate between UGT1A1 polymorphisms (UGT1A1) and adverse events. Modified XELIRI (irinotecan 200 mg/m2 on day 1, capecitabine 1600 mg/m2 on days 1 to14 every 3 weeks) has shown non inferiority of overall survival compared with FOLFIRI based on "Asian XELIRI ProjecT" (AXEPT) as second line chemotherapy for patients with mCRC. In this preplanned analysis of the AXEPT trial, we evaluated the relationship between UGT1A1 and the efficacy and safety of irinotecan-based chemotherapy. Methods Patients were randomized FOLFIRI ± bevacizumab (BV) or modified XELIRI ± BV based on UGT1A1 results (wild type, heterozygosity, and homozygosity). With regard to irinotecan dosage in both treatment arms, the reduced dosage (150mg/m2) were administered in case of homozygosity. Assessed endpoints were overall survival (OS), progression free survival (PFS), overall response rate (ORR), relative dose intensity (RDI) and safety. Result UGT1A1 was available for all 650 randomized patients (wild type, 309 (47.5%) heterozygosity, 291 (44.8%) and homozygosity, 50 (7.7%)). Median OS was of patients with a wild/hetero/homo was 14.3, 18.3 and 9.1 months in FOLFIRI arm and 18.1, 16.3 and 13.0 months in mXELIRI arm, respectively. Median PFS of patients with a wild/hetero/homo was 6.8, 8.8 and 4.8 months in FOLFIRI arm and was 8.3, 8.7 and 6.5 months in mXELIRI arm, respectively. Grade 3, 4 toxicities of special interests (wild/hetero/homo) were neutropenia (35.9%/50.4%/45.8% in FOLFIRI arm and 17.0%/15.7%/21.7% in mXELIRI arm), febrile neutropenia (5.9%/2.3%/4.2% in FOLFIRI arm and 1.4%/4.3%/8.7% in XELIRI arm), and diarrhea (1.3%/6.0%/0% in FOLFIRI arm and 4.8%/10.7%/0% in mXELIRI arm). Conclusions mXELIRI±BV was showed the good efficacy and well tolerated in patients with all UGT1A1 polymorphisms. mXELIRI+BV could be an alternative to FOLFIRI as a standard second line backbone treatment for mCRC.

3548 Background: Elderly patients are often intolerable in combination of cytotoxic agents. Recently, Trifluridine/tipiracil plus bevacizumab has been shown as good candidate for the vulnerable patients. We aimed to assess the efficacy and safety of trifluridine/tipiracil plus bevacizumab in elderly patients with metastatic colorectal cancer. Methods: Patients aged 70 years and older with previously untreated, unresectable, metastatic colorectal cancer, who were not deemed to be candidates for oxaliplatin-based or irinotecan-based chemotherapy regimens, were included in this trial. Treatment consisted of trifluridine/tipiracil (35 mg/m2 orally a day on day 1-5 and day 8-12) with bevacizumab (5mg/kg intravenously on day 1 and day 15), given every 4 weeks until disease progression. The primary endpoint was progression-free survival (PFS). The secondary endpoints were response rate (ORR), Overall survival (OS) and adverse events (AEs). Results: Between 2017 January and 2018 March, 39 patients were enrolled in this study. The characteristics of patients were male/female : 17/22, median age : 77.5 (range: 70-88) and PS: 0/1 : 31/8. The ORR of 37 patients were assessed by the central review committee. The best response was 40.5(15/37) % (95% CI: 24.8-57.9), and the disease control rate was 86.5 (32/37) % (95% CI: 71.2–95.5). The AEs which were frequent as grade 3 or 4 were leucopenia (71.8 %), neutropenia (48.7 %), anorexia (12.8 %), febrile neutropenia (10.3 %) and fatigue (10.3 %). No treatment related death was reported. Conclusions: The combination of trifluridine/tipiracil plus bevacizumab is an effective and well-tolerated regimen for elderly patients with metastatic colorectal cancer. Hematological adverse events were need for caution. The primary endpoint of PFS will be presented in the end of this year. Clinical trial information: UMIN000025241.

3560 Background: Regorafenib (REG) and trifluridine/tipiracil (FTD/TPI) have been recognized as standard treatments for patients (pts) with refractory metastatic colorectal cancer (mCRC). Because these drugs have limits on efficacy benefit for some pts, we are necessary to select pts who may be better not to receive REG or FTD/TPI. However, no reports are available on how to predict pts with early mortality after initiation of these drugs. Methods: We retrospectively evaluated pts with mCRC who were registered in a multicenter observational study (the REGOTAS study). The main inclusion criteria were ECOG PS of 0–2, refractory or intolerant to fluoropyrimidines, oxaliplatin, irinotecan, and anti-VEGF and anti-EGFR therapy (if KRAS wild type), and no prior use of REG or FTD/TPI. Predictive factors for early mortality (≤ 12 weeks from initiation of REG or FTD/TPI) were evaluated by multivariate analysis for survival with all variables with P values of

647 Background: Trifluridine/tipiracil (FTD/TPI) plus bevacizumab (Bmab) combination therapy has shown a promising activity with manageable safety profile in patients (pts) with heavily pretreated metastatic colorectal cancer (mCRC). The aim of this multicenter, phase Ib/II study was to assess the activity and safety of biweekly FTD/TPI with Bmab combination for pts with mCRC who were refractory or intolerant to standard therapies. Methods: Inclusion criteria were ≥ 20 years; histologically confirmed unresectable mCRC; refractory or intolerant to fluoropyrimidine, irinotecan, oxaliplatin, anti-VEGF therapy, and anti-EGFR therapy (for tumors with wild-type RAS); ECOG PS 0 or 1; evaluable lesion according to the RECIST version 1.1. Phase Ib part is designed to determine the recommended phase II dose (RP2D), and pts received the RP2D in phase Ib part were included in efficacy and safety populations. The primary endpoint in phase II part was an investigator assessed progression-free survival rate at 16 weeks (16w-PFS) with a hypothesis of 15% considered unacceptable and 38.7% deemed promising. Given a one-sided α of 0.025 and statistical power of 90%, a minimum of 40 pts were required for phase II part. Results: From October 2017 to January 2018, totally 46 pts were enrolled (6 pts in phase Ib and 40 pts in phase II). The RP2D was determined to be 5 mg/kg for Bmab and 30 mg/m2 for FTD/TPI in phase Ib. Of the 44 eligible pts (median age, 69; male, 55%; PS 0, 57%; right-sided primary, 29.5%), 16w-PFS rate was 40.9 % (95% CI: 26.3 to 56.8 %) and the null hypothesis of 16w-PFS rate ≤ 15% was rejected (p < 0.0001). Response rate and disease control rate were 0 % (95 %CI: 0 to 6.6 %) and 59.1 % (95%CI: 43.3 to 73.7 %), respectively. With a median follow up of 5.86 months (range, 1.53-9.79), median PFS was 4.25 months (95% CI: 2.54 to 5.57). Grade 3 or higher adverse events were hypertension (40.9%), neutropenia (11.4 %), leucopenia (11.4 %), anemia (9.1 %), anorexia (9.1 %), nausea (6.8 %), hyperbilirubinemia (6.8 %) and proteinuria (6.8 %). Conclusions: Bi-weekly FTD/TPI plus Bmab showed promising anti-tumor effect with acceptable toxicities. Clinical trial information: UMIN000029198.

624 Background: Previous preclinical study reported that a combination of PANI with FTD/TPI demonstrated synergistic antitumor activity (Baba, 2017); however, no clinical study has been reported in this combination yet. Therefore, we conducted a phase I/II study to evaluate the efficacy and safety of this combination in pts with RAS wt mCRC. Here, we report the results of final analysis, including follow-up. Methods: Eligible pts had RAS wt mCRC refractory or intolerant to fluoropyrimidines, irinotecan, oxaliplatin, or angiogenesis inhibitors, and had never been treated with anti-EGFR antibodies, FTD/TPI, or regorafenib (REG).Pts received four-week cycles of PANI (every two weeks) and FTD/TPI (twice daily, days 1 to 5 and 8 to 12). The primary endpoint was frequency of dose-limiting toxicity (DLT) in phase I and progression-free survival (PFS) rate at 6 months (M) in phase II. With a PFS rate at 6 M of 48% deemed promising and 29% judged unacceptable, and assuming a one-sided significance level of 5%, the necessary sample size to achieve a power of 80% was estimated to be 47 pts (target sample size, 52 pts). Results: Since no DLT occurred in phase I, the recommended dose was determined to be 6 mg/kg for PANI and 35 mg/m2 for FTD/TPI. In phase II with a median follow-up of 16.5 M, the PFS rate at 6 M (n = 54) was 33.3% (90% CI: 22.8–45.3; p = 0.24), and median PFS and overall survival were 5.8 M (95% CI: 4.5–6.5) and 14.1 M (95% CI: 12.2–19.3), respectively. The response rate and disease control rate were 37.0% and 81.4%, respectively. The most common grade 3 or higher adverse events (n = 55) were neutropenia (10.9%), febrile neutropenia (9.1%), stomatitis (9.1%), and dermatitis acneiform (9.1%). Subsequent therapy was given to 39 pts (72.2%), including 25 pts (46.3%) treated with REG. Subgroup analyses stratified by age, PS, and primary lesion will be reported at the time of conference presentation. Conclusions: PANI combined with FTD/TPI showed favorable antitumor activity with an acceptable safety profile for previously treated RAS wt mCRC, although the primary endpoint of PFS rate at 6 M did not meet the prespecified threshold. Clinical trial information: NCT02613221.

54 Background: Anti-programmed death-1 (PD-1) monoclonal antibody, nivolumab, enhances antitumor activity by inhibiting the interaction of PD-1 and programmed death-1 ligand 1 (PD-L1) and has shown efficacy for advanced gastric cancer (AGC) in the salvage line. However, specific subsets of immune cells predominantly activated during the period of anti-PD-1 therapy for AGC have not been clarified. Methods: Peripheral blood mononuclear cells of 20 AGC patients treated with nivolumab were prospectively obtained before the initial and second administrations of nivolumab, and at the time of progressive disease (PD). The proportion of immune cell subsets were systematically analyzed by flow cytometry, including the expression of costimulatory and coinhibitory molecules such as T-cell immunoglobulin and mucin domain 3 (TIM-3), Lymphocyte-activation gene 3 (LAG-3), T-cell immunoreceptor with Ig and ITIM domains (TIGIT), cytotoxic T cell antigen-4 (CTLA-4), CD28, OX40, and inducible T cell costimulator (ICOS). Association between changes in the proportion of the subsets and therapeutic effect were analyzed. Results: Median progression free survival (PFS) of the whole patients was 51 days (95% CI 35–83). After a single course of nivolumab, patients showed a significant increase in activated effector memory and activated effector subsets of CD4+/CD8+ T cells (p = 0.018, 0.018, 0.032, 0.024). At the time of PD, proportions of myeloid dendritic cell, IgM memory B cell and Tfh-Th1/17 cell subsets decreased (p = 0.024, 0.013, 0.0039). On the other hand, LAG3 positive CD4+/CD8+ T cells, TIM-3 positive CD4+/CD8 T cells increased at the time of PD (p = 0.013, 0.032, 0.042, 0.042). Significant positive correlations were found between PFS and the proportion of LAG3 positive CD4+/CD8+ T cells (p = 0.0056, 0.0054), OX 40 positive CD4+/CD8+ T cells (p = 0.0034, 0.0006) prior to the initial nivolumab therapy. Conclusions: Nivolumab therapy enhances activation of effector memory and effector subsets of CD4+/CD8+ T cells. The expression level of LAG3 and OX40 on T cells might be correlated with efficacy of nivolumab therapy.

509 Background: Molecular-targeted drugs are known to have angiogenesis-inhibiting properties, and thus can inhibit angiogenesis inside the tumor tissue to cause necrosis, even if the tumor diameter is unchanged. We retrospectively investigated relationship between imaging change associated with regorafenib (REGO) treatment and the treatment outcome in Japanese mCRC. Methods: Eligibility included ECOG-PS 0 or 1, treated with REGO with lung or liver metastasis, started dose with 120 or 160mg/day of regorafenib and duration of treatment (DOT) must be 35 days or more (excluding interruption). Patients (Pts) were performed baseline CT within 28 days before and first CT assessment were between eight and 12 weeks after start of regorafenib. The main objective of this analysis is to investigate the correlation between the imaging change and outcome. As imaging change, onset or increase of Cavitation of lung lesion (CLL), morphologic response of liver lesion (MRL), Change of liver metastasis density (CLD) were evaluated. In all cases, independent two radiologists are evaluating radiological change after regorafenib treatment. Results: We finally screened 671 cases and 231 cases were eligible. The pts background was male/female 147/84, median age 64.0 (range: 32-83), median DOT of REGO 86 days (range: 35-818). The pts with lung metastasis were 153, and with liver metastasis were 166. CLL were positive in 69 (40.0%) pts. The median progression free survival (PFS) of the pts with/without CLL were 3.2/2.4 months (HR 0.794; 95% CI 0.584-1.080). Median overall survival (OS) of the pts with/without CLL were 10.5/9.0 months (HR 1.058; 95% CI 0.751-1.489). Median OS of pts with/without CLL in female were 11.4/7.9 months (HR 0.630; 95% CI 0.352-1.127). The MRL and CLD of liver metastasis were analyzed in 147 / 91 pt. Median OS of pts with/without MRL were 9.9/8.2 months (HR 1.015; 95% CI 0.581-1.774) and Median OS with/ without CLD were 11.6/7.0 months (HR 0.604; 95% CI 0.353-1.031). Conclusions: Cavitation of lung metastasis may predict PFS of the pts but not OS. Change of Liver metastasis density were predictor of favorable outcome to regorafenib. (UMIN000023329).

In late December 2015, a 69-year-old woman presented with general malaise and palpitation lasting a few days. She had choroidal malignant melanoma with liver and bone metastases and had undergone 3 cycles of anticancer treatment with an anti-PD-1 (programmed cell death protein 1) antibody nivolumab (2 mg/kg of body weight every 3 weeks) from October 2015 to early December 2015. Two weeks had elapsed since the last treatment with nivolumab. On physical examination, blood pressure was 121/83 mm Hg and heart rate 110 beats per minute. ECG showed ST-segment elevation in leads II, III, and aVF. A bedside rapid assay for cardiac troponin T was positive, and the concentrations of creatine kinase and creatine kinase MB-isozyme were increased to be 728 IU/L and 48.7 U/L, respectively. Echocardiography …

TAS-102 is an anti-metabolite which demonstrated activity against multidrug-resistant advanced colorectal cancer. Its major toxicities are hematological disorders.Background, TAS-102 efficacy, toxicities and outcomes for patients with multidrug-resistant advanced colorectal cancer from six Institutions of the Kyushu Medical Oncology Group were retrospectively surveyed.Forty-three patients, including fragile patients due to declining performance status and other comorbidities (37%) were analyzed. Efficacy was reflected in an objective overall response of 3%, median progression-free survival of 74 days (2.5 months) and median overall survival of 229 days (7.6 months). The most frequent Common Terminology Criteria for Adverse Events grade 3/4 adverse events were neutropenia (44%), leukopenia (26%) and anemia (23%). Febrile neutropenia was found in 7%. Sub-group analysis demonstrated an improved outcome on treatment with the sequence regorafenib-TAS-102.TAS-102 was safely administered to modestly fragile patients with equivalent efficacy to that for the non-fragile population. Further investigation of sequential treatment using regorafenib and TAS-102 is needed.

4038Background: Addition of trastuzumab to cisplatin and fluoropyrimidine-based doublet chemotherapy is the standard first-line treatment for patients with human epidermal growth factor receptor 2 ...

4011Background: Trastuzumab (Tmab) is a key drug for HER2-positive breast and gastric or gastro-esophageal junction (G/GEJ) cancer. While continuous use of Tmab beyond progression (TBP) showed a be...