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Alpha-Fetoprotein Producing Gastric Cancer (AFPGC) is an aggressive subgroup of gastric cancer. Recently ramucirumab has shown survival benefits in hepatocellular carcinoma, but only in those with higher Alpha-Fetoprotein (AFP) levels. However, the efficacy of ramucirumab-containing chemotherapy in AFPGC remains unclear.We retrospectively assessed 352 patients who received ramucirumab-containing chemotherapy between June 2015 and December 2019. AFPGC was defined when serum AFP levels were elevated at diagnosis and correlated with the disease state during treatment. Non-AFPGC was defined when serum AFP levels were normal at diagnosis.Among the 352 patients, 28 patients were defined as AFPGC and 246 patients were defined as non-AFPGC. AFPGC was characterized by high frequency of liver metastasis and low frequency of peritoneal metastasis compared to non-AFPGC. Ramucirumab containing chemotherapy showed higher response rates in AFPGC (39.1% vs 24.8%, p = 0.198) and disease control rates (86.9% vs 61.5%, p = 0.028) than those of non-AFPGC, respectively. Median progression-free survival (PFS) was 5.5 months (95%CI 3.9-7.1) in AFPGC and 4.0 months (95%CI 3.6-4.6) in non-AFPGC (HR: 0.91, 95% CI 0.61-1.36, p = 0.66), and median overall survival (OS) was 10.7 months (95% CI 7.4-20.8) in AFPGC and 9.2 months (95% CI 8.1-10.4) in non-AFPGC (HR: 0.72, 95% CI 0.48-1.08, p = 0.11), respectively. In multivariate analysis, AFPGC was not a negative prognostic factor both for PFS and OS.Ramucirumab containing chemotherapy showed higher response and comparable survival in AFPGC compared to those of non-AFPGC. Considering the generally poor prognosis of AFPGC, ramucirumab-containing chemotherapy might be a promising treatment option in AFPGC.

Background Accelerated tumor growth during immunotherapy in pre-existing measurable lesions, hyperprogressive disease (HPD), has been reported. However, progression of non-measurable lesions and new lesions are frequently observed in patients with advanced gastric cancer (AGC). Methods This retrospective study involved AGC patients at 24 Japanese institutions who had measurable lesions and received nivolumab after ≥ 2 lines of chemotherapy. HPD was defined as a ≥ two-fold increase in the tumor growth rate of measurable lesions. The pattern of disease progression was classified according to new lesions in different organs and ascites appeared/increase of ascites. Results Of 245 patients, 147 (60.0%) showed progressive disease (PD) as the best response and 41 (16.7%) showed HPD during nivolumab monotherapy. There was no significant difference in overall survival (OS) between patients with HPD and those with PD other than HPD (median OS 5.0 vs 4.8 months; hazard ratio [HR] 1.0, 95% confidence interval [CI] 0.6–1.5; p = 1.0). Fifty-three patients developed new lesions in different organs and 58 had appearance/increase of ascites; these patients showed shorter OS than those without each of these features (median OS 3.3 vs 7.1 months, HR 1.8, 95% CI 1.2–2.7, p = 0.0031 for new lesions, and 3.0 vs 7.8 months, HR 2.6, 95% CI 1.8–3.8, p Conclusions New lesions in different organs and appearance/increase of ascites, rather than the original definition of HPD, are the patterns of disease progression associated with poor prognosis in AGC patients receiving nivolumab whose best response was PD.

Colorectal cancer with liver metastasis (CLM) has high postoperative recurrence rates; therefore, optimizing perioperative treatment is imperative. Postoperative carcinoembryonic antigen (CEA) can aid in detecting minimal residual disease in colon cancer following curative resection. This study aimed to identify the potential role of serum CEA following liver resection in patients with CLM.This retrospective study was conducted at the Cancer Institute Hospital of the Japanese Foundation for Cancer Research from 2004 to 2018 and enrolled patients with CLM who underwent complete resection of primary tumors and CLM. Associations between perioperative CEA levels and characteristics of recurrence were investigated.Recurrence was detected during a median follow-up period of 90.1 months in 343 (54.2%) out of 633 analyzed patients. Patients in the postoperative CEA level5 ng/ml group had a significantly higher recurrence rate (75.7% versus 50.0%, p0.01) and shorter time until recurrence (4.4 versus 36.9 months, p0.01) than those in the postoperative CEA level ≤ 5 ng/ml group. Multivariate analysis revealed that postoperative CEA level5 ng/ml was an independent predictor, with hazard ratios of 2.77 (p0.01) for recurrence-free survival (RFS) and 3.18 (p0.01) for overall survival (OS). Additionally, RFS was significantly shorter among patients in the postoperative CEA level5 ng/ml group who did not have normalized CEA levels following adjuvant chemotherapy than among those in the normalized CEA group.The postoperative and post-adjuvant chemotherapy CEA levels in the CEA level5 ng/ml group may be predictors of RFS and OS.

Background In the past decade, several successful clinical trials provided new therapeutic agents approved for advanced gastric cancer (AGC). This study evaluated whether these practice-changing results actually altered the clinical practice. Patients and Methods We retrospectively reviewed medical records of treatment-naive AGC patients who received combination chemotherapy of fluoropyrimidine and platinum between 2007 and 2018 and divided them into three groups: Groups A (2007-10), B (2011-14), and C (2015-2018), respectively. We compared the clinicopathological features, treatment details, and clinical outcomes among the three groups. Results In total, 1004 consecutive patients were enrolled (A; n = 254, B; n = 300, and C; n = 450). The number of patients with poor performance status, older age, esophagogastric junction adenocarcinoma, and primary tumor increased during the study period. All groups had similar median overall survival (OS); ~16 months) without any statistical difference but steady prolongation of survival was observed in the adjusted with imbalance prognostic factors among groups (B/A; hazard ratio, HR 0.82, 95% C.I 0.68-0.98, C/A; HR 0.72, 95% CI 0.60-0.86); OS of HER2-positive AGC patients was clearly improved (HER2-positive vs HER2-negative in Group B, HR 0.80, 95% CI 0.60-1.06; Group C, HR 0.68, 95% CI 0.51-0.90) but that of diffuse-type AGC patients remained dismal. Conclusions The increasing availability of chemotherapy options potentially contributed to improved survival of AGC patients, but expanded chemotherapeutic indications made the survival benefit inconspicuous in the whole population. Future therapeutic development for the AGC subset not adequately receiving benefit from previous clinical trials is warranted.

Purpose: Palliative care should be provided for terminal cancer patients, but the remaining question is how oncologists are providing palliative care. Herein, we evaluated the effectiveness of palliative care provided via video telemedicine. Methods: Terminal cancer patients receiving the best supportive care were enrolled and divided into two groups: telemedicine and no telemedicine. The primary endpoint was quality of life (QOL), which was evaluated using the difference in the Functional Assessment of Cancer Therapy–General (FACT-G) scores between baseline and at the 1-month follow-up. Secondary endpoints included depression measured using the Center for Epidemiologic Studies depression (CES-D) scale, overall survival (OS), and patient satisfaction. Results: Overall, 50 patients were included in this study,with 25 patients in each group. FACT-G decreased by 0.30 vs 5.90 points in the telemedicine and no telemedicine groups, respectively. Although there was no significant difference (P = 0.088), the telemedicine group tended to maintain better QOL. CES-D increased by 0.96 vs 3.52 points in the telemedicine and no telemedicine groups, respectively. Depressive tendency was lower in the telemedicine group; however, there was no significant difference (P = 0.27). Median survival time (MST) was 7.82 (3.30 – 14.59) vs 6.37 (2.33 – 11.04) months in the telemedicine and no telemedicine groups, respectively, and the HR was 0.67 (95%CI 0.33 – 1.34, P = 0.25). Conclusion: There was a trend toward improved QOL in patients receiving video telemedicine. It is desirable to further evaluate the effectiveness of palliative care with telemedicine and link it to clinical applications.

Background Circulating tumor DNA (ctDNA) is a biomarker with potential to reflect comprehensive genomic information and overcome intratumor heterogeneity. In contrast, carcinoembryonic antigen (CEA) is a conventional tumor marker for predicting recurrence, survival, and chemotherapeutic efficacy in patients with metastatic colorectal cancer (mCRC). However, the relationship between them remains unclear. Here, the relationship between plasma ctDNA and CEA levels was evaluated to clarify the advantages and disadvantages of their clinical use. Methods A total of 110 patients with mCRC underwent chemotherapy were enrolled. Amplicon‐based plasma genomic profiling of 14 genes that are commonly mutated in CRC by next‐generation sequencing was compared to the CEA level and tumor diameter using Spearman’s correlation coefficient. Results The overall concordance rate between the ctDNA and CEA levels was 75.5% (83/110). The correlation coefficient between the ctDNA and CEA levels was lower in the group of patients without liver and lymph node metastases (r = 0.18, p = 0.44) than in the group of patients with liver metastasis (r = 0.48, p, Tumor diameter and ctDNA and CEA levels highly correlated in metastatic colorectal cancer patients with liver metastases. Status of ctDNA and CEA may not be consistent in metastatic colorectal cancer (mCRC) patients without liver metastasis or with low tumor volume. Both results should be considered when deciding a treatment strategy for mCRC patients without liver metastases.

Background/aim Primary tumor location and RAS and BRAF V600E mutations are predictors of the efficacy of epidermal growth factor receptor (EGFR) inhibitors. However, there are limited reports on their effects on the outcomes of third-line chemotherapy with EGFR inhibitors in metastatic colorectal cancer (mCRC) patients. Patients and methods We retrospectively collected the clinical data of KRAS exon 2 wild type (WT) mCRC patients treated with EGFR inhibitor monotherapy or EGFR inhibitor plus irinotecan as third-line chemotherapy. The association between primary tumor location, RAS (KRAS exon 3, 4 or NRAS), BRAF V600E, and PIK3CA mutational status, and treatment outcome was evaluated. Results A total of 72 patients were included in this study. In multivariate analysis, RAS (p=0.004) and BRAF mutations (p=0.00008) were independent factors for shorter PFS. Poor performance status (p=0.01) and BRAF mutation (p=0.00002) were independent factors for shorter OS, whereas primary tumor location and PIK3CA mutation did not influence survival. Conclusion Additional analysis of RAS and BRAF mutations could contribute to the selection of patients who are likely to benefit from third-line EGFR inhibitors, regardless of primary tumor location.

Immune checkpoint inhibitors (ICPI) have been reported to be effective in various carcinomas. They excessively activate the immune system, resulting in frequent immune-related adverse events (irAEs). Colitis induced by ICPI is one of the most common and is known as immune-mediated colitis (IMC). Although IMC and inflammatory bowel disease (IBD) are similar in many respects, there are very few reports of IMC in patients with preexisting IBD such as ulcerative colitis (UC) and Crohn's disease (CD). Whether preexisting IBD is concerned with the development of the colitis is not well known. Here, we reported the case who developed severe ulcerative colitis which started from IMC. It is an important case to follow the time course of the colitis developed. Our conclusion indicated that frequent colonoscopy was important for the management of IMC in a patient who has suffered chronic inflammatory disease, such as UC.

Purpose Immune checkpoint inhibitors (ICIs) have been approved for various types of cancer; however, they cause a broad spectrum of immune-related adverse events (irAEs). The association between the development of irAEs and the clinical benefit remains uncertain. We aimed to evaluate the association of irAEs and the treatment efficacy in real-world practice. Patients and Methods We conducted a retrospective study on patients with recurrent or metastatic non-small-cell lung cancer, malignant melanoma, renal cell carcinoma, or gastric cancer who received anti-PD-1/PD-L1 antibodies (nivolumab, pembrolizumab, or atezolizumab) at the Keio University Hospital between September 2014 and January 2019. We recorded treatment-related AEs from medical records and graded them using the Common Terminology Criteria for Adverse Events version 4. We performed an overall survival (OS) analysis using a Cox proportional hazards model and the shared frailty model. Results Of 212 patients eligible for this study, 108 experienced irAEs and 42 developed multiple irAEs. The median OS was significantly longer in the irAEs than in the no-irAE group (28.1 months vs 12.7 months; hazard ratio [HR], 0.49; 95% confidence interval [CI], 0.33-0.73; P = 0.0004). Moreover, the OS of patients with multiple irAEs was significantly longer than that of patients with a single irAE (42.3 months vs 18.8 months; HR, 0.473; 95% CI, 0.346-0.647; P < 0.0001). Conclusion Our single-center retrospective study revealed a significant tendency associating the development of multiple irAEs with favorable prognoses.

Although RAS and PIK3CA mutations have been associated with resistance to anti-EGFR antibody in colorectal cancer or trastuzumab in breast cancer, their implications for trastuzumab resistance in HER2-positive advanced gastric cancer (AGC) remains unclear. We aimed to assess the relationship between trastuzumab efficacy and mutation status in the HER family signaling pathway.This study retrospectively evaluated patients with HER2-positive AGC who received first-line trastuzumab-containing chemotherapy between March 2011 and November 2015. Multiplex genotyping, including KRAS, NRAS, PIK3CA, and BRAF, was then performed using the Luminex Assay, after which KRAS amplification was measured using quantitative real-time reverse transcription-polymerase chain reaction. Thereafter, the association between genetic alterations and clinical outcomes were evaluated.KRAS mutation (MT) was detected in 6 of 77 patients (7.8%), whereas KRAS amplification was found in 15 of 67 patients (22%). No mutations in NRAS, PIK3CA, or BRAF were identified. The KRAS MT group showed significantly worse response rates (16.7% vs. 66.2%, P = 0.016), progression-free survival [median, 4.8 vs. 11.6 months; hazard ratio (HR), 3.95; 95% CI, 1.60-9.76; P = 0.0029], and overall survival (11.5 vs. 23.6 months; HR, 3.80; 95% CI, 1.56-9.28; P = 0.033) compared to the KRAS wild-type group. KRAS amplification had no effect on clinical outcomes.KRAS mutation was an independent prognostic factor for poor survival and might predict insufficient trastuzumab efficacy, whereas KRAS amplification showed no prognostic significance during trastuzumab treatment. Further investigations are warranted to confirm the predictive value of KRAS status in HER2-positive AGC.

Global studies have been planned to achieve early approval of the new agent especially in cancer chemotherapy. On the other hand, it is important to consider the difference in efficacy among each region. As medical approval in Japan means reimbursement of medical cost, new drug is required to show its effectiveness in the medical situation in Japan, and the Japanese subgroup data is important. Especially in the gastric cancer field, where there is a large difference in survival time and surgical outcome between Japan and outside Japan need to consider Japanese domestic data. But characteristic of Japanese subgroup is the number of target patients is small, high censored case due to longer survival and the background factors are not even. So the interpretation of the data requires caution because of these robustness.

Various malignancies exhibit high microsatellite instability (MSI-H) or mismatch repair deficiency (dMMR). The MSI-IVD kit, a polymerase chain reaction (PCR)-based method, was the first tumor-agnostic companion diagnostic to detect MSI status in MSI-H solid tumors. Recently, next-generation sequencing (NGS), which can also detect MSI-H/dMMR, has been made clinically available; however, its real-world concordance with PCR-based testing of MSI-H/dMMR remains to be investigated. The co-primary end points included the positive and negative predictive values of MSI-H/dMMR. A retrospective analysis of 80 patients who had undergone both MSI testing and NGS between July 2015 and March 2021 was conducted. Five patients were confirmed to have MSI-H in both examinations. Among the 75 patients diagnosed as microsatellite stable (MSS) by PCR-based testing, one with pancreatic cancer was diagnosed as having MSI-H after NGS. One patient with pancreatic cancer was diagnosed as having MSS in both tests was found to have a mutation in MLH1 by NGS, which was confirmed as dMMR by IHC staining. NGS had positive and negative predictive values of 100% (5/5) and 98.7% (74/75), respectively, for MSI-H. The concordance between NGS and PCR-based testing was 98.8% (79/80). Thus, NGS can be useful for evaluating MSI/MMR status in clinical practice and can be an important alternative method for detecting MSI-H/dMMR in the future.

The SARS-CoV-2 was first identified in December 2019 in Wuhan, China. Since then, the ongoing COVID-19 pandemic has drastically changed the healthcare system, including cancer treatments worldwide. Since March 2020 in Japan, cancer patients faced a crisis; they suffered from delays or restrictions in cancer treatment during the initial outbreak. At present, we can perform cancer treatment as usual. Most of the treatments depend on continuous infection control by cancer patients and their families. However, the need to recognize cancer treatment management during the COVID-19 pandemic is crucial. Cancer treatment practice, purpose, risk factors, and the evidence during clinical trials should be comprehensively evaluated and adapted for each patient. Moreover, there is a need to discuss care planning between healthcare professionals, patients, and their families in advance. The COVID-19 vaccine could be essential for cancer patients. In this article, we review cancer treatment points for implementing whole-person care, including advanced care planning for patients with gastrointestinal malignancies, during the COVID-19 pandemic.

Background: Various malignancies exhibit high microsatellite instability (MSI-H) or mismatch repair deficiency (dMMR). The MSI-IVD kit, which can detect MSI status using a polymerase chain reaction (PCR)-based method, was approved as the first tumor-agnostic companion diagnostic for pembrolizumab in patients with MSI-H solid tumors in Japan. Recently, next-generation sequencing (NGS), which can also detect MSI-H/dMMR, has been made clinically available. However, the real-world concordance in MSI-H/dMMR between the PCR-based testing and NGS is yet to be thoroughly investigated.Methods: A retrospective study was conducted to evaluate the utility of MSI testing using PCR-based testing and NGS assay in patients eligible for both MSI testing and any NGS platform. Co-primary endpoints included positive and negative predictive values of MSI-H/dMMR.Results: Between December 2018 and June 2020, 40 patients underwent both PCR-based MSI testing and NGS assay for MSI. Two patients with gastric neuroendocrine carcinoma and ovarian cancer were confirmed to have MSI-H/dMMR in both examinations. Among the 38 patients diagnosed as microsatellite stable by PCR-based testing, 2 (5.2%) with pancreatic cancer were diagnosed as MSI-H after NGS analyses. NGS had positive and negative predictive values of 100% (2/2) and 94.7% (36/38), respectively, for MSI-H, while the concordance between NGS and PCR-based testing was 94.9% (38/40).Conclusion: Similar to PCR-based MSI testing, NGS can be useful for evaluating MSI/MMR status in clinical practice and could be an important alternative method for detecting MSI-H/dMMR in the future.

Primary tumor location and RAS and BRAF V600E mutations are predictors of the efficacy of epidermal growth factor receptor (EGFR) inhibitors. However, there are limited reports on their effects on the outcomes of third-line chemotherapy with EGFR inhibitors in metastatic colorectal cancer (mCRC) patients.We retrospectively collected the clinical data of KRAS exon 2 wild type (WT) mCRC patients treated with EGFR inhibitor monotherapy or EGFR inhibitor plus irinotecan as third-line chemotherapy. The association between primary tumor location, RAS (KRAS exon 3, 4 or NRAS), BRAF V600E, and PIK3CA mutational status, and treatment outcome was evaluated.A total of 72 patients were included in this study. In multivariate analysis, RAS (p=0.004) and BRAF mutations (p=0.00008) were independent factors for shorter PFS. Poor performance status (p=0.01) and BRAF mutation (p=0.00002) were independent factors for shorter OS, whereas primary tumor location and PIK3CA mutation did not influence survival.Additional analysis of RAS and BRAF mutations could contribute to the selection of patients who are likely to benefit from third-line EGFR inhibitors, regardless of primary tumor location.

The aim of this study was to determine the risk factors for immune-related adverse events (irAEs) induced by immune checkpoint inhibitors. The authors conducted a retrospective study in which patients with malignant melanoma, non-small-cell lung cancer, gastric cancer or renal cell carcinoma who received anti-PD-1/PD-L1 antibodies were included. Of 247 patients, 118 developed a total of 182 irAEs. In the multivariate Fine–Gray regression analysis, serum albumin level ≥3.6 g/dl (hazard ratio: 1.62; 95% CI: 1.10–2.39; p = 0.015) and history of Type I hypersensitivity reactions (hazard ratio: 1.48; 95% CI: 1.02–2.14; p = 0.037) were significantly associated with the development of irAEs. High serum albumin levels and history of Type I hypersensitivity reactions are risk factors for irAEs.

Background: Despite the proven efficacy of immune checkpoint inhibitors (ICIs) against various types of malignancies, they have been found to induce immune-related adverse events, such as enterocolitis; however, the clinical features of ICI-induced enterocolitis remain to be sufficiently elucidated, which is significant, considering the importance of early detection in the appropriate management and treatment of ICI-induced enterocolitis. Therefore, the current study aimed to determine the utility of capsule endoscopy as a screening tool for ICI-induced enterocolitis. Methods: This single-center, prospective, observational study was conducted on patients with malignancy who received any ICI between April 2016 and July 2020 at Keio University Hospital. Next, second-generation capsule endoscopy (CCE-2) was performed on day 60 after ICI initiation to explore the entire gastrointestinal tract. Results: Among the 30 patients enrolled herein, 23 underwent CCE-2. Accordingly, a total of 23 findings were observed in 14 (60.8%) patients at any portion of the gastrointestinal tract (7 patients in the colon, 4 patients in the small intestine, 2 patients in both the colon and the small intestine, and 1 patient in the stomach). After capsule endoscopy, 2 patients (8.7%) developed ICI-induced enterocolitis: both had significantly higher Capsule Scoring of Ulcerative Colitis than those who had not developed ICI-induced enterocolitis (p = 0.0455). No adverse events related to CCE-2 were observed. Conclusions: CCE-2 might be a safe and useful entire intestinal tract screening method for the early detection of ICI-induced enterocolitis in patients with malignancies.

3528 Background: The CpG island methylator phenotype (CIMP), important for carcinogenesis, is a predictor of prognosis and chemotherapy sensitivity in colorectal cancer. However, there is a lack of consensus of CIMP markers, and thus, more comprehensive methylation markers are required to reliably predict the clinical outcomes. Previously, we reported that genome-wide DNAmethylation statuscould predict the effect of epidermal growth factor receptor (EGFR) inhibitors more accurately than previously reported methylation classifications (Ouchi et al. Cancer Sci 2015). Moreover, we had developed a DNA methylation assay based on MethyLight to reflect genome-wide DNA methylation status and reported its usefulness in predicting prognosis in patients with metastatic colorectal cancer (mCRC) treated with EGFR inhibitors as a third-line chemotherapy (Ouchi et al. Cancer Sci 2022). This study aimed to clarify the effects of genome-wide DNA methylation status on clinical outcomes in patients with mCRC treated with first-line EGFR inhibitors. Methods: We enrolled 241 patients with mCRC, who received chemotherapy plus EGFR inhibitors as a first-line treatment, and analyzed the associations between genome-wide DNA methylation status using a novel comprehensive methylation marker panel and clinical outcomes and evaluated the predictive power and value of the methylation status. Results: Total 169 patients were included in the final analyses. The frequency of highly methylated CRC (HMCC) was 8.9% (15/169). The characteristics of patients with HMCC included right-sided primary tumor location (P = 0.042), undifferentiated histology (P = 0.047), and BRAFV600E mutation (P < 0.001). Patients with HMCC showed worse clinical outcomes than those with low methylated CRC in terms of response rate (P = 0.017), progression-free survival (PFS; P = 0.004), and overall survival (P = 0.019). In the multivariate analysis, peritoneal metastasis (Hazard ratio (HR): 2.24, P = 0.017), methylation status (HR: 3.04, P = 0.037), and BRAFV600E mutations (HR: 5.83, P = 0.0001) were independent factors for shorter PFS. Conclusions: Genome-wide DNA methylation status may be an independent predictor of first-line EGFR inhibitors in patients with mCRC.

178 Background: Colorectal cancer with liver metastases (CLM) has high post operative recurrence rates, and optimizing the perioperative treatment is imperative. Post operative carcinoembryonic antigen (CEA) can help detecting minimal residual disease in colon cancer after curative resection. Methods: The aim of this study was to identify the potential role of serum CEA after liver resection in patients with CLM. This study was conducted at the Cancer Institute Hospital, Japanese Foundation for Cancer Research from 2004 to 2018. Patients with CLM who underwent complete resection of primary tumors and liver metastases were enrolled in this study. We studied the associations between the perioperative CEA levels and characteristics of recurrence. Results: Recurrence was detected during the median follow-up time of 50.9 months in 343 (54.1%) of the total 633 patients analyzed. Patients with postoperative CEA (>5) group had a significantly higher recurrence rate (75.7% vs 50.0%, p < 0.01), with a shorter time until recurrence (4.4 months vs 36.9 months, p < 0.01) than those with a postoperative CEA level (≤5) group. In multivariate analysis, a postoperative CEA level >5 ng/ ml was an independent predictor, with the highest hazard ratio for both recurrence free survival (RFS) and overall survival (OS) (RFS: 2.77, 95% confidence interval [CI] 2.14–3.60, p 5) group who did not have normalized CEA levels after adjuvant chemotherapy compared to normalized CEA group (3.3 months vs 18.5 months, p = 0.008). Conclusions: The postoperative CEA and postadjuvant chemotherapy CEA level in the CEA level (>5) group after surgery may be a predictor of RFS and OS.

37 Background: The survival benefit of FOLFOXIRI plus bevacizumab (Triplet) over Doublet in patients (pts) with BRAFV600E-mutant metastatic colorectal cancer (mCRC) remains controversial. We compared Triplet therapy with Doublet and explored the pts subgroups that could benefit from intensive chemotherapy (chemo) using real-world data. Methods: WJOG13219G was a multicenter, retrospective registry-based study of pts with BRAFV600E-mutant mCRC who received first-line doublet or triplet chemo with/out molecular targeted agents in January 2014–December 2019. Primary analysis focused on pts who received VEGF inhibitor-containing chemo. To adjust pts background, the inverse probability of treatment weighting (IPTW) method based on propensity scores calculated by age, ECOG PS, and disease status (recurrent/metastatic) was used. Results: A total of 232 pts from 33 hospitals were registered. After excluding 18 pts treated with anti-EGFR antibody-containing regimen and 44 without any targeted agents, 79 pts with Triplet and 91 with Doublet were analyzed. Baseline pts disposition was as follows: median age, 61 y; male proportion, 51%; PS 0/1/≥2, 63%/32%/5%; recurrent/metastatic, 26%/74%; and right/left primary, 68%/32%. Significant differences were noted in age and PS between the two groups. At median follow-up of 24.0 months, no statistical difference was noted in progression-free survival (PFS) (median 9.7 months of Triplet vs. 7.8 months of Doublet, HR = 0.89, P = 0.49) and overall survival (OS) (median 18.7 vs. 18.3 months, HR = 0.87, P = 0.52). The objective response rate was 53% in the Triplet group and 41% in Doublet (P = 0.10). Curative surgery after chemo was more frequent in the Triplet group than in Doublet (13% vs. 3%, P = 0.02). Two pts (3%) in the Triplet group and 6 (7%) in Doublet received immunotherapy as subsequent chemo; 13 (16%) and 6 (7%) also received BRAF inhibitor-containing therapy. IPTW analysis showed no difference between the two groups in PFS (HR = 0.82, P = 0.07) and OS (HR = 0.92, P = 0.57). In the subgroup analysis, pts with right-sided primary tumor in the Triplet group showed favorable trends of PFS (HR, 0.87; 95% CI, 0.65–1.16) and OS (HR, 0.71; 95%CI, 0.50–1.01), whereas pts with left-sided tumor in the Triplet group showed the reverse trends of PFS (HR, 1.17; 95% CI, 0.77–1.78) and OS (HR, 1.68; 95% CI, 0.97–2.91). Conclusions: Some baseline characteristics were significantly different between real-world pts in the Triplet and Doublet groups. Although the Triplet group did not show any survival benefit compared with Doublet in the original and IPTW cohorts, pts with right-sided BRAFV600E-mutant mCRC could benefit from Triplet therapy.

258 Background: An acceleration of tumor growth during immunotherapy, (hyperprogressive disease [HPD]: defined as >2 times increase in tumor growth rates during nivolumab compared with prior chemotherapy, Champiat S, 2017) has been reported. We reviewed the prevalence and clinical outcomes of HPD in AGC patients treated with nivolumab, and reported that there were no differences either in progression-free survival (PFS) or overall survival (OS) between patients with HPD and those with PD other than HPD (Suzuki T, ASCO Gastrointestinal Cancers Symposium 2020). Then, we hypothesized that PD in unmeasurable lesion (ascites representing peritoneal metastasis) and appearance of new lesions, which are not included in definition of HPD, might have influenced the prognosis of AGC. Methods: The subjects of this retrospective study were 245 AGC patients with measurable disease who received nivolumab after failure of >2 chemotherapy regimens, and their responses were assessed at least 3 times (during prior therapy, before and after nivolumab) in 24 institutions. We explored the impact on prognosis of HPD, new lesion, increase of ascites in AGC patients receiving nivolumab 3 mg/kg or 240 mg/body intravenously every 2 weeks. We divided patients to 4 group according to new lesions at different organ/increase of ascites: Group (G) 1 (-/-), G 2 (+/-), G 3 (-/+), G 4 (+/+). Results: One hundred forty-seven patients (60%) showed PD, and their PFS and OS were 1.5 months(M) and 4.8 M, while those of 41 patients (16.7%) with HPD were 1.4 M and 5.0 M. Fifty-three patients showed appearance of new lesions at different organ and 58 patients showed increase of ascites (31 patients showed both). Survival outcomes of the 4 groups are shown in the Table. Patients with appearance of new lesions at different organ showed shorter prognosis compared with patients without it (median OS: G 2+4 vs G 1+3, 3.3 M vs 7.1 M; hazard ratio [HR], 1.8 [95% CI: 1.2–2.7]; p = 0.003). Also, patients with increase of ascites showed shorter prognosis compared to patients with stable/decrease of ascites (median OS: G 3+4 vs G 1+2, 3.0 M vs 7.8 M; HR, 2.6 [95% CI: 1.8–3.8]; p < 0.001). More of patients with increase of ascites could not receive subsequent chemotherapy after disease progression than others (G 1+2 vs G 3+4, 51.7% [46/89] vs 75.9% [44/58]; p = 0.03). Large tumor size, number of prior lines of chemotherapy, and high neutrophil-to-lymphocyte ratio at baseline were associated with G 4. Conclusions: Appearance of new lesions at different organ and increase of ascites, not HPD, were disease progression pattern associated with poor prognosis in AGC patients receiving nivolumab.[Table: see text]

377 Background: Nivolumab has demonstrated a survival benefit for advanced gastric cancer (AGC). However, hyperprogressive disease (HPD) has been reported in various cancers. Methods: The subjects of this retrospective study were AGC patients with measurable disease who received nivolumab, and their tumors were assessed at least 3 times (during prior therapy, before and after nivolumab) in 24 institutions. Tumor growth rates (TGR) during nivolumab were compared to those during prior therapy as reported (Champiat S, 2017). HPD was defined as an increase in TGR > 2-fold. Results: 218 patients were identified as the subjects. While 33 (15.1%) partial response (PR) were achieved, 130 patients (59.6%) showed progression disease (PD), 38 of whom were classified as HPD (17.4%) and 2 patients showed pseudo progression (1.0%). The median progression-free survival (PFS) was 1.9 months (95% CI: 1.9–2.4) and the median overall survival (OS) was 8.5 months (95% CI: 7.1–9.6) in all patients. While patients with PD showed shorter prognosis compared with non-PD patients (median PFS: 1.5 months vs 6.4 months, hazard ratio; 6.0 [95% CI: 4.3–8.4]; p < 0.0001; median OS: 4.7 months vs not reached, hazard ratio; 4.1 [95% CI: 2.8–6.3]; p < 0.0001), there were no differences either in PFS or OS between patients with HPD and those with PD other than HPD (median PFS: 1.5 months vs 1.6 months, hazard ratio; 1.3 [95% CI: 0.9–2.0]; p = 0.1194; median OS: 5.0 months vs 4.6 months, hazard ratio; 1.0 [95% CI: 0.6–1.5]; p = 0.8695). Histological type, liver metastases, carbohydrate antigen 19-9 (CA19-9) level were associated with HPD. Conclusions: HPD was observed 17.4% in AGC patients treated with nivolumab. There were no differences either in PFS or OS between patients with HPD and those with PD other than HPD. Clinicopathological characteristics might be a predict factor for HPD.

Background Prognosis for locally advanced gastric cancer (LAGC), such as clinical T4 disease, bulky nodal metastases, type 4 and large type 3 gastric cancer, was not satisfactory even by D2 gastrectomy followed by adjuvant chemotherapy. Neoadjuvant chemotherapy is another promising approach. We conducted a multi-institutional, single-arm, open label, phase II study (Clinical trial information: UMIN000018661). The aim of this study was to evaluate the efficacy and safety of the neoadjuvant chemotherapy of G-SOX followed by gastrectomy with D2/3 lymph node dissection for LAGC. Methods Eligibility criteria included histologically proven adenocarcinoma of the stomach; clinical T4; clinically resectable gastric cancer of type 4 or large type 3 (over 8 cm); bulky nodal metastases around major branched arteries to the stomach; resectable peritoneal dissemination (pathological CY1 or P1, except for clinical CY1 or P1). Patients received two cycles of neoadjuvant chemotherapy with S-1 (80 mg/m2, p.o., days 1-14 followed by 1 week rest) and oxaliplatin (130 mg/m2 at day 1), followed by D2 or higher surgery with no residual disease. Patients with pathological R0/1 resection received S-1 (80 mg/m2, p.o., days 1-28 followed by 2 week rest) for 1 year as adjuvant chemotherapy. Primary endpoint was curative resection rate. Results Forty-one patients were enrolled from 11 institutions. Of the patients, 39 patients (95%) completed the two courses of neoadjuvant chemotherapy of G-SOX, 37 (90%) received gastrectomy, and 36 (87.8%) received curative resection (R0/1). Pathological response rate after neoadjuvant chemotherapy of G-SOX was 40.5%. Most frequent drug-related adverse events during neoadjuvant chemotherapy of G-SOX were anemia (76%), neutropenia (66%), anorexia (63%) and peripheral sensory neuropathy (63%). No treatment related deaths were observed. Conclusions Neoadjuvant chemotherapy of G-SOX is a feasible and one of the promising strategies for patients with LAGC. Clinical trial identification UMIN000018661. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure H. Satake: Honoraria (self): Taiho; Honoraria (self): Yakult. M. Kotaka: Honoraria (self): Taiho; Honoraria (self): Yakult. T. Kato: Honoraria (self): Taiho; Honoraria (self): Yakult. A. Tsuji: Honoraria (self): Taiho; Honoraria (self): Yakult. All other authors have declared no conflicts of interest.

Background Immune checkpoint inhibitors (ICIs) have been approved in various type of cancers. Although ICIs are less toxic than cytotoxic chemotherapy, they cause various immune-related adverse events (irAEs). A cooperation with experts is needed to diagnose and treat irAEs properly. The aim of this study was to evaluate frequency and management of irAEs in a real-world practice. Methods We conducted a retrospective study of patients(pts) who received ICIs (ipilimumab, nivolumab, pembrolizumab, atezolizumab or avelumab) at Keio university hospital between September 2014 and January 2019. Treatment-related AEs were retrospectively evaluated from medical records and graded using Common Terminology Criteria for Adverse Events version 4. Results ICIs were administered in 299 pts with lung cancer (n = 123), malignant melanoma (n = 63), renal cell carcinoma (n = 37), gastric cancer (n = 29), head and neck cancer (n = 26), urothelial cancer (n = 19), Merkel cell carcinoma and microsatellite instability-high ovary cancer (n = 1). A total of 209 pts experienced any grade of AEs. In 60 pts experienced grade ≥3 AEs, pneumonitis and ALT increased (5.3%) were most frequently identified, followed by adrenal insufficiency (3.0%) and diarrhoea (2.7%). No cancer-type specific tendency was observed. Pts who were treated with ipilimumab experienced ≥3 AEs more frequently than those with anti-PD1 antibodies (p = 0.0003). Regarding the treatment to grade ≥3 AEs, all pts with pneumonitis received therapeutic intervention by respiratory physicians. Although only 63% of diarrhoea and 50% of ALT increased pts had an examination by gastroenterologists or hepatologists, those who needed immunosuppressive treatment were supported by experts appropriately. Conclusions The incidence of ICI-related AEs in our hospital was comparable to previous reports. The cooperation with experts for irAEs would be important for proper management of irAEs.

Backgroud Recent studies reported that anti-PD-1 antibody increases the sensitivity of subsequent chemotherapy in several types of cancer. However, there is no evidence for the efficacy of subsequent chemotherapy after nivolumab in patients with gastric cancer. Method We retrospectively assessed clinical data of patients with metastatic or unresectable gastric cancer who were treated with nivolumab in Keio university hospital between September 2017 and January 2019. Tumor response and prognosis of subsequent chemotherapy after nivolumab were evaluated. Tumor response was evaluated according to Response Evaluation Criteria for Solid Tumors ver 1.1. Result Of 34 patients treated with nivolumab, 12 patients received subsequent chemotherapy after cessation of nivolumab (CapeOX n = 6, irinotecan n = 3, others n = 3). Response rate and disease control rate were 25% and 42%, respectively. Median progression-free survival (PFS) and median overall survival were 2.5 months and 4.5 months, respectively. In all 3 patients achieved partial response by subsequent chemotherapy, nivolumab was administered as third-line therapy and continued over 9 months with stable disease. Durable response was observed in two patients treated with CapeOX and irinotecan (PFS 15.7 and 15.6 months, respectively). These two patients survive more than 2 years after cessation of nivolumab due to progressive disease. Conclusion Although sample number was limited, higher response rate was observed in patients with subsequent chemotherapy after nivolumab compared to previous reports of salvage line chemotherapy without nivolumab. The mechanism and biomarker of hypersensitivity for subsequent chemotherapy should be elucidated.