3518 Background: Rechallenge with anti-EGFR monoclonal antibody (EGFR mAb) showed certain activities in patients (pts) with RAS/ BRAF V600E wild-type (wt) metastatic colorectal cancer (mCRC), particularly in pts with negative plasma RAS (p RAS) mutation by circulating-tumor DNA (ctDNA) assay at ‘just before’ the rechallenge therapy. However, the efficacy is unknown in pts with RAS/ BRAF wt mCRC whose p RAS was converted to positive once during or after EGFR mAb. Therefore, we conducted REMARRY, a prospective longitudinal study to investigate the p RAS dynamics, and PURSUIT trials, a phase II trial to investigate the efficacy of EGFR mAb rechallenge in pts with p RAS wt just before rechallenge therapy. Methods: The eligibility criteria of REMARRY trial included RAS/ BRAF V600E wt mCRC; ECOG PS 0-1; CR or PR during EGFR mAb; and a refractory ≤ 2 months from the last administration of EGFR mAb. p RAS status by the BEAMing method was prospectively monitored at timepoints of progression on EGFR mAb and each subsequent therapy. The eligibility criteria of PURSUIT trial included enrollment in the REMARRY trial with confirmed p RAS wt prior to enrollment in PURSUIT trial; being refractory or intolerant to fluoropyrimidine, oxaliplatin, and irinotecan; and ≥ 4 months of EGFR mAb-free interval. Study treatment was rechallenge with panitumumab + irinotecan (6 mg/kg + 150 mg/m2 q2wks). Primary endpoint was a confirmed objective response rate (ORR) according to RECIST v1.1. The required number of pts was 45, with a null ORR of 10%, an expected ORR of 25%, power of 85%, and one-sided α of 0.05. Results: Between May 2019 and May 2021, 183 pts with 343 timepoints (median, 2) were enrolled in REMARRY trial from 27 institutions, and 50 pts were enrolled in PURSUIT trial; median age, 68 years; left-sided primary, 44 pts; prior EGFR mAb, 1st/2nd/≥3rd lines was 28/6/16 pts; and p RAS status at progression on prior EGFR mAb, wt/mutant (mt)/unknown in 31/7/12 pts. Confirmed ORR and disease control rate were 14% (90% CI, 7.8%–23.9%) and 80% (95% CI, 67.0%–88.8%), respectively. In addition, 4 pts showed an unconfirmed PR. With a median follow-up time of 8.7 months, median progression-free survival was 3.6 months (95% CI, 3.0 – 4.7 months). The subgroup analysis showed a significantly higher confirmed ORR in pts with a longer EGFR mAb-free interval than a shorter one (> vs. < 365 days, 44.4% vs. 7.3%, p = 0.0037). Without any unexpected safety signals, 58.5% of pts had ≥ grade 3 adverse events. Of 31 patients with wt p RAS at progression on prior EGFR mAb, 5 had a confirmed response (ORR, 16%), whereas no response was observed in patients with 7 p RAS mt (ORR, 0%) (p = 0.25). Conclusions: The primary endpoint of confirmed ORR was not met; however, pts with p RAS wt at progression on prior EGFR mAb may benefit from rechallenge with, implying a lack of or worse response if p RAS becomes positive even once during or after EGFR mAb. Clinical trial information: REMARRY: UMIN000036424 PURSUIT: jRCTs031190096.

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3506 Background: The ’’Neo RAS’’ phenomenon refers to RAS mutant (MT) metastatic colorectal cancer (mCRC) that becomes RAS wild-type (WT) following treatment. This Neo RAS WT population might represent a novel indication for EGFR inhibitors, which are less effective in RAS MT mCRC. The incidence and clinicopathological characteristics of Neo RAS WT mCRC using plasma cell-free DNA (cfDNA) next generation sequencing has not been defined. Methods: As part of a large-scale nationwide screening platform (SCRUM-Japan GOZILA), 478 patients with an initial diagnosis of RAS MT mCRC by tissue analysis (MEBGEN RASKET-B) who received systemic therapy underwent cfDNA testing (Guardant 360) prior to later lines of treatment. Based on the cfDNA results, we evaluated the clinicopathological characteristics of those with Neo RAS WT and RAS MT. Neo RAS WT was defined as no RAS MT ( KRAS or NRAS) detected in plasma and was assessed in the overall cohort (Cohort A) and in the subgroup with at least one somatic alteration detected in plasma (Cohort B) to exclude those with insufficient tumor DNA shedding. Results: Median age at the time of blood sampling was 62.0 years old, and 257 (51.9%) were men. 160 (32.3%) and 319 (64.4%) had right-sided tumors and multi-organ metastases. The lungs were the most frequent site of metastasis (60.2%), followed by liver (57.4%), lymph nodes (28.9%), and peritoneum (28.5%). The prevalence of Neo RAS WT was 19.0% (91/478) in Cohort A and 9.8% (41/429) in Cohort B. The frequency of Neo RAS WT in tumors originally with KRAS exon 2 MT tended to be lower than in those with other RAS MT (18.1% vs 25.4%, P = 0.21 in Cohort A, 9.0% vs 15.4%, P = 0.14 in Cohort B). There were significant differences in the prevalence of Neo RAS WT between patients with single organ vs multi-organ metastases (P < 0.001 in Cohort A, P = 0.004 in Cohort B), absence vs presence of liver metastasis (P < 0.001 in both Cohort A and B), lymph node metastasis (P = 0.006 in Cohort A), peritoneal metastasis (P = 0.002 in group A), and bone metastasis (P = 0.029 in Cohort A), testing immediately prior to 2nd through to 4th line treatment vs later lines (P = 0.007 in Cohort A), immediate prior use of regorafenib (P = 0.027 in Cohort A) and any history of vascular endothelial growth factor inhibitors (P = 0.003 in Cohort A, P = 0.035 in Cohort B). In the logistic regression multivariate analysis, absence of liver metastasis (odds ratio [OR], 5.83; P < 0.001 in Cohort A, OR, 2.84; P = 0.005 in Cohort B), absence of lymph node metastasis (OR, 2.18; P = 0.034 in Cohort A) and tissue RAS MT other than KRAS exon 2 (OR, 2.35; P = 0.049 in Cohort B) were significantly related to the emergence of Neo RAS WT. Among 6 Neo RAS WT patients tretd with EGFR inhibitors, one had partial response and another one had stable disease for at least 6 months. Conclusions: Liver and lymph node metastasis and RAS MT other than those in KRAS exon 2 are factors associated with the development of Neo RAS WT mCRC. EGFR inhibitors might be effective treatment.

TPS3623 Background: Immune checkpoint inhibitor (ICI) was reported to show durable responses in patients with MSI-H (Microsatellite Instability-High) metastatic colorectal cancer (mCRC). On the other hand, for patients with MSS (Microsatellite Stable) mCRC, ICI monotherapy achieved no response. Recently, WNT/β-catenin signaling has been reported to be involved in the elimination of tumor-infiltrating lymphocytes and the resistance of anti-PD-L1 antibodies. CRC is representative cancer with WNT/β-catenin pathway activation. Furthermore, STAT3 has also been reported to be a key driver of this immune evasion. Considering these rationales, the blocking of these signaling pathways with ICI may enhance antitumor immune response. Therefore, we initiated phase I/II study to assess efficacy and safety for the combination of BBI608, which blocks STAT3 and WNT/β-catenin signaling, with pembrolizumab in patients with mCRC. Methods: The eligibility criteria were patients with gastrointestinal cancer not responded to or intolerant of standard chemotherapies (SOC) for phase I part, and MSS mCRC refractory or intolerant to fluoropyrimidine, irinotecan, oxaliplatin, and anti-EGFR antibody (if wild-type RAS) for Cohort B in phase II part. For Cohort A, MSI-H mCRC refractory or intolerant to the SOC, irrespective of anti-EGFR antibody are investigated. Phase I part was designed to determine the recommended phase II dose in a “3+3” cohort-based dose escalation design of BBI608 (240mg BID every day on level 1 and 480mg BID every day on level 2) with pembrolizumab (200mg/body q3w). Primary endpoint of the phase II part is Immune-related objective response rate (irORR) determined by their Response Evaluation Criteria In Solid Tumors (irRECIST). A null hypothesis and alternative hypothesis for cohort B are irORR = 5% and 20%, respectively. Required sample size for Cohort B was 40 with a one-sided alpha of 5% and power of 90%. Required sample size for Cohort A (10 patients) was determined in an exploratory manner. We also investigate biomarker study using paired samples of both tumor biopsy and blood. The enrollment to phase I part began in November 2016. Clinical trial information: NCT02851004. Clinical trial information: NCT02851004.

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459 Background: The DESTINY-Breast04 data demonstrated the antibody-drug conjugate trastuzumab deruxtecan (T-DXd) was also effective for metastatic breast patients (pts) with HER2-low expression. Now that the HER2-low expressed cancer is categorized as an independent subset in breast cancer patients. It is unknown whether patients with the HER2-low expression are distinguishable from the HER2 negative or positive and are potential candidates for the anti-HER2 therapy in advanced gastric cancer (AGC) patients. Methods: We retrospectively reviewed the medical records of AGC pts who received standard chemotherapy with platinum containing regimens as the first-line treatment between Jan, 2011 and Dec, 2018 at the Cancer Institute Hospital of the JFCR. AGC pts were classified according to the HER2 status using immunohistochemistry (IHC) and in situ hybridization (ISH) as follows; HER2 negative (IHC 0), HER2-low (IHC 1+ or 2+/ISH-) and HER2 positive (IHC2+/ISH+ or 3+). This study was conducted to investigate the clinicopathological features and prognosis of HER2-low AGC pts compared with HER2 negative and positive. Results: A total of 734 AGC pts were received HER2 testing and classified into three groups according to HER2 status (HER2 negative; n=410, HER2-low; n=154, HER2 positive; n=170). The proportion of male (negative; 61.5%, low; 63.6% and positive; 69.4%), intestinal histology (negative; 21.0%, low; 44.2% and positive; 59.8%), liver metastases (negative; 18.3%, low; 24.8% and positive; 46.5%), higher serum CEA level (>ULN) (negative; 32.2%, low; 41.6% and positive; 56.5%) and higher serum CA19-9 level (>ULN) (negative; 34.1%, low; 36.7% and positive; 56.5%) were gradually increased along with HER2 expression level. The proportion of peritoneum metastasis (negative; 56.3%, low; 44.8% and positive; 21.8%) was decreased along with the HER2 expression level. One hundred and fifty-two pts (89.4%) received combination chemotherapy with trastuzumab in the first-line treatment. Sixteen pts received trastuzumab in the HER2-low (n=3) and HER2 negative (n=13) in the clinical trial. The median survival time (MST) of pts with HER-low was the same with that of HER2 negative (15.7ms). The statistically significant difference was observed in OS between the HER2-low and HER2 positive (HR 1.43 95% CI: 1.12-1.83, P=0.003). Conclusions: AGC Pts with HER2-low have intermediate clinicopathological features between HER2 negative and positive. A Novel effective anti-HER2 therapy for the HER2-low expressed tumor would be warranted in AGC treatment.