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Association between immune-related adverse events and prognosis after immune checkpoint inhibitor in hepatocellular carcinoma: A meta-analysis and systematic review.
566 Background: Immune checkpoint inhibitors (ICIs) have become the preferred treatment for unresectable hepatocellular carcinoma (HCC). Conflicting data exist regarding the prognostic value of immune-related adverse events (irAEs) in these patients. We aimed to explore potential the association between irAEs and prognosis in HCC patients treated with ICIs. Methods: We searched PubMed, Scopus, Web of Science, and CENTRAL databases for articles published from inception to June 2024 using keywords including ICI, HCC, and irAEs. Two reviewers independently screened studies for eligibility and relevant data. A random effects model was used for statistical analysis, and subgroup analysis was performed by the grade of irAEs. Results: Of 3,028 studies, 25 (n=4,116 patients) met criteria for inclusion. Atezolizumab plus bevacizumab was the most common treatment regimen (n=10 studies). About half (49.5%) of patients experienced irAEs. irAEs were associated with increased objective response rate (ORR) (pooled OR: 1.72; 95% CI: 1.36 – 2.19, I 2 =39%), higher complete response rate (pooled OR: 1.45; 95% CI: 1.21-1.74, I 2 =74%), and longer progression-free survival (PFS) (pooled HR: 0.66; 95% CI: 0.52-0.84, I 2 =71%). Although irAEs were associated with longer overall survival, this difference was not statistically significant (pooled HR: 0.83; 95% CI: 0.62 – 1.11, I 2 =73%). Subgroup analysis showed a survival benefit for patients with grade 1-2 irAEs (pooled HR: 0.50; 95% CI: 0.36-0.67, I 2 =0%) but not for those with grade 3-4 irAEs (pooled HR: 0.95; 95% CI: 0.24-3.72, I 2 =84%). Conclusions: The development of irAEs is associated with a favorable prognosis in HCC, including improved PFS and higher ORR. A survival benefit was noted in patients with mild irAEs, but not in those with severe irAEs. Future studies are needed to determine if a differential survival benefit relates to the continuation vs. discontinuation of ICI therapy.
Phase I/Ib study of afatinib with capecitabine in patients with refractory solid tumors and pancreaticobiliary cancers.
594 Background: The epidermal growth factor receptor (EGFR) and ErbB2/HER2 signaling is overactive in many solid tumors. Afatinib, an irreversible inhibitor of ErbB signaling, downregulates thymidine synthase and synergizes with capecitabine in preclinical models. This phase I trial evaluated the safety, maximum tolerated dose (MTD) and preliminary efficacy of afatinib plus capecitabine in patients (pts) with refractory solid tumors and pancreatic ductal adenocarcinoma (PDA) and biliary tract cancers (BTC). Methods: The phase I study had a 3+3 design with capecitabine 1000 mg/m 2 twice daily (BID) on days 1-14 and afatinib 20 mg, 30 mg or 40 mg daily (QD) in 21-day cycles. In phase Ib, 15 pts each with PDA and BTC were treated at MTD. Results: 41 pts enrolled from November 2016 to October 2021, who received a median of 2 (range 1-5) prior therapies. No dose-limiting toxicities were observed. The MTD was 40 mg afatinib QD plus 1000 mg/m 2 capecitabine BID. Grade 3 treatment related adverse events were diarrhea (12.2%) and nausea (4.9%). Among 36 response evaluable pts, best response was 1 partial response (PR, 3%) in a pt with KRAS wild type (WT)/EGFR amplified BTC, and 8 stable diseases (SD, 22%), with disease control rate (DCR) of 25%. PDA pts (n=20) had DCR of 24%, median progression-free (PFS) and overall survival (OS) of 1.9 months (95% CI 1.05, 2.03) and 3.2 months (95% CI 2.01, 5.82) respectively. BTC pts (n=18) had DCR of 31%, median PFS and OS of 1.9 months (95% CI 1.55, 3.39) and 4.6 months (95% CI 1.88, 6.09), respectively. Eight pts with cancers with EGFR/HER2/HER3 pathway alterations, most KRAS WT (n=6), had DCR of 29%, and median PFS and OS of 2.1 months (95% CI 1.05, 4.14) and 3.5 months (95% CI 1.64, 6.09), respectively. Conclusions: Afatinib plus capecitabine is tolerable but does not have significant efficacy in pts with refractory PDA/BTC, including in KRAS WT cancers with EGFR/HER2/HER3 alterations. Clinical trial information: NCT02451553 .
Acquired gene alterations potentially related to resistance to anti-HER2 therapy in HER2-positive metastatic colorectal cancer (mCRC).
277 Background: While HER2-targeted therapies benefit patients (pts) with advanced HER2-positive mCRC, the development of resistance remains inevitable. This study aims to explore the landscape and frequency of genetic alterations putatively associated with acquired resistance to anti-HER2 therapy in HER2-positive mCRC. Methods: In this retrospective-multicenter international study involving Mayo Clinic, Duke Cancer Center and National Cancer Center Hospital East (Japan), we descriptively compared comprehensive genomic analyses from tissue or blood samples of pts with HER2-positive CRC pre-treatment and post-treatment with HER2-targeting agents. Results: A total of 36 pts were included in this study. 29 (80%) had HER2-positive mCRC as confirmed by immunohistochemistry (IHC) and fluorescent in situ hybridization (ISH), the remaining pts had HER2 amplification detected on blood or tissue . 34/36 (94%) pts were administered their first anti-HER2 agent after progressing on ≥2 prior lines of treatment. The most common anti-HER2 regimen administered was trastuzumab/pertuzumab (50%, 18/36), followed by trastuzumab-tyrosine kinase inhibitors (TKIs) (tucatinib or neratinib) (30%, 11/36) and trastuzumab deruxtecan (14%, 5/36). Putative genomic mechanisms of acquired resistance were detected in 72% (26/36), while the remaining pts lacked new genomic alterations that might explain resistance to anti-HER2 therapy, suggesting alternative escape mechanisms. Acquired alterations in downstream or alternate bypass pathways were identified in 72% (26/36) of pts; most commonly in the RAS/RAF pathway and in EGFR (34.6%, 9/26 each), followed by 27% (7/26) of pts with MET point mutations (mts) and amplification; activating muts in PI3K/AKT and in 27% (7/26), most commonly CDK12 (60%, 4/7) . HER2 receptor alterations were detected in 3 pts (8.3%), all of whom received trastuzumab-tucatinib and included HER2 L755S, HER2 V777L, HER2 D769Y, HER2 G727A and HER2 S310F, which are known to cause resistance to , however, information about tucatinib resistance is not yet available. Other altered pathways included AR, RB, NOTCH and HRD. Two pts lost HER2 expression on blood and tissue NGS post anti-HER2 therapy. Conclusions: The emergence of resistance might be in part related to acquired alterations that constitutively activate signaling pathways parallel or downstream of HER2, bypassing HER2 inhibition. Additional histologic studies, deep mutational scanning, larger populations and correlative analysis are needed to validate these findings.
Perioperative chemotherapy with either S-1 or 5-fluorouracil plus oxaliplatin and docetaxel for locally advanced gastric or gastroesophageal junction adenocarcinoma: A prospective trial and matched comparison.
396 Background: Perioperative triplet chemotherapy improves the survival and surgical outcome of patients with locally advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma in addition to curative surgery. 5-fluorouracil (5-FU), docetaxel, oxaliplatin and leukovorin (FLOT) has been suggested as the treatment of choice. S-1, an oral fluoropyrimidine chemotherapeutic, also shows compelling efficacy as one of the triplet backbone and is exempt from a prolonged infusion time. However, a comparison over efficacy and tolerability between S-1 or 5-FU-containing triplet has not been investigated. Methods: The study contains two parts. The first part was a prospective single-arm multi-centered phase II trial with eight cycles of perioperative leucovorin, oxaliplatin, docetaxel and S-1 (LOTS) in patients with ≥T3 any N or ≥T2N(+) non-metastatic gastric/GEJ adenocarcinoma. The primary endpoint was the treatment response assessed by pathological tumor regression (TRG). After confirming the result passing the statistical threshold, we compared them with an identical and independent patient population who received perioperative FLOT under a prospective observation. A propensity score matching (PPSM) was used to balance the heterogeneity between the two groups. The efficacy, survival and tolerability were compared in a post-hoc manner. Results: From Feb 2017 to Jan 2024 with a comparable median follow-up time (LOTS, 18.7 ms; FLOT, 18.9 ms), a total of 45 and 154 patients were enrolled and received either LOTS or FLOT treatment. After a one-to-two PPSM procedure, the baseline characteristics of patients were comparable (LOTS, n=45; FLOT, n=90). Patients had similar curative resection rates (LOTS, 91%; FLOT, 86%; p=.359) and above nearly complete pathological regression rates (TRG 0-1: LOTS, 23%; FLOT, 27%; p=.669). The 24-ms recurrence-free (RFS) and overall survival (OS) rates were also comparable (LOTS vs. FLOT: 66 vs. 59% in RFS, p=.463; 73 vs. 68% in OS, p=.491). The toxicities were tolerable, except that more diarrhea and nausea events were reported in the LOTS group, whereas neutropenia, thrombocytopenia and mucositis were significantly prominent in the FLOT group. Conclusions: Perioperative LOTS shows reasonable therapeutic efficacy and survival as compared with FLOT in patients with locally advanced gastric/GEJ cancer. While the toxicity profile is distinctive from FLOT, it could be a potential alternative regimen with the convenience to save the prolonged infusion time. Clinical trial information: NCT04999332 . Pathological outcome. Prior to LOTS treatment (n=45) After LOTS treatment (n=43) Prior to FLOT treatment (n=90) After FLOT treatment (n=86) p in LOTS vs. FLOT CAP TRG, n (%) 0.669 0 - - 1 (2.3) - - 3 (3.5) 1 - - 9 (20.9) - - 20 (23.3) 2 - - 14 (32.6) - - 23 (26.7) 3 - - 19 (44.2) - - 40 (46.5)
An Analysis of Components and Enhancement Strategies for Advancing Memristive Neural Networks
AbstractAdvancements in artificial intelligence (AI) and big data have highlighted the limitations of traditional von Neumann architectures, such as excessive power consumption and limited performance improvement with increasing parameter numbers. These challenges are significant for edge devices requiring higher energy and area efficiency. Recently, many reports on memristor‐based neural networks (Mem‐NN) using resistive switching memory have shown efficient computing performance with a low power requirement. Even further performance optimization can be made using engineering resistive switching mechanisms. Nevertheless, systematic reviews that address the circuit‐to‐material aspects of Mem‐NNs, including their dedicated algorithms, remain limited. This review first categorizes the memristor‐based neural networks into three components: pre‐processing units, processing units, and learning algorithms. Then, the optimization methods to improve integration and operational reliability are discussed across materials, devices, circuits, and algorithms for each component. Furthermore, the review compares recent advancements in chip‐level neuromorphic hardware with conventional systems, including graphic processing units. The ongoing challenges and future directions in the field are discussed, highlighting the research to enhance the functionality and reliability of Mem‐NNs.
Patterns of immune checkpoint inhibitor utilization and PD-L1 testing in advanced gastroesophageal cancers using real-world data.
370 Background: Globally, gastroesophageal cancer (GEC) is a leading cause of morbidity and mortality, with poor 5-year overall survival (OS). The addition of immune checkpoint inhibitors (ICIs) such as nivolumab and pembrolizumab to chemotherapy has resulted in significant improvement in OS of those patients (pts) with metastatic GEC (mGEC), most notably in those with tumors exhibiting high PD-L1 CPS scores. However, the pattern of ICI utilization in associated PD-L1 testing since the adoption of this treatment (tx) has yet to be elucidated. We evaluated the patterns of ICI utilization and PD-L1/CPS testing in the first-line tx of mGEC pre and post FDA approval of ICI use in this setting. Methods: Pts ≥ 18 years of age, with recurrent/metastatic squamous or adenocarcinoma GEC diagnosed after 2011 were included from the de-identified nationwide Flatiron Health, electronic health record-derived database. We presented the proportion of pts receiving ICI therapy, stratified by line of tx, as well as the proportion of patients who received PD-L1 testing at 6-month intervals. Pts demographics and clinical characteristics, including age, gender, race, ECOG score, documented insurance, and stage at diagnosis (dx) were described and compared using T or Wilcoxon rank-sum tests for continuous variables, and chi-square or Fisher’s exact tests for categorical data. We compared tx rates and PDL-1 testing across four time points: time 1: Jan-June 2020, prior to ASCO data presentation; time 2: July-Dec 2020, ASCO data presentation; time 3: Jan- June 2021, FDA label change; time 4: July 2021 to 6 m after FDA label change using Chi-square test. Results: A total of 9,573 pts were included with 1,593 (16.6%) receiving ICI-based tx. Among these, 62.3% were White, 7% Black. Descriptive statistics indicated that pts with ICI- tx tend to be younger (median age 65y vs. 66.7; (p <0.001). Within the total cohort, 74% pt were dx before FDA approval of ICI tx, while 26% pts were dx after FDA approval. PD-L1 testing was conducted in 4,065 (42.5%) pts. A total of 1,268 (13%) pts received first-line ICI-based tx. Of these, 154 pts (12.1%) were treated before FDA approval, while 1,114 pts (87.9%) received tx following FDA approval. The rate of first-line ICI tx significantly increased at each subsequent time point Time 2: 11.2% (p <0.0001), Time 3: 32.9% (p <0.0001), Time 4: 37.4% (p <0.0001). PD-L1 testing rates also increased over time, particularly after FDA label change. Testing rates at Time 1 was 68%. Comparatively, testing rates at subsequent time points were: Time 2 (67.2%; p 0.88), Time 3 (71.5%; p 0.324) and Time 4 (77.4%; p=0.004). Conclusions: The approval of ICIs for first-line tx of mGEC led to a significant increase in both ICI utilization and PD-L1/CPS testing rates. Despite these advancements, ongoing disparities in tx access and testing highlight the need for further research and efforts to ensure equitable care.
Evaluation of CSF1R as a potential prognostic biomarker in colorectal cancer (Alliance).
285 Background: Immune checkpoint inhibitors (ICIs) have shown limited efficacy in colorectal cancer (CRC) outside of mismatch repair (MMR) deficient/microsatellite instability-high (MSI-H) tumors. Most CRC cases are MMR proficient /microsatellite stable and demonstrate resistance to ICIs, attributed to the tumor microenvironment. Colony Stimulating Factor 1 Receptor (CSF1R), a regulator of tumor-associated macrophages, has emerged as a potential target due to its association with poor prognosis in CRC. Methods: Data from 433 metastatic CRC (mCRC) patients in the CALGB/SWOG 80405 trial were analyzed. CSF1R RNA was extracted from formalin-fixed, paraffin-embedded tumor samples and sequenced. Patients were divided into tertiles of CSF1R expression (high, medium, low). Progression-free survival (PFS) and overall survival (OS) were compared using Kaplan-Meier curves, log-rank tests, and Cox proportional hazards models. Subgroup analyses were conducted based on liver metastases, treatment type (Bevacizumab, Cetuximab, FOLFOX, FOLFIRI), and MSI status. Results: Low CSF1R expression (CSF1R-L) was associated with significantly better survival outcomes. Median PFS was 12.9 months for CSF1R-L, compared to 11.2 and 9.2 months for CSF1R-M and CSF1R-H (p = 0.003). Median OS was 35.8 months for CSF1R-L versus 32.5 and 24.4 months for CSF1R-M and CSF1R-H (p = 0.00086). Stratification by liver metastases showed that CSF1R-L remained a strong prognostic factor only in patients with liver metastases. There were no significant survival differences based on CSF1R expression in bevacizumab-treated patients. However, in cetuximab-treated patients, CSF1R-L tumors had significantly longer PFS (12.9 vs 8.8 months, p = 0.037) and OS (35.8 vs 21.4 months, p = 0.002) than CSF1R-H tumors. Similarly, in FOLFOX-treated patients, CSF1R-L tumors showed longer PFS and OS (p = 0.018 and p = 0.013, respectively), and in FOLFIRI-treated patients, OS was significantly longer for CSF1R-L tumors (42.2 vs 24.7 months, p = 0.022) than CSF1R-H tumors. Conclusions: Our data suggests that CSF1R expression may serve as a prognostic biomarker in CRC, with lower expression potentially linked to improved survival, particularly in patients with liver metastases. These findings warrant further investigation of CSF1R as a possible prognostic and predictive biomarker, as well as a potential therapeutic target in CRC. Clinical trial information: NCT00265850 .
Impact of combined resection of pancreas on long-term survival in patients with gastric cancer.
359 Background: In patients with advanced gastric cancer invading adjacent organs, extended multivisceral resection is required to achieve R0 resection. However, the survival benefit of combined resection of pancreas remains controversial. We investigated the safety and efficacy of combined pancreatic resection in gastric cancer. Methods: This study included 64 patients who underwent gastrectomy with pancreatectomy (pancreaticoduodenectomy (PD) or distal pancreatectomy with splenectomy (PS)) for primary gastric cancer with invasion to the pancreas by primary tumor or lymph node metastasis and invasion to the duodenum. Patients who underwent R2 resection were excluded. Short- and long-term outcomes were assessed. Results: PD was performed in 18 patients (28.1%) and PS in 46 patients (71.9%). Macroscopic invasion to the pancreas by primary tumor was observed in 47 patients (73.4%), by lymph node in 13 patients (20.3%), and the invasion to the duodenum by primary lesion was in 4 patients (6.3%). Pathologically, pancreatic invasion was confirmed in 27 out of 47 patients (57.4%). Postoperative intra-abdominal infectious complications (PIIC) of Clavien-Dindo (CD) Grade III or higher were observed in 33 patients (51.6%). The most common postoperative complication was pancreatic fistula, which was observed in 31 patients (48.4%). There was no mortality within 30 days after surgery. Univariate analysis revealed that invasion the duodenum was highly associated with PIIC (p=0.038). Twelve patients (18%) resulted in R1 resection due to positive peritoneal cytology in 11 patients and positive surgical margin in one patient. The 5-year overall survival (OS) rate was 42.9%, which was 53.6% in R0 resection and 0% in R1 resection. Multivariate analysis revealed R1 resection was an independent prognostic factor for OS (HR:5.315, p<0.001). The 5-year recurrence-free survival (RFS) rate was 44.5%. The 5-year RFS rate was significantly worse in patients with PIIC (28.7%) than in patients without it (58.7%). Multivariate analysis revealed that PIIC was an independent prognostic factor for RFS (HR:2.345, p=0.036). Conclusions: Pancreatic resection for gastric cancer is considered safe and effective when R0 resection is possible. However, surgeon should pay particular attention to avoid the postoperative complications.
Multiscale Understanding of Anion Exchange Membrane Fuel Cells: Mechanisms, Electrocatalysts, Polymers, and Cell Management
AbstractAnion exchange membrane fuel cells (AEMFCs) are among the most promising sustainable electrochemical technologies to help solve energy challenges. Compared to proton exchange membrane fuel cells (PEMFCs), AEMFCs offer a broader choice of catalyst materials and a less corrosive operating environment for the bipolar plates and the membrane. This can lead to potentially lower costs and longer operational life than PEMFCs. These significant advantages have made AEMFCs highly competitive in the future fuel cell market, particularly after advancements in developing non‐platinum‐group‐metal anode electrocatalysts, anion exchange membranes and ionomers, and in understanding the relationships between cell operating conditions and mass transport in AEMFCs. This review aims to compile recent literature to provide a comprehensive understanding of AEMFCs in three key areas: i) the mechanisms of the hydrogen oxidation reaction (HOR) and the oxygen reduction reaction (ORR) in alkaline media; ii) recent advancements in the synthesis routes and structure‐property relationships of cutting‐edge HOR and ORR electrocatalysts, as well as anion exchange membranes and ionomers; and iii) fuel cell operating conditions, including water management and impact of CO2. Finally, based on these aspects, the future development and perspectives of AEMFCs are proposed.
Results of a phase 2 trial of ramucirumab plus docetaxel as second-line treatment for patients with advanced gastric cancer (HGCSG 1903).
447 Background: Ramucirumab (RAM) has shown efficacy in combination with paclitaxel (PTX) or irinotecan in the second-line treatment of advanced gastric cancer (AGC). However, the efficacy and safety regarding the combination therapy of RAM and docetaxel (DTX) have not been reported. We hypothesized that RAM plus DTX for patients with AGC could be as effective as RAM plus PTX and could reduce the incidence of neuropathy. Methods: HGCSG 1903 was a non-randomized, single arm, phase 2 trial carried out at 20 institutes in Japan. AGC patients with refractory or intolerance to primary chemotherapy were eligible. RAM (8 mg/kg on day1 and 15) plus DTX (60 mg/m 2 on day1) combination therapy administered in 28-day cycle were continued until disease progression or emergence of adverse events requiring discontinuation. The primary endpoint was response rate (RR) with threshold value of 10.7% and an expected value of 27.9%. A total of 35 cases are planned for registration. The secondary endpoints were overall survival (OS), progression-free survival (PFS), and safety. This trial was registered with Japan Registry of Clinical Trials, number jRCTs011200010. Results: Between Nov 2020 and Dec 2023, 36 patients were enrolled. Median age was 70 (range, 36–82); female/male were 7/29; ECOG PS 0/1, 16/20, respectively. One patient did not initiate study treatment at the onset of bowel obstruction after enrollment. In the efficacy and safety analysis set of 35 patients, RR was 25.7% (95%C.I., 12.5–43.3%) and disease control rate was 74.3% (95%C.I., 56.7–87.5%). Median OS and PFS were 11.9 months (95%C.I., 3.0–20.7) and 3.1 months (95%C.I., 2.1–4.2), respectively. Grade 3 or higher adverse events that occurred in more than 5% of patients were neutropenia (68.6%), leucopenia (57.1%), febrile neutropenia (17.1%), hypertension (14.3%), anorexia (11.4%), anemia (8.6%), and fatigue (5.7%). Grade 4 neutropenia occurred in 60.0% of patients. The protocol was amended to allow primary G-CSF prophylaxis during study period. The number of patients who received primary G-CSF prophylaxis after the amendment was 7/13 (53.8%). Neuropathy occurred in 65.7% of all grades, with no incidence of grade 3 or higher. No death and new safety signals with a causal relation to study treatment were observed. Conclusions: The primary endpoint of response rate was met in HGCSG 1903. Although neutropenia and febrile neutropenia may be more frequent, they were manageable. RAM plus DTX might be considered as an option for second-line treatment of patients with AGC. Clinical trial information: jRCTs011200010.
Evaluating the relative treatment efficacy of CD40 agonist mitazalimab in combination with mFOLFIRINOX in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) using unanchored indirect treatment comparisons (ITCs).
723 Background: Mitazalimab, a human CD40 agonistic IgG1antibody has demonstrated encouraging results in combination with mFOLFIRINOX (mFFX) in the phase 2 single arm trial OPTIMIZE-1 in patients with mPDAC. We conducted unanchored ITCs to assess the relative efficacy of mitazalimab + mFFX vs FOLFIRINOX (FFX) / mFFX and NALIRIFOX (NFX), the most effective therapies to date. Methods: Using data from OPTIMIZE-1 and published data from five RCTs identified via a literature review, matching-adjusted indirect comparisons (MAIC) and simulated treatment comparisons (STC), two commonly used ITC methods for health technology assessment (1) were conducted to balance effect modifiers and prognostic factors between trials. Analysis outcomes were overall survival (OS), objective response rate (ORR), and progression free survival (PFS). Reconstructed survival data from FFX, mFFX, and NFX studies were pooled together for the comparison with FFX/mFFX (Pool #1) and FFX/mFFX/NFX (Pool #2) pooled studies. Results: In the STC analysis mitazalimab + mFFX showed a significantly higher OS versus Pool #1 [hazard ratio (HR): 0.64; 95% CI: 0.46 – 0.87] and #2 [HR: 0.65; 95% CI: 0.47 – 0.87], corresponding to an improvement in median OS by 3.4 and 3.3 months respectively. The OS HRs of study-level pairwise comparisons ranged from 0.57 (95% CI: 0.39 – 0.80) to 0.85 (95% CI: 0.53 – 1.39) with only one non-significant comparison. MAICs showed similar trends, although the comparison with Pool #1 was close to statistical significance (HR: 0.68; 95% CI: 0.45 – 1.02). Results of the PFS and ORR comparisons are shown in the table below. Conclusions: Literature based ITCs show a significantly better efficacy of mitazalimab + mFFX versus the current available therapies in patients with mPDAC. These trends will have to be confirmed in a randomized Phase 3 study. 1. Phillippo DM et al, 2019. Clinical trial information: NCT02829099 . ITC results – HR (for OS and PFS) and odds ratios (for ORR) and their 95% CIs. STC MAIC Comparator study OS PFS ORR OS PFS ORR PRODIGE 4 (FFX) 0.57 (0.39 – 0.80) 0.63 (0.44 – 0.88) 1.62(0.87 – 2.99) 0.60 (0.40 – 0.89) 0.56 (0.37 – 0.82) 1.55(0.84 – 2.87) PANOPTIMOX (FFX) 0.58 (0.39 – 0.84) 0.68 (0.47 – 0.98) 1.17(0.59 – 2.30) 0.60 (0.38 – 0.94) 0.67(0.44 – 1.02) 1.04(0.52 – 2.05) AVENGER500 (FFX) 0.71 (0.50 – 0.98) 1.15(0.82 – 1.60) 1.35(0.75 – 2.42) 0.69(0.46 – 1.03) 1.11(0.76 – 1.62) 1.30(0.72 – 2.34) SWOGS1313 (mFFX) 0.85(0.53 – 1.39) 0.89(0.57 – 1.36) 0.90(0.43 – 1.89) 0.91(0.55 – 1.50) 0.86(0.55 – 1.33) 0.88(0.42 – 1.86) Pool #1 0.64 (0.46 – 0.87) 0.81(0.59 – 1.10) 1.33(0.77 – 2.32) 0.68(0.45 – 1.02) 0.81(0.56 – 1.18) 1.20(0.69 – 2.09) NAPOLI-3 (NFX) 0.68 (0.49 – 0.93) 0.85(0.61 – 1.17) 0.97(0.55 – 1.71) 0.67 (0.46 - 0.97) 0.83(0.58 – 1.20) 0.92(0.52 – 1.62) Pool #2 0.65 (0.47 – 0.87) 0.82(0.60 – 1.11) 1.17(0.68 – 2.02) 0.68 (0.47 – 0.99) 0.84(0.59 – 1.19) 1.11(0.64 – 1.91)
Extra-hepatic (ehCCA) and intra-hepatic cholangiocarcinomas (iCCA): A genomic landscape comparison of peri-hilar (phCCA), common bile duct (cbdCCA) and gallbladder (gbCCA) with iCCA.
630 Background: Metastatic CCAs have poor prognosis. Comprehensive genomic profiling (CGP) was used to compare genomic alterations (GA) in phCCA, with cbdCCA, gbCCA and iCCA. Frequencies of GA in therapy targets such as FGFR2, IDH, ERBB2 & BRAF, & Immuno-oncology (IO) drug response predictors (MSI status, TMB & PDL1) were examined. Methods: DNA extracted from 110 cases of phCCA, 743 cases of cbdCCA, 2983 cases of gbCCA and 9178 cases of ihCCA underwent hybrid capture based CGP to evaluate classes of genomic alterations (GA), MSI status, TMB levels, genomic ancestry, genomic signature, HRD score and germline status. phCCA cases were confirmed at surgery and pathology as originating from either left, right or common hepatic ducts. cbdCCA cases were confirmed by cbd biopsies or Whipple procedures. PD-L1 expression was determined by IHC using the Dako 22C3 assay using tumor proportional score (TPS) system. Results: The pt age distributions were similar; female gender was more frequent in gbCCA. gbCCA featured higher GA/tumor (P=.0001). The frequencies of FGFR2 & IDH1 targetable GA in phCCA, cbdCCA and gbCCA were uncommon especially when compared iCCA (P<.0001). GA in BRAF, CDKN2A, MTAP and PIK3CA in gbCCA were like phCCA and cbdCCA. At 16.5%, the frequency of GA in ERBB2 were highest in gbCCA and in all ehCCA when compared with iCCA (P<.0001). The frequencies of KRAS GA including KRAS G12C were greater in both phCCA and cbdCCA when compared with gbCCA (P=.0015) and iCCA (P.0001). TP53 GA were highest in gbCCA (P=.0007). IO biomarker frequencies were similar in all. The frequencies of HRD positive (gLOH) status and MMR genomic signature were similar in all. Conclusions: ehCCA subtypes feature characteristic GA profiles that have potential to influence therapy selection with lower frequencies of FGFR2 & IDH1 when compared with iCCA. In contrast, targetable ERBB2 & KRAS G12C are more frequent in ehCCA than iCCA, and highest in gbCCA & cbdCCA. peri-hilarCCA cbdCCA P-value (phCCA vs cbdCCA) gbCCA P-value (phCCA vs gbCCA) ihCCA P-value (phCCA vs iCCA) BRAF 3.6% 4.7% NS 2.4% NS 5.1% NS ERBB2 14.5% 10.6% NS 16.5% NS 5.1% 0.002 FGFR2 0.9% 2.0% NS 1.5% NS 11.7% 0.001 IDH1 3.6% 0.8% NS 0.6% NS 13.9% 0.006 KRAS 29.1% 46.2% 0.015 14.2% 0.0015 19.8% 0.071 TP53 45.5% 63.8% 0.011 65.7% 0.0007 33.9% 0.061 MSI-high 1.8% 1.3% NS 1.2% NS 1.8% NS TMB≥10 mut/mb 3.6% 4.2% NS 5.2% NS 3.6% NS PD-L1 low positive 21.1% 31.3% NS 23.5% NS 23.7% NS
Room‐Temperature Magnetic Antiskyrmions in Canted Ferrimagnetic CoHo Alloy Films
Abstract Magnetic antiskyrmions, the anti‐quasiparticles of magnetic skyrmions, possess alternating Bloch‐ and Néel‐type spin spirals, rendering them promising for advanced spintronics‐based information storage. To date, antiskyrmions are demonstrated in a few bulk materials featuring anisotropic Dzyaloshinskii–Moriya interactions and a limited number of artificial multilayers. Identifying novel film materials capable of hosting isolated antiskyrmions is critical for memory applications in topological spintronics. Herein, the formation of room‐temperature antiskyrmions in single ferrimagnetic CoHo rare‐metal alloy films of varying thicknesses, observed using Lorentz transmission electron microscopy is reported. Furthermore, rotating magnetic fields ( H ) are proposed to facilitate antiskyrmion nucleation and enhance their areal density by an order of magnitude compared to that in the same area under individual vertical H . In addition, experimental and phenomenological analysis confirm that antiskyrmion nucleation can be attributed to spin reorientation involving spontaneous canted magnetism, as evidenced by polarized neutron reflectometry. Micromagnetic simulations further show that the antiskyrmion density significantly depends on the magnitude of the rotating field. These findings expand the family of known antiskyrmion‐hosting materials and provide insights into their formation mechanisms, thus serving as a basis for their application in topological spintronics.
Personalized ctDNA monitoring to assess the recurrence of early stage pancreatic cancer after surgery.
774 Background: Up to 80% of patients with resected pancreatic cancer recur within 2 years. Here, we assessed the feasibility and accuracy of a personalized, tumor-informed circulating tumor DNA (ctDNA) test for early warning of recurrence risk during long-term surveillance. Methods: This study retrospectively analyzed 43 patients who underwent radical surgery for pancreatic cancer between November 2021 and June 2023 at the Comprehensive Cancer Centre of Drum Tower Hospital, Clinical Cancer Institute of Nanjing University. A personalised panel was constructed to detect ctDNA in plasma based on whole-exon mutation information from tumour tissue. A total of 139 ctDNA samples were obtained from periods including postoperative, during adjuvant therapy, and post-treatment. Results: Until the last follow-up time (May 13, 2024), a personalised ctDNA monitoring panel was successfully constructed for 35 (81.4%) stage I-III patients with a median follow-up of 11.82 months (range: 2-17.8 months). A total of 16 patients experienced recurrence within 15.7 months (range: 5.4-30 months), with a median lead time from first positive ctDNA to imaging recurrence of 3.6 months (range: 1-9.3 months). ctDNA positivity was detected in 25.8% (8/31) of ctDNAs at the landmark time point (postoperative prior to adjuvant therapy), with a positive predictive value (PPV) of 75% (6/8) and a negative predictive value (NPV) of 69.6% (16/23). Patients with positive ctDNA at the landmark time point had inferior DFS (6.9 months vs undefined. HR 3.955, P=0.007) and OS (15 months vs undefined. HR 5.599, P=0.001) compared to those with negative ctDNA. When integrating longitudinal time points, PPV and NPV were 68.2% (15/22) and 91.7% (11/12), respectively. For all 16 relapsed patients, the sensitivity of positive ctDNA detected longitudinally was 93.75% (15/16). The ctDNA-MRD status at longitudinal time points had a more significant difference with DFS (undefined vs 12.6 months. HR 5.096, P=0.002) and OS (undefined vs 21 months. HR 6.487, P=0.038). Conclusions: Personalized ctDNA surveillance is effective in identifying high recurrence risk after pancreatic surgical resection. Long-term longitudinal warning of arbitrary ctDNA positivity suggests a recurrence probability of up to 93.75%; therefore, full ctDNA dynamic monitoring is essential. And ctDNA monitoring will be further used to guide the decision-making in the clinic to prolong patient survival.
Racial disparities in secondary metastasis in patients with hepatocellular carcinoma: A 5-year National Inpatient Sample study.
523 Background: Hepatocellular carcinoma (HCC), a primary liver malignancy, is one of the leading causes of cancer-related mortality worldwide. The incidence and outcomes of HCC vary significantly across racial groups. Secondary metastasis, a key factor in disease progression and prognosis, also appears to differ by race, though these disparities remain poorly understood. This study aims to explore how race influences the metastatic progression of HCC, providing valuable insights into potential racial differences in disease outcomes. Methods: A retrospective analysis of National Inpatient Sample (NIS) data from 2016 to 2020 was conducted, identifying adults with HCC using International Classification of Diseases, Tenth Revision (ICD-10) codes, and categorizing them based on the presence of metastasis. The primary outcome was racial differences in organ metastasis. Multivariable logistic regression models were used to adjust for potential confounders and to evaluate the impact of race on all metastatic patterns, with Caucasians as the reference category. Statistical significance was defined as p-values ≤ 0.05. Results: The study cohort included 236,985 adult patients with HCC, of whom 34,875 had secondary metastasis. The cohort was predominantly male (77.37%), with 22.63% female. The racial distribution was 52.61% Caucasian, 19.08% African American, 15.04% Hispanic, and 13.27% from other racial groups. After adjusting for confounders, African American patients had significantly higher odds of lung (aOR 1.42, P<0.001), bone (aOR 1.51, P<0.001), and brain metastasis (aOR 1.47, P=0.02), but lower odds of adrenal gland metastasis (aOR 0.74, P=0.003) compared to Caucasians. Asian/Pacific Islander patients demonstrated increased odds of lung (aOR 2.00, P<0.001) and brain metastasis (aOR 1.95, P=0.02). In contrast, Hispanic patients had lower odds of abdominal lymph node (aOR 0.69, P=0.008) and bone metastasis (aOR 0.83, P=0.007). Conclusions: This study highlights significant racial disparities in the metastatic patterns of hepatocellular carcinoma, emphasizing the need to consider these differences in clinical management and treatment strategies for HCC patients. Further research is required to investigate the underlying causes of these disparities and their impact on long-term survival.
EQUITY GI: A prospective study to enhance quality, inclusivity, and trial participation in Black patients with gastrointestinal cancer.
TPS843 Background: Black individuals, including African Americans, experience a disproportionate cancer burden and exhibit the lowest survival rates among all racial groups for gastrointestinal (GI) cancers. The EQUITY GI study seeks to address the significant health disparities encountered by Black patients with GI cancers in the areas of biomarker testing, evidence-based care, clinical trial participation, and health literacy. Our central hypothesis postulates that a comprehensive approach—encompassing appropriate biomarker testing, ensuring evidence-based treatments, support for clinical trial participation, and health literacy initiatives—is essential to effectively mitigate health disparities among Black patients with GI cancers. Methods: The primary objective of this study is to promote equitable care for Black patients with GI cancers by ensuring appropriate biomarker testing and the delivery of evidence-based care. The secondary objectives include promoting clinical trial participation and enhancing health literacy. The specific goals are to increase the rate of evidence-based care, including biomarker testing, to ≥80%, increase the clinical trial enrollment rate from 5% to 15%, and improve the Cancer Health Literacy Test-30 (CHLT-30) score by 30%. Following a comprehensive assessment of the care gap, several initiatives will be implemented: 1. Tracking biomarker testing through a clinical information tracking tool (EQUITY-GI Oncotracker), 2. Providing guidance to treating providers through a molecular tumor board, 3. Facilitating referrals for clinical trials through navigators, and 4. Implementing health literacy interventions measured by CHLT-30 score. We aim to enroll 200 patients over 18 months. With this expected enrollment, the power to detect a ≥60% absolute improvement in the biomarker testing rate (from the current 20% to the expected ≥80%) is over 98%, using a two-sided chi-square test with a significance level of 0.05. To demonstrate an improvement in the clinical trial enrollment rate from 5% to 15%, 18 black patient will be required to get enrolled in a clinical trial through the referrals generated from the current project. To detect a 30% improvement in the mean CHLT-30 score (17 to 22) following health literacy interventions, at least 120 patients will be required, using a two-sided paired t-test with a significance level of 0.05.
Utilization of circulating tumor DNA (ctDNA) testing in biliary tract cancers.
644 Background: There is limited data to guide surveillance in biliary tract cancers (BTCs) following resection. Minimal residual disease (MRD) assays utilize circulating tumor DNA (ctDNA) to detect early recurrence. Current data is limited on the use of ctDNA in biliary tract cancers in conjunction with surveillance imaging. In this study, we aim to elucidate the role of ctDNA monitoring in patients with biliary tract cancers who have undergone curative resection. Methods: We conducted a retrospective search at a tertiary care and several satellite settings to identify patients with BTCs who underwent curative surgery and subsequently had ctDNA monitoring. We collected demographic variables, disease characteristics, treatment regimens, and follow-up data. The primary endpoint of the analysis is recurrence-free survival (RFS), comparing patients with detectable ctDNA to those with negative ctDNA post-surgery. Kaplan-Meier analysis and Log-Rank tests were performed to evaluate RFS, and Cox proportional hazards(PH) models were employed for both univariate and multivariate analyses. Results: We identified 36 pts with a median age of 72 (34-87) yrs at diagnosis. In this study cohort, 22 (59%) were female, 32 (88%) were white, and 3 (8%) were African American. 12 (33%) pts were ctDNA positive at any point during surveillance, while the remainder were ctDNA negative. In the ctDNA-positive group, recurrences developed in 7 out of 12 (58%) pts. In the ctDNA negative group, only 2 out of 24 (8.3%) pts developed recurrences. The median time to recurrence following primary surgery was 10.7 months, while the time to ctDNA positivity following surgery was 7.8 months. The median time from ctDNA positivity to recurrence was 1.1 months. Pts with ctDNA positivity had a significantly lower 1-year RFS of 47.62% (95% CI: 7.5%-81%) compared to those with ctDNA negativity (85%, 95% CI: 60%-95%; p = 0.0008). Multivariate analysis demonstrated that ctDNA positivity at any point was associated with a significantly higher risk of recurrence (HR: 21.8, 95% CI: 2.3–203, p<0.0001). Conclusions: In pts with BTCs who underwent resection, ctDNA testing had independent prognostic value. Further prospective trials are needed to help define the role of ctDNA in this patient population. Baseline demographics and clinical characteristics of patients who were ctDNA positive vs. negative. Characteristics Patients with Biliary Tract Cancers who were ctDNA positive Patients with Biliary Tract Cancers who were ctDNA negative N 12 24 Age in years, median (range) 72 (62 – 87) 72 (34 - 85) Sex n (%) Male 7 (58) 8 (33) Female 5 (42) 16 (67) Race n (%) White 12 (100) 20 (83) Black/African American 0 (0) 3 (13) Asian 0 (0) 1 (4) Primary Tumor Location n (%) ICC 4 (33) 11 (46) ECC 4 (33) 5 (21) GBC 2 (17) 6 (25) AC 2 (17) 2 (8) Margin Status n (%) Positive 2 (17) 3 (13) Negative 10 (83) 21 (87) Clinical Stage I 0 (0) 1 (4) II 2 (17) 12 (50) III 8 (66) 10 (43) IV 2 (17) 0 (0) Unknown 0 (0) 1 (3)
Updated efficacy results of ASKB589 combined with CAPOX and PD-1 inhibitor as first-line treatment for metastatic gastric/gastro-esophageal junction (G/GEJ) adenocarcinoma from a phase Ib/II study.
454 Background: ASKB589 is a non-fucosylated fully human IgG1 monoclonal antibody that binds CLDN18.2 with high affinity, specificity, and improved ADCC and CDC activities. Previous findings indicated that ASKB589 exhibited a well-tolerated safety profile at doses up to 20 mg/kg and demonstrated promising antitumor effects. A dose of 6 mg/kg has been selected for further evaluation. Here, we present the updated data from dose expansion part in NCT05632939 study. Methods: This phase 1b/2 study was consisted of dose-escalation part and dose-expansion part. The expansion part aimed to assess the safety and efficacy of ASKB589 combined with CAPOX plus a PD-1 inhibitor as the initial treatment for advanced G/GEJ cancer with CLDN18.2 positive, regardless of PD-L1 expression. CLDN18.2 and PD-L1 expression were evaluated through IHC analysis using clone DS-3 and clone E1L3N at a central lab. All pts were given ASKB589 intravenously at a dosage of 6 mg/kg. Responses were assessed by RECIST 1.1 every 6 weeks. Adverse events were graded using CTCAE v5.0. Results: As of July 29, 2024, 49 evaluable pts with CLDN18.2 M/H expressions (≥2+ membrane staining intensity in ≥40% of tumor cells) regardless of PD-L1 CPS score. Forty pts (81.6%) achieved a partial or complete response, with a confirmed objective response rate (cORR) of 73.5% (95%CI: 58.9, 85.1). The median duration of response was 11.14 months (6.93, NE). Three subjects underwent surgical treatment as a result of tumor reduction following treatment. All 49 pts achieved SD or better with a disease control rate of 100%. cORR was 76.2% and 74.1% in the CPS<1 and CPS<5 groups, respectively. Of all treated pts (N=50), PFS rate at 9 months was 58.1% (95% CI: 42.2, 71.0) and OS rate at 12 months was 77.1% (95% CI: 61.2, 87.2). Mature PFS and OS data will be reported at the time of the conference. The safety profile of the triplet is generally consistent with the safety data of ASB589 plus CAPOX combination in first-line G/GEJ cancer pts presented previously, which was mainly characterized by manageable on-target-off-tumor effects, including hypoalbuminemia, nausea, and vomiting. Conclusions: The combination of ASKB589 with CAPOX and a PD-1 inhibitor as the initial treatment for pts with G/GEJ cancer was well tolerated with no unexpected safety signals. It has shown a high confirmed ORR, 100% disease control, deep and durable antitumor activity, regardless of PD-L1 expression levels. A phase 3 study of the triple regimen for the 1L G/GEJ cancer is actively enrolling pts in China. Clinical trial information: NCT05632939 . cORR based on CLDN18.2 and PD-L1 expression. n/N (%) PD-L1CPS<1 PD-L1CPS 1-5 PD-L1 CPS≥5 Total CLDN18.2 M&HcORR 16/21(76.2%) 7/10 (70.0%) 13/18 (72.2%) 36/49 (73.5%) CLDN18.2 Moderate cORR 2/3(66.7%) 0/1(0.0%) 6/9(66.7%) 8/13(61.5%) CLDN18.2 High cORR 14/18(77.8%) 7/9(77.8%) 7/9(77.8%) 28/36(77.8%)
A phase 2 study to assess the safety and efficacy of FLX475 (tivumecirnon) combined with pembrolizumab in patients with advanced or metastatic gastric cancer.
426 Background: Regulatory T-cells (T regs ) suppress anti-tumor immunity by migrating into tumors via CCL17/CCL22 chemokines binding to CCR4. FLX475 (tivumecirnon), a selective CCR4 antagonist, inhibits T reg recruitment, enhancing the effector T-cell (T eff ) response in the tumor microenvironment. Preclinical studies demonstrate that FLX475 increases the T eff /T reg ratio and boosts anti-tumor efficacy, both as monotherapy and in combination with checkpoint inhibitors (CPI). Here, we present findings on the safety and efficacy of FLX475 with pembrolizumab in a Phase 2 trial, aimed at improving therapeutic outcomes in advanced or metastatic gastric cancer (GC) patients. Methods: This Phase 2, open-label study (NCT04768686) assesses the safety and efficacy of FLX475 combined with pembrolizumab in advanced or metastatic GC patients. Patients received FLX475 100 mg PO QD and pembrolizumab 200 mg IV Q3W. Cohort 1 included CPI-naïve Epstein-Barr Virus (EBV)-negative GC patients who had progressed on at least two prior treatments. Cohort 2 included CPI-naïve EBV-positive GC patients who had received at least one prior treatment. Both cohorts were selected based on high CCR4 ligand expression and T reg enrichment, expected to enhance treatment response. The primary objective of the study was to assess the anti-tumor efficacy of the study treatment, as assessed by the investigator using RECIST 1.1. Results: A total of 20 patients were enrolled in the study, with 10 patients in each cohort. The combination of FLX475 and pembrolizumab was well-tolerated across both cohorts. The most common treatment-related adverse events occurred in more than 10% of patients across cohorts were QTc prolongation (35.0%), and pruritus (15.0%), which were manageable and consistent with the known profiles of the individual agents. In Cohort 2, the confirmed objective response rate (ORR) was 60.0% (95% CI: 26.2 to 87.8). The median time to response (mTTR) was 2.7 months, with a median duration of response (mDOR) of 17.3 months. The median progression-free survival (mPFS) for this cohort was 10.4 months, while the median overall survival was not reached. In Cohort 1, no objective responses were observed, and the best response achieved was stable disease. The relationship between treatment outcomes and biomarkers including CCR4 expression levels and the T eff :T reg ratio was confirmed in exploratory analyses. Conclusions: The combination of FLX475 with pembrolizumab was well-tolerated and showed promising anti-tumor activity and durable responses in patients with advanced or metastatic EBV-positive GC. Clinical trial information: NCT04768686 . Cohort 1 (EBV (-) GC)N=10 Cohort 2 (EBV (+) GC)N=10 ORR n (%)(95% CI) 0 (0.0)(-) 6 (60.0)(26.2, 87.8) mTTR Months (95% CI) - 2.7 (1.2, -) mDOR Months (95% CI) - 17.3 (2.7, -) mPFS Months (95% CI) 1.4 (1.1, 1.5) 10.4 (1.0, -)
Phase 1/2 study of XTX101, a tumor-activated, Fc-enhanced anti-CTLA-4 monoclonal antibody, in combination with atezolizumab in patients with advanced solid tumors and in MSS CRC.
206 Background: XTX101 is an investigational tumor-activated, Fc-enhanced, high affinity binding aCTLA-4 designed to block CTLA-4 and deplete regulatory T cells upon activation in the tumor by proteases. XTX101 also contains mutations designed to enhance Fcγ receptor binding. Fc enhancement augments FcγR co-engagement on antigen presenting cells and has been linked with efficacy of aCTLA-4 combinations in patients (pts) with “cold tumors”, including microsatellite stable (MSS) colorectal cancer (CRC). Parts 1A/1B of the study evaluated XTX101 monotherapy in pts with advanced solid tumors. XTX101 was generally well tolerated with limited peripheral XTX101 activation (~13%) compared to evidence of XTX101 activation in the tumor microenvironment (73-96%, in n=2 on-treatment tumor biopsies). A durable partial response (PR) and resolution of hepatic metastases was observed in a pt with PD-L1 negative NSCLC at the monotherapy recommended phase 2 dose (RP2D) of 150 mg once every six weeks (Q6W) [1]. Methods: Part 1C evaluated the safety and feasibility of XTX101 in combination with atezolizumab in pts with advanced solid tumors using 3+3 dose escalation to establish the RP2D. Phase 2 is enrolling pts with MSS CRC with at least 1 prior regimen for metastatic CRC. Initial safety and anti-tumor activity data from Phase 2 in ~20 pts will be presented. Results: As of July 15, 2024, 15 pts were enrolled in Part 1C: MSS CRC (n=12), esophageal cancer, NSCLC, and ampullary carcinoma (n=1 each). Median age 69 and 3 prior lines of therapy (1-12). Across all XTX101 dose levels (75 mg to 150 mg), treatment-related adverse events (TRAEs) of any grade with >10% incidence included infusion reactions (n=4), fatigue and diarrhea (n=2 each), no G4 or G5 TRAEs were reported. In Part 1C, 2 pts experienced a dose limiting toxicity: 1 pt had G3 colitis, and 1 pt had G3 liver enzyme elevation (both were at the XTX101 150 mg dose level and resolved with immunosuppression). Two unconfirmed PRs were reported: in a pt with MSS CRC, including resolution of a liver target lesion, and in a pt with ampullary carcinoma (accompanied by a Ca 19-9 decrease from 700 to 41). In addition, a decrease in intra-tumoral Tregs was observed in paired tumor biopsies from a pt. The combination RP2D was established as XTX101 100 mg Q6W and atezolizumab 1200 mg once every three weeks (Q3W), and enrollment in the Phase 2 part of the study for pts with MSS CRC is ongoing at the RP2D. Conclusions: In Part 1C dose escalation, the combination of XTX101, a tumor-activated, Fc-enhanced aCTLA-4, and atezolizumab was generally well tolerated in pts with advanced solid tumors and demonstrated initial evidence of anti-tumor activity in cold tumors. These data support the initiation of an ongoing Phase 2 study evaluating the combination in pts with MSS CRC with and without liver metastases. 1. Davar ESMO IO 2023. Clinical trial information: NCT04896697 .