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Transcriptomic features of Epstein-Barr virus-associated gastric cancer based on PD-L1 status.
489 Background: Epstein-Barr virus (EBV)-associated gastric cancer (EBVaGC) accounts for 5-10% of all gastric cancers and has a relatively favorable prognosis compared to other subtypes. While the genomic profile of EBVaGC has been previously reported to exhibit extensive CpG island methylation, elevated levels of PD-L1/2, and an absence of TP53 mutations, transcriptomic features remain less explored. The response to immunotherapy of EBVaGC has been various. This study comprehensively investigates the transcriptomic characteristics of EBVaGC in relation to PD-L1 status. Methods: RNA sequencing was conducted on formalin-fixed, paraffin-embedded samples from 27 EBV-positive and 12 EBV-negative patients with HER2-negative gastric cancer. Gene expression was quantified using the RSEM package. Predict-IO, a machine learning-based predictive algorithm developed at Auristone Pte Ltd based on initial work done at the Genome Institute of Singapore (GIS), assessed the likelihood of a patient responding to immunotherapy based on transcriptome expression data. PD-L1 immunohistochemistry was performed using the 22C3 pharmDx assay, and status was classified by CPS. Results: A total of 200 differentially expressed genes (DEGs; log2FC > 2, FDR < 0.05) were identified in EBV-positive versus negative samples, with 157 genes down-regulated and 43 genes up-regulated. Upregulated genes included immune response related genes such as DMBT1, IDO1, PLA2G2A, and IL13RA2, while downregulated genes were primarily associated with cell adhesion, including LAMA1 and CCN6. In the EBV positive group, immune response pathways were enriched; however, within the PD-L1-Low group (CPS < 1), activated signaling pathways such as MYC, E2F, and MTORC1 were observed. Conversely, the PD-L1-High group (CPS ≥ 5) exhibited upregulated snoRNAs. In the EBV negative group, the PD-L1-Low cohort displayed suppressed immune response and ECM remodeling factors, whereas the PD-L1-High cohort showed enrichment of ECM remodeling factors. The Predict-IO Score, which predicts immunotherapy response, was significantly higher in EBV-positive compared to EBV-negative samples ( p = 0.003), and scores were elevated in the PD-L1-High group compared to the PD-L1-Low group. Conclusions: In summary, EBVaGC includes subsets of different PD-L1 expression patterns with distinct activated signaling pathways, differences in ECM remodeling factors, and varying Predict-IO Scores. With these information, we could properly select the responsive patients to immunotherapy among EBVaGC.
Dual versus single immune checkpoint blockade for patients with metastatic colorectal cancer harboring microsatellite instability: The Saint-Antoine immunoMSI score.
168 Background: Anti-PD1 monotherapy (mono) and anti-PD1 plus anti-CTLA4 therapies (combo) are validated for metastatic colorectal cancer (mCRC) harboring microsatellite instability and/or mismatch repair deficiency (MSI/dMMR). We aimed at assessing the efficacy of combined anti-CTLA4 and anti-PD1 blockade versus anti-PD1 monotherapy and identifying which subgroups benefit more from the combo. Methods: All patients (pts) with MSI/dMMR mCRC treated by anti-PD1 ± anti-CTLA4 included in the prospective monocenter immunoMSI cohort were analyzed. The choice between monotherapy or combination therapy varied according to open studies and regulatory approvals, without taking pt characteristics into account. Datalock date was April 23, 2024. Main endpoints were progression-free survival (PFS) per iRECIST and overall survival (OS) estimated with the Kaplan-Meier method. Univariate Cox proportional hazards models were used to estimate hazard ratios with CI. The interactions between studied subgroups and the treatment group were modelized by adding in a single Cox model the studied subgroups, the treatment group parameters, and their interaction term. Results: Among 210 pts, 97 were treated combo and 113 with mono. Baseline characteristics were similar in both groups. 25% and 17% were in first line, respectively. Median follow-up was 4.4 years: 4.1 years for combo and 5.4 years for mono. Combo was associated with better PFS (HR=0.48; 95%CI 0.31-0.76) and OS (HR=0.49; 0.29-0.84). Best observed response rates were: 78% of objective responses, 17% of stable diseases and 5% disease progressions with combo versus 60%, 25% and 15% with mono. Subgroup analyses showed significant differential effect of the treatment group for gender (PFS HR=0.21 vs 0.87 for females and males, P-interaction: 0.0067), liver metastases (PFS HR=0.30 vs 0.79 for pts without liver mets and those with liver mets, P-interaction: 0.0479) and sidedness (PFS HR=0.27 vs 0.64 for left-sided and right-sided mCRC, P-interaction=0.0922), but not RAS / RAF mutations. We computed a predictive score based on gender (female: 2 points), no liver met (1 point) and left side (1 point). PFS HR was 0.1 (0.03-0.33) for the group ≥3 points (N=67), 0.66 (0.36-1.23) for the group with 1-2 points (N=113) and 1.54 (0.50-4.70) for the group with 0 point (N=30). Conclusions: Combined CTLA4 and PD1 blockade is associated with improved PFS and OS compared to anti-PD1 alone in MSI/dMMR mCRC. The subgroup deriving the highest benefit of the combo seems to be female pts with left sided tumor and no liver met. Data from the randomization between nivolumab versus nivolumab + ipilumumab in the CheckMate-8HW phase III study are expected.
A phase 2, multicenter, open-label study of AlloStim combined with anti-PD-L1immunotherapy as 4L therapy in patients with MSS/pMMR metastatic colorectal cancer.
TPS318 Background: Microsatellite stable (MSS)/mismatch repair proficient (pMMR) metastatic colorectal cancer (mCRC) are immunologically 'cold' tumors that do not respond to immunotherapy. Cold tumors represent a formidable hurdle for checkpoint blockade immunotherapy approaches. Therefore, there is a need for novel strategies that could reprogram mCRC cold tumors to become inflamed hot tumors in a manner that might potentially convert low tumor mutational burden (TMB) tumors into checkpoint blockade responsive tumors. AlloStim is an experimental allogeneic, non-genetically manipulated, Th1-like activated living cell immunotherapy derived from healthy unrelated blood donors. The mechanism of action is designed to convert immunologically cold tumors into inflamed hot tumors. A case study of a single 3L MSS/pMMR mCRC patient primed with AlloStim followed by combination anti-PD-1/anti-CTLA4 checkpoint blockade resulted in a rare objective tumor response (Hirschfeld, et al, Translational Medicine Communications (2024) 9:15). The AlloStim priming results in an abundance of infiltrating interferon-gamma producing Th1 cells. Interferon-gamma has been shown to increase expression of PD-L1 in the TME. Therefore, it is hypothesized that the combination of AlloStim with an anti-PD-L1 checkpoint inhibitor might optimally evoke anti-tumor immune responses in this immunotherapy-refractory MSS/pMMR mCRC population. Methods: The study is a phase 2, multicenter, single-arm clinical trial of MSS/pMMR mCRC subjects in 4L that have been previously treated with an oxaliplatin-containing and irinotecan-containing chemotherapy regimen, anti-EGFR (RAS wt and left-sided), anti-VEGF and have progressed on 3L TAS-102 +/- bevacizumab or regorafenib or fruquinitinib. The study is evaluating weekly AlloStim priming from day 0 to day 49 followed by combination of AlloStim IV infusion (q2w) followed a week later by anti-PD-L1 (avelumab 800mg/q2w) from days 63 to day 98. Objective tumor response and disease control rate are the primary end-points. Overall survival is the secondary end-point. Clinically stable patients at day 112 can continue in an expansion phase with another round of combination AlloStim and avelumab from day 119 to day 154. CT scans are conducted at baseline, day 56 after AlloStim priming, day 112 after combination of alternating q2w infusions of AlloStim and avelumab and day 168 in all patients. CT scans will be analyzed by independent central readers using RECIST 1.1. Up to 50 patients will be enrolled with an interim analysis performed to assess efficacy after 20 patients become evaluable. The study is open and has not yet enrolled any patients at time of submission. Clinical trial information: NCT06557278 .
Prognostic and biological divergence of upper gastrointestinal adenocarcinomas.
350 Background: Esophageal (EAC), gastroesophageal junction (GEJ) or gastric (GAC) adenocarcinoma share similar etiologies and treatment approaches. However, it is not clear if they possess similar or different prognostic and biological characteristics. We aimed to examine overall survival (OS) in associations of the common genomic alterations with these three anatomically closely linked adenocarcinomas. Methods: Eligible patients had recurrent or de novo metastatic GAC, GEJAC or EAC whose tumors had undergone next generation sequencing (NGS) performed from November 2017 to December 2023. We used Cox regression modeling to examine the association between GAC, GEJAC, EAC and OS, adjusting for demographics, performance status, Charlson comorbidity index, receipt of chemotherapy, and HER2 overexpression or amplification (HER2 positive), p53 (mutp53 ) , KRAS (mutKRAS), CDKN2A , PIK3CA co-mutations and MYC amplification. Results: Of 875 total eligible patients, 173 had EAC, 276 had GEJAC and 426 had GAC. GEJAC had substantially better OS than EAC (HR = 0.68, [95% CI, 0.54-0.86]), and modestly better OS than GAC (HR = 0.85, [95% CI, 0.67-1.09]). HER2 positivity was associated with substantially better OS among EAC (HR = 0.62; [95% CI, 0.40-0.96]) and GEJAC (HR = 0.59; [95% CI, 0.38-0.87]) but not among GAC (HR = 0.98; [95% CI, 0.78-1.23]) patients. In addition, p53 gain-of-function versus non-gain-of-function mutations were associated with substantially worse OS among GAC (HR = 1.41; [95% CI, 0.98-2.01]) but not among EAC or GEJAC. MutKRAS was associated with substantially worse OS among EAC (HR = 1.81; [95% CI, 1.10-2.99]) but not among GEJAC or GAC. Surprisingly, MYC amplification was associated with dramatically better OS among EAC (HR = 0.19; [95% CI, 0.08-0.42]) but substantially worse OS among GEJAC (HR = 1.98, 95% CI, 1.14-3.40]) and GAC (HR = 1.75; [95% CI, 1.10-2.80]). Conclusions: GEJAC, EAC and GAC possess substantially different OS that appears differentially associated with HER2 status, mutp53, mutKRAS and MYC amplification. These results suggest distinct prognostic and biological characteristics of these three anatomically closely linked adenocarcinomas that could have important implications in clinical practice and on further investigations on their biological and topological mechanisms.
Sex differences in toxicities and survival outcomes among patients with stage III colorectal cancer receiving adjuvant fluoropyrimidine monotherapy: A pooled analysis of four randomized controlled trials (JCOG2310A).
116 Background: Fluoropyrimidine agents are the key component of adjuvant chemotherapy for pathological stage III colorectal cancer (CRC). Western studies have shown that female sex is associated with favorable survival outcomes after surgery, yet a risk factor for fluoropyrimidine-related adverse events (AEs) during adjuvant chemotherapy. However, it remains unclear whether there are sex differences in the treatment outcomes in this setting among the Japanese population. Methods: Patients enrolled in four randomized controlled trials (JCOG0205, JCOG0404, JCOG0910, and JCOG1006) who received adjuvant fluoropyrimidine monotherapy for pathological stage III CRC were analyzed. Incidences of AEs and survival outcomes (relapse-free survival [RFS], and overall survival [OS]) were compared between males and females. Multivariable logistic regression analyses were performed to evaluate associations between sex and the development of AEs. Multivariable Cox regression analyses were performed using Cox proportional hazard models to evaluate associations between sex and survival outcomes. Results: A total of 3170 patients (male, n = 1654; female, n = 1516) were included in the analysis. Compared with male patients, female patients were more likely to require dose reduction (male, 20.4%; female: 28.8%, p < 0.0001) and had low completion proportions of adjuvant chemotherapy (male, 81.7%; female, 77.0%, p = 0.0011). Female patients experienced higher incidences of any-grade hematological and non-hematological AEs (Table). Female sex was associated with higher incidences of grade 3/4 hematological AEs (odds ratio [OR]: 1.702 [95% CI 1.272–2.278], p = 0.0003) and non-hematological AEs (OR: 1.666 [95% CI 1.373–2.020], p < 0.0001). Female sex was identified as a favorable prognostic factor for RFS (hazard ratio [HR]: 0.729 [0.627–0.848], p < 0.0001) and OS (HR: 0.796 [0.653–0.970], p = 0.0238). Conclusions: Sex differences had implications for the development of AEs and survival outcomes of Japanese patients with pathological stage III CRC who received adjuvant fluoropyrimidine monotherapy. Incidences of adverse events. Adverse event Any grade Grade 3/4 Male% (95% CI) Female% (95% CI) p-value Male% (95% CI) Female% (95% CI) p-value Any hematological toxicity 63.7 (61.3–66.0) 83.9 (82.0–85.8) <0.0001 5.0 (4.0–6.1) 8.9 (7.5–10.4) <0.0001 Any non-hematological toxicity 93.3 (92.0–94.5) 96.1 (95.0–97.0) 0.0006 13.3 (11.7–15.1) 20.8 (18.8–22.9) <0.0001
Real-world (RW) treatment patterns and clinical outcomes of patients treated with sequential regorafenib and trifluridine/tipiracil ± bevacizumab (BEV) for metastatic colorectal cancer (mCRC) in the United States (US) community oncology setting: The SEQRT2 study.
62 Background: Both Regorafenib (R) and Trifluridine/Tipiracil (T) ± BEV are widely used treatments for mCRC in later lines. This RW study evaluated optimal sequencing and associated outcomes among patients who initiated R and T in sequential lines of therapy (LOT) between LOT1-LOT6 within community oncology settings in the US. Methods: A retrospective study utilizing electronic medical record data from The US Oncology Network examined adult patients with mCRC who initiated R and T ± BEV sequentially between 09/01/2015 and 11/30/2022 (index date), with follow-up until 05/31/2023. Treatment patterns, overall survival (OS) and time to next treatment (TTNT) after sequence were assessed overall, R first (R-T) and T first (T-R). Multivariable Cox regression adjusting for age, sex, ECOG, tumor stage, and prior medication, assessed the association of factors with OS and TTNT. Results: In total, 308 mCRC patients initiating R and T (R-T, 156 pts [140 R-T and 16 R-T+BEV]; T-R, 152 pts [136 T-R and 16 T+BEV-R]) met study criteria. Baseline demographic (mean age 63 yrs, males 55%) and clinical characteristics (70% colon cancer, 58% ECOG 0-1) were similar between the cohorts. Most patients initiated index therapies at the third line of therapy (LOT3) (49% R-T, 45% T-R). The median (IQR) sequence duration was 7.4 (5.6), 6.7 (4.4), and 7.0 (4.7) months, respectively in patients with R-T, T-R, and overall. The median (95% CI) OS was 12.8 (11.2, 14.1) months among R-T and 10.2 (8.8, 11.9) months among T-R patients. Compared to R-T, the adjusted HR for the T-R sequence was 1.2 (95% CI 0.9–1.6; p=0.2). The median (95% CI) TTNT was 9.3 (8.4, 10.3) and 8.6 (7.8, 9.4) months, for R-T and T-R, respectively; the adjusted HR was 1.1 (95% CI 0.8–1.4; p=0.62). Conclusions: Patients initiating R first appeared to have a longer duration of treatment and survival, although not statistically significant. The one-year median duration of survival in this real-world setting confirms the importance of access to these treatments in patients with mCRC and can inform physicians regarding the choice of medications while sequencing therapies in mCRC. Clinical outcomes among R-T and T-R mCRC patients. Variable Level R-T (± BEV)[N 1 = 156] T (± BEV) -R[N 1 = 152] Adjusted 3,4 HR 5 (95% CI)[R-T Reference] Effect OverallSurvival Months – median (95% CI) 12.8(11.2, 14.1) 10.2(8.8, 11.9) 1.20 (0.91, 1.58) 0.20 TTNT 2 Months – median (95% CI) 9.3(8.4, 10.3) 8.6(7.8, 9.4) 1.07 (0.83, 1.37) 0.62 1 Entire R-T and T-R cohorts are presented since 16 patients in each cohort initiated T+BEV. 2 Time To Next Treatment. 3 Overall Survival adjusting for age, gender, stage at diagnosis, ECOG, prior anti-VEGF treatment. 4 Time To Next Treatment adjusting for age, gender, stage at diagnosis, and line of therapy. 5 Hazard Ratio.
Gender and ethnic disparities in hepatocellular carcinoma: Trends in incidence rates across U.S. populations from 2000 to 2021.
524 Background: Hepatocellular carcinoma (HCC) is a primary malignancy of the liver strongly associated with liver cirrhosis and the etiologies producing cirrhosis. As such, racial and ethnic factors might affect incidence rates of HCC resulting in disparities. While disparities have been reported, the effect of gender within certain populations, particularly Hispanic and non-Hispanic White ancestry, have not been fully explored. This study looks at the changing incidence rates of HCC in the US amongst different populations with a particular focus on the impact of gender on incidence. Methods: Incidence rates of HCC between 2000 and 2021 among different sexes within racial and ethnic groups in the United States were analyzed utilizing delay-adjusted data from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) program. Annual percent change (APC) was calculated by using Joinpoint Regression software. Results: Overall, HCC incidence rates since 2014 to 2021 show a slight decrease (APC, -0.06). While Hispanic men HCC incidence rates declined from 2012 to 2021 (APC, -0.44), Hispanic women incidence have had a steady increase since 2000 (APC, +2.52). Non-Hispanic Black men (APC, -3.07) rates vastly declined from 2015 to 2021 while non-Hispanic black women interestingly experienced a slight decrease in incidence from 2013 to 2021 (APC, -0.34). Non-Hispanic White men experienced stagnant rates of HCC since 2014 (APC, -0.05) while non-hispanic white women (APC, +3.59) showed increasing trends in HCC incidence since 2003. For comparison, non-Hispanic Asian/Pacific Islander men (APC, -2.19) and women (APC, -2.36), which both experienced a decline since 2007. This analysis was repeated without significant change. Further corroborations are necessary to validate these findings. Conclusions: These findings show that while the incidence rates of HCC overall have decreased, this benefit appears to be largely driven in male populations. In contrast, in women, and particularly Hispanic and Non-Hispanic White women, incidence rates have been increasing. This phenomenon likely reflects the changes in etiologies of cirrhosis and HCC. Surveillance strategies and screening might need to be optimized to reflect these trends.
Incidence of mediastinal lymph node positivity in patients undergoing robotic transthoracic esophagectomy.
379 Background: Esophageal cancer is increasing in incidence worldwide. Robotic approaches have quickly become mainstream due to the improved visualization and possible increase in nodal harvest. There remains significant debate on the utility of mediastinal lymph node dissection in esophageal cancer patients. We sought to analyze the incidence of mediastinal lymph node positivity and to evaluate its impact on survival in patients with esophageal cancer undergoing robotic assisted trans-thoracic esophagectomy (RATE). Methods: Utilizing a prospectively maintained esophageal database, we identified patients who were diagnosed with EC and underwent RATE between 2009-2024. We then identified patients with positive lymph nodes and stratified by location (celiac or mediastinal). Baseline univariate comparisons were made for continuous variables using both the Mann-Whitney U and Kruskal Wallis tests. Pearson’s Chi-square test was used to compare categorical variables. Survival analysis was performed via Kaplain-Meier method. Results: We identified 201 patients who underwent RATE with a median age of 70 (41-91). There were 160 (79.6%) males and 41 (20.4%) females. The mean BMI was 26.5 ± 5.5 and mean ASA score was 3.1 ± 0.6. Adenocarcinoma was the predominate histology at 162(80.6%). Locally advanced T3/T4 tumors were identified in 53 (26.4%) patients and 63(31.3%) had clinical node + disease. Neoadjuvant therapy was utilized in 159(79.1%) patients. The median lymph nodes resected 18 (14 – 22), and length of hospitalization 8 (7 – 11) days. The 30 and 90-day mortality were 2.2% and 2.6% respectively. R0 resections was performed in 200 (99.5%) of patients and the pathologic complete response rates were 42.1%. The incidence of mediastinal lymph node positivewas 6.3% vs 76.3% abdominal. There were 17.6% of patients that had both mediastinal and abdominal lymph nodes positive. The median survival was 23 months for abdominal LN+, 19.5 months for mediastinal LN+ p=0.23. Multivariate analysis revealed that age, neoadjuvant radiation, nodal positivity were predictors of survival. Conclusions: The incidence of mediastinal positive lymph nodes are much higher than previously reported. Perhaps the improved visualization and manipulation of tissue with robotic approaches have enhanced our ability to resect these nodes. Mediastinal lymph node positivity is a poor prognostic factor for survival in patients undergoing robotic esophagectomy. Given these findings, we would continue to support aggressive nodal resection in patients diagnosed with esophageal cancer.
The safety and short-term efficacy of neoadjuvant chemotherapy in elderly patients with resectable locally advanced esophageal squamous cell carcinoma.
433 Background: The standard treatment for resectable locally advanced esophageal squamous cell carcinoma (LA-ESCC) is neoadjuvant chemotherapy followed by surgery. However, the efficacy and safety of neoadjuvant chemotherapy for patients aged 76 or older have not been established because the JCOG1109 trial, which established the current standard of care, was limited to patients younger than 76 years. In our hospital, even patients aged 76 or older are treated with docetaxel, cisplatin, and 5-FU (DCF) or 5-FU / leucovorin, oxaliplatin, and docetaxel (FLOT), if the patient's general condition and organ function are maintained, but there have been few reports on the efficacy and safety of these therapies for elderly population. Methods: The subjects were 76 years old or older resectable LA-ESCC patients diagnosed as cT1N1-3M0, cT2-3N0-3M0, and cT1-3N0-3M1 (UICC-TNM 8th), who received at least one cycle of neoadjuvant DCF or FLOT in our institution from 2014 to 2023. Adverse events (CTCAE ver. 5.0) and histopathological responses were evaluated. Results: Patients who received neoadjuvant DCF (D group) and FLOT (F group) were 19 and 25, respectively. Patients background in the D / F group was as follows; median age 76 / 78 (years), male 84% / 64%, PS1 37% / 64%, clinical, T3 74% / 84%, clinical N1 32% / 52%, N2 47% / 32%, clinical stage III 53% / 64%, stage IVB 21% / 28%. Of the 19 patients in the D Group, 17 completed 3 cycles of treatment (completion rate 89%), 18 underwent surgery, including 2 patients who discontinued during the treatment (1 with disease progression and 1 with adverse event), and 1 underwent CRT. Of the 25 patients in the F group, 16 completed 4 cycles of treatment (completion rate 64%), 22 underwent surgery, including 8 patients who discontinued during the treatment (1 with disease progression, 6 with adverse events, and 1 with other), 2 underwent CRT, and 1 was placed on best supportive care. In the D and F groups, hematological toxicities were more common in the F group, especially grade 3 or more neutropenia was 26% / 96%, but febrile neutropenia was similar at 5% and 12%, respectively. Nonhematological toxicities were more common in the F group for all grades (nausea 42% / 64%, anorexia 63% / 80%, and fatigue 52% / 88%, while grade 3 or more toxicity was not significantly different from the D group (nausea 0% / 4%, anorexia 0% / 4%, and fatigue 5% / 4%). In the 18 patients of the D group and 22 patients of the F group who underwent surgery, R0 resection was performed in 94% / 95%, and pathological complete response (pCR) was 11% / 23%, respectively. Conclusions: Neoadjuvant triplet chemotherapy was well tolerated and resulted in high R0 resection rates and pathological responses even in patients aged 76 or older. Further investigation with long-term follow up is warranted to elucidate the clinical benefit of neoadjuvant chemotherapy for elderly LA-ESCC patients.
Does chemotherapy regimen matter for first-line immunochemotherapy in low programmed cell death ligand 1 (PD-L1)-expressing esophageal squamous cell carcinoma (ESCC)? A systemic review and meta-analysis.
395 Background: Anti-programmed death 1 (PD-1) therapy plus chemotherapy has become standard first-line therapy for patients with high PD-L1-expressing advanced ESCC. The benefit for patients with low PD-L1-expressing ESCC remains debatable. Methods: Eligible studies were phase III trials investigating anti-PD-1/PD-L1 therapy plus chemotherapy (immunochemotherapy) vs chemotherapy as first-line therapy of advanced ESCC. Study-level pooled analyses of hazard ratios (HR) for progression-free survival (PFS) and overall survival (OS) with corresponding 95% confidence intervals (CI), were used to compare the different groups in random-effects model. PD-L1 expression levels with tumor proportion score (TPS) ≥ 1% vs < 1%, tumor area positivity (TAP) ≥ 10% vs < 10%, and combined positive score (CPS) ≥ 10 vs < 10 were collectively categorized as high vs low PD-L1 expression. The impact of two different chemotherapy regimens, TP (paclitaxel plus platinum) and PF (platinum pus fluoropyrimidine), stratified by PD-L1 expression levels, on the survival benefit of immunochemotherapy vs chemotherapy was investigated. Results: Eight randomized controlled trials including 4733 subjects were enrolled. Immunochemotherapy vs chemotherapy was associated with significantly improved PFS and OS irrespective of PD-L1 expression levels or chemotherapy regimens (Table). The PFS and OS benefits were more pronounced in high PD-L1 group than low PD-L1 group. In patients with high PD-L1 expression, the PFS and OS benefits were not significantly different between two chemotherapy regimen subgroups. However, in patients with low PD-L1 expression, the PFS benefit was more significant in TP subgroup than PF subgroup, and OS benefit trended to be in favor of TP subgroup. Conclusions: The addition of anti-PD-1/PD-L1 therapy to TP chemotherapy may associate with more significant survival benefit than to PF chemotherapy in advanced ESCC with low PD-L1 expression. Population PFS (immunochemotherapy vs chemotherapy) OS (immunochemotherapy vs chemotherapy) HR(95% CI) P value(subgroup differences) HR(95% CI) P value(subgroup differences) All patients 0.63 (0.57-0.69) 0.69 (0.64-0.74) High PD-L1 group 0.54 (0.49-0.60) P < 0.01 0.60 (0.53-0.67) P < 0.01 Low PD-L1 group 0.71 (0.62-0.81) 0.78 (0.70-0.87) TP group 0.56 (0.50-0.62) P < 0.01 0.66 (0.59-0.74) P = 0.32 PF group 0.68 (0.62-0.75) 0.72 (0.65-0.79) Among high PD-L1 patients TP subgroup 0.56 (0.45-0.69) P = 0.75 0.60 (0.46-0.78) P = 0.90 PF subgroup 0.53 (0.45-0.62) 0.59 (0.50-0.69) Among low PD-L1 patients TP subgroup 0.59 (0.48-0.74) P = 0.01 0.72 (0.55-0.93) P = 0.32 PF subgroup 0.82 (0.72-0.94) 0.84 (0.72-0.97)
Treatment sequences in patients with metastatic colorectal cancer in Japan: Real-world evidence of 1 <sup>st</sup> - to 5 <sup>th</sup> -line treatments.
76 Background: The development of later-line drugs for metastatic colorectal cancer (mCRC) has expanded treatment options for systemic chemotherapy in patients with mCRC. However, few studies have investigated patients who received later-line treatment in a real-world setting, and available information on treatment sequences and transition rates from early- to later-line treatments is limited. Methods: This was a retrospective study using hospital administrative data collected by MDV (Medical Data Vision, Tokyo, Japan) from April 2008 through February 2023 in Japan. Treatment regimens were derived from standard treatments recommended in the Japanese guidelines. The study population was determined using an algorithm from a similar study previously conducted in Japan. Our analysis focused on patients who started CRC surgery or 1 st -line treatment after January 2017 to reflect recent late-line real-world practice. Transition rates from 1 st - to 5 th -line treatment were calculated, and treatment sequences were summarized using a Sankey diagram. Logistic regression was performed to identify the factors associated with the transition from 2 nd - to 3 rd -line treatment. Results: A total of 722,005 patients with a CRC diagnosis record were identified in the MDV database. Of these, 26,456 patients were included in the study population. The median age was 69 years and 61.4% of patients were male. The rates of transition to subsequent lines from 1 st to 5 th line ranged from 65.7% to 70.4% (1 st to 2 nd 68.3%; 2 nd to 3 rd 70.4%; 3 rd to 4 th 69.9%; 4 th to 5 th 65.7%). Among 8528 patients who received 2 nd -line treatment, ~70% of patients (6006) continued 3 rd -line treatment, and 30% of patients (2522) received best supportive care. Comparing these 2 patient groups, younger age (<65 years, OR: 1.50, 95%CI: 1.35-1.67; p<0.001) and longer treatment durations of 1 st (≥180 days, OR: 1.26, 95%CI: 1.14-1.39; p<0.001) and 2 nd (≥120 days, OR: 1.67, 95%CI: 1.52-1.84; p<0.001) lines were significant factors for 3 rd -line treatment continuation. Prior therapy with oxaliplatin or irinotecan plus molecular targeted drugs was also associated with a higher likelihood of proceeding to 3 rd -line treatment (OR: 1.42, 95%CI: 1.28-1.58; p<0.001). Conclusions: In this study, ~70% of patients were able to transition to subsequent lines at the time of each line transition. However, 30% of patients were unable to continue treatment in real-world practice. To increase treatment continuation rates and maintain patient quality of life, new treatment options and further research are necessary to meet patients’ treatment needs, especially in the later-line treatment setting where unfavorable effects from previous treatments are accumulated.
Efficacy and safety of durvalumab and gemcitabine-based chemotherapy combined with or without lenvatinib in advanced biliary tract cancer.
595 Background: Immunotherapy in combination with gemcitabine-based chemotherapy, has now become the standard first-line treatment for advanced biliary tract cancer (BTC). Some small-sample studies have shown that immune checkpoint inhibitors (ICIs), when used in combination with lenvatinib and chemotherapy as first-line therapy, exhibit high anti-tumor activity in BTC. Therefore, we conducted a retrospective study to assess the efficacy and safety of durvalumab and gemcitabine-based chemotherapy with or without lenvatinib, in combination for advanced BTC in the real world. Methods: Between January 2021 and September 2024, patients with advanced BTC who received either durvalumab combined with or without lenvatinib, along with gemcitabine-based chemotherapy, were enrolled in this study. The study endpoints were overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and safety. Results: Thirty patients with advanced BTC were included in this study. Fourteen (46.7%) patients had received durvalumab combined with lenvatinib plus chemotherapy. For all the patients, the median OS was 9.5 months(95% CI: 4.98-14.02), and the median PFS was 5.9 months(95% CI: 4.56-7.24). ORR was 43.4% and DCR was 76.7%. Patients with lenvatinib treatment had a longer median PFS (7.1 vs. 4.6 months, P = 0.06) compared with the non-lenvatinib treatment group. However, the median OS was shorter in patients with lenvatinib treatment group (9.0 vs. 9.5 months, P = 0.915). ORR and DCR in patients with lenvatinib were 57.1% and 92.9%, respectively. However, in patients without lenvatinib treatment group, ORR and DCR were only 31.2% and 62.5%, respectively. All patients experienced adverse events (AEs), addition of lenvatinib does not increase the risk of AEs. The data is still being updated. Conclusions: Durvalumab and gemcitabine-based chemotherapy combined with or without lenvatinib has shown to be effective and safe in routine practice. Regarding lenvatinib, its addition has only improved the DCR, ORR, and PFS, but has not been able to prolong OS.
Real-world treatment patterns among U.S. adults with unresectable hepatocellular carcinoma (uHCC) eligible for locoregional therapy (LRT).
547 Background: Treatment (tx) in uHCC has mostly relied on locoregional liver-directed tx, such as transarterial chemoembolization (TACE) or radioembolization (TARE), but recent pharmacotherapy advances have provided more tx options. This study aims to describe current real-world tx patterns and clinical outcomes of uHCC eligible for LRT. Methods: uHCC patients enrolled in TARGET-HCC (an ongoing, 5-year, longitudinal, observational cohort of HCC patients receiving usual care at academic and community sites in the U.S.), who initiated tx between 6/1/2020-6/1/2023 were included and followed until 12/31/2023 (data cutoff). Patients receiving curative HCC tx (ablation, resection, or transplant) or with metastatic HCC, portal vein involvement, or Child-Pugh-C liver disease at diagnosis (dx) were excluded. Patient and disease characteristics, and txs data were abstracted from electronic health records. Index tx was defined as first tx after dx, with a 30-day grace period for combination txs. Subsequent tx was defined as first tx after the grace period; for index systemic therapies, the subsequent tx differed from the index tx. Real-world progression-free survival (rwPFS) was defined as time from index tx to first event: radiological progression (including new lesions, extrahepatic involvement, vascular invasion, or >20% increase in tumor burden from baseline), death, or hospice entry. Real-world time to progression (rwTTP) was defined as time from index tx to first radiological progression. Results: A total of 115 patients were included; mean age was 65.1 years and 77% were male. At dx, 41% of patients were BCLC B, 14% were non-metastatic BCLC C, and 38% were BCLC A with lesion >5 cm, rapidly progressive disease, or contraindications to LRT. Tx initiation with TACE/TARE was common, either alone (n=59, 51%) or in combination with systemic tx (n=5, 4%). Among patients initiating systemic tx (n=46 ,40%), 30 received IO-IO (immuno-oncology) combinations, 12 received IO only, and 4 received a TKI only (tyrosine kinase inhibitor). Following index tx, 21 (18%) patients died receiving no subsequent tx and 27 (23%) were censored at data cutoff. Among those who received subsequent tx (n=67, 58%), there was heterogeneity in tx choice: TACE/TARE (n=32), systemic tx (n=16) other LRT (n=10), multimodal therapy (n=5), and transplant (n=4). We observed 60 progression events and 38 deaths corresponding to a median rwPFS and rwTTP of 7.9 (95% CI: 5.0, 13.3) months and 11.3 (95% CI: 6.7, 28.9) months, respectively. Conclusions: Our results showed high variability in management of uHCC eligible for LRT with TACE/TARE commonly utilized. Tx choice may be influenced by factors beyond staging criteria. Prognosis for uHCC eligible for LRT remains poor, and further research on adaptive, multimodal tx strategies is needed to inform tx guidelines and improve outcomes.
Is treatment delivery of perioperative FLOT therapy in locally advanced OGA associated with recurrence-free survival?
391 Background: Although perioperative FLOT therapy is a standard for locally advanced oesophagogastric adenocarcinoma (LA-OGA), completing all cycles, especially in the adjuvant chemotherapy (ACT) phase, is often challenging. This study examined the survival impact of treatment delivery in LA-OGA patients receiving FLOT therapy. Methods: 423 patients who underwent radical resection at The Royal Marsden Hospital from 2017 to 2023 were screened. Major inclusion criteria included patients with LA-OGA (cT2≤ and Nany or Tany and N+), treated with FLOT (at least one cycle of neoadjuvant chemotherapy) and radical resection, with an ECOG performance status of 0–2. Patients were divided into therapy incomplete (Tx Incomp, less than eight cycles of FLOT) and therapy (Tx comp) groups. We performed univariate and multivariate analyses, as well as propensity score matching (PSM) analysis, to evaluate whether treatment delivery was associated with recurrence-free survival (RFS) and overall survival (OS). Kaplan-Meier curves and restricted mean survival times (RMST) up to 36 months were used to evaluate the survival time. The primary endpoint was the 3-year RFS and OS rate. Results: Of the screened patients, 210 met the inclusion criteria, with 79 (38%) in the Tx Incomp and 131 (62%) in the Tx comp group, and 50 (24%) patients did not receive ACT. The median follow-up time was 26.5 months. The 3-year RFS and OS rates in the Tx Incomp and Tx comp groups after PSM were 54% vs 59% (p=0.14) (RMST difference: 4.04 months, p=0.09) and 58% vs 78% (p=0.04) (RMST difference: 6.15 months, p<0.001), respectively. Multivariable analysis showed a significant impact of Tx comp on OS (HR 0.53, 95% CI: 0.32-0.88). In the subgroup of ypN-positive patients, a significant difference of RMST in OS rate was observed between those who started ACT and those who did not start ACT (RMST difference: 7.89 months, p=0.01), whereas no significant difference was found in the ypN-negative group (RMST difference: 0.65 months, p=0.75). Conclusions: This study suggests that completing FLOT therapy is associated with better OS. The impact of ACT might differ according to ypN stage.
A liquid biopsy analysis of exosomal miRNA to detect lymph node metastasis in early gastric cancer.
469 Background: Additional surgical resection is required to achieve a complete cure in patients with early gastric cancer (EGC) due to the potential risk for lymph node metastasis (LNM) after pathological analysis. However, LNM is estimated to occur in approximately 10% of patients with high-risk EGC. In this study, we investigated a blood-based liquid biopsy assay of exosomal miRNA for the noninvasive detection of LNM in patients with high-risk EGC. Methods: Two genome-wide miRNA expression profiling datasets (GSE164174 and TCGA) were analyzed to prioritize biomarkers in pretreatment plasma samples from clinical training and validation cohorts of GC patients. An integrated exosomal miRNA panel was developed and a risk stratification model combining the miRNA panel with clinical risk factors was established. Results: Using comprehensive expression profiling of public datasets, we identified a transcriptomic panel of four miRNAs (miR-34b, miR-130a, miR-375, and miR-627) that robustly identified patients with LNM [area under the curve (AUC) = 0.86, 95% confidence interval (CI) = 0.77-0.92]. We assessed panel performance in a training cohort (AUC=0.86, 95% CI=0.67-0.96) and validated it in an independent validation cohort (AUC=0.84, 95% CI=0.64-0.95). Our risk stratification model was more accurate than the panel and was an independent predictor of LNM identification (AUC=0.97). Conclusions: A novel noninvasive, liquid biopsy-based method for patients with EGC may predict those traditionally classified as high-risk patients with LNM who are unlikely to benefit from surgical resection.
XPO1 inhibition as a clinically viable strategy to enhance durability of response to KRAS <sup>G12D</sup> inhibitor in pancreatic ductal adenocarcinoma.
736 Background: The OFF State (GDP bound) KRASG 12D inhibitor MRTX1133 is currently being evaluated in pancreatic ductal adenocarcinoma (PDAC) patients. Nevertheless, as with other OFF state KRAS G12C inhibitors sotorasib and adagrasib, the KRAS G12D inhibitor may yield only a modest increase in disease-free survival due to emergence of drug resistance. This underscores the need to identify strategies that can enhance the efficacy of KRAS inhibitors in PDAC. Nuclear protein transport plays an important role in several pro-tumorigenic pathways and has been shown to be a therapeutic vulnerability in KRAS mutant cancers. XPO1 is the major nuclear exporter and plays a pivotal role in shuttling various critical tumor suppressors, genome surveillance proteins, and transcription factors out of the nucleus and is frequently overexpressed in various cancers, including PDAC. In this study, we employed a KRAS G12D inhibitor resistant model and evaluated its sensitivity to nuclear exporter protein inhibitor. Methods: We examined the cytotoxic and molecular effects of KRAS G12D inhibitor MRTX1133 in combination with nuclear transport inhibitor eltanexor in KRAS G12D inhibitor resistant models. The preclinical antitumor efficacy of the combination was evaluated in KRAS G12D mutant PDAC cell derived xenograft (CDX) subcutaneous and orthotopic models. Results: Eltanexor treatment reversed MRTX1133 resistance in vitro yielding suppressed proliferation of KRAS G12D mutant 2D and 3D cultures of PDAC cell lines and patient derived primary tumors cells. High throughput P-kinome analysis showed suppression of a larger repertoire of MAPK substrates in combination treatment compared to single agent group. Eltanexor and MRTX1133 combination led to reduction in protein expression of KRAS downstream effectors and cell cycle markers. Furthermore, a combined administration of eltanexor and MRTX1133 at sub-optimal doses resulted in remarkable tumor growth inhibition in multiple subcutaneous and orthotopic KRAS G12D mutant mice models. Moreover, eltanexor as a maintenance therapy also prevented tumor relapse indicating durability of response in PDAC. Conclusions: This is the first study demonstrating that nuclear transport inhibitors can overcome KRAS G12D inhibitor MRTX1133 resistance in PDAC cells. This study provides a rationale for combining MRTX1133 with eltanexor for the treatment of PDAC patients with KRAS G12D mutant tumors.
Efficacy of plogosertib (CYC149462), a novel orally bioavailable PLK1 inhibitor, on patient-derived models of colorectal cancer.
209 Background: Colorectal cancer (CRC) is the third most common cancer in adults in the United States. Given the relative rapid cell division in cancer cells compared to most normal cells, drugs targeting mitosis and other cell cycle checkpoints are of interest in CRC treatment. One multi-tasking protein in cell division is polo-like kinase 1 (plk1). Plk1 is a serine threonine kinase that is highly expressed during mitosis and involved in a variety of functions, including spindle assembly, chromosome segregation, G2/M transition, and cytokinesis. Encouragingly, its expression is also significantly higher in CRC compared to normal mucosa, which makes it an attractive cancer-specific target in CRC. In this study, we sought to evaluate the efficacy of plogosertib (CYC149462), a novel plk1 inhibitor, in a series of preclinical models of advanced CRC. Methods: Fourteen CRC patient-derived organoids (PDOs) were generated from patients who underwent biopsy or resection for their primary or metastatic CRC under an IRB approved protocol at Duke University. Diagnosis of CRC is confirmed in PDOs using H&E and IHC. Subsequently, PDOs were treated with plogosertib in a range of concentrations from 256pM to 100µM. Drug screens were performed for standard of care agents 5FU, oxaliplatin, and SN38. Viability was assessed with Cell-Titer Glo (CTG) 72 hours after treatment. Using a matched PDX, mice were treated with vehicle or 40 mg/kg daily of plogosertib via oral gavage for 2 weeks, 5 days per week. Cell cycle analysis was performed by flow cytometry, and localization of DNA during mitosis was done by fluorescence staining. Results: CRC PDOs were more sensitive to plogosertib (CYC149462) than 5FU, and oxaliplatin, with significantly lower IC 50 values (518.86±377.47nM for plogosertib vs. 38.87±45.63µM for 5FU, and 37.78±39.61µM for oxaliplatin respectively (ANOVA, P < 0.05). Subsequently, we validated our findings in vivo using a matched PDX in which plogosertib treatment led to significant tumor growth inhibition compared to vehicle (t-test, p < 0.05) without serious adverse effects. Furthermore, we showed that plogosertib induces dysfunction in alignment of chromosomes and subsequent G2/M cell cycle arrest (p < 0.05). Conclusions: Together, our study shows that pharmacological inhibition of Plk1 using plogosertib represents a promising therapeutic approach for advanced CRC.
Risk of residual tumor following removal of a malignant colorectal polyp with high-risk features.
136 Background: National guidelines recommend surgery when pathology analysis of a colorectal polyp reveals high-risk features: positive margin/piecemeal resection (PM/PR), lymphovascular/perineural invasion (LVI/PNI), poor differentiation (PD), or tumor budding (TB). However, some patients choose to avoid surgery, with its morbidity and quality-of-life implications, despite the risk of residual disease. Methods: This single-center cohort study determined the rates of luminal or lymph node disease and distant metastasis in patients who underwent surgery and patients who underwent observation following removal of a malignant colorectal polyp with high-risk features between 2015 and 2022. Results: Of 336 patients who underwent a polypectomy for a malignant polyp in the colon (n = 226) or rectum (n = 110), 312 had a PM/PR, 96 had LVI/PNI, 47 had PD, and 45 had TB; 208 patients (62%) underwent surgery, and 128 (38%) underwent observation. Patients with a malignant polyp in the rectum were more likely to undergo observation than patients with a malignant polyp in the colon (79 [72%] vs. 49 [22%] patients; P < 0.01). In the surgery group, 19 patients (9%) had residual luminal disease, 39 patients (19%) had lymph node disease, and 5 patients (2%) had distant metastasis. In the observation group, disease was identified in 14 patients (11%): regrowth in the lumen, 7 patients (9%); regrowth in lymph nodes, 5 patients (6%); distant metastasis, 1 patient (1%); regrowth with distant metastasis, 1 patient (1%). The 12 cases of regrowth were salvaged: resection, 4 patients; local excision, 2 patients; chemoradiotherapy, 6 patients. Conclusions: The risk of residual disease following removal of a malignant colorectal polyp with high-risk features is considerable. Patients concerned about the morbidity of surgery and postsurgery quality of life should be counseled about this risk, as well as the availability of effective salvage options. High-risk features (HRF) Surgery(n = 208) Observation (n = 128) Luminal/LN disease at surgery(n = 51; 25%) Luminal/LN regrowth during observation(n = 12; 9.4%) Distant metastasis(n = 7; 2.1%) PM/PR (n = 312; 93%) 193 119 49 (25%) 12 (10%) 7 (2.2%) LVI/PNI (n = 96; 29%) 56 40 16 (29%) 3 (7.5%) 3 (3.1%) PD (n = 47; 14%) 33 14 11 (33%) 0 1 (2.1%) TB (n = 45; 13%) 20 25 5 (25%) 1 (4.0%) 1 (2.2%) 1 HRF (n = 215; 64%) 141 74 31 (22%) 8 (11%) 4 (1.9%) 2 HRF (n = 78; 23%) 39 39 11 (28%) 4 (10%) 1 (1.3%) 3 HRF (n = 35; 10%) 25 10 8 (32%) 0 2 (5.7%) 4 HRF (n = 6; 1.8%) 2 4 1 (50%) 0 0
Retrospective study evaluating the genomic landscape of anal squamous cell carcinoma using liquid biopsy.
8 Background: Advanced-stage squamous cell carcinoma of the anus (aSCCA) is a rare malignancy. Diagnostic biopsies are often inadequate for tissue-based genomic profiling, thus genomic profiles are largely unexplored in this setting. We assessed liquid biopsy NGS results of aSCCA patients (pts) and described genomic profiles by age and sex. To our knowledge, we are the first to describe genetic alterations by liquid biopsy in this patient population. Methods: Pts with aSCCA who underwent circulating tumor DNA (ctDNA) NGS with Guardant360 assays from 2017 to 2024 were included. Frequency of alterations were assessed based on sex and age (18-49 years (yrs), ≥50 yrs). Co-occurrence patterns were assessed using cBioPortal. Demographics were extracted from test requisition forms. Statistical analyses via two sided t-tests were performed with significance defined as p<0.05. Results: 646 pts with aSCCA had non-synonymous ctDNA alterations detected; 69.2% (N=447) were female and 30.8% (N=199) male. Median age was 66 yrs (32-94) with 9.9% (N=64) <50 yrs and 90.1% (N=582) ≥50 yrs. Most frequently altered genes were PIK3CA (17.3%), TP53 (9.8%), ATM (7.8%), EGFR (4.3%), and BRCA2 (4.2%). More unique genes were altered in ≥50 yrs cohort [53 mutations, 38 genes with copy number amplification (CNA)] vs <50 yrs cohort (30 mutations, 66 CNA). Most frequent genes altered in <50 yrs cohort were TP53 (17.6%), PIK3CA (13.2%), EGFR (11.0%), APC (4.4%), and MET (4.4%). PIK3CA (16.7%), TP53 (12.2%), ATM (8.8%), BRCA2 (5.5%), and EGFR (3.4%) were most frequent in ≥50 yrs cohort. More genes were altered in females (64 mutations, 32 CNA) vs. males (56 mutations, 41 CNA). Most frequent alterations in females were PIK3CA E545K (3.4%), PIK3CA CNA (2.8%), PIK3CA E542K (1.9%), and ATM CNA (1.0%) vs in male pts being PIK3CA E545K (4.8%), PIK3CA CNA (3.3%), PIK3CA E542K (3.3%), EGFR CNA (1.6%), TERT promoter (1.0%). Overall, PIK3CA and TP53 alterations were mutually exclusive (odds ratio 0.43, p<0.001). Conclusions: Liquid biopsy is feasible in patients with aSCCA. Most frequently detected alterations and CNAs were in PIK3CA and TP53 in aSCCA which is consistent with prior studies evaluating aSCCA tumor NGS in tissue-based assays. Alterations varied across age and sex. PIK3CA E545K and E542K alterations were detected frequently in this population and have on-label therapies for non-aSCCA indications which may be a source for clinical consideration in this cancer type in the future. This data illustrates the importance of liquid biopsy NGS to also screen for clinical trial enrollment in a disease which is poorly responsive to standard therapy. Additional research is warranted to further elucidate genomic profiles for clinical applications of this rare tumor.
Scalable Synthesis of 2D ErOCl with Sub‐meV Narrow Emissions at Telecom Band
AbstractVan der Waals (vdWs) materials are promising candidates for hetero‐integration with silicon photonics toward miniaturization and integration. VdWs materials like molybdenum telluride and black phosphorus, despite being prominent, exhibit air sensitivity, and their room temperature emissions can be significantly broadened by tens of meV. Here, a self‐encapsulation strategy is developed to scalably synthesize robust 2D vdWs ErOCl with sub‐meV narrow emissions at the telecom C‐band. Diverse 2D rare earth materials are also grown via chemical vapor deposition (TmOCl, YbOCl, HoOCl, DyOCl, SmOCl, NdOCl, TbOCl, GdOCl, EuOCl, and PrOCl), demonstrating the strategy's generalizability. The as‐grown ErOCl exhibits high crystalline quality and excellent ambient and thermal stability (300 °C). Photoluminescence analysis reveals a series of narrow emissions across the visible to near‐infrared spectrum. The ErOCl's emission at the telecom band is narrowest among 2D luminescent materials, and suitable for integrating with photonic chips. Temperature‐dependent photoluminescence spectra facilitate the understanding of emission mechanisms, analyzed using a crystal field perturbation model. Moreover, these emissions can be tuned by external magnetic fields. This research not only pioneers a novel strategy for synthesizing 2D rare earth materials but also paves the way for innovative building blocks in the realm of on‐chip optical communications.