6-month Survival Research Articles

Mosunetuzumab plus Pola-CHP compared with Pola-R-CHP in previously untreated DLBCL: final results from a Phase II study.

This Phase II study evaluated mosunetuzumab plus cyclophosphamide, doxorubicin, prednisone, and polatuzumab vedotin (Pola-M-CHP) versus Pola-rituximab (R)-CHP for first-line treatment of diffuse large B-cell lymphoma (DLBCL). Patients were randomized 2:1 to receive 6 cycles of Pola-M-CHP or Pola-R-CHP on Day 1 of each 21-day cycle. Mosunetuzumab was administered intravenously via step-up dosing during Cycle 1 and at 30 mg on Day 1 of subsequent cycles. The primary endpoint was Independent Review Committee-assessed complete response (CR) rate by positron emission tomography-computed tomography. Overall, 62 patients were enrolled and received Pola-M-CHP (n = 40) or Pola-R-CHP (n = 22). CR rates were similar in both arms (72.5% with Pola-M-CHP versus 77.3% with Pola-R-CHP); the 24-month investigator-assessed progression-free survival rate was 70.8% (95% CI, 55.6-86.1) with Pola-M-CHP versus 81.8% (95% CI, 65.7-97.9) with Pola-R-CHP. The most common adverse event (AE) was cytokine release syndrome (68.4%; mostly Grade 1 [52.6%], and primarily confined to Cycle 1) with Pola-M-CHP and neutropenia/neutrophil count decreased (54.5%) with Pola-R-CHP. Neutropenia/neutrophil count decreased was the most frequently observed Grade ≥3 AE in both arms (Pola-M-CHP: 36.8%; Pola-R-CHP: 22.7%). Rates of Grade ≥3 AEs (86.8% versus 59.1%), serious AEs (63.2% versus 13.6%), and AEs leading to treatment discontinuation (13.2% versus 0%) were higher with Pola-M-CHP than Pola-R-CHP, respectively. Pharmacodynamic changes were supportive of mosunetuzumab's mechanism of action and its addition to the Pola-CHP combination. Pola-M-CHP, although an active combination, did not demonstrate a clinical benefit over Pola-R-CHP in this small study. This trial was registered at www.clinicaltrials.gov as #NCT03677141.

Phase II trial of nab-paclitaxel plus ramucirumab in combination with nivolumab for unresectable advanced or recurrent gastric cancer after progression on first-line treatment including fluoropyrimidine, platinum, and anti-PD-1/PD-L1 antibody (PADDLE).

Patients with advanced gastric cancer (AGC) have poor survival after first-line treatment containing an anti-programmed death-1/ligand 1 (PD-1/PD-L1) antibody. Accumulating evidence suggests rationales for continuing immunotherapy beyond progression, synergistic effects between immune checkpoint inhibitors and angiogenesis inhibitors, and a preferable combination of steroid-free chemotherapy with immunotherapy. These rationales imply that nanoparticle albumin-bound (nab)-paclitaxel plus ramucirumab in combination with nivolumab (anti-PD-1 antibody) may enhance anti-tumor effects as second-line treatment. Therefore, we hypothesized that this triplet regimen may improve clinical outcomes in patients with AGC who experienced disease progression on first-line treatment including anti-PD-1/PD-L1 antibody. The PADDLE trial, which is sponsored by Ono Pharmaceutical, is an investigator-initiated, multicenter, open-label, single-arm, prospective phase II trial conducted at six institutions in Japan. Key eligibility criteria are as follows: (1) advanced gastric or esophagogastric junction cancer, (2) histologically confirmed diagnosis of adenocarcinoma, (3) refractory to first-line treatment including fluoropyrimidines, platinum, and an anti-PD-1/PD-L1 antibody, (4) performance status of 0-1, and (5) at least one measurable lesion. Patients are to receive nab-paclitaxel (100 mg/m2 weekly, with a 1-week rest after 3 consecutive weeks), ramucirumab (8mg/kg every 2 weeks), and nivolumab (240mg/body every 2 weeks). The primary endpoint is 6-month progression-free survival (PFS) rate. The target number of patients was set at 45 based on threshold and expected 6-month PFS rates of 35% and 60%, respectively, with a one-sided alpha error of 0.05 and power of 0.95. Secondary endpoints include objective response rate, disease control rate, PFS, overall survival, duration of response, time to response, and safety. Biomarker analyses of serial blood and tumor samples are planned to clarify predictive markers and molecular mechanisms underlying treatment resistance by multifaceted analytical methods (e.g., flow cytometry, DNA sequencing [DNAseq]/RNA sequencing [RNAseq]). Recruitment started in November 2022. The PADDLE trial is expected to clarify the efficacy of nab-paclitaxel plus ramucirumab in combination with nivolumab as second-line treatment in patients with AGC refractory to first-line treatment including an anti-PD-1/PD-L1 antibody and to identify potential biomarkers for predicting clinical responses in patients with AGC undergoing this triplet regimen. jRCT2031220448.

Real world study on combining local interventions with systemic therapy in unresectable hepatocellular carcinoma

Combining local interventions with tyrosine kinase inhibitors (TKIs) plus anti-PD-1 antibodies in a triple therapy has demonstrated remarkable anti-tumor efficacy and facilitated conversion resection in patients with initially unresectable hepatocellular carcinoma (HCC). However, the long-term survival outcomes remain largely unexplored. This study focused on a cohort of consecutive patients who underwent triple therapy for initially unresectable HCC at the authors’ hospital between January 2020 and December 2022. Specifically, patients who exhibited a positive response to triple therapy and fulfilled the criteria for hepatectomy were selected for liver resection. Additionally, investigation assessed association between clinical factors and successful achievement of conversion resection, as well as postoperative recurrence. The study cohort comprised 79 patients, among whom 20 individuals (25.3%) underwent R0 resection subsequent to the initiation of triple therapy. Notably, patients without extrahepatic disease and those who exhibited a radiographic response to triple therapy were more likely to be eligible for curative resection. Importantly, hepatectomy independently associated with a favorable overall survival (HR, 0.388; 95% CI, 0.177–0.847; P = 0.017). Other independent risk factors related to overall survival contained extrahepatic metastasis (HR, 2.152; 95% CI, 1.076–4.302; P = 0.030), tumor number ≥ 4 (HR, 2.058; 95% CI, 1.001–4.234; P = 0.049) and radiological remission (HR, 0.233; 95% CI, 0.071–0.768; P = 0.017). For the 20 patients who underwent surgery, 12-month recurrence-free survival and overall survival rates were respectively 43.3% and 66.6%. The triple therapy demonstrated favorable prognostic outcomes and manageable safety profiles in patients with initially unresectable HCC.

Developing clinical prognostic models to predict graft survival after renal transplantation: comparison of statistical and machine learning models

IntroductionRenal transplantation is a critical treatment for end-stage renal disease, but graft failure remains a significant concern. Accurate prediction of graft survival is crucial to identify high-risk patients. This study aimed to develop prognostic models for predicting renal graft survival and compare the performance of statistical and machine learning models.MethodologyThe study utilized data from 278 renal transplant recipients at the Ethiopian National Kidney Transplantation Center between September 2015 and February 2022. To address the class imbalance of the data, SMOTE resampling was applied. Various models were evaluated, including Standard and penalized Cox models, Random Survival Forest, and Stochastic Gradient Boosting. Prognostic predictors were selected based on statistical significance and variable importance.ResultsThe median graft survival time was 33 months, and the mean hazard of graft failure was 0.0755. The 3-month, 1-year, and 3-year graft survival rates were found to be 0.979, 0.953, and 0.911, respectively. The Stochastic Gradient Boosting (SGB) model demonstrated the best discrimination and calibration performance, with a C-index of 0.943 and a Brier score of 0.000351. The Ridge-based Cox model closely followed the SGB model’s prediction performance with better interpretability. The key prognostic predictors of graft survival included an episode of acute and chronic rejections, post-transplant urological complications, post-transplant nonadherence, blood urea nitrogen level, post-transplant regular exercise, and marital status.ConclusionsThe Stochastic Gradient Boosting model demonstrated the highest predictive performance, while the Ridge-Cox model offered better interpretability with a comparable performance. Clinicians should consider the trade-off between prediction accuracy and interpretability when selecting a model. Incorporating these findings into the clinical practice can improve risk stratification and personalized management strategies for kidney transplant recipients.

Diagnostic and Prognostic Value of Serum Golgi Protein 73 in Patients With Hepatitis B Virus-Associated Acute-on-Chronic Liver Failure.

The prognosis and severity of hepatitis B virus-associated acute-on-chronic liver failure (HBV-ACLF) cannot be well-identified by serum biomarkers. The present study aims to determine the role of serum Golgi protein 73 (GP73) in predicting the prognosis and severity of liver necrotizing inflammation induced by HBV-ACLF. A total of 427 chronic HBV-infected patients were included for the present study. Among these patients, 179 patients had chronic hepatitis B (CHB), 96 patients had HBV-related liver cirrhosis (LC), and 152 patients had HBV-ACLF. The baseline and dynamic changes in serum GP73 levels were measured and compared in CHB, LC and HBV-ACLF patients. The serum GP73 levels were significantly greater in HBV-ACLF patients when compared to CHB and LC patients. Furthermore, serum GP73 demonstrated excellent performance in distinguishing HBV-ACLF from CHB and LC, with an area under the curve of 0.969 and 0.824, respectively. In the logistic regression analysis, a high GP73 level was identified as an independent risk factor associated with death within 3 months, and the optimal cut-off level was 274.59 ng/mL. The serum GP73 levels significantly decreased and remained stable at approximately 6 months for survivors. Serum GP73 may serve as a valuable biomarker for the diagnosis and prognosis prediction of HBV-ACLF patients.

Immune checkpoint inhibitors (ICIs) in deficient mismatch repair (dMMR)/microsatellite instability (MSI) non-colorectal cancers: Real world Indian data and the use of alternative dosing.

347 Background: Immune checkpoint inhibitors, predominantly pembrolizumab and dostarlimab, have been approved in deficient mismatch repair (dMMR)/ microsatellite instability (MSI) non-colorectal cancers. There is also an emerging data to suggest significant clinical activity for low-dose ICIs (LD-ICIs) in these cancers. Methods: A multi-institutional retrospective analysis in Indian patients with dMMR/MSI-H advanced/metastatic non-colorectal carcinomas treated with ICIs (irrespective of dose or schedule) between 2017 and 2024 was conducted. The primary objective of the study was to evaluate 12-month Overall survival (OS) for the whole cohort as well as LD-ICI and standard dose ICI (SD-ICI) cohorts, while other secondary objectives included assessment of overall response rates (ORR) (assessed by RECIST v1.1 as per local radiological reporting), 12-month progression free survival (PFS) and incidence of immune related adverse events (IRAEs). Results: A total of 51 patients were available for analysis. The most common tumour types were gastrointestinal (64%, commonly gastric cancer, oesophageal cancer and cholangiocarcinoma) and endometrial cancers (23%). Eighty-four percent of patients received ICI monotherapy, while the remaining 16% received varying combinations of ICIs with chemotherapy and tyrosine kinase inhibitors. Nivolumab was used in 24 patients (47%) while pembrolizumab was used in 17 patients (33%). With a median follow-up of 14 months, 12-month OS was 72% and 12-month PFS was 62% in the entire cohort. The corresponding 12-months OS and 12-month PFS for those receiving SD-ICIs (n=29) was 69% and 62%, while it was 72% and 64%, respectively for the LD-ICIs cohort (n=22). The ORR was 61%, with 10 patients (20%) achieving complete response (CR) and 21 (41%) achieving partial response (PR). The most common IRAEs (all grades) were fatigue (62%), thyroid disturbances (37%), and pruritus (23%). Conclusions: The current study from India highlights the importance of treating non-colorectal dMMR/MSI-H cancers with ICIs and shows outcomes commensurate with published trial data. Within the confines of a small retrospective study with a short follow-up, low dose ICIs should be explored in these patients in scenarios where standard dosing schedules are not feasible due to logistic reasons. Key Words – Low dose immunotherapy; non-colorectal dMMR/MSI-H cancers; Overall survival.

Predictive role of circulating tumor DNA for locally advanced esophageal squamous cell carcinoma before surgery.

476 Background: A precise preoperative tumor monitoring method that reflects tumor burden during neoadjuvant treatment is required to guide individualized perioperative treatment strategies for esophageal squamous cell carcinoma (ESCC). This study examined the clinical significance of preoperative circulating tumor DNA (ctDNA) in the plasma of patients undergoing neoadjuvant chemotherapy (NAC) followed by esophagectomy. Methods: Plasma samples were collected longitudinally for ctDNA analysis as well as genomic DNA from primary lesions from patients with histologically confirmed ESCC who received neoadjuvant chemotherapy (NAC) followed by subtotal esophagectomy. Next-generation sequencing was used to identify mutations in both the plasma and primary tumors. We evaluated the relation ship between ctDNA alterations and recurrence in patients with locally advanced ESCC. Results: Pretreatment samples from 25 patients (100%) showed the same mutations in both ctDNA and primary tumors; therefore, they were classified as ctDNA-positive before treatment. In the cohort of 25 patients analyzed, those who tested positive for ctDNA after NAC had a significantly higher risk of recurrence; the 36-month recurrence-free survival rates were 92% for ctDNA-negative patients and 8% for ctDNA-positive patients (p < 0.001). Conclusions: Preoperative ctDNA status may be a promising prognostic biomarker that can be assessed before surgery in patients with ESCC who received NAC. Expanded cohort validation will allow for more personalized multidisciplinary treatment approaches for ESCC tailored to ctDNA analysis.

The 5-factor modified frailty index as a prognostic factor following stereotactic radiosurgery for metastatic disease to the brain from non-small cell lung cancer: A multi-center cohort analysis.

Non-small cell lung cancer (NSCLC) patients often develop brain metastases (BMs), complicating management. We have shown that increasing frailty is associated with decreased overall survival (OS) and central nervous system progression free survival (PFS) for patients undergoing stereotactic radiosurgery (SRS) to BMs. Leveraging the International Radiosurgery Research Foundation, we sought to expand upon these findings, in NSCLC specifically. Across four institutions, 193 patients with (≥1) NSCLC derived BMs with minimum 3months of clinical/radiographic follow-up were analyzed. Primary outcomes included OS and PFS. Patients were stratified utilizing the mFI-5 into pre-frail (0-1), frail (2), and severely frail (3+). Increased frailty was associated with diminished OS (frail hazard ratio (HR)=2.49, 95% CI [1.61-3.85]; severely frail HR = 2.65, 95% CI [1.57-4.45]). The 6-month post-SRS survival rate was 86.1%, 69.5% and 54.5% for pre-frail, frail and severely frail patients, respectively (p<0.001). Frailty was not significantly predictive of time to PFS on multivariate Cox Proportional Hazards analysis although there was a trend towards diminished PFS with increasing frailty (median PFS was 18.4, 8.0, and 7.4months for pre-frail, frail, and severely frail, respectively (p=0.11). As age>65 was also predictive of shorter OS (HR=1.78, 95% CI [1.23-2.56]). We generated a novel scoring system incorporating age and frailty status. The median survival of patients that scored 0, 1, 2, and 3 points were 21.1, 18.3, 8.9, and 5.6months, respectively (p<0.001). The area under the curve of the validation cohort using a logistic regression model was 0.77. Our results indicate that the MFI-5 is a promising metric with application at the point of care to provide decision support for patients with NSCLC derived BMs.

A phase 2 study of amplitude-modulated radiofrequency electromagnetic fields (AM RF EMF) in metastatic pancreatic cancer.

TPS790 Background: Patients with advanced pancreatic adenocarcinoma (PDC) that progresses after first-line therapy face limited treatment options. Despite advances in systemic therapy, the prognosis for PDC is dismal, with a five-year overall survival (OS) of about 5% . Due to the high morbidity of this disease, there is a critical need for innovative treatments to improve patient outcomes. TheraBionic P1, a hand-held device, delivers tumor specific radio frequencies via a spoon-shaped antenna placed on the patient's tongue. The FDA and EMA have confirmed the safety of the device for amplitude-modulated electromagnetic field (AM-EMF) therapy. Improved efficacy outcomes were reported with AM RF EMF in other solid organ tumors including pancreatic cancer in preliminary studies. Preclinical and clinical evidence suggests that AM-EMF can inhibit tumor growth and was recently approved for use in hepatocellular cancer. The safety and clinical activity observed with AM RF EMF, paired with the unmet medical need for additional effective therapies in pancreatic cancer, provided a strong rationale for further clinical investigation. This protocol evaluates the efficacy and tolerability of AM RF EMF in combination with standard of care frontline therapy, gemcitabine and nab-paclitaxel for metastatic PDC. Methods: This is an ongoing, single-center, Phase II, non-randomized study using a Simon two-stage minimax design to assess the efficacy of AM-EMF in combination with gemcitabine/nab-paclitaxel as a first-line treatment in metastatic pancreatic cancer. Gemcitabine and nab-paclitaxel are administered per standard care. AM RF EMF are delivered to patients with a spoon-shaped applicator placed on the tongue three daily 60-minute treatments. Patients will be assessed for response every 8 weeks. Treatment is continued until progression or toxicity. The primary objective of this study is to evaluate the efficacy of the combination of nab-paclitaxel, gemcitabine, and AM RF EMF in improving 6-month overall survival rates in patients with metastatic PDC. Secondary objectives evaluate the safety, tolerability, profession free survival, objective response rate and disease control rate. Exploratory objectives evaluate change in CA19-9 and quality of life using FACT-General (FACT-G) and determine any possible correlation with clinical outcomes. Key eligibility includes treatment-naïve, histologically confirmed metastatic PC, age eighteen years old or greater, ECOG 0-1, and optimal organ function. Clinical trial information: NCT05776524 .

FOLFIRI-ramucirumab (FOLFIRI-Ram) versus ramucirumab-paclitaxel (Ram-Pac) in the second line (2L) for patients with advanced upper gastrointestinal (UGI) cancer: A real-world propensity-score matched analysis of survival.

377 Background: The approach to 2L treatment of advanced UGI (gastric, esophageal, and gastroesophageal junction) cancers is guided primarily by the results of the RAINBOW trial, a global randomized phase III trial that demonstrated the benefit of Ram-Pac over paclitaxel. However, the onset of peripheral neuropathy limits its use in the palliative-intent setting. The RAMIRIS trial demonstrated the feasibility of 2L FOLFIRI-Ram compared to Ram-Pac, however it failed to meet the prespecified endpoint of ≥ 65% 6-month overall survival (OS). Despite this, FOLFIRI-Ram has emerged as an alternative 2L regimen and now endorsed in major society guidelines. Yet, comparative outcomes between FOLFIRI-Ram and Ram-Pac therapy in the real world are lacking. Methods: This study used the nationwide Flatiron Health electronic health record-derived deidentified database. During the study period (January 2011-June 2024), longitudinal patient-level data were derived from approximately 280 cancer clinics. Patients were eligible for inclusion if they had advanced unresectable or metastatic UGI cancer and received 2L treatment with either FOLFIRI-Ram or Ram-Pac. Demographics and lab values at the time of 2L initiation were extracted. Given anticipated imbalances in sample size, patients were matched 1:6 (FOLFIRI-Ram:Ram-Pac) for inclusion into the analytic dataset using a greedy match based on a logit model to predict propensity scores from key clinical and laboratory characteristics. The primary endpoint was OS from the start of 2L therapy, analyzed using the Kaplan-Meier method, log-rank test, and Cox proportional hazards model. A hybrid approach was used to construct a multivariate Cox model. Results: A total of 15,908 patients were included in the database, of whom 5189 received a 2L treatment. Of these, 631 patients received 2L Ram-Pac and 40 received 2L FOLFIRI-Ram. After matching, the final sample size was 240 patients who received Ram-Pac and 40 who received FOLFIRI-Ram. Baseline clinical and laboratory characteristics were well-balanced. The median OS from initiation of 2L FOLFIRI-Ram was 9.7 months (95% CI 6.9-12.3) and 7.6 months with 2L Ram-Pac (95% CI 6.3-9.2 months). The hazard ratio (HR) for death with FOLFIRI-Ram was 0.77 (95% CI 0.52-1.15, log-rank P=0.20) in reference to Ram-Pac. The adjusted HR death for FOLFIRI-Ram after adjustment for baseline albumin and white blood cell count was 0.87 (95% CI 0.58-1.30, p=0.49) in the final multivariate model. Conclusions: This real-world propensity-score matched analysis of patients with advanced UGI cancers receiving FOLFIRI-Ram or Ram-Pac supports the ongoing use of FOLFIRI-Ram in the 2L as an alternative to Ram-Pac. These data are consistent with results from the RAMIRIS study, however further prospective study is needed.

Obesity and biliary tract cancers: Changing epidemiology.

643 Background: The incidence of biliary tract cancers (BTC) continues to rise (Sung et al. 2024). The reasons remain ill-defined. Over 70% of patients are diagnosed without identifiable predisposing factors. Obesity and overweight have emerged as putative contributors. We examined the epidemiologic and molecular characteristics of patients with BTC, with a focus on body mass index (BMI) at presentation and overall survival (OS). Methods: A retrospective cohort study of patients diagnosed with BTC at Memorial Sloan Kettering was conducted from January 2022 to December 2023. Patients were divided based on BMI into: obese (BMI≥30 kg/m 2 ) and non-obese (BMI&lt;30 kg/m 2 ). We collected patients' baseline demographics, and results of somatic next generation sequencing using the MSK-IMPACT platform and compared between obese and non -obese groups using Fisher’s exact test for categorical and Wilcoxon rank sum test for continuous variables. OS was calculated from date of diagnosis, estimated using Kaplan-Meier methods and compared between groups using log rank test. Results: A total of 142 patients were identified. The table summarizes the baseline characteristics including age, BMI, sex, stage at diagnosis, family history, history of malignancy, and race. Obesity was significantly associated with family history of malignancy and white race. Among surviving patients (n=93), with a median follow-up of 13.8 months, 6-month, 1-year, and 2-year overall survival (OS) rates were 85% [95%CI: 80%-92%], 71% [95%CI: 64%-79%], and 54% [95%CI: 43%-68%] respectively. OS was not statistically different among obese and non-obese patients. However, when stratifying OS by BMI and gender, obese males were noted to have inferior OS compared to obese females (6-mo OS 75% and 90% respectively), though not statistically significant. Genetic sequencing did not reveal a specific molecular pattern in either group. Conclusions: Obesity appears not to be associated with young age, stage, or particular somatic alterations in this limited study. OS was not statistically different among obese and non-obese patients. Males with obesity appeared to have a worse prognosis. This observed gender-based difference needs to be further studied, and if confirmed further research is needed to explore potential factors that may explain the clinical observation. Baseline characteristics. Characteristics Overall n=142 Obese (BMI≥30 kg/m 2 ) n=54 Non-Obese (BMI&lt;30 kg/m 2 )n=88 p-value Age 68 (35-91) 69 (35-87) 67 (36-91) &gt;0.9 BMI (kg/m 2 ) 28.1 (16.6-48.5) 33.5 (30-48.5) 24.7 (16.6-29.6) Sex female/male 79 (56%)/63 (44%) 32 (59%)/22 (41%) 47 (53%)/41 (47%) 0.6 Stage Localized/advanced 21 (15%)/121 (85%) 11 (20%)/ 43 (80%) 10 (11%)/ 78 (89%) 0.3 Family history of cancer 91 (65%) 41 (76%) 50 (57%) 0.030 History of second malignancy 26 (18%) 12 (22%) 14 (16%) 0.4 Race White African Asian Other 99 (70%)12 (8.5%)20 (14%)11 (7.7%) 44 (81%)4 (7.4%)1 (1.9%)5 (9.3%) 55 (63%)8 (9.1%)19 (22%)6 (6.8%) 0.004

A multicenter, prospective phase II trial of second-line aflibercept plus FOLFIRI in patients with metastatic colorectal cancer refractory to anti-EGFR agents (HGCSG1801): Updated analyses.

147 Background: The HGCSG1801 trial evaluated the treatment outcomes of aflibercept (AFL) plus FOLFIRI for patients(pts) with metastatic colorectal cancer (mCRC) refractory to an oxaliplatin-based regimen combined with an anti-EGFR agent. Here we report results of the updated efficacy, safety, and a biomarker analysis. Methods: This was a prospective open-label phase II trial. AFL (4 mg/kg iv) followed by FOLFIRI (irinotecan 180 mg/m 2 , leucovorin 200 mg/m 2 iv, bolus 5-fluorouracil [5-FU] 400 mg/m 2 , and infusional 5-FU 2400 mg/m 2 /46 h) was given every 2 weeks until progression or unacceptable toxicities. The primary endpoint was 6-month progression-free survival (PFS) rate, and the secondary endpoints included overall survival (OS), PFS, overall response rate (ORR), disease control rate (DCR), and adverse events. Angiogenic factors were analyzed in plasma sample using a Luminex multiplex assay using the Cox proportional hazards model. This study was sponsored by the Non-Profit Organization Hokkaido Gastrointestinal Cancer Study Group and supported by a grant from Sanofi. Results: Forty-three pts were enrolled between November 2019 and October 2022. The data cut-off date was April 30, 2024. The 6-month PFS rate was 59.0% (90% confidence interval [CI], 45.8–72.1%). Median PFS and OS were 7.3 months (95% CI, 5.5–11.0 months) and 18.8 months (95% CI, 12.9–26.6 months), respectively. The ORR was 20.9% (95% CI, 10.0–36.0%) and DCR was 88.4% (95% CI, 74.9–96.1%). No deaths and no new safety signals with a causal relation to the study treatment were observed. A biomarker analysis using pretreatment plasma samples showed a trend toward better PFS in pts with low VEGF-A (hazard ratio [HR] 0.40 [95% CI, 0.18-0.91]), TSP-2 (HR 0.40 [95% CI, 0.18-0.88]) or IL-8 levels (HR 0.43 [95% CI, 0.20-0.93]). There was also a trend toward better OS in pts with low levels of TSP-2 (HR 0.30 [95% CI, 0.11-0.81]) or TIMP-1 (HR 0.20 [95% CI, 0.06-0.69]). Conclusions: These updated data further support the activity and manageable safety profile of AFL plus FOLFIRI for pts with mCRC who failed an oxaliplatin-based regimen combined with an anti-EGFR agent. It was suggested the association between some angiogenic factors in plasma samples and the activity of AFL plus FOLFIRI in mCRC. Clinical trial information: jRCTs011190006 .

First-line iparomlimab and tuvonralimab (QL1706) or iparomlimab (QL1604) + bevacizumab (BEV) for unresectable hepatocellular carcinoma (HCC): Updated results from the phase Ib/II DUBHE-H-106 study.

579 Background: Novel treatment options for unresectable HCC are needed. Iparomlimab and tuvonralimab are anti-PD-1 and anti-CTLA-4 antibodies, respectively. The DUBHE-H-106 study aims to assess safety and efficacy of first-line QL1706 or QL1604 + BEV for HCC. Preliminary data have been reported on 2023 ASCO Annual Meeting. Here, we report updated results. Methods: This study consists of three cohorts. Systemic therapy-naive adult patients (pts) with HCC, ≥ one measurable untreated lesion per RECIST v1.1, BCLC stage B–C, Child-Pugh score ≤ 7, not amenable to or progression after locoregional therapy, ECOG performance status of 0–1 were eligible. In Cohort A, six pts received QL1706 5 mg/kg + BEV 15 mg/kg Q3W. If ≤ two pts had dose-limiting toxicities (DLT), another six pts would be enrolled. If ≤ three of twelve pts had DLT, the safe dose of BEV would be determined, and eight more pts would be enrolled. Otherwise, enrollment of another dose group (QL1706 5 mg/kg + BEV 7.5 mg/kg Q3W) would initiate, using the same procedure. If number of DLT exceeded the criteria, further dose reduction of BEV or study termination would be discussed. Then 40–60 pts were randomized 1:1 to Cohort A or B. In Cohort B, pts received QL1604 200 mg + BEV (safe dose) Q3W. Enrollment of Cohort C would initiate according to the preliminary results of Cohort A and B. Pts received QL1706 7.5 mg/kg + BEV (safe dose) Q3W, using the same procedure in Cohort A. If ≤ three of twelve pts had DLT, 8–28 more pts would be enrolled. Results: Between Jun 2021 and Dec 2023, Cohort A, B, and C included 50, 26, and 40 pts, respectively. Baseline data were balanced in each cohort. All pts were in the safety set. No DLT was reported. Incidences of adverse events (AE) were similar in three cohorts. Efficacy evaluable set included 47, 26, and 37 pts in three cohorts. Numerically, QL1706 + BEV showed better efficacy compared to QL1604 + BEV, and higher response and 12-month progression-free survival (PFS) rates were found in Cohort C vs Cohort A. Detailed results were shown in Table. Conclusions: First-line QL1706 or QL1604 + BEV showed acceptable toxicities and promising efficacy for unresectable HCC. QL1706 7.5 mg/kg + BEV 15 mg/kg Q3W may have better anti-tumor activity and were recommended for trials in future. Clinical trial information: NCT05603039 . Endpoints Cohort A Cohort B Cohort C Treatment-related AE (TRAE) 43 (86%) 25 (96%) 37 (92%) Grade ≥ 3 TRAE 24 (48%) 14 (54%) 16 (40%) Serious TRAE 11 (22%) 9 (35%) 10 (25%) Immune-related AE 27 (54%) 9 (35%) 22 (55%) TRAE leading to dose interruption 23 (46%) 16 (62%) 16 (40%) Objective response, n (%; 95% CI) 18 (38%; 25%–54%) 6 (23%; 9%–44%) 16 (43%; 27%–61%) Disease control, n (%; 95% CI) 35 (74%; 60%–86%) 18 (69%; 48%–86%) 30 (81%; 65%–92%) Median PFS (95% CI), months 7.0 (3.1–9.6) 5.4 (2.4–11.0) 7.0 (4.2–not evaluable) 12-month PFS rate (95% CI) 26.8 (14.7–40.4) 24.4 (9.9–42.1) 40.9 (24.3–56.9)

Trastuzumab emtansine as second-line therapy in HER2 positive advanced biliary tract cancers: Single arm prospective phase II clinical trial (TAB-3 trial).

584 Background: HER2 overexpression or amplification is a therapeutic target of interest in advanced BTC, especially gallbladder cancers (GBC). Limited studies evaluate the role of T-DM1 in these groups of cancers. Methods: This study was an investigator-initiated, open-label, single-arm, phase II trial in patients (pts) aged 18 years or older with HER2-positive (defined as IHC 3+ or IHC 2+, and FISH positive), advanced BTCs who had previously received systemic therapy (irrespective of prior additional HER2 targeted therapy). Pts received T-DM1 at 3.6mg/kg q 3 -weekly till disease progression (PD), unacceptable toxicities, or patient choice. The primary end-point of the study was an improvement in 3-month progression-free survival (PFS) from 50% (historical cohort) to 70% in the study arm. Secondary endpoints included overall response rates (ORR), disease control rate (DCR), overall survival (OS), and incidence of grade 3 and 4 treatment-related adverse events (TRAE). Results: From July 2023 to July 2024, ‘52’ pts with HER2-positive BTC were screened, and 40 enrolled in the study. A majority of patients had GBC (95%) and most commonly received combination chemotherapy with gemcitabine-cisplatin, with or without nab-Paclitaxel (78%). Six patients (15%) had previously received trastuzumab in combination with chemotherapy. A majority of patients (n=24; 60%) had rapid progression (within 3 months) on prior systemic therapy. With a median follow-up of 7.1 months [95% confidence interval (CI): 5.1-9.1] , 24 patients had disease progression with a 3-month PFS of 51.2% (95% CI: 33.4 - 69) and median PFS of 3.1 months (95% CI: 2.3-3.8); median OS was 7.1 months (95% CI: 5.1-9.1). Partial responses (PR) were seen in 5 patients (12.5 %) and 8 had stable disease (20 %) for a disease control rate of 32.5 %. Patients without rapid disease progression on prior therapy (n=16; 40%) had a 3-month PFS of 70% (95% CI: 44.8 - 95.2) and median PFS of 4.9 months (95% CI: 2.9-6.9). Grade 3 and grade 4 TRAE in the overall cohort were noted in 11 patients (28%), with the commonest being grade 2 fatigue in 6 patients and grade 3 thrombocytopenia in 2 patients. Conclusions: T-DM1 was well tolerated in pre-treated HER2 positive advanced BTCs, but did not statistically improve PFS in comparison to historical data. Patients who did not have rapid progression on prior systemic therapy appeared to have a more favorable survival in comparison to rapid progressors and the role of T-DM1 in such favorable cohorts can be explored in larger studies. Clinical trial information: CTRI/2023/07/055785.

Zanzalintinib (XL092) alone or in combination with atezolizumab in patients (pts) with refractory metastatic colorectal cancer (mCRC): Results from an expansion cohort of the phase 1 STELLAR-001 study.

127 Background: VEGFR tyrosine kinase inhibitors (TKIs) in combination with immune checkpoint inhibitors (ICIs) have demonstrated clinical activity in pts with previously treated mCRC, particularly in pts without liver metastases (LM). Zanzalintinib (zanza) is a novel, oral, multitargeted TKI with activity against VEGFR, MET, and TAM kinases. Here, we present results from the randomized expansion cohort of pts with previously treated non-MSI-H/dMMR mCRC receiving zanza ± atezolizumab (atezo) in the phase 1 STELLAR-001 study (NCT03845166). Methods: Adults (aged ≥18 y) with locally advanced or metastatic CRC that was RAS -wildtype, who were refractory/intolerant to prior standard of care (5-FU–based treatment ± targeted therapies) and had an ECOG PS of 0/1, were enrolled. Pts with MSI-high or dMMR CRC, or who had received prior treatment with a PD-L1/PD-1 targeting ICI, regorafenib, and/or TAS-102, were excluded. Pts were randomized 1:1 to receive zanza+atezo (100 mg QD + 1200 mg Q3W) or single-agent zanza (100 mg QD). Objectives were to evaluate median (m)OS, investigator-assessed ORR, and mPFS per RECIST 1.1, and safety. Results: As of May 6, 2024, 107 pts were enrolled (zanza+atezo, n=54; zanza, n=53). In the zanza+atezo/zanza groups, median age was 61/60 years, 39%/51% had an ECOG PS of 1, pts had a median 2.5/3.0 (range, 1–5) prior lines of therapy, and 31%/32% did not have LM. With a median follow-up of 15 months across both arms, the mOS was 14.3 and 11.1 months for zanza+atezo and zanza, respectively (HR 0.75, 95% CI 0.45–1.26), confirmed ORR was 7.4% and 1.9% (all partial responses), mPFS was 4.0 and 3.0 months (HR 0.68, 0.44–1.04), and DCR was 59% and 55%. In pts without LM, mOS was not reached and 12.5 months (HR 0.46, 0.15–1.36) with 6-month survival rates of 88% and 65%, confirmed ORR was 18.0% and 5.9%, mPFS was 8.2 and 3.3 months (HR 0.40, 0.16–1.0), and DCR was 76% and 59%. The most common treatment-related adverse events (TRAEs) were diarrhea (zanza+atezo, 52%; zanza, 49%), nausea (54%, 36%), and decreased appetite (41%, 36%). Grade 3/4 TRAEs occurred in 48% of pts with zanza+atezo and 40% with zanza (Grade 4 in 3.7% and 0); a Grade 5 TRAE occurred in 1 pt (2%) in each group. 89% and 94% of pts had discontinued study treatment. Zanza was discontinued due to TRAEs in 11% and 8% of pts; atezo was discontinued due to TRAEs in 9% (zanza+atezo). Biomarker analysis is ongoing and results will be presented. Conclusions: Clinical activity was observed with zanza both as a single agent and in combination with atezo in this cohort of heavily pretreated pts with mCRC. Greater activity was seen with zanza+atezo versus zanza alone, particularly in pts without LM. Both treatments were generally well tolerated. Evaluation of zanza+atezo versus regorafenib is ongoing in the phase 3 STELLAR-303 study in non-MSI-H/dMMR mCRC (NCT05425940). Clinical trial information: NCT03845166 .

Real-world Child-Pugh scores and outcomes of patients with hepatocellular carcinoma at a high-volume center.

569 Background: Hepatocellular carcinoma (HCC) is the most common primary liver cancer and most often occurs in the setting of cirrhosis. Patients (pts) with advanced HCC are not eligible for curative intent therapies such as ablation, surgical resection, or liver transplantation. For the past five years, immune checkpoint inhibitor (ICI)-based systemic therapy regimens have been the mainstay of first-line treatment for pts with advanced HCC. Most trials assessing ICI-containing regimens, including IMBRAVE150 and HIMALAYA, excluded pts with Child-Pugh (CP) scores worse than A. Unfortunately, fewer than half of pts maintain a CP A score at the time of HCC diagnosis and referral to medical oncology. Real-world data on CP scores of patients undergoing ICI-based therapy for advanced HCC at the time of medical oncology referral and treatment start are lacking. Methods: Pts who initiated treatment with either atezolizumab plus bevacizumab (A+B) or durvalumab plus tremelimumab (D+T) in the Ochsner Health system between 1/1/20 and 12/31/23 were included in this analysis. CP scores were calculated at the time of their initial medical oncology visit and again at the time of their first systemic therapy cycle. Pt demographics and clinical outcomes were analyzed. Results: 200 pts were identified in this study, 159 of whom (79.5%) were male. Median age at treatment start was 66.8 years. 117 pts (58.5%) were Caucasian and 63 pts (31.5%) were African American (AA). 152 and 48 pts received A+B and D+T, respectively. At the time of first medical oncology visit, 58 pts (29%) were classified as CP B (n=51) or C (n=7). At the treatment start date, 82 pts (41%) were classified as CP B (n=73) or C (n=9). The median survival across all groups was 10.5 m. Median survival CP A, B, and C pts were 15.4, 7.6, and 1.6 months (m), respectively. 6-month survival rates for CP A, B, and C pts were 75.7%, 52.2%, and 0%, respectively. 12-month survival rates for CP A, B, and C pts were 58.2%, 35.1%, and 0%, respectively. There was no statistically significant difference in CP score at either time point between Caucasian and AA pts. Conclusions: Although pts with CP scores worse than A were not included in the pivotal studies that have established recent standard of care therapies for pts with advanced HCC, a significant proportion of pts being treated with ICI-based regimens have at least CP B liver disease, with a poorer prognosis in that subset of pts. Extremely poor survival rates for those with CP C scores argue against use of ICI-based treatment for these pts. In this analysis, no significant difference was observed in CP scores between Caucasian and AA pts.

Alteration of gut microbiota in patients with advanced hepatocellular carcinoma.

641 Background: Hepatocellular carcinoma (HCC) is the most common primary liver cancer and the third leading cause of cancer-related death worldwide. Despite advancements in treatment, such as novel combinations of immunotherapy and targeted therapy or dual immunotherapy, the prognosis remains poor due to a lack of predictive biomarkers for treatment response. Gut microbiota alterations have been proposed as both potential diagnostic biomarker and predictive biomarker. However, data in this field are not well-established and are mostly derived from studies conducted in China and Western countries, which may not fully reflect the situation in Thailand. Methods: Fecal samples were collected from pre-treated advanced HCC patients who visited medical oncology outpatient clinic at Srinagarind hospital, Khon Kaen University (HCC group = 27) and analyzed using 16S rRNA sequencing of gut microbiota. Additional sequenced data from a healthy population (Control group = 31) who had no underlying disease and had normal liver ultrasonography were retrieved from a previous study conducted by Khon Kaen University (Cholangiocarcinoma Screening and Care Program, CASCAP). The datasets were compared using the Wilcoxon rank-sum test to analyze the alteration of gut microbiota between HCC group and control group. Results: The HCC group exhibited significantly lower biodiversity index (p&lt; 0.001) than control group in terms of richness, Shannon diversity index and Simpson’s index. The HCC group had significantly higher relative abundance of the phylum Proteobacteria (p&lt; 0.001), Firmicutes (p&lt; 0.001) and a lower abundance of the phylum Actinobacteria (p&lt; 0.001) compared to the control group. Additionally, the HCC group had significantly higher relative abundance of Stenotrophomonas, Granulicatella, Ruminococcus, Blautia, Phascolarctobacterium, Butyricoccus, Streptococcus, Escherichia-Shigella, Flavonifractor, Haemophilus and Lachnospira at the genus level. Further analysis of relative abundance of gut microbiota at the genus level and clinical prognostic parameters showed positive correlation between Streptococcus and 6-month survival status. Conclusions: Gut microbiota profile in patients with advanced HCC was significantly altered from healthy control group. This could be the evidence of microbial dysbiosis and may potentially be biomarker for prognosis.

Clinical results of a phase 1 trial evaluating a HER2 directed CAR-T product selective for the tumor microenvironment (TME) in patients with GI and other solid tumor malignancies.

449 Background: A major limitation of CAR-T in solid tumors has been the inability to safely target antigens shared between healthy and malignant tissue. One approach to improving selectivity is to regulate CAR affinity through the unique metabolism of the tumor microenvironment (TME). This first in human trial evaluated an autologous (41BB) CAR-T product encoding a tumor metabolism regulated HER2 CAR. Methods: This Phase 1, dose escalation, basket trial evaluated the safety, tolerability, pharmacokinetics and efficacy in 12 patients (pts) with HER2 IHC 3+ / FISH + Stage IV r/r solid tumor malignancies (gastric, esophageal, colorectal, breast). They had failed multiple lines of therapy (66.7% patients had failed 4~10 lines of therapies previously). Dose cohorts of 3E5 (n=3), 1E6 (n=3), or 1E7 (n=6) CAR-T cells/kg were evaluated with a 28-day in-patient DLT observation period. Cell product was manufactured from whole blood, with a 12-day closed process and release on day 17. Lymphodepletion regimen was 500 mg/m 2 Cy and 30 mg/kg 2 Flu X 3 prior to infusion of CAR-T. Results: Data cutoff 09/16/24. All 12 patients were evaluable for safety and efficacy. No DLTs, ICANS or SAEs were observed. For HER2 positive normal tissues of special concern (e.g. cardiomyocytes), longitudinal functional, biochemical and clinical cardiovascular tests showed no signs of OTOT. One patient experienced Grade 2 CRS and recovered. No AE’s lead to study discontinuation. In one patient, there were two Grade 3 AEs attributed to product (neutropenia and hypoxia); both which resolved. With a median follow-up of 302 days for cohort 3, 12-month survival rate in this cohort is 83.3%, compared to the 12-month survival rate of 33.3% for cohorts 1 and 2 combined. Encouraging signals of efficacy were observed with an ongoing (at 24 wks) deep PR (100% reduction SLD) in a GC patient. The median peak copy number of CAR-T cells in peripheral blood (n=12) was 1,818 copies/µg DNA (range 403 – 10,466). Conclusions: The tumor metabolism regulated HER2 CAR-T product was generally well tolerated, with no DLTs, and evidence of radiologic objective response in patients with gastroesophageal cancer. Combined, the safety and activity observed in this study suggests that a previously challenging solid tumor antigen may be safely targeted by a CAR with affinity regulated by the metabolism of the TME. Enrollment for the study was complete as of 28-Feb-2024 (NCT04511871). Clinical trial information: NCT04511871 .

External Validation of Twelve Existing Survival Prediction Models for Patients with Spinal Metastases.

Survival prediction models for patients with spinal metastases may inform patients and clinicians in shared decision-making. To externally validate all existing survival prediction models for patients with spinal metastases DESIGN: Prospective cohort study using retrospective data PATIENT SAMPLE: 953 patients OUTCOME MEASURES: Survival in months, area under the curve (AUC), and calibration intercept and slope METHOD: This study included patients with spinal metastases referred to a single tertiary referral center between 2016-2021. Twelve models for predicting 3, 6, and 12-month survival were externally validated Bollen, Mizumoto, Modified Bauer, New England Spinal Metastasis Score, Original Bauer, Oswestry Spinal Risk Index (OSRI), PathFx, Revised Katagiri, Revised Tokuhashi, Skeletal Oncology Research Group Machine Learning Algorithm (SORG-MLA), Tomita, and Van der Linden. Discrimination was assessed using (AUC) and calibration using the intercept and slope. Calibration was considered appropriate if calibration measures were close to their ideal values with narrow confidence intervals. In total, 953 patients were included. Survival was 76.4% at 3 months (728/953), 62.2% at 6 months (593/953), and 50.3% at 12 months (479/953). Revised Katagiri yielded AUCs of 0.79 (95%CI 0.76;0.82) to 0.81 (95%CI 0.79;0.84), Bollen yielded AUCs of 0.76 (95%CI 0.73;0.80) to 0.77 (95%CI 0.75;0.80), and OSRI yielded AUCs of 0.75 (95%CI 0.72;0.78) to 0.77 (95%CI 0.74;0.79). The other nine prediction models yielded AUCs ranging from 0.59 (95%CI 0.55;0.63) to 0.76 (95%CI 0.74;0.79). None of the twelve models yielded appropriate calibration. Twelve survival prediction models for patients with spinal metastases yielded poor to fair discrimination and poor calibration. Survival prediction models may inform decision-making in patients with spinal metastases, provided that recalibration using recent patient data is performed. This study was funded by the AOSpine under the Discovery & Innovation award (AOS-DIA-22-012-TUM). A total amount of CHF 40,000 ($45,000) was received.

P-2295. Risk Factors for and Impact of Enteric Gram-negative Infections on Lung Transplant Clinical Outcomes

Abstract Background Bacterial infections such as Pseudomonas aeruginosa (PsA) and S. aureus lead to increased morbidity post-lung transplant. Less is known about the impact of enteric gram-negative (GNR) infections. This study’s aim was to assess risk factors for developing GNR infections within 6-months of transplant and associated 1-year outcomes compared to lung transplant recipients (LTR) with other bacterial infections or uninfected LTR. Table 1 Characteristics and Outcomes of LTR with post-transplant GNR infections, other bacterial infections, and no infection Methods A single-center retrospective study of LTR between January 2017 and October 2023 was performed. Donor/recipient characteristics, microbiologic data, and 1-year clinical outcomes were analyzed. Results During the study period, 327 patients had a lung transplant with a greater than 30-day survival. 77 (23%) had GNR infections, 64 (20%) had either PsA, S. aureus, or Streptococcal infections (infect), and 186 (57%) did not have a bacterial infection within 6-months post-transplant. The GNR infections were: 18% Enterobacter cloacae complex, 16% E.coli, 25% Klebsiella sp., 7% Acinetobacter sp., 1% Serratia sp., 1% Citrobacter sp., 7% Burkholderia sp., 19% Stenotrophomonas sp., 6% others. Infections included: 19% bacteremia, 91% pneumonia, 5% empyema, 4% mediastinitis, 1% other. Donor, recipient, and perioperative characteristics were similar amongst the cohorts. A similar proportion of LTR donors were colonized with GNR, PsA, and S. aureus in the 3 cohorts pre-transplant. A greater proportion of the GNR cohort had delayed chest closure, required dialysis, mechanical ventilation, and/or ECMO for &amp;gt;48 hours, and had a longer ICU and index hospitalization compared to the other cohorts [Table 1]. The median time to infection was similar for the GNR and infect cohorts (52 and 51 days), but a greater proportion of the GNR cohort developed chronic kidney disease or respiratory failure. 6-month and 1-year survival were less in the GNR cohort but not statistically significant. Conclusion LTR with more complicated post-operative courses were more likely to develop enteric GNR infections which led to increased post-transplant morbidities. Pre-transplant GNR colonization was not a risk factor for GNR infection post-transplant. Strategies to minimize post-transplant enteric GNR infections need further study. Disclosures All Authors: No reported disclosures