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Human brain organoids identify glioma inhibitors

EXO1 is a key gene for lung-resident memory T cells and has diagnostic and predictive values for lung adenocarcinoma

Identification of ABHD6 as a lysophosphatidylserine lipase in the mammalian liver and kidneys

Neoadjuvant therapy in T3 and T4 colon cancer: Is there a promising future?

144 Background: Neoadjuvant chemotherapy (NAC) is increasingly being considered over standard upfront surgery followed by adjuvant chemotherapy for locally advanced colon cancer. Studies have been underpowered to look at the impact of NAC on overall survival (OS) in individual clinical T stages. Methods: A nationwide retrospective analysis using the National Cancer Database to evaluate patients with clinical stage T3 and T4 colon adenocarcinomas from 2010 to 2020. Cox proportional hazards model was used to evaluate the impact of NAC approach compared to upfront surgery on OS. Clinical and pathological T stages were compared among those who underwent upfront surgery to evaluate accuracy of clinical T staging. Results: Total of 60,557 patients were identified - 2,313 patients undergoing NAC and 58,245 undergoing upfront surgery. In the past decade, use of NAC increased from 1.73% to 12.13%. In our multivariable survival analysis combining clinical T3 and T4 patients, we observed a worse OS in the NAC group (HR 1.16, 95% CI 1.07-1.26). We found no OS benefit for patients undergoing NAC approach for clinical stage T3 (HR 1.13, 95% CI 0.99-1.28) but found a significant OS benefit for patients undergoing NAC approach for clinical stage T4 (HR 0.85, 95% CI 0.77-0.95). We observed that clinical T4 stage was accurately staged in 90.48% with overstaging in 9.52%; clinical T3 stage was accurately staged in 95.24% with overstaging in 2.18% of patients. Conclusions: Our analysis demonstrated OS benefit of the NAC approach in T4 colon adenocarcinoma but not in T3. The study highlights the importance of evaluating survival benefit of NAC separately for T3 and T4 colon adenocarcinoma in future studies, and the challenges of accurate clinical staging of colon cancer for NAC planning.

Claudin 18.2 determination in locally advanced gastric and gastroesophageal adenocarcinoma treated with neoadjuvant chemotherapy.

492 Background: Gastric and esophago-gastric adenocarcinoma (GAC) represent a major unmet need. For tumors amenable with curative intent, prognosis remains poor with 5-year survival rates below 40%. Several strategies have been added to surgery including peri-operative chemotherapy which represents the standard of care for locally advanced GAC. Claudins is a family of transmembrane junctional proteins which acts in paracellular permeability, transport and communication. Claudin 18.2 (CLDN), a tissue-specific variant, is physiologically expressed in both gastric mucosa and gastric cancer. In metastatic GAC, CLDN positivity settles around 40% of cases and the addition of target therapy zolbetuximab to chemotherapy resulted in a significant improvement in overall survival. However, limited data are present about CLDN in early-stage disease. The aim of our study is to assess rates of expression of CDLN in locally advanced GAC treated with neoadjuvant chemotherapy and correlate it with clinical outcomes. Methods: We conducted a multi-omics prospective trial at IEO enrolling patients with locally advanced GAC treated with peri-operative chemotherapy and surgery. Pre-chemotherapy endoscopic samples were selected for CDLN determination. Positive cases were defined as moderate-to-strong membranous staining in ≥ 75% of tumor cells by IHC using the VENTANA CLDN18 (43-14A) Assay. CLDN expression was analyzed for correlation with pathologic complete response (pCR), tumor regression grade (TRG), event‐free survival (EFS), and overall survival (OS). Survival was calculated using Kaplan–Meier method and log-rank tests. Statistical analyses were performed using SPSS software (version 29.0.2.0). Results: We included 48 patients, 67% male, median age 62 years (35-78). 31 tumors originated from gastric body, 14 from the junctional region and 4 from distal esophagus. Most frequent histotypes were diffuse (43%) and tubular (39%). Five cases (11%) presented microsatellite instability. All patients received neoadjuvant chemotherapy, mainly FLOT (92%) and underwent surgery, with 93% of R0 resection. Three patients (6%) achieved pCR and 18 had a TRG 1A or B. Of the total, 20 cases were defined as positive (42%). After a median follow-up of 20 months, 12 patients relapsed and 3 died. No significant association was observed for CDLN positivity and pCR or TRG1 rate, as well as for primary site or histotype. PFS and OS were not statistically different according to claudin status, even though numerically shorter in CDLN positive cases (PFS: 31 vs 33 months, p=.43; OS: 36 vs 39 months, p =.10). Conclusions: In our study of locally advanced GAC, rate of CDLN positivity was 40%, similarly to advanced stage. However, no differences in pCR rate, regression grade and survival outcomes have been observed. Larger studies and longer follow-up are required to assess the impact of CDLN in early-stage GAC.

Rates and risk factors for recurrence of hepatocellular carcinoma after initial complete remission in response to transcatheter arterial chemoembolization: A systematic review and meta-analysis.

612 Background: Transcatheter arterial chemoembolization (TACE) is used for palliative treatment of patients with inoperable hepatocellular carcinoma (HCC). Despite remarkable initial remission rates, frequent recurrences of HCC after TACE have resulted in questionable survival benefit. Our investigation aimed to study the rates and risk factors for HCC recurrence following remission after TACE. Methods: Comprehensive search of 5 databases (EMBASE, Web of Science, PubMed, CINAHL, ClinicalTrials.gov) was conducted to yield 4263 studies, which were screened based on prespecified inclusion and exclusion criteria. Outcomes assessed were total recurrence rate; 6-month, 1, 2, and 3-year cumulative recurrence rates; and 1 and 3-year survival rates for patients with and without recurrence. Meta-analysis was conducted by the random-effects model and heterogeneity was assessed by the I 2 statistic and 95% prediction interval. Systematic review of risk factors for recurrence was performed. Results: Twelve studies and 1,152 patients who underwent complete remission in response to TACE were included. The pooled rate of total recurrence was 60% (95% CI 53-67%). The pooled 6-month, 1-year, 2-year, and 3-year cumulative recurrence rates were 26% (95% CI 18-33%), 33% (95% CI 22-43%), 49% (95% CI 34-64%), and 62% (95% CI 53-71%), respectively. The pooled 1-year survival rates for patients with and without recurrence were 94% (95% CI 89-99%) and 99% (95% CI 99-100%), respectively. The pooled 3-year survival rates for patients with and without recurrence were 61% (95% CI 31-90%) and 91% (95% CI 81-100%). Heterogeneity was considerable based on the 95% prediction interval. Predominant risk factors for recurrence were larger tumor size, multinodularity, portal vein thrombosis, and higher AFP levels. Conclusions: HCC frequently recurs after initial remission achieved through TACE, with differences in survival rates between patients with and without recurrence. Identifying high-risk patients based on tumor size, multinodularity, portal vein thrombosis, and AFP levels could improve long-term outcomes.

VEGF-A as a prognostic indicator in advanced gastric and colorectal cancers and correlation with immune suppression involving myeloid-derived suppressor cells (MDSC).

250 Background: VEGF-A is important molecule should be controlled in cancer treatment since hypoxic and immunosuppressive conditions of tumor microenvironment are induced by VEGF-A. Myeloid-derived suppressor cells (MDSC), activated by chronic inflammation and VEGF-A, play critical roles in immunosuppression in patients with cancer. Methods: Serum levels of VEGF-A were measured by ELISA and circulating levels of MDSC were measured by Flow Cytometry (CD11b+, CD14-, CD33+). Patients with gastric and colorectal cancers were divided into two groups, high VEGF group (serum VEGF-A>330pg/ml) and lo group (≤330pg/ml). Results: Prognosis of stages III and IV gastric cancer with high VEGF-A was significantly worse than in low VEGF-A group, while difference was not significant in stages I and II. In colorectal cancer, the results were exactly same as found in gastric cancer. The levels of MDSC were significantly correlated with the levels of VEGF-A in patients with gastric and colorectal cancers. The levels of VEGF-A were also correlated with inflammatory markers including CRP and NLR (neutrophil to lymphocyte ratio), and inversely did to stimulation index of lymphocyte proliferation (SI: parameter of cellular immune reaction) and nutritional parameters such as albumin or rapid turnover protein. Conclusions: The observation in the present study suggest that VEGF-A is closely associated with inflammation-associated disease progression especially in advanced stages, and serve as useful marker of immunosuppression involving MDSC and prognosis in patients with gastric and colorectal cancers.

DNA-PKcs inhibitor causes genomic alterations

Spatiotemporal simulation of blue-green space pattern evolution and carbon storage under different SSP-RCP scenarios in Wuhan

Betagenin ameliorates diabetes by inducing insulin secretion and β-cell proliferation

Neoadjuvant chemotherapy with FOLFOXIRI for high-risk relapsed locally advanced colon cancer: A single-arm phase II trial.

201 Background: To evaluate the safety and efficacy of neoadjuvant chemotherapy (NAC) with three drug-intensity chemotherapy (oxaliplatin, irinotecan, and fluorouracil [FOLFOXIRI]) in patients with high-risk factors for recurrence and metastasis of locally advanced colon cancer (hr-LACC). Methods: A single-arm, open-label, phase II trial was conducted at West China Hospital of Sichuan University from July 2020 to Oct 2023. Patients with T4a/b or (and) N2/fused lymph nodes) and no distant metastases were considered as the hr-LACC patients. Eligible enrolled patients received four cycles of NAC with FOLFOXIRI followed by surgery and adjuvant chemotherapy with capecitabine and oxaliplatin (CAPOX) for two to five cycles or single-agent capecitabine for five cycles or observation. The primary endpoint was the rate of TRG grade 0-2 according to the criteria of NCCN guideline. Results: Of 72 patients enrolled (median age 53 [18-74] years,65 were T4a/b [90.2%], 66 were N2 [91.6%]), 58 patients (80.6%) completed four cycles of FOLFOXIRI. Three patients (4.2%) achieved clinical complete response. Twenty-eight patients (39.4%) obtained clinical partial response. The most common adverse event (AE) was nausea (86.1%, 62/72); grade 3-4 AEs occurred in 37 of 72 patients (51.4%).R0 resection was achieved in 64 of 64 patients, and the TRG (0-2) rate was 87.5% (56/64). The pathologic complete response rate was 7.8% (5/64). The proportions of pT0-2 and pN0 were 21.9% and 68.8%, respectively. Only three (4.7%) patients had prolonged hospital stay due to perioperative complications. No patient died within 30 days and 90 days after surgery. The 2-year tumor recurrence rate was 17.2%. Conclusions: For patients with hr-LACC, NAC with FOLFOXIRI regimen was safe and effective. Longer follow-up and larger clinical studies are needed to validate this innovative regimen. Clinical trial information: NCT05018182 .

The impact of protein-energy malnutrition on clinical outcomes in hospitalized gastric cancer patients: A population-based analysis.

503 Background: Protein-energy malnutrition (PEM) is considered an adverse prognostic factor in various clinical conditions. Patients with gastric cancer are at an increased risk of malnutrition because of factors such as loss of appetite due to the tumor, difficulty swallowing, malabsorption, and metabolic changes caused by the cancer. However, the implications of protein-energy malnutrition (PEM) in gastric cancer patients are not well studied. Through this study, we wanted to examine how PEM affects clinical outcomes in hospitalized patients with gastric cancer. Methods: We used the National Inpatient Sample (NIS) from 2018 to 2020 to detect patients with a primary diagnosis of gastric cancer and a secondary diagnosis of protein energy malnutrition (PEM). We used the chi-square and student T-test to analyze categorical and continuous variables. Confounders were adjusted using multivariable regression analysis, and the adjusted odds ratio (aOR) was calculated. Results: We detected a total of 1673915 patients with the primary diagnosis of gastric cancer using ICD-10 codes. Of them, 401,739 (24%) of the patients had a secondary diagnosis of PEM. The mean age of the patients was 66 years (p-value <0.01). Of these, 56% of the patients were male, while the remaining 44% were female (p-value <0.001). Based on race, 68% of the patients belonged to the White Race, 12% were African Americans, and 11% were Hispanics (p-value <0.001). It was observed that the presence of PEM was associated with higher mortality (aOR 1.6, p-value <0.001). There was also higher hospitalization cost ($109522 vs. 75725, p-value <0.001) and mean length of stay (LOS) (9.1 days vs. 5.6 days, p-value <0.001). PEM in gastric cancer patients was also associated with higher odds of sepsis (aOR 1.6, p-value <0.001), gastritis (aOR aOR 1.2, p-value <0.001), gastrointestinal (GI) bleeding (aOR 1.1, p-value <0.001) and acute kidney injury (AKI) (aOR 1.7, p-value <0.001). Conclusions: Our study demonstrates that protein-energy malnutrition (PEM) is associated with increased mortality, higher hospitalization costs, and longer stays in hospitalized gastric cancer patients. These findings emphasize the need for regular nutritional assessment and management to improve clinical outcomes in this population. Comparison of outcomes in hospitalized gastric cancer patients with and without protein-energy malnutrition (PEM). Hospital Outcomes Gastric Cancer Patients with PEM Gastric Cancer Patients without PEM Adjusted Odds ratio (aOR) 95% Confidence Interval P-value Mortality 9.1% (n=36999) 5.3% (n=68100) 1.6 1.5-1.7 <0.001 Length of Stay 9.1 5.6 3.0 2.7-3.3 <0.001 Sepsis 10% (n=41915) 6.4% (n= 82035) 1.6 1.5-1.6 <0.001 Gastritis 3.9% (n=16174) 3.3% (n=41879) 1.2 1.1-1.31 <0.001 GI Bleeding 7.1% (n= 28949) 6% (n= 28949) 1.1 1.0-1.2 <0.001 AKI 28% (n=117439) 19% (n=1268134) 1.7 1.7-1.8 <0.001

Real-world validation of the Khorana risk score in gastric cancer patients receiving immune checkpoint inhibitors.

363 Background: Thrombosis is a common cancer-related complication, particularly in gastric cancer. Studies show that immune checkpoint inhibitors (ICIs) increase the risk of venous thromboembolism (VTE) and arterial thrombosis. The Khorana risk score is widely used to assess thrombosis risk before starting chemotherapy. This study aimed to validate the Khorana score in gastric cancer patients receiving ICIs using a large global database. Methods: We used the TriNetX Global Collaborative Network, which contains de-identified data from over 120 million patients. We included patients diagnosed with gastric cancer who received ICIs between January 2014 and July 2023. The Khorana risk score was calculated based on lab values and BMI within two weeks before ICI initiation. Patients were divided into two cohorts: elevated risk (score 3-6) and intermediate risk (score 2). Cox-proportional hazard analyses were conducted over a one-year follow-up. The primary outcome was VTE (deep vein thrombosis [DVT] and pulmonary embolism [PE]). Secondary outcomes were arterial thrombosis, including myocardial infarction (AMI) and ischemic stroke, and all-cause mortality. Results: The study included 551 patients, with 362 in the intermediate risk and 189 in the elevated risk cohorts. The mean age was 64 in both cohorts, with the elevated group consisting of more males (76% vs. 63%) and a higher proportion of Black patients (11% vs. 6%). Pembrolizumab (49%) and nivolumab (47%) were the most used ICIs. Patients with elevated risk had a significantly higher risk of VTE (HR 1.74, 95% CI 1.18-2.58), DVT (HR 1.82, 95% CI 1.07-3.10), and PE (HR 1.74, 95% CI 1.07-2.84). However, no significant associations were found with arterial thrombosis (HR 1.28, 95% CI 0.74-2.20), including cerebral infarction (HR 1.05, 95% CI 0.51-2.16), or AMI (HR 1.46, 95% CI 0.70-3.05). The elevated risk cohort also had significantly higher mortality (HR 1.44, 95% CI 1.11-1.87). Conclusions: An elevated Khorana risk score is associated with a higher risk of VTE, but not arterial thrombosis, in gastric cancer patients treated with ICIs. Further studies are needed to determine how the Khorana score can be applied to predict ICI-related thrombosis and guide prophylactic anticoagulation. Outcomes Khorana risk score 3-6 Khorana risk score 2 Hazard ratio(95% CI) P-value(Log-rank) At risk patients Cases At risk patients Cases Venous thromboembolism 189 45 362 58 1.74 (1.18-2.58) 0.005 Deep vein thrombosis 189 25 362 30 1.82 (1.07-3.10) 0.025 Pulmonary embolism 189 29 362 36 1.74 (1.07-2.84) 0.025 Arterial thrombosis 189 21 362 34 1.28 (0.74-2.20) 0.375 Cerebral infarction 189 11 362 22 1.05 (0.51-2.16) 0.901 Acute myocardial infarction 189 12 362 17 1.46 (0.70-3.05) 0.317 All-cause mortality 189 93 362 145 1.44 (1.11-1.87) 0.006

Longitudinal ctDNA measurements for treatment response monitoring in patients with metastatic colorectal cancer undergoing systemic therapy: The ORCA trial.

220 Background: Precise monitoring of treatment response may support and improve treatment decision-making in patients with metastatic colorectal cancer (mCRC). The PLCRC-ORCA study aimed to explore the clinical applicability of personalized ctDNA testing for treatment response monitoring in patients with mCRC. Methods: The prospective, observational ORCA study is a substudy of the Prospective Dutch ColoRectal Cancer cohort (PLCRC). After informed consent, blood samples were collected before initiating first line of treatment (baseline) and subsequently every 8-9 weeks during routine clinical care. ctDNA levels were analyzed using a clinically validated, personalized, tumor-informed 16-plex PCR NGS assay (Signatera™, Natera, Inc). Results: The majority of patients (45/49) had blood samples collected at both baseline and the first on-treatment time point. At baseline, 43/45 (95.6%) patients were ctDNA-positive with a median concentration of 63.5 mean tumor molecules per mL (MTM/mL; range 0.08 to 16,200). In a multivariate linear regression model including metastatic site at baseline and resection status of the primary tumor, ctDNA levels at baseline were lower in patients with metastatic disease limited to the lung (n = 4; p < 0.001) or peritoneum (n = 6; p = 0.002) compared to patients with liver-limited metastases. Moreover, primary tumor resection was independently associated with lower levels of ctDNA at baseline (p = 0.05). At the first measurement on-treatment, 13/45 patients (28.9%) were ctDNA-negative and 32/45 (71.1%) patients were ctDNA-positive with ctDNA levels ranging from 0.04 to 318 MTM/mL. Reduction in ctDNA levels relative to baseline was observed in 42/45 (85.7%) patients while two patients exhibited increased ctDNA levels. One patient had undetectable ctDNA levels at baseline and on treatment. Among the 30 patients with detectable but reduced ctDNA levels on treatment, the median ctDNA levels decreased 55-fold (95% CI: 26–600). Conclusions: The levels of ctDNA in patients with mCRC are influenced by the metastatic site and are lowest among patients with metastases limited to the lung and peritoneum. Our data suggest that clinical applications of ctDNA testing for treatment response monitoring should take the baseline ctDNA levels into account when interpreting ctDNA dynamics. Correlation of ctDNA status with radiological treatment response is underway and will be reported during the conference.

Engineered T cells traverse new terrain

Study on the effects of fissure geometric characteristics on the mechanical behavior and failure mechanism of granite under uniaxial compression test

Receptor-independent regulation of Gα13 by alpha-1-antitrypsin C-terminal peptides

Real-world assessment of MDM2 amplification and survival among patients with advanced or metastatic biliary tract cancer in the United States.

544 Background: There are few real-world studies on biliary tract cancer (BTC), especially those related to biomarkers for potential novel targeted therapies. The aim of this study was to provide additional information of the prevalence of biomarkers, treatment patterns, and clinical outcomes of patients with BTC in the US, with a focus on patients with mouse double minute 2 homolog ( MDM2 ) amplified, tumor protein 53 wild type (TP53 WT) BTC. Methods: This was an observational cohort study using deidentified data from the Flatiron Health-Foundation Medicine BTC Clinico-Genomic Database, which included patients with advanced or metastatic BTC who underwent genomic analysis and received antineoplastic therapy in the US between January 1, 2013 and June 30, 2023. Three cohorts were created: 1) 1L+ cohort that included all patients that initiated 1 st line (1L) therapy during the study period, 2) 2L+ cohort that included all patients that initiated 2 nd line (2L) therapy during the study period, and 3) MDM2 amp + TP53 WT cohort that included patients in the 1L+ cohort that had MDM2 amplified (≥ 8 copies), TP53 WT. The prevalence of select biomarkers was assessed, as well as treatment patterns, and clinical outcomes including time to next therapy (TTNT) and overall survival (OS). Results: A total of 1,548 patients met the selection criteria for the 1L+ cohort, of whom, 875 initiated 2L therapy (2L+ cohort), and 55 had MDM2 amplified, TP53 WT BTC ( MDM2 amp + TP53 WT cohort). In the 1L+ cohort, 66 (4.3%) had MDM2 amplification and 872 (56.3%) had TP53 WT. The most common treatment regimens were cisplatin/gemcitabine (44.5%, 50.7%, 41.8% of patients in the 1L+, 2L+, and MDM2 amp + TP53 WT cohorts, respectively) at 1L and FOLFOX (12.9%, 22.9%, 16.4% of patients, respectively) at 2L. The median (95% CI) OS from start of 1L was 10.7 (10.0 – 11.3) months for the 1L+ cohort and 11.9 (10.4 – 17.7) months for the MDM2 amp + TP53 WT cohort. The median OS from the start of 2L was 8.0 (7.2 – 8.8) months for 2L+ cohort. Furthermore, the median TTNT was similar between 1L+ cohort and MDM2 amp + TP53 WT cohort, 5.3 (5.0 – 5.7) and 4.8 (4.0 – 7.6) months, respectively. The median TTNT from the start of 2L in the 2L+ cohort was 4.3 (3.8 – 4.6) months. We will present co-mutation data in MDM2 amp + TP53 WT cohort. Conclusions: The MDM2 amplification and TP53 WT status does not appear to be a prognostic biomarker in advanced/metastatic BTC with similar median TTNT and OS in the 1L+ and MDM2 amp + TP53 WT cohorts. Targeted treatments may help improve OS among these patients and thus further research into these treatments and how they impact survival is warranted.

Tetravalent death receptor 5 (DR5) agonist ozekibart (INBRX-109) + FOLFIRI in 2L+ colorectal adenocarcinoma (CRC): Preliminary results from a phase 1 study.

129 Background: DR5, a proapoptotic receptor, is selectively expressed on tumor vs normal cells, making it an attractive target. DR5 binds to its ligand, TRAIL, resulting in DR5 multimerization and apoptosis; greater DR5 clustering enhances downstream effects. Ozekibart is a next-generation, recombinant, humanized, tetravalent DR5 agonist that is based on a single-domain antibody platform and precisely engineered to balance agonism and safety. Ozekibart previously demonstrated an acceptable safety profile and clinical benefit in chondrosarcoma (1), prompting a phase 2, randomized trial (ChonDRAgon; NCT04950075). An ongoing phase 1 study (NCT03715933) is evaluating ozekibart in various solid tumors, including 2L+ CRC, for which effective therapies are lacking. We present preliminary results of ozekibart + FOLFIRI in 2L+ CRC (data cutoff: Aug 9, 2024). Methods: Parts 1 (single-agent dose escalation) and 2 (single-agent dose expansion; recommended phase 2 dose [RP2D] ozekibart 3 mg/kg IV Q3W) of this 3-part, open-label trial are complete. Part 3 (combination dose expansion with chemo) is ongoing in pts with CRC, Ewing sarcoma, or SDH-deficient GIST. Pts with locally advanced or metastatic, unresectable CRC who received oxaliplatin-based chemo were eligible for part 3. Pts with chronic liver disease were ineligible. Pts in the part 3 CRC cohorts (N=13; enrollment complete) received ozekibart 1 mg/kg (n=5) or 3 mg/kg (n=8) IV Q28D (1 cycle) + FOLFIRI Q14D (FOLFIRI could be stopped after ≥6 cycles); in 4/5 pts, ozekibart dose was escalated to 3 mg/kg (RP2D). The primary endpoint is safety; clinical response is an exploratory endpoint. Results: In total, 13 pts with CRC (male, 62%) received ozekibart + FOLFIRI. Median age was 60. All pts had metastatic disease; median number of prior lines of therapy was 2 (range, 1-6). At data cutoff, 2 pts remained on treatment. Ozekibart-related adverse events (AEs) were reported in 85% of pts (grade ≥3, 31%) and led to ozekibart interruption in 3 pts and discontinuation in 1 pt. One combo-related AE (neutropenic sepsis) led to death. The most common ozekibart-related AEs were nausea (n=5) and diarrhea, fatigue, and increased alanine aminotransferase (each n=4). Four pts (31%) had responses (all partial). Disease control rate (response + stable disease) was 77% (10/13) and durable (>180 days) in 46% (6/13) of pts. Most pts had tumor shrinkage. Median PFS was 7.85 mo. Conclusions: Ozekibart + FOLFIRI showed encouraging preliminary efficacy, including PRs and durable disease control, as 2L+ therapy in pts with CRC. Given these promising data, a new expansion cohort (C4d) is open to validate these findings in a more homogeneous population. Eligible pts will have had 2 or 3 prior lines of systemic therapy (irinotecan allowed but not in the immediately prior line) and must have archival or fresh biopsy tissue. 1. Subbiah. Clin Cancer Res. 2023. Clinical trial information: NCT03715933 .

Redefining the use of a first-line FOLFIRINOX-like regimen in older patients with metastatic pancreatic cancer.

681 Background: Prospective elderly-specific data for treating pancreatic cancer are scarce. First-line treatment with triplet chemotherapy (e.g., FOLFIRINOX) is often too toxic for older adults (OA). An alternating regimen of FOLFOX and FOLFIRI (aFOLFIRINOX) has demonstrated efficacy and decreased toxicity in patients with colon cancer. This ongoing multicenter phase II trial evaluates the tolerability and efficacy of aFOLFIRINOX in OA with metastatic pancreatic adenocarcinoma (mPDAC). Herein we report the interim safety analysis results. Methods: Eligible patients (goal n=37) ≥65 years old with measurable untreated mPDAC, ECOG PS 0-2, receive standard doses of FOLFOX alternating with FOLFIRI every 2 weeks for up to 6 months. Patients can continue treatment thereafter at the discretion of their physician. The primary endpoint is rate of treatment-limiting grade ≥3 adverse events (TLAE) per CTCAE v5.0 in the first 8 weeks of therapy. These toxicities are defined as treatment-related grade 3 non-hematologic AE persisting > 2 weeks despite best supportive care, grade 3 anemia or thrombocytopenia, grade >3 neuropathy, or any grade > 4 AE. The study is powered to detect a 20% improvement in grade ≥3 TLAE: null vs alternate: 45% vs 65% of patients without TLAE at 8 weeks. Secondary endpoints include progression free & overall survival (PFS & OS) and objective response rate (ORR). FACT-G and PROMIS-10 quality of life (QOL) surveys and geriatric assessments are collected and will be correlated with treatment outcomes. Results: 21 eligible patients were included in the interim safety analysis: 11 male, 10 female; median age:73 (range 65-82); 18 patients had ECOG PS 0-1. 16 (76%) patients did not experience TLAE as defined above. TLAE included neutropenia, thromboembolism, and hypokalemia, and are similar to reported toxicity with FOLFOX and FOLFIRI in this patient population. One patient died of their disease within 8 weeks of treatment initiation and another within 2 weeks due to pulmonary embolism deemed unrelated to treatment. Of the 18 patients evaluable for response, ORR was 11% (partial response: n =2), Disease Control Rate was 89% (stable disease: n =14). 7 patients completed 6 months of treatment on study. Conclusions: The interim safety analysis of this clinical trial fulfilled the predefined futility rule without excess treatment-limiting or unexpected toxicity among OA with mPDAC treated with first-line aFOLFIRINOX, suggesting this may be a reasonable treatment option in this patient population. Trial is ongoing for evaluation of efficacy data of this regimen. Clinical trial information: NCT05360732 .