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A phase II, randomized study of JMT101 in combination with irinotecan and SG001 versus regorafenib in patients with metastatic colorectal adenocarcinoma (mCRC).
TPS314 Background: Epidermal growth factor receptor (EGFR) inhibitorcombined withchemotherapy based on5-FU with oxaliplatin and irinotecanis the first-line treatment of wild-type RAS mCRC.JMT101 is a humanized monoclonal IgG1 antibody targeting EGFR. Previous trials showed that JMT101 monotherapy or in combination with chemotherapy had demonstrated a promising anti-tumor activity in advanced solid tumors with good safety profiles. EGFR inhibitor might have a synergetic effect with immunocheckpoint inhibitor (ICI) by activating innate and adaptive immune response. SG001 is a fully humanized and high-affinity immunoglobulin G4 monoclonal antibody that targets programmed death-1 (PD-1), which also had encouraging efficacy in advanced solid tumors. Therefore, EGFR antibody in combination with chemotherapy plus ICI is worthy exploration in patients with mCRC. Methods: This is a phase II, multicenter, open-label, two-part study. Part I is a safety run-in, followed by part II randomized treatment. Eligible patients are histologically confirmed mCRC without MSI-H/dMMR, wild-type RAS and BRAF, who progressed on at least 2 prior systemic therapy with chemotherapy based on 5-FU with oxaliplatin and irinotecan, with or without cetuximab and bevacizumab (both parts); no prior treatment with regorafenib, fruquintinib, or TAS-102 (part II). Safety run-in data will be analyzed after 3-6 patients have received JMT101 6 mg/kg plus irinotecan 180 mg/m 2 plus SG001 240 mg Q2W. Upon dose confirmation, 90 patients with mCRC will be randomized into three arms (1:1:1) to receive JMT101 plus irinotecan plus SG001, or JMT101 plus irinotecan, or regorafenib monotherapy. Primary endpoints include incidence of dose limiting toxicities (DLT) and adverse events (part I) and objective response rate (ORR) as per RECIST v1.1 by investigator (part II). Secondary endpoints include JMT101 and SG001 pharmacokinetic profile, antidrug antibodies (ADA) (both parts), disease control rate (DCR), duration of response (DOR), progression free survival (PFS), and overall survival (OS), as well as safety (part II). Prespecified goal for safety run-in part was met; randomized treatment part accrual began in February 2024. Clinical trial information: NCT06089330 .
Biological and therapeutic impact of tumor mutational burden in microsatellite instability/mismatch repair-deficient (MSI/dMMR) metastatic colorectal cancer (mCRC) treated with immune checkpoint inhibitors (ICI).
272 Background: Microsatellite instability (MSI) is linked to hypermutability and response to ICI(s), especially in colorectal cancer. The predictive impact of tumor mutational burden (TMB) in ICI-treated MSI/dMMR metastatic colorectal cancer remains controversial, with some studies suggesting low TMB as a potential biomarker of resistance to ICI(s). We aimed to investigate the biological relevance of TMB in MSI/dMMR mCRC and its impact on survival outcomes in ICI(s)-treated patients (pts). Methods: MSI/dMMR mCRC pts treated with ICI(s) from the NIPICOL trial (NCT03350126) and the immunoMSI prospective monocentric cohort with available data from whole exome sequencing (WES) and RNA-sequencing (RNA-seq) were included. All cases were centrally assessed for MSI and dMMR status. TMB was calculated as described (Dupain et al., BMC, 2024). The search for a cutpoint able to optimize the difference in survival between 2 groups of patients with low and high-TMB was applied. The main endpoint was progression free survival (PFS) by iRECIST criteria. The cohort (NIPICOL, immunoMSI) was included as a covariate in the analysis of differential gene expression and pathway enrichment, with various tumor mutational burden (TMB) thresholds evaluated, specifically 10 and 30 mutations per megabase (mut/Mb). Results: A total of 99 pts were analyzed, with 4 (4%) excluded after central MSI/dMMR status review. Of these, 52 received anti-PD1 plus anti-CTLA4 therapy, while 43 received anti-PD1 alone. Median follow-up was 25 months. Median TMB was 51.8 mut/Mb (IQR: 35.9-74.9). TMB was not predictive of patient PFS, whatever the TMB threshold applied, including cutpoints already reported in the literature, the 2-year PFS rates being 80% versus 80% for TMB ≤ 10 and > 10 mut/Mb, and 79% versus 82% for TMB ≤ 30 and > 30 mut/Mb, respectively. Multivariate analysis including treatment type confirmed no association between TMB and PFS (HR 1.00, 95% CI [0.97–1.04]). TMB levels were not linked with specific signalling pathways related to immune checkpoints or antigen presentation as evaluated by RNA-seq with Gene Set Enrichment Analysis (GSEA) at a TMB threshold of 10 or 30 mut/Mb. However pathways involved in cell proliferation (e.g., “cell cycle”, “DNA replication”) were increased in TMB high (adjusted p-value <0.05). RNA-seq signature quantification and deconvolution analysis revealed similar cell populations (e.g., fibroblasts, B cells, T cells) between high and low TMB groups at a TMB threshold of 10 and 30 mut/Mb. Conclusions: TMB has no survival impact for patients with ICI(s)-treated dMMR/MSI mCRC and does not discriminate two biologically distinct subpopulations. Other biomarkers should be developed for personalized medicine amongst these patients.
Advanced Polymeric Nanoparticles for Cancer Immunotherapy: Materials Engineering, Immunotherapeutic Mechanism and Clinical Translation
AbstractCancer immunotherapy, which leverages immune system components to treat malignancies, has emerged as a cornerstone of contemporary therapeutic strategies. Yet, critical concerns about the efficacy and safety of cancer immunotherapies remain formidable. Nanotechnology, especially polymeric nanoparticles (PNPs), offers unparalleled flexibility in manipulation‐from the chemical composition and physical properties to the precision control of nanoassemblies. PNPs provide an optimal platform to amplify the potency and minimize systematic toxicity in a broad spectrum of immunotherapeutic modalities. In this comprehensive review, the basics of polymer chemistry, and state‐of‐the‐art designs of PNPs from a physicochemical standpoint for cancer immunotherapy, encompassing therapeutic cancer vaccines, in situ vaccination, adoptive T‐cell therapies, tumor‐infiltrating immune cell‐targeted therapies, therapeutic antibodies, and cytokine therapies are delineated. Each immunotherapy necessitates distinctively tailored design strategies in polymeric nanoplatforms. The extensive applications of PNPs, and investigation of their mechanisms of action for enhanced efficacy are particularly focused on. The safety profiles of PNPs and clinical research progress are discussed. Additionally, forthcoming developments and emergent trends of polymeric nano‐immunotherapeutics poised to transform cancer treatment paradigms into clinics are explored.
Phase II study of niraparib and dostarlimab for the treatment of germline or somatic homologous recombination repair mutated (HRD) metastatic pancreatic cancer.
727 Background: PARP inhibition (PARPi) is a standard maintenance therapy for patients (pts) with germline BRCA1/2 mutations in pancreatic cancer. Combination of PARPi therapy and immunotherapy has potential to increase efficacy and may offer benefit beyond germline BRCA1/2 . Methods: We performed a multisite single-arm phase 2 study using the highly potent PARPi niraparib with anti-PD1 drug dostarlimab in pts with germline or somatic HRD mutations in BRCA1/2, PALB2, RAD51C/D, or BARD1 . Pts were required to have metastasis, progressed on ≥1 regimen, and prior platinum-exposure unless refused/intolerant. Pts were treated with niraparib 200 mg orally once daily continuously. Dostarlimab 500 mg was administered IV every 3 weeks for 4 cycles, then 1000 mg IV every 6 weeks. The primary endpoint was disease control rate (DCR) at 12 weeks (DCR12) using iRECIST criteria. At least 8 pts with DCR12 in the first 19 eligible pts (41%) would be considered promising for further trials. Results: 22 pts were enrolled from Dec 2020 to Oct 2023. Two pts withdrew prior to receiving therapy, and 2 were later found to be ineligible, leaving 18 eligible pts for final analyses. Median age was 63.0 yrs, 39% male, 94% non-Hispanic white, 1 black (6%). 17 pts were platinum exposed, 7 were platinum-refractory, and 5 had previously progressed on PARPi maintenance. Mutation distribution was: BRCA2 13/18 (72%), BRCA1 4/18 (22%), BARD1 2/18 (11%). One pt had both BRCA1 (somatic) and BRCA2 (germline) mutations. Germline mutations were identified in 14/18 (78%). DCR12 was achieved in 5/18 (27.8%), so the primary endpoint (>41%) was not met. Pts received a median 2 cycles (range 1-8) of niraparib + dostarlimab. No clinical factors were significantly associated with improved DCR12 (all p > 0.05) in subgroup analyses, but we did observe the following statistically nonsignificant associations. Pts who were platinum-refractory had a lower DCR12 compared to those not (14.3% vs. 36.4%). Counterintuitively, PARPi exposed/refractory pts had a higher DCR12 than non-exposed/non-refractory (50 vs 17% exposed/nonexposed and 40% vs 23% refractory/nonrefractory). Pts with germline mutations had a higher DCR12 compared to those without (38.5% vs. 0%). Non- BRCA2 mutations had a higher DCR12 than those with BRCA2 mutations (50% vs.17%), with highest DCR12 rates among BRCA1 patients (67%). Tolerability was in line with similar combinations, with 60% non-hematologic Gr3 or higher, including fatigue (15%), AST increase (10%), nausea/vomiting (10%), sepsis (10%). Two grade 5 events were not attributed to treatment. Conclusions: PARPi plus anti-PD1 checkpoint inhibition was not sufficiently active as later line therapy in metastatic pancreatic cancer for the majority of patients with HRD mutations. Additional molecular analyses to elucidate predictive markers of sensitivity/resistance are ongoing. Clinical trial information: NCT04493060 .
Circulating tumor DNA as a marker of recurrence risk in stage III colorectal cancer: The α-CORRECT study.
302 Background: Patients with stage III CRC undergo surgery and adjuvant chemotherapy. Evaluation of MRD using a highly sensitive and specific, tumor-informed ctDNA assay may help predict which patients will have a recurrence. Methods: Patients with stage III CRC were enrolled after surgery in an observational study across 19 Pennsylvanian hospitals between 2016-2020. Tumor tissue and serial blood samples (every 3 months for years 1-3, biannually for years 4-5) were collected. Following whole exome sequencing (WES) of the tumor and selection of 50 – 200 somatic variants, a personalized MRD assay was used to measure ctDNA status of each sample. Three timepoints were used to analyze the association of ctDNA with recurrence: the single sample post-surgical (PS) and post-definitive therapy (PDT) timepoints, and the surveillance period, which included the PDT and subsequent samples. Primary endpoint was the association of ctDNA status during surveillance with recurrence-free survival (RFS). Results: A total of 124 patients with 1029 ctDNA results were analyzed. Almost all patients (96.0%) received adjuvant chemotherapy, primarily with an oxaliplatin-based regimen. On average, patients had 10 (SD = 4.5) blood draws and the median follow-up was 4.8 years. WES identified 172 (range 50 – 200) somatic variants per patient on average. Patients who were ctDNA positive during surveillance had a significantly higher likelihood of recurrence than patients who remained ctDNA negative (HR 49.6, 95% CI: 16.6 – 148.3; ctDNA status as time-dependent variable). At all timepoints, ctDNA detection was strongly associated with recurrence (Table). In multivariable analyses, ctDNA was strongly prognostic for recurrence but CEA was not. The median lead time between positive ctDNA result and a clinical diagnosis of recurrence was 10.4 months. Conclusions: In this cohort of patients with stage III CRC with long-term follow-up, a tumor-informed ctDNA assay using up to 200 variants was strongly prognostic for recurrence at all timepoints. Hazard ratios (HR), sensitivity, and specificity, with 95% confidence intervals (95% CI), for the association of ctDNA status with recurrence-free survival (RFS) at the surveillance, postsurgical (PS), and post-definitive therapy (PDT) timepoints (three-year RFS for the PS and PDT timepoints are also shown). Timepoint Statistic Result Surveillance(N = 111) HR(95% CI) 49.6**(16.6 – 148.3) Sensitivity(95% CI) 20/22 = 90.9%(72.2 – 97.5%) Specificity(95% CI) 82/87 = 94.3%(87.2 – 97.5%) PS(N = 88) HR(95% CI) 9.6**(3.2 – 29.5) Sensitivity(95% CI) 14/18 = 77.8%(54.8 – 91.0%) Specificity(95% CI) 53/66 = 80.3%(69.2 – 88.1%) RFS at 3 yrsctDNA(+), ctDNA(-) 54.5%, 96.1% PDT(N = 97) HR(95% CI) 16.7**(6.9 – 40.3) Sensitivity(95% CI) 10/21 = 47.6%(28.3 – 67.6%) Specificity(95% CI) 75/76 = 98.7%(92.9 – 99.8%) RFS at 3 yrsctDNA(+), ctDNA(-) 18.2%, 90.0% *P< 0.001, **P<0.0001.
A phase II study of fruquintinib plus sintilimab as a second-line therapy for advanced gastric and gastroesophageal junction adenocarcinoma (GC/GEJC): Updated results.
407 Background: Preliminary results of the open-label, single-arm phase II study (NCT05625737) had demonstrated the combination of fruquintinib and sintilimab as a second-line therapy had a promising anti-tumor activity and an acceptable safety profile in pts with advanced GC/GEJC (ASCO-GI 2024. Poster 332). Here, we update the results with a focus on subgroup analyses. Methods: Patients (pts) aged 18-75 years who were HER2-negative and had failed first-line standard treatment were enrolled. Eligible pts received 4mg of fruquintinib orally once daily on days 1-14 and 200 mg of sintilimab intravenously on day 1, with treatment repeated every 3 weeks. An optimal Simon two-stage design was employed. The primary endpoint was objective response rate (ORR). Secondary endpoints included disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety. Results: At data cut-off (August 25, 2024), 29 pts (7 in the first stage; 22 in the second stage) with median age 51 (range 33–73) years old had been enrolled. 41.4% were male, 37.9% had ECOG PS 1, 69% had lymph node metastasis and 72.4% had previously received immunotherapy. Among the 24 efficacy evaluable pts, the ORR was 33.3% (95% CI 15.6–55.3) and DCR was 66.7% (95% CI 44.7–84.4). After a median follow-up of 13.14 months, the median PFS was 5.13 (95% CI: 2.73–7.03) months and OS result was pending maturity. Pts who had lymph node metastasis exhibited higher ORR compared to pts without lymph node metastasis (ORR-47.1 vs 0%). In particular, pts without prior immunotherapies were more likely to achieve higher response rate (37.5 vs 33.3%) and had an obvious trend for longer PFS than pts with prior immunotherapies (9.00 vs 5.13 months). Majority of treatment-emergent adverse events (TEAEs) were grade 1-2 and the most frequently reported ones (≥20%) were white blood cell decreased (33%), hypertriglyceridemia (25%), lymphocyte count decreased (21%), abdominal pain (21%) and decreased appetite (21%). Grade 3/4 TEAEs occurred in only one patient, consisting of increased blood bilirubin levels, aspartate transaminase elevation, and alanine transaminase elevation. Conclusions: Fruquintinib combined sintilimab was well tolerated, with encouraging antitumor activity as second-line treatment for advanced GC/GEJC, especially in pts without prior immunotherapies. Further studies in larger cohorts to validate these findings are warranted. Clinical trial information: NCT05625737 .
PO<sub>4</sub><sup>3−</sup> Tetrahedron Assisted Chelate Engineering for 10.67%‐Efficient Antimony Selenosulfide Solar Cells
AbstractAnisotropic carrier transport and deep‐level defect of antimony selenosulfide (Sb2(S,Se)3) absorber are two vital auses restraining the photovoltaic performance of this emerging thin‐film solar cell. Herein, chelate engineering is proposed to prepare high‐quality Sb2(S,Se)3 film based on hydrothermal deposition approach, which realizes desirable carrier transport and passivated defects by using tetrahedral PO43− ion in dibasic sodium phosphate (Na2HPO4, DSP). The PO43− Lewis structure, on one hand in the form of [(SbO)3(PO4)] chelate, can adsorb on the polar planes of cadmium sulfide (CdS) layer, promoting the heterogeneous nucleation, and on the other hand, the tetrahedral PO43− inhibits horizontal growth of (Sb4S(e)6)n ribbons due to size effects, thus achieving desirable [hk1] orientation. Moreover, the introduction PO43− effectively passivates the antisite defect SbS1. These synergistic effects have effectively improved carrier transport and reduced non‐radiative recombination of the Sb2(S,Se)3 absorber. Consequently, the DSP‐modified Sb2(S,Se)3 device efficiency increases from 8.59% to 10.67%.
Clinical outcomes of immunotherapy in metastatic pancreatic carcinoma: A systematic review and meta-analysis.
688 Background: Metastatic pancreatic carcinoma is one of the most challenging malignancies to treat. Traditional treatment modalities such as chemotherapy and radiation therapy have shown limited efficacy. This meta-analysis aims to investigate immunotherapy as a potential therapeutic option for metastatic pancreatic carcinoma. Methods: PubMed, Cochrane, Embase, and Clinicaltrials.gov were searched as per PRISMA guidelines. Data extraction was conducted independently by two reviewers, and any discrepancies were resolved through discussion. Pooled analysis was performed using the ‘meta’ package by Schwarzer et al. in the R programming language (version 4.16-2). Results: 834 patients from the 17 studies reporting immunotherapy outcomes in metastatic pancreatic carcinoma were included in this systematic review and meta-analysis. The studies included (There were) were 4 phase I (23.5%), 2 phase Ib (11.8%), 1 phase Ib/II (5.9%), and 5 phase II (29.4%), 1 retrospective study (5.9%) and 4 prospective studies (23.5%). The median age of the patients was 61 years and 55.6% (398/716) were male. Immunotherapies included were GVAX, tremelimumab, Mesothelin-specific Chimeric Antigen Receptor T cells, durvalumab, pembrolizumab, canerpaturev, Sotigalimab, nivolumab, CO-1.01, allogeneic natural killer cell immunotherapy, Anti-EGFR chimeric antigen receptor-modified T cells, bispecific antibody armed T cells, and clivatuzumab tetraxetan. The median follow-up duration was 17.8 months. The median overall survival was 7.9 months, and the median progressive-free survival was 4.6 months. The pooled overall response rate was calculated at 16% (95% CI 0.09-0.26, I2=70, p<0.01, n= 426) and the pooled partial response rate was 13% (95% CI 0.09-0.26, I2= 67%, p<0.01, n= 272). The pooled stable disease was calculated to be 28% (95% CI, 0.2-0.39, I2= 59%, p<0.01, n=277). The pooled progressive disease was 36% (95% CI, 0.23-0.52, I2=34%, p=0.22, n=68). The most common overall adverse effects were anemia, diarrhea, and thrombocytopenia. Conclusions: This meta-analysis demonstrates that novel immunotherapies have promising results on metastatic pancreatic cancer. Future new clinical trials with a follow-up on current early-phase results are needed.
Optimizing clinical trial design to mitigate racial disparities in pancreatic cancer clinical trial enrollment.
682 Background: Participation in pancreatic ductal adenocarcinoma (PDAC) clinical trials remains dismal among patients from minoritized groups. This study aimed to investigate if clinical trial design, including eligibility criteria, affects representation of minoritized populations. Methods: United States Phase I-IV PDAC clinical trials between 2000-2020 were extracted from the ClinicalTrials.gov database. The Surveillance, Epidemiology, and End Results (SEER) database was used to determine cancer incidence linked with years of trial enrollment. Enrollment fraction (EF) was defined as the number of trial participants divided by the incidence of PDAC in each racial and ethnic group. Representation Quotient (RQ) was defined as the proportion of trial participants divided by proportion of PDAC incidence for each subgroup, where underrepresentation was RQ <1.0. Results: 8451 patients from 228 unique PDAC clinical trials were analyzed. 55.7% (n=128) and 44.3% (n=102) trials reported racial and ethnic demographic data, respectively. Non-Hispanic Black (NHB), Non-Hispanic Asian/Pacific Islander (NHAPI), Non-Hispanic American Indian/Alaskan Native (NHAIAN), and Hispanic patients were underrepresented (Table). NHB patients were more likely to be underrepresented in trials for metastatic PDAC disease (89.4% vs. 73.8% of trials, p=0.035). NHB patients demonstrated an increase in median RQ (0.28 vs. 0.48) in trials from 2000-2010 vs. 2011-2020, while Hispanic patients had a decreased median RQ (0.36 vs. 0.25). Trials with renal insufficiency exclusion criteria without cutoffs or explicit methodology were more likely to accrue NHB patients (RQ 0.88 vs. 0.46, p=0.02), whereas trials that used a creatinine cutoff or the modified Cockcroft-Gault (CG) formula did not significantly affect RQ. Other eligibility criteria including cardiac history, HIV, Hepatitis B/C, and receipt of neoadjuvant therapy did not significantly affect RQ for any racial or ethnic group. Trial location and funding source did not affect RQ for any group. Conclusions: Systemic barriers persist in minority enrollment in PDAC clinical trials. Clinical trial design optimizing inclusive eligibility requirements is a first feasible step in increasing minority clinical trial enrollment. Racial and ethnic representation in pancreatic ductal adenocarcinoma clinical trials. Enrollment Fraction (Median, IQR) Representation Quotient (Median, IQR) NHW 0.28 (0.12-0.62) 1.17 (1.09-1.24) NHB 0.15 (0-0.33) 0.47 (0-0.87) NHAPI 0 (0-0.23) 0 (0-0.45) NHAIAN 0 (0-0) 0 (0-0) Hispanic 0.07 (0-0.21) 0.26 (0-0.68) *Abbreviations: Interquartile Range (IQR), Non-Hispanic Black (NHB), Non-Hispanic Asian/Pacific Islander (NHAPI), Non-Hispanic American Indian/Alaskan Native (NHAIAN).
Assessment of nutritional status in elderly patients with gastroesophageal cancer: A post hoc analysis.
389 Background: Elderly patients with gastroesophageal cancer (GEC) frequently suffer from malnutrition due to tumor location and treatment-related toxicity. Malnutrition is associated with increased morbidity and mortality in this population. This study investigates the relationship between body mass index (BMI), Mini Nutritional Assessment (MNA) scores, unintentional weight loss (UWL), and chemotherapy toxicity while identifying key factors influencing nutritional status. Methods: This post hoc analysis utilized data from a prospective, multicenter study of patients aged 65 and older with all stages of GEC undergoing chemotherapy. Nutritional assessments were conducted using validated tools, focusing on BMI, MNA, and UWL over three months post enrollment. We defined malnourished patients as those with abnormal BMI (<18.5 or >30), low MNA (0-11), and significant UWL (≥10%). We analyzed associations between nutritional status and geriatric assessment comorbidities, depression score, functional status, cognition, hospitalization, treatment toxicity, and social support using Fisher’s exact tests. Results: Eighty-two patients were enrolled, with a median age of 73 years (range 65-91 years). The cohort was predominantly male (74%) and primarily presented with stage III-IV disease (82%), most receiving first-line therapy (79%). Primary sites included gastric (32%), esophageal (43%), and gastroesophageal junction (26%). Notably, 34% of patients had abnormal BMI, with 2 patients classified as underweight (BMI <18.5) and 19 as obese (BMI >30). Approximately 69% reported UWL, of 10% or greater. MNA scores indicated malnutrition in about 66% of patients (severe (0-7): 15 patients; moderate (8-11): 37 patients), while 31% scored within the normal range (12-14).Hospital admissions were significantly higher in patients with low MNA (33% vs. 3%; p=0.002) and UWL (29% vs. 8%; p=0.047). No significant correlations were observed between nutritional status and treatment type, treatment toxicity, or other geriatric assessment variables, including functional status and social support. Conclusions: MNA and UWL are effective indicators of nutritional status in elderly GEC patients, while BMI is not a reliable measure. Malnutrition significantly correlates with increased hospital admissions, highlighting the need for reliable tools to measure malnutrition to implement necessary interventions. Further research is required to explore the broader implications of malnutrition on treatment outcomes and quality of life in this vulnerable population.
Radiomics-based prediction of HCC response to atezolizumab/bevacizumab.
636 Background: Advanced hepatocellular carcinoma (HCC) treatment has evolved with the introduction of atezolizumab/bevacizumab, showing improved outcomes over sorafenib. However, the response varies among patients, particularly between viral and non-viral etiologies. This study aimed to develop and evaluate multimodal prediction models combining quantitative imaging and clinical markers to predict treatment response in HCC patients. Methods: From March 2020 to May 2023, patients with advanced HCC treated with atezolizumab/bevacizumab were retrospectively identified from six centers in Germany and Austria. Patients underwent baseline contrast-enhanced liver MRI and follow-up imaging to assess therapy response. Machine learning models, including RandomForestClassifier, were developed for radiomics, clinical, and combined datasets. Hyperparameter tuning was performed using RandomizedSearchCV, followed by cross-validation to evaluate model performance. Results: The study included 103 patients, with 70 achieving disease control (DC) and 33 experiencing disease progression (PD). Key findings included significant differences in treatment response and progression-free survival between DC and PD groups. The radiomics model, using 14 selected features, achieved 73.1% accuracy and a ROC AUC of 0.635 on the test set. The clinical model, with 4 selected features, achieved 73% accuracy and a ROC AUC of 0.649 on the test set. The combined model showed improved performance with 69% accuracy and a ROC AUC of 0.753 on the test set. Hyperparameter tuning further enhanced the combined model's accuracy to 80.1% and ROC AUC to 0.771 on the test set. Conclusions: The hybrid model combining clinical and radiological data outperformed individual models, providing better predictions of response to atezolizumab/bevacizumab in HCC patients.
Cetuximab and vemurafenib plus liposomal irinotecan (II), leucovorin and fluorouracil for BRAF <sup>V600E</sup> -mutated advanced colorectal cancer (IMPROVEMENT2): A multicenter, open-label, randomized controlled trial.
TPS316 Background: Current first-line treatment regimen for advanced colorectal cancer with BRAF V600E gene mutation is chemotherapy combined with anti-angiogenic drug, but the efficacy is somewhat limited. Theoretically, targeting BRAF V600E mutation is an effective treatment strategy and has achieved success in lung cancer and melanoma. However, the objective response rate (ORR) is below 5% in colorectal cancer, suggesting that BRAF V600E mutation in colorectal cancer may have different feedback regulation mechanisms compared to other cancer types. Combining chemotherapy (such as 5-fluorouracil plus irinotecan) with BRAF/EGFR targeted therapy may potentially achieve good efficacy. Subsequently, we conducted the IMPROVEMENT (NCT03727763) study, which showed an objective response rate (ORR) of 85% and a disease control rate of 100% with this regimen, significantly higher than those with chemotherapy combined with anti-angiogenic drug. The recent BREAKWATER study showed similar trends. To further validate the efficacy and safety of this regimen, we designed a randomized controlled trial. Methods: IMPROVEMENT2 (NCT06603376) is a multicenter, open-label, randomized controlled trial in patients with histologically or cytologically confirmed advanced colorectal cancer. Adult patients who are previously untreated in the metastatic setting, have a confirmed BRAF V600E mutation, measurable disease per Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1, and Eastern Cooperative Oncology Group performance status of 0-1 are eligible. Patients who received previous treatment in the adjuvant setting but experienced metastasis or recurrence within 12 months are permitted. A total of 75 eligible patients will be randomly assigned (2:1) to receive liposomal irinotecan(Ⅱ) 60 mg/m 2 , leucovorin 400 mg/m 2 , fluorouracil 2800 mg/m 2 , and cetuximab 500 mg/m 2 on day 1 of each 14-day cycle plus oral vemurafenib 720 mg twice daily, or liposomal irinotecan(Ⅱ) 60 mg/m 2 , leucovorin 400 mg/m 2 , fluorouracil 2800 mg/m 2 , and bevacizumab 5 mg/kg on day 1 of each 14-day cycle. Treatment will be continued until disease progression or unacceptable toxicity. The primary endpoint is ORR per RECIST 1.1 by blinded independent central review (BICR). Key secondary endpoints are depth of response, progression-free survival per RECIST 1.1 by BICR, overall survival, and safety. The study is actively enrolling patients. Clinical trial information: NCT06603376 .
The prevalence and prognostic significance of <i>KRAS G12C</i> mutation in metastatic colorectal cancer.
289 Background: Kristen rat sarcoma virus ( KRAS ) mutations are reported in 40-45% of colorectal cancer (CRC), and they are associated with poor prognosis. KRAS G12C mutation is reported in 3-4% of CRC patients and may be associated with worse prognosis compared to RAS non-G12C mutations. Here, we explored the prevalence and prognostic significance of KRAS G12C mutation compared to RAS non-G12C and BRAF V600E in a cohort of CRC patients from a tertiary cancer center in the United States (US). Methods: The cBioCancer Genomics Portal was used to obtain genomic data. The prevalence of KRAS G12C mutation, RAS non-G12C ( KRAS G12D, KRAS G13D, KRAS G12V, KRAS A146T, KRAS G12A, KRAS G12S, KRAS G13C, KRAS V14I, KRAS Q61H, KRAS G12R, KRAS Q61R, KRAS K117N, NRAS Q61K , NRAS Q61R , NRAS Q61L , NRAS Q61H , NRAS G13D , NRAS G13C NRAS G13R NRAS G12D , NRAS G12C , NRAS G12V, NRAS G12V and NRAS G60V ) mutations and BRAF V600E mutations was calculated. The median overall survival (mOS) was explored in CRC (MSK, Cancer Cell 2018 cohort). Patients in this cohort were not treated with KRAS G12C targeted therapy. Survival analysis was performed using the Kaplan-Meier method with log-rank test comparisons. Results: In this cohort of patients with stage IV CRC (N=1134), the prevalence of KRAS G12C mutation in patients with stage IV CRC was 3.1%. In patients with RAS non-G12C mutations, BRAF V600E mutation, and RAS/BRAF V600E wild-type (WT), the prevalence was 41.7%, 7.5%, and 47.7% respectively. The mOS in KRAS G12C mutation, RAS non-G12C mutations, BRAF V600E mutation, and RAS/BRAF V600E WT was 65 months (m), 55m, 19m and 105m respectively. Compared to RAS non-G12C , the mOS of CRC patients with KRAS G12C was (65m vs 55m, p=0.54) . Compared to patients with BRAF V600E mutation, the mOS was better in patients with KRAS G12C (65m vs. 19m, p <0.0001) and in patients with RAS non-G12C (55m vs. 19m, p <0.0001). Conclusions: The prevalence of KRAS G12C mutation in this cohort was relatively similar to other reports at 3.1%. Consistent with several other reports, there was no statistically significant difference in the mOS between patients with KRAS G12C mutation and patients with RAS non-G12C mutations. Patients with BRAF V600E mutations had worse mOS compared to patients with KRAS G12C mutation and RAS non-G12C mutations. The reported high mOS in this cohort is possibly due to selection bias (patients able to afford and receive treatment at this tertiary center).
Polyproline‐Polyornithine Diblock Copolymers with Inherent Mitochondria Tropism
AbstractMitochondria play critical roles in regulating cell fate, with dysfunction correlating with the development of multiple diseases, emphasizing the need for engineered nanomedicines that cross biological barriers. Said nanomedicines often target fluctuating mitochondrial properties and/or present inefficient/insufficient cytosolic delivery (resulting in poor overall activity), while many require complex synthetic procedures involving targeting residues (hindering clinical translation). The synthesis/characterization of polypeptide‐based cell penetrating diblock copolymers of poly‐L‐ornithine (PLO) and polyproline (PLP) (PLOn‐PLPm, n:m ratio 1:3) are described as mitochondria‐targeting nanocarriers. Synthesis involves a simple two‐step methodology based on N‐carboxyanhydride ring‐opening polymerization, with the scale‐up optimization using a “design of experiments” approach. The molecular mechanisms behind targetability and therapeutic activity are investigated through physical/biological processes for diblock copolymers themselves or as targeting moieties in a poly‐L‐glutamic (PGA)‐based conjugate. Diblock copolymers prompt rapid cell entry via energy‐independent mechanisms and recognize mitochondria through the mitochondria‐specific phospholipid cardiolipin (CL). Stimuli‐driven conditions and mitochondria polarization dynamics, which decrease efficacy depending on disease type/stage, do not compromise diblock copolymer uptake/targetability. Diblock copolymers exhibit inherent concentration‐dependent anti‐tumorigenic activity at the mitochondrial level. The diblock copolymer conjugate possesses improved safety, significant cell penetration, and mitochondrial accumulation via cardiolipin recognition. These findings may support the development of efficient and safe mitochondrial‐targeting nanomedicines.
Pathologic Response of Phase III Study: Perioperative Camrelizumab Plus Rivoceranib and Chemotherapy Versus Chemotherapy for Locally Advanced Gastric Cancer (DRAGON IV/CAP 05)
PURPOSE This multicenter, randomized phase III trial evaluated the efficacy and safety of perioperative camrelizumab (an anti–PD-1 antibody) plus low-dose rivoceranib (a VEGFR-2 inhibitor) and S-1 and oxaliplatin (SOX) (SOXRC), high-dose rivoceranib plus SOX (SOXR), and SOX alone (SOX) for locally advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma. METHODS Patients with T3-4aN + M0 G/GEJ adenocarcinoma were randomly assigned (1:1:1) to receive perioperative treatment with SOXRC, SOXR, or SOX. The primary end points were pathologic complete response (pCR) and event-free survival. The Independent Data Monitoring Committee recommended stopping enrollment in the SOXR group on the basis of the safety data of the first 103 randomly assigned patients in the three groups. The patients were then randomly assigned 1:1 to the SOXRC or SOX groups. This report presents the pCR results obtained per protocol for the first 360 randomly assigned patients who had the opportunity for surgery in the SOXRC and SOX groups. RESULTS In the SOXRC and SOX groups, of the 180 patients in each group, 99% and 98% of patients received neoadjuvant therapy, 91% and 94% completed planned neoadjuvant therapy, and 86% and 87% underwent surgery, respectively. The pCR was significantly higher in the SOXRC group at 18.3% (95% CI, 13.0 to 24.8) compared with 5.0% (95% CI, 2.3 to 9.3) in the SOX group (difference of 13.7%; 95% CI, 7.2 to 20.1; odds ratio of 4.5 [95% CI, 2.1 to 9.9]). The one-sided P value was <.0001, crossing the prespecified statistical significance threshold of P = .005. Surgical complications and grade ≥3 neoadjuvant treatment-related adverse events were 27% versus 33% and 34% versus 17% for SOXRC and SOX, respectively. CONCLUSION The SOXRC regimen significantly improved pCR compared with SOX alone in patients with G/GEJ adenocarcinoma with a tolerable safety profile.
Association of early tumor shrinkage with survival in patients with HER2-positive advanced gastric cancer treated with trastuzumab deruxtecan.
360 Background: Trastuzumab deruxtecan (T-DXd), an antibody-drug conjugate composed of an anti-human epidermal growth factor receptor 2 (HER2) antibody and a cytotoxic topoisomerase I inhibitor, has been approved as third or later-line treatment for unresectable HER2-positive advanced gastric cancer (AGC) based on the results of phase II DESTINY-Gastric 01 trial. However, there are few studies on real-world clinical outcomes and clinicopathological factors associated with efficacy of T-DXd in patients with HER2-positive AGC. Methods: This single-center retrospective study enrolled patients with AGC treated with T-DXd as third- or later-line chemotherapy between March 2018 and December 2023. Early tumor shrinkage (ETS) was defined as the relative change in the sum of longest diameters of RECIST target lesions at 8 ± 2 weeks compared with baseline. Prognostic outcomes were assessed using the log-rank test and Cox proportional hazards regression model. Results: A total of 57 patients were enrolled. The median age was 66 years (range, 31–82); 68% were male; 79% had HER2 3+; 23% had pulmonary metastasis; 67% were treated with T-DXd in the third-line setting. At a median follow-up of 27.6 months, the median progression-free survival (PFS) was 4.5 months (95% confidence interval [CI], 3.8–5.5), and the median overall survival (OS) was 7.3 months (95% CI, 4.9–9.4). Among 40 patients with target lesions, the overall response rate was 35.0% and the disease control rate was 90.0%. Patients with ETS had notably longer PFS (median PFS (months) 8.6 vs 4.1, P < 0.01) and OS (median OS (months) 9.1 vs 6.1, P < 0.01) than those without ETS. In multivariate analysis, ETS was associated with significantly longer PFS (hazard ratio [HR], 0.23; 95% CI, 0.08–0.63; P = 0.004) and OS (HR, 0.27; 95% CI, 0.12–0.65; P = 0.004), whereas pulmonary metastasis was associated with significantly shorter OS (HR 2.46, 95% CI, 1.07–5.65; P = 0.03). Conclusions: This study showed that achieving an ETS was significantly associated with a favorable prognosis in patients with HER2-positive AGC treated with T-DXd.
Clinical and Molecular Characteristics of High-Risk, Recurrent, or Metastatic Endometrial Cancer That Is Human Epidermal Growth Factor Receptor 2–Low
PURPOSE Recent success of human epidermal growth factor receptor 2 (HER2)–targeted antibody-drug-conjugate trastuzumab-deruxtecan in HER2-low and HER2-positive tumors has sparked interest in examining the HER2 status of tumors not traditionally associated with HER2 amplification. Despite the increasing number of systemic treatment options, patients with advanced endometrial cancer (EC) still face a poor prognosis. This study evaluates HER2-low status in over 800 EC, correlating HER2 with both molecular and clinical features. METHODS HER2 status was determined by immunohistochemistry (IHC) and dual in situ hybridization (DISH) on four studies of previously classified high-risk EC (PORTEC-3 and Medical Spectrum Twente cohort), recurrent or metastatic EC (DOMEC), and a primary stage IV cohort. EC was classified as HER2-negative (IHC 0), HER2-low (IHC 1+/2+ without amplification), or HER2-positive (IHC 3+ or DISH-confirmed amplification). Survival analysis was performed using the Kaplan-Meier method. Cox proportional hazards models assessed the independence of any prognostic impact of HER2 status. RESULTS HER2 status was determined in 806 EC: 74.8% were HER2-negative, 17.2% HER2-low, and 7.9% HER2-positive. HER2-low was found across all molecular classes and histotypes. The highest rates of HER2-low and HER2-positive tumors were in recurrent or metastatic EC (35.6% and 15.6%), followed by primary stage IV EC (29.9% and 12.4%) and high-risk EC (14.2% and 6.8%). HER2 status had no independent prognostic value. CONCLUSION A quarter of high-risk, metastatic, or recurrent EC exhibited HER2 overexpression. The presence of HER2 overexpression in all clinical and molecular categories highlights the need for broad testing and offers treatment options for a wide range of patients.
The effect of renin-angiotensin system inhibitors on patients with pancreatic cancer receiving systemic treatment: A retrospective cohort study from TriNetX US collaborative networks.
734 Background: This study aimed to assess the impact of renin-angiotensin system inhibitors, including angiotensin receptor blockers (ARBs) and angiotensin-converting enzyme inhibitors (ACEIs), on patients with pancreatic cancer undergoing systemic chemotherapy. Methods: We conducted a global, retrospective collaborative network analysis using TriNetX data from January 1, 2014, to December 31, 2023, to explore this question. The study captured data on pancreatic cancer diagnoses, comorbidities, medications, and survival outcomes. Propensity score matching (PSM) was used to create 1:1 matched groups. Hazard ratios (HR) with 95% confidence intervals (95% CI) were calculated to assess survival outcomes, while the Kaplan–Meier method was employed to evaluate survival probabilities. Subgroup analyses were performed based on sex, age, surgery, race, and comorbidities. Results: The study included 1,861 patients who were on ARBs/ACEIs and 4,875 patients who were not on these medications at baseline. After 1:1 propensity score matching, both groups were well-balanced with 1,627 patients each. Compared to the non-ARBs/ACEIs group, patients receiving ARBs/ACEIs demonstrated significantly better overall survival (HR: 0.846, 95% CI: 0.753–0.949). Subgroup analyses revealed significantly improved survival outcomes in patients on ARBs/ACEIs, including those without surgery (HR: 0.846, 95% CI: 0.749–0.956), males (HR: 0.762, 95% CI: 0.640–0.908), patients aged 65 years and older (HR: 0.801, 95% CI: 0.709–0.906), and White patients (HR: 0.806, 95% CI: 0.704–0.924). Notably, similar survival benefits were observed in patients with comorbidities such as diabetes, ischemic heart disease, dyslipidemia, and hypertension. Conclusions: In the largest TriNetX matched cohort study on pancreatic cancer, the use of ARBs/ACEIs was associated with a reduced risk of overall mortality. However, prospective studies are needed to further evaluate the effects of concomitant ARB/ACEI use in patients with pancreatic cancer undergoing systemic treatment.
More isn't always better: Expanding and refining prognostic methylation signatures for pancreatic ductal adenocarcinoma.
769 Background: In our previous study, we developed protein-informed methylation signatures from a chemoresistance gene panel (RGp, n=122) curated from the literature, identifying 28 signatures with strong prognostic value in The Cancer Genome Atlas (TCGA) pancreatic ductal adenocarcinoma (PDA) database. To enhance the clinical utility of this panel, we incorporated methylation changes from genes with known prognostic (PGp) and diagnostic (DGp) significance in PDA to form a composite gene panel (CGp-PDA) and repeated our analysis. We hypothesized that epigenetic changes in these genes reflect protein expression and that deriving signatures from them could help identify patients at risk of treatment failure. Methods: We assembled a composite gene panel (CGp-PDA) of 206 genes (122 RGp + 26 PGp + 82 DGp) through a literature review spanning from January 1970 to April 2024. These PGp and DGp genes are unique, as cell-free DNA methylation changes in them have established prognostic and diagnostic value, respectively in PDA. The same cohort of pancreatic ductal adenocarcinoma (PDA) patients (n=184) from our previous study was analyzed. We applied elastic net multivariate analysis to calculate survival outcomes and generated Kaplan-Meier plots using our gene panel, optimizing values for 𝛼 and λ over 100 iterations. Results: Our analysis identified 20 signatures with cytosines followed by a guanine residue (CpG) site in genes from our panel. The number of CpG sites in these signatures ranged from 3 to 4248. The most effective signature featured 17 CpG sites (22 months [m] vs. 67m, p=0.03), followed by signatures with 3 (16m vs. 49m, p=0.009) and 12 (17m vs. 36m, p=0.02) CpG sites. The 4248 CpG site signature demonstrated the poorest prognostic value among the signatures (17m vs. 21m, p=0.01). Some signatures included multiple CpG sites within a single gene. Notably, KCNH2 reappeared in several signatures, as in the prior study. Expanding our RGp to CGp-PDA did not produce more (20 vs. 28) signatures or improved prognostic value. Conclusions: Targeted methylation signatures, supported by robust preclinical or translational evidence of their impact on treatment resistance, can be clinically valuable for informing treatment selection and prognosis. We may need to shift our focus from machine learning-based broad methylation or transcriptomic analyses to more targeted investigations.
Transarterial chemoembolization (TACE) combined with camrelizumab and apatinib versus TACE alone in the treatment of unresectable hepatocellular carcinoma eligible for embolization: A multicenter, open-label, randomized, phase 2 study (CAP-ACE).
LBA522 Background: Transarterial chemoembolization (TACE) has been established as a standard treatment for hepatocellular carcinoma (HCC) eligible for embolization. Combining immunotherapy and tyrosine kinase inhibitors (TKIs) with TACE can potentially enhance antitumor activity by activating the immune system and inhibiting tumor neovascularization. This study investigated whether the addition of camrelizumab and apatinib to TACE could bring better survival benefits. Methods: This open-label, randomized phase 2 study (NCT04559607) was conducted at 23 sites in China. Patients with unresectable HCC eligible for embolization were randomly assigned to receive either TACE combined with camrelizumab (200 mg once every 3 weeks) and apatinib (250 mg once daily; TACE-CA) or TACE alone. The stratification factors for randomization included vascular invasion (yes vs. no), prior use of TKIs (yes vs. no), and number of prior TACE (0 vs. 1-2). Prior immunotherapy was not allowed. The primary endpoint was progression-free survival (PFS) assessed by investigators according to the Response Evaluation Criteria In Cancer of the Liver (RECICL), analyzed in intention-to-treat population. Results: Between Dec 28, 2020 and Oct 29, 2023, 200 patients were randomized (100 in each group). Median age was 58.5 years (IQR, 51.5-65) and 57.0 years (IQR, 51-65.5) in the TACE-CA and TACE groups, respectively; most patients had Barcelona Clinic liver cancer (BCLC) stage B-C disease (86.0% and 86.0%). As of October 16, 2024, the median follow-up duration was 13.6 months (IQR, 8.2-20.5). Median PFS per RECICL was significantly longer in the TACE-CA group compared with the TACE group (11.0 months [95% CI, 8.8-13.8] vs. 3.1 months [95% CI, 2.0-4.1]; hazard ratio, 0.3, P<0.0001). The objective response and disease control rates were 65.0% (95% CI, 54.8-74.3) and 87.0% (95% CI, 78.8-92.9) in the TACE-CA group and 30.0% (95% CI, 21.2-40.0) and 63.0% (95% CI, 52.8-72.4) in the TACE group, respectively. Overall survival data are immature. Grade ≥3 treatment-related adverse events (TRAEs) occurred in 76.6% (72/94) of patients with TACE-CA and 24.3% (25/103) of patients with TACE. The most common grade ≥3 TRAEs were increased aspartate aminotransferase (AST; 29 [30.9%]), increased alanine aminotransferase (ALT; 23 [24.5%]), hypertension (13 [13.8%]), and decreased platelet count (11 [11.7%]) in the TACE-CA group, and increased ALT (16 [15.5%]) and increased AST (15 [14.6%]) in the TACE group. Conclusions: The addition of camrelizumab and apatinib to TACE can significantly prolong progression-free survival in patients with unresectable HCC eligible for embolization, with a manageable safety profile. Clinical trial information: NCT04559607 .