Docrates Cancer Center

The phase III VELOUR trial demonstrated improved outcomes with aflibercept plus FOLFIRI in patients with metastatic colorectal cancer previously treated with oxaliplatin-based regimens. We retrospectively evaluated the prognostic and predictive impact of RAS/BRAF mutations, intrinsic consensus molecular subtype (iCMS), and tumour sidedness in 439 profiled patients. Targeted sequencing identified RAS mutations in 57.5% and BRAF mutations in 10.0% of evaluable tumours; 34.2% of tumours with complete genotyping were RAS/BRAF wild-type. Transcriptomic profiling classified 66.5% of tumours as iCMS2 and 33.5% as iCMS3. RAS/BRAF wild-type tumours showed numerically improved overall survival (OS) and progression-free survival (PFS) with aflibercept, whereas no clear benefit was observed in RAS-mutant tumours. iCMS subtyping was strongly prognostic, with iCMS2 patients demonstrating longer OS and PFS than iCMS3 (OS HR 0.57, 95%CI 0.45-0.72; PFS HR 0.70, 95%CI 0.56-0.88). Exploratory integrated analyses suggested OS benefit in RAS/BRAF wild-type iCMS2 tumours (HR 0.56, 95%CI 0.33-0.96) and a significant PFS advantage in bevacizumab-pretreated iCMS3 tumours (HR 0.41, 95%CI 0.20-0.85, q = 0.032). Right-sided tumours were associated with poorer OS, but no significant treatment interaction was observed. These findings support integrating genomic and transcriptomic biomarkers to refine patient selection for anti-VEGF therapy, warranting validation in prospective studies. ClinicalTrials.gov number: NCT00561470, registered 15 November 2007.

BackgroundProstate cancer (PCa) precise surgical resection remains a critical challenge due to positive margins compromising outcomes. This study sought to explore the safety and efficacy of DGPR1008, a novel near-infrared (NIR) prostate-specific membrane antigen (PSMA)-targeted fluorescent contrast agent, in fluorescence-guided surgery (FGS) of PCa.MethodsThis single-center, open-label, prospective, single-arm, exploratory study was carried out in The Fourth Affiliated Hospital of Soochow University, China. Patients newly diagnosed with PCa (a Gleason score ≥7) were eligible for enrollment. All patients underwent laparoscopic radical prostatectomy (LRP) with pelvic lymph node dissection (PLND) using DGPR1008. Four dose cohorts were studied: dose cohort A, which received 0.06 mg/kg of DGPR1008 24 h preoperatively; dose cohort B, which received 0.03 mg/kg of DGPR1008 24 h preoperatively; dose cohort C, which received 0.03 mg/kg of DGPR1008 12 h preoperatively, and dose cohort D, which received 0.045 mg/kg of DGPR1008 24 h preoperatively. Safety and efficacy were assessed.ResultsFrom July, 2023 to January, 2024, 14 eligible patients were included in the study. In total, 32 adverse events (AEs) were observed. One patient (7.1%) presented with four serious adverse events (SAEs), including urinary fistula, infected lymphocele, wound complications, and acute exacerbation of chronic obstructive pulmonary disease. None of the AEs or SAEs was found to be associated with the administration of DGPR1008. Compared with the other dose cohorts, DGPR1008 showed the highest sensitivity (80.6%) for detecting PCa in vivo in dose cohort B. Further, dose cohort B provided the highest target-to-background ratio (TBR) through all phases of tumor imaging, both in vivo and ex vivo, on the gross and fixed tissue. DGPR1008 enabled the real-time visualization of tumor-positive surgical margins, and had a sensitivity of 90% in vivo and 100% ex vivo.ConclusionsDGPR1008 is safe and well tolerated, and may be used in the intraoperative identification of primary PCa and positive surgical margins. Dose cohort B (0.03 mg/kg, 24 h preoperatively) is optimal for efficacy and TBR.

BackgroundOncolytic viruses (OVs) are promising immunotherapeutics to treat immunologically cold tumors. However, research on the mechanism of action of OVs in humans and clinically relevant biomarkers is still sparse. To induce strong T-cell responses against solid tumors, TILT-123 (Ad5/3-E2F-d24-hTNFa-IRES-hIL2, igrelimogene litadenorepvec) was developed. TILT-123 encodes two transgenes: tumor necrosis alpha (TNFa) and interleukin-2 (IL-2). TUNIMO (NCT04695327) was a phase I clinical trial using TILT-123 in patients with advanced solid tumors aiming to assess the safety, efficacy, and immunological effects of TILT-123. Research presented in this study evaluated the immunological effects of TILT-123 in the TUNIMO trial by using biological samples collected from the patients during the study, with an objective to leverage the findings to develop possible biomarkers of response and gain insights into possible synergistic combination treatments.Methods20 patients with advanced solid tumors were treated with TILT-123. Response to therapy was assessed with contrast-enhanced CT and fluorodeoxyglucose positron emission tomography, along with overall survival (OS) calculation. Biological samples from patients were collected in the form of blood and tumor biopsies. Collected samples were analyzed with immunohistochemistry, transcriptomics, proteomics, and flow cytometry.ResultsTILT-123 induced cyclical decreases in blood lymphocyte count, and more substantial blood lymphocyte count correlated with better radiographical response and longer OS. Lymphocyte count findings were confirmed with external control dataset of 96 patients. More substantial lymphocyte count change was linked to stronger immune activation in plasma proteome after intravenous TILT-123 and the presence of TILT-123 mRNA in tumors. Regarding other assays. tumor biopsies profiled showed increased amounts of CD8+ T cells, CD4+ T cells and NK cells after intravenous TILT-123, but not after intratumoral TILT-123. Transcriptional differences were seen in tumors after intravenous therapy and intratumoral therapy, with patients benefitting therapy showing stronger downregulation of immune activation at all time points.ConclusionsTILT-123 therapy induced accumulation of effector lymphocytes in tumors. Peripheral lymphocyte count decrease is a promising biomarker for assessing oncolytic adenovirus therapy response.

The purpose of this study was to evaluate the predictive features of baseline F-18-fluorodeoxy-D-glucose positron emission tomography (18F-FDG PET)/computed tomography (CT) parameters in patients with dedifferentiated liposarcomas (DDLPSs) and well-differentiated liposarcomas (WDLPSs) receiving systemic treatment. A total of 24 patients with liposarcoma who underwent longitudinal 18F-FDG PET/CT in systemic therapy were included. All volumetric segmentation of each tumor section and semiquantitative imaging parameters were extracted from the axial field of view from both PET and CT images. Maximum, mean, and minimum standardized uptake values (SUVmax, SUVmean, and SUVmin), Hounsfield units (HUs), and their respective changes from baseline and posttreatment were calculated. The voxel values from unenhanced CT images were correlated with PET-derived parameters. The 18F-FDG uptake decreased by more than 56% on average in responders for both SUVmax and SUVmean in DDLPS. There was a decrease in HUmax in DDLPS among responders. Using AUC > 0.8 as a reasonable predictor, we found that the ratios of SUVmaxD/HUmean, SUVmaxD/HUmedian, and SUVmeanD/HUmedian at baseline were significant indicators of the response to treatment in patients with liposarcoma. The changes in SUVmean and not just SUVmax parameters could be considered as accurate tumor response indicators. For the first time, we introduced baseline SUV/HU ratios as a valuable diagnostic tool in predicting liposarcoma treatment outcomes. This ability was not revealed by classic semiquantitative PET or CT parameters at baseline.

Prostate cancer (PCa) is the most common cancer and the second leading cause of cancer-related death in men. Previous studies have shown that the poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitors (PARPis) improve the treatment response of patients with metastatic castration-resistant PCa (mCRPC). However, the efficacy and safety of various PARPis in mCRPC patients remain unclear, presenting a significant challenge for clinicians when making treatment decisions. To address this, this study conducted two indirect comparisons to evaluate the efficacy and safety of four PARPis (olaparib, niraparib, rucaparib, and talazoparib) in patients with mCRPC. A systematic review and network meta-analysis (NMA) using Bayesian statistics was conducted. A comprehensive literature search was performed of the PubMed, Web of Science, Cochrane Library, Embase, and China National Knowledge Infrastructure (CNKI) databases to identify relevant studies from the inception to November 8, 2023, using search terms such as "PARP inhibitor", "olaparib", "rucaparib", "niraparib", "talazoparib", and "mCRPC". Phase 2/3 randomized controlled trials (RCTs) related to PARPi therapy and novel hormonal therapy in patients with mCRPC were included in the analysis. The targeted outcomes included radiographic progression-free survival (rPFS), overall survival (OS), adverse events (AEs), and grade ≥3 AEs. Four reviewers screened the titles and abstracts independently to assess the eligibility of each article. Two researchers independently extracted data from the included studies. The risk of bias and quality of the studies were assessed using the Risk-of-Bias 2 tool. Six high-quality phase 2/3 clinical trials, comprising 3,205 individuals, were selected for the systematic review and NMAs. Two NMAs were conducted due to the different designs of the six clinical trials. The indirect comparison with a random-effects model of olaparib, niraparib, and talazoparib showed that olaparib significantly improved rPFS with a hazard ratio (HR) of 0.67 [95% confidence interval (CI): 0.46-0.96]; however, no such significant difference was observed in relation to olaparib and rucaparib. In terms of OS, no significant difference was observed among olaparib, niraparib, and talazoparib. In relation to the AEs, the PARPi interventions using olaparib, niraparib, and talazoparib increased the rates of grade ≥3 AEs with odds ratios (ORs) of 2.0 (95% CI: 0.89-5.3), 3.0 (95% CI: 1.3-7.4), and 3.7 (95% CI: 1.1-12.0), respectively. In the rank probability analysis, according to the surface under the cumulative ranking (SUCRA), olaparib ranked first, followed by niraparib, and talazoparib. Most of the included studies were assessed to be at low risk of bias. Olaparib significantly improved rPFS among olaparib, niraparib, and talazoparib. Talazoparib exhibited the highest SUCRA value. Regarding safety, olaparib and rucaparib did not significantly increase the incidence of grade ≥3 AEs. When making personalized treatment decisions, clinicians should consider individual patient characteristics, treatment efficacy, and potential AEs.

5562 Background: Platinum-resistant or refractory ovarian cancer remains a hard-to-treat disease given the poor prognosis and survival rates. Immune checkpoint inhibitors (ICI; such as pembrolizumab) have not been approved in this indication. Igrelimogene litadenorepvec (Ad5/3-E2F-d24-hTNF-IRES-hIL2; TILT-123), is an oncolytic adenovirus encoding for IL-2 and TNFa, designed to selectively lyse tumor cells while recruiting and activating T-cells, turning immunologically cold tumors hot. The combination of these therapies is appealing as TILT-123 should allow pembrolizumab to be more active, while pembrolizumab should delay emergence of T-cell exhaustion. Methods: PROTA (NCT05271318) is a multicenter open-label phase 1 clinical trial initiated to investigate the safety of TILT-123 in combination with pembrolizumab, in participants bearing ovarian cancer resistant or refractory to platinum-based therapy. In a 3+3 dose-escalation design, TILT-123 was administered intravenously and intratumorally/intraperitoneally to participants with an injectable tumor or carcinomatosis. Pembrolizumab (200mg/Q3wk) was not altered. Eligibility criteria included adequate hepatic and renal functions, and WHO/ECOG performance status of 0-1. Primary endpoint was safety by day 92 evaluated based on adverse events, laboratory values, vital signs, and electrocardiogram. Secondary endpoints included anti-tumor response (RECIST1.1/iRECIST), CA125 levels, pharmacokinetics, transduction of tumors, immune response towards the virus and tumors. Data cutoff was 22Jan2024. Results: 15 patients were enrolled with a median age of 66 (36-78) years, and 14 were evaluable for treatment response with RECIST 1.1/iRECIST. 8 patients were platinum-resistant, and 7 patients were platinum-refractory. Majority of patients had WHO/ECOG performance status 1. Prevalent cancer histology was epithelial ovarian cancer, with some fallopian tube cancer and primary peritoneal cancer. Dose-limiting toxicities were not observed. Frequent grade 1-4 treatment-related AEs (>30% of patients) were anemia, nausea, lymphocyte count decreased, fever and diarrhea. Stable disease (SD) by RECIST1.1 was achieved in 64.3% of evaluable patients and CA125 decreased below baseline in 50% of the patients at least in one timepoint. Median PFS and OS in all patients were 105 and 280 days, respectively. In patients with SD on day 92 by RECIST1.1, median OS was 293 days and median PFS was 174 days. Tumor biopsies indicated the presence of virus and induction of T-cells in injected and non-injected lesions. Conclusions: Combination of TILT-123 and pembrolizumab is safe and appears to induce disease control in a difficult-to-treat patient population. Investigation of TILT-123, pembrolizumab and pegylated liposomal doxorubicin is ongoing in similar patients. Clinical trial information: NCT05271318 .