Patients Experienced Disease Progression Research Articles

The Diagnosis and Management of Cutaneous Metastases from Melanoma.

Melanoma is one of the deadliest skin tumors, accounting for almost 90% of skin cancer mortality. Although immune therapy and targeted therapy have dramatically changed the prognosis of metastatic melanoma, many patients experience disease progression despite the currently available new treatments. Skin metastases from melanoma represent a relatively common event as first sign of advanced disease or a sign of recurrence. Skin metastases are usually asymptomatic, although in advanced stages, they can present with ulceration, bleeding, and superinfection; furthermore, they can cause symptoms related to compression on nearby tissues. Treatments vary from simple surgery resections to topical or intralesional local injections, or a combination of these techniques with the most recent systemic immune or target therapies. New research and studies should focus on the pathogenesis and molecular mechanisms of the cutaneous metastases of melanoma in order to shed light on the mechanisms underlying the different behavior and prognoses of different patients.

Deep Learning Can Predict Bevacizumab Therapeutic Effect and Microsatellite Instability Directly from Histology in Epithelial Ovarian Cancer

Epithelial ovarian cancer (EOC) remains a significant cause of mortality among gynecologic cancers, with the majority of cases being diagnosed at an advanced stage. Before targeted therapies were available, EOC treatment relied largely on debulking surgery and platinum-based chemotherapy. Vascular endothelial growth factors have been identified as inducing tumor angiogenesis. According to several clinical trials, anti–vascular endothelial growth factor-targeted therapy with bevacizumab was effective in all phases of EOC treatment. However, there are currently no biomarkers accessible for regular therapeutic use despite the importance of patient selection. Microsatellite instability (MSI), caused by a deficiency of the DNA mismatch repair system, is a molecular abnormality observed in EOC associated with Lynch syndrome. Recent evidence suggests that angiogenesis and MSI are interconnected. Developing predictive biomarkers, which enable the selection of patients who might benefit from bevacizumab-targeted therapy or immunotherapy, is critical for realizing personalized precision medicine. In this study, we developed 2 improved deep learning methods that eliminate the need for laborious detailed image-wise annotations by pathologists and compared them with 3 state-of-the-art methods to not only predict the efficacy of bevacizumab in patients with EOC using mismatch repair protein immunostained tissue microarrays but also predict MSI status directly from histopathologic images. In prediction of therapeutic outcomes, the 2 proposed methods achieved excellent performance by obtaining the highest mean sensitivity and specificity score using MSH2 or MSH6 markers and outperformed 3 state-of-the-art deep learning methods. Moreover, both statistical analysis results, using Cox proportional hazards model analysis and Kaplan-Meier progression-free survival analysis, confirm that the 2 proposed methods successfully differentiate patients with positive therapeutic effects and lower cancer recurrence rates from patients experiencing disease progression after treatment (P < .01). In prediction of MSI status directly from histopathology images, our proposed method also achieved a decent performance in terms of mean sensitivity and specificity score even for imbalanced data sets for both internal validation using tissue microarrays from the local hospital and external validation using whole section slides from The Cancer Genome Atlas archive.

OS13.5.A MOLECULAR CHARACTERISTICS AND PROGNOSTIC BIOMARKERS OF CENTRAL NEUROCYTOMA

Abstract BACKGROUND Central neurocytomas (CN) are intraventricular brain tumors predominantly arising in young adults. Long-term prognosis is favorable in the majority of cases, whereas a considerable proportion of patients experience disease progression. Progression risk is currently assessed morphologically based on the presence of histological signs of atypia and/or an elevated ki67 proliferation index (&amp;gt;3%). The molecular profile and etiology of CN remains elusive and molecular biomarkers for risk stratification have not been identified yet. MATERIAL AND METHODS We analyzed a retrospective multi-institutional cohort of 108 CNs by genome-wide DNA methylation profiling. DNA whole exome sequencing was performed in 12 cases. Follow-up information was available for 45 patients. RESULTS The histological diagnosis of neurocytoma was epigenetically confirmed in 96 cases. 12/108 cases (11%) were assigned to another methylation class based on the v12.5 Heidelberg Brain Tumor Classifier. Median age at diagnosis was 29 years, distribution among sexes was equal. Based on morphology and immunohistochemistry, tumors were diagnosed as classical CN (n = 71), CN with increased proliferation (n = 10) and atypical CN (n = 15). In 49/72 cases (68%, NA=24), an elevated Ki67 above 3% was reported. DNA whole exome sequencing revealed no recurrent genetic alterations. Most copy number profiles were balanced (n = 87), while some cases (n = 9) showed individual chromosomal alterations (e.g. chr. +5, n = 3). Tumor recurrence was observed in 16/45 (36%, NA = 51) of cases. Median progression-free survival (PFS) after the initial diagnosis was 72 months, none of the patients died (observation time: range 3 - 141 months). In 16 cases, surgery was followed by adjuvant radiotherapy, predominantly in patients with subtotal resection (STR: n = 11, 69%; GTR: n = 5). There was no significantly different outcome between classical and atypical CNs (n = 45; median PFS 73 months vs. 26 months, p-value = 0.067) and cases with low vs. elevated Ki67 (n = 45; median PFS NA vs. 72 months, p-value = 0.44). CONCLUSION Preliminary data of our study indicate that histological diagnosis and Ki67 proliferation rate were not associated with PFS in epigenetically defined neurocytomas. Further research using clinical and molecular covariates is necessary to identify novel biomarkers to predict recurrence risk and benefit from adjuvant radiotherapy.

Predictive factors for disease progression after salvage radiation therapy in biochemical recurrent patients treated by radical prostatectomy.

Salvage radiation therapy (SRT) is standard treatment for patients after radical prostatectomy (RP). However, the optimal timing of SRT remains to be elucidated. We retrospectively reviewed 133 prostate cancer (PCa) patients who underwent SRT for biochemical recurrenceafter RP. Disease progression was defined as repeated prostate-specific antigen (PSA) level more than 0.2ng/mL, greater than the post-SRT nadir or radiographic progression. A receiver operating characteristic curve analysis was used to identify the optimal pre-SRT PSA level for predicting progression after SRT. Cox regression analyses were performed to elucidate the association between clinicopathologic characteristics and disease progression. Fifty-one PCa patients (38.4%) experienced disease progression after SRT. The optimal cutoff value of the pre-SRT PSA for predicting disease progression was 0.44ng/mL. In multivariable analysis, pre-SRT PSA >0.44ng/mL was a significant independent predictor of post-SRT disease progression [hazard ratio (HR): 2.02, P=0.02]. Although the pre-SRT PSA >0.44ng/mL did not maintain its independent association with disease progression in the multivariable analysis of patients with adverse pathology (HR: 1.63, P=0.22), PSA within 4weeks after RP as a continuous variable was significantly associated with disease progression (HR: 1.19, P=0.04). Our results highlight thatin PCa patients who undergo RP, SRT should be performed before their PSA reaches 0.44ng/mL. In patients with adverse pathology disease, a high PSA level within the 4weeks after RP might identify those who are likely to have disease progression, andthese patients might require systemic therapy.

Mitral valve aneurysms: echocardiographic characteristics, formation mechanisms, and patient outcomes.

The accurate etiology of mitral valve aneurysm (MVA) formation is not completely understood, and the most effective management approach for this condition remains controversial. We retrospectively analyzed 20 MVA patients who underwent either surgical interventions or conservative follow-ups at the Zhongnan Hospital of Wuhan University between 2017 and 2021. We examined their clinical, echocardiographic, and surgical records and tracked their long-term outcomes. Of the 20 patients, 12 were diagnosed with MVA using transthoracic echocardiography, seven required additional transesophageal echocardiography for a more definitive diagnosis, and one child was diagnosed during surgery. In all these patients, the MVAs were detected in the anterior mitral leaflet. We found that 15 patients (75%) were associated with infective endocarditis (IE), whereas the remaining patients were associated with bicuspid aortic valve and moderate aortic regurgitation (AR) and mild aortic stenosis (5%), congenital heart disease (5%), elderly calcified valvular disease (5%), mitral valve prolapse (5%), and unknown reasons (5%). Of the 17 patients who underwent hospital surgical interventions, two died due to severe cardiac events. The remaining 15 patients had successful surgeries and were followed up for an average of 13.0 ± 1.8 months. We observed an improvement in their New York Heart Association functional class and mitral regurgitation and AR degrees (P-value < 0.001). During follow-up, only one infant had an increased left ventricular end-diastolic diameter and left ventricular end-systolic diameter, whereas the remaining 14 patients had decreased values (P < 0.001). In addition, none of the three conservatively managed patients experienced disease progression during the 7-24 months of follow-up. We recommend using echocardiography as a highly sensitive method for MVA diagnosis. Although most cases are associated with IE or AR, certain cases still require further study to determine their causes. A prompt diagnosis of MVA in patients using echocardiography can aid in its timely management.

Tumor Microenvironment Landscape of NSCLC Reveals Resistance Mechanisms for Programmed Death-Ligand 1 Blockade After Chemoradiotherapy: A Multicenter Prospective Biomarker Study (WJOG11518L:SUBMARINE)

IntroductionThe PACIFIC regimen of consolidation therapy with the programmed cell death-ligand 1 inhibitor durvalumab after definitive concurrent chemoradiation therapy has become a standard of care for individuals with unresectable stage III NSCLC. Nevertheless, approximately half of the treated patients experience disease progression within 1 year, with the mechanisms of treatment resistance being poorly understood. We here performed a nationwide prospective biomarker study to explore the resistance mechanisms (WJOG11518L:SUBMARINE). MethodsA total of 135 patients with unresectable stage III NSCLC who received the PACIFIC regimen were included for comprehensive profiling of the tumor microenvironment by immunohistochemistry, transcriptome analysis, and genomic sequencing of pretreatment tumor tissue and flow cytometric analysis of circulating immune cells. Progression-free survival was compared on the basis of these biomarkers. ResultsThe importance of preexisting effective adaptive immunity in tumors was revealed for treatment benefit regardless of genomic features. We also identified CD73 expression by cancer cells as a mechanism of resistance to the PACIFIC regimen. Multivariable analysis of immunohistochemistry data with key clinical factors as covariables indicated that low CD8+ tumor-infiltrating lymphocyte density and the high CD73+ cancer cells were independently associated with poor durvalumab outcome (hazard ratios = 4.05 [95% confidence interval: 1.17–14.04] for CD8+ tumor-infiltrating lymphocytes; 4.79 [95% confidence interval: 1.12–20.58] for CD73). In addition, whole-exome sequencing of paired tumor samples suggested that cancer cells eventually escaped immune pressure as a result of neoantigen plasticity. ConclusionsOur study emphasizes the importance of functional adaptive immunity in stage III NSCLC and implicates CD73 as a promising treatment target, thus providing insight forming a basis for development of a new treatment approach in NSCLC.

Relapse Timing Is Associated With Distinct Evolutionary Dynamics in Diffuse Large B-Cell Lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is cured in more than 60% of patients, but outcomes remain poor for patients experiencing disease progression or relapse (refractory or relapsed DLBCL [rrDLBCL]), particularly if these events occur early. Although previous studies examining cohorts of rrDLBCL have identified features that are enriched at relapse, few have directly compared serial biopsies to uncover biological and evolutionary dynamics driving rrDLBCL. Here, we sought to confirm the relationship between relapse timing and outcomes after second-line (immuno)chemotherapy and determine the evolutionary dynamics that underpin that relationship. Outcomes were examined in a population-based cohort of 221 patients with DLBCL who experienced progression/relapse after frontline treatment and were treated with second-line (immuno)chemotherapy with an intention-to-treat with autologous stem-cell transplantation (ASCT). Serial DLBCL biopsies from a partially overlapping cohort of 129 patients underwent molecular characterization, including whole-genome or whole-exome sequencing in 73 patients. Outcomes to second-line therapy and ASCT are superior for late relapse (>2 years postdiagnosis) versus primary refractory (<9 months) or early relapse (9-24 months). Diagnostic and relapse biopsies were mostly concordant for cell-of-origin classification and genetics-based subgroup. Despite this concordance, the number of mutations exclusive to each biopsy increased with time since diagnosis, and late relapses shared few mutations with their diagnostic counterpart, demonstrating a branching evolution pattern. In patients with highly divergent tumors, many of the same genes acquired new mutations independently in each tumor, suggesting that the earliest mutations in a shared precursor cell constrain tumor evolution toward the same genetics-based subgroups at both diagnosis and relapse. These results suggest that late relapses commonly represent genetically distinct and chemotherapy-naïve disease and have implications for optimal patient management.

Immune Checkpoint Inhibitor Rechallenge in Renal Cell Carcinoma: Current Evidence and Future Directions.

Immune checkpoint inhibitor-based therapies represent the current standard of care in the first-line treatment of advanced renal cell carcinoma. Despite a clear benefit in survival outcomes, a considerable proportion of patients experience disease progression; prospective data about second-line therapy after first-line treatment with immune checkpoint inhibitors are limited to small phase II studies. As with other solid tumors (such as melanoma and non-small cell lung cancer), preliminary data about the clinical efficacy of rechallenge of immunotherapy (alone or in combination with other drugs) in renal cell carcinoma are beginning to emerge. Nevertheless, the role of rechallenge in immunotherapy in this setting of disease remains unclear and cannot be considered a standard of care; currently some randomized trials are exploring this approach in patients with metastatic renal cell carcinoma. The aim of our review is to summarize main evidence available in the literature concerning immunotherapy rechallenge in renal carcinoma, especially focusing on biological rationale of resistance to immune checkpoint inhibitors, on the published data of clinical efficacy and on future perspectives.

Safety and Clinical Response to Combined Immunotherapy with Autologous iNKT Cells and PD-1+CD8+ T Cells in Patients Failing First-line Chemotherapy in Stage IV Pancreatic Cancer.

A phase I clinical trial was conducted to assess the safety and feasibility of invariant natural killer T (iNKT) cells combined with PD-1+CD8+ T cells in patients with advanced pancreatic cancer and failing the first-line chemotherapy. Fifteen eligible patients were enrolled, of whom 9 received at least three cycles of treatment each. In total, 59 courses were administered. Fever was the most common adverse event, peaking at about 2-4 hours after cell infusion and reverting within 24 hours without treatment in all patients. Influenza-like reactions such as headache, myalgia, and arthralgia were also observed in 4, 4, and 3 of the patients, respectively. In addition, vomiting and dizziness were prevalent, while abdominal pain, chest pain, rash, and stuffy nose were rare adverse events, each reported in 1 patient. Side effects above grade 2 were not observed. Two patients achieved partial regression, while 1 patient experienced disease progression assessed 4 weeks after the third course. Three patients are still alive at the time of writing and have progression-free survival longer than 12 months. The overall survival time has been extended to over 12 months in 6 of the 9 patients. No constant changes of CD4+ T, B, and NK cells were recorded except for elevated CD8+ T cells after the first course. The combination of autologous iNKT cells and PD-1+CD8+ T cells was a safe therapeutic strategy against advanced pancreatic cancer. The patients exhibited a potentially promising prolonged survival time. Further study appears warranted to evaluate the efficacy of these combined cell infusions in pancreatic cancer. This trial was included in the clinical trial which was registered in ClinicalTrials.gov (ID:NCT03093688) on March 15, 2017. There is an unmet need for novel, more effective, and tolerable therapies for pancreatic cancer. Here we present a phase I clinical trial employing iNKT cells combined with PD-1+CD8+ T cells in 9 patients with advanced pancreatic cancer and failing the first-line chemotherapy. The combined immunotherapy was shown to be feasible in the enrolled patients with limited side effects and optimistic clinical responses, which could bring opportunity of therapeutic advancement.

DURTRERAD: A phase II open-label study evaluating feasibility and efficacy of durvalumab (D) and durvalumab plus tremelimumab (DT) in combination with radiotherapy (RT) in non-resectable locally advanced HPV-negative head and neck squamous cell carcinoma (LA-HNSCC).

2611 Background: Concurrent platinum-based chemo-RT is the standard treatment for LA-HNSCC, despite of limited efficacy in poor-risk patients and long-term toxicity. Targeting PD-L1 with D has activity in recurrent/metastatic (RM)-HNSCC, and the combination with the CTLA4 targeting agent T was considered to augment the immunotherapy efficacy of a chemotherapy-free regimen. Thus DURTRERAD was designed as a randomized two-arm phase II study to investigate, whether D or DT combined with RT was feasible in the patient population and a 1-year progression free survival rate of 50% was reached. Methods: The phase II study planned to enroll 60 patients in each treatment arm. Key selection criteria were patients with advanced HPV negative unresectable HNSCC planned for definitive radiotherapy. Treatments: First dose of immunotherapy 14 days prior to start of RT (70Gy over 7 weeks). D (1500mg q 3 weeks x 13) or DT (D: 1500mg q 3 weeks x 13 + T: 4 x 75 mg in weeks 5,9,13,17). Planned treatment duration was 51 weeks in both arms. Treatment was considered feasible in case of &lt;10% treatment discontinuations. An interim analysis for feasibility was planned after treatment of 6 patients per arm and a futility analysis was performed after treatment of 18 patients, resulting in premature closure of the trial. Results: Patient accrual in 4 centers in Germany from 9/2018 - 9/2020. The interim feasibility analysis of DT revealed that 5/6 patients stopped treatment due to 1 grade 5 and 1 grade 4 immune related AE and 3 non-immune related AEs, respectively. Thus, the DT arm was prematurely terminated, and only the D monotherapy arm continued. Futility analysis of D monotherapy: One of 12 patients stopped treatment due to immune related toxicity, and 7 patients experienced disease progression on treatment or died within the first year. The median PFS was 39 weeks, the 1 year PFS rate was 42%. Conclusions: Even though D was previously proven as an active agent in RM-HNSCC, and there DT was not associated with increased toxicity, DT in combination with RT was not feasible in our poor prognostic, vulnerable patient cohort of HPV negative LA-HNSCC. D monotherapy in combination with RT was well tolerated, but revealed a low level of efficacy, when administered in the trial schedule, starting 2 weeks prior to RT. Similar to results in lung cancer, start of immunotherapy after completion of radiotherapy may be of interest. Clinical trial information: NCT03624231 .

Long-term outcome for patients with advanced non‒small-cell lung cancer treated by autologous cytokine-induced killer (CIK) cell immunotherapy in combination with sintilimab plus chemotherapy: NSCLC-CCICC-002.

9096 Background: Autologous cytokine-induced killer (CIK) cell immunotherapy in combination with Sintilimab demonstrated robust antitumor activity and safety in the phase Ib CCICC-002 study (NCT03987867) of Non‒Small-Cell Lung Cancer. Long-term outcomes in patients are reported herein. Methods: Systemic therapy naïve patients received platinum-based doublet chemotherapy, Sintilimab (PD1 inhibiter), and CIK cells every 3 weeks for 4 cycles, then maintenance treatment with Sintilimab in squamous and with Sintilimab plus pemetrexed in non-squamous NSCLC until disease progression or unacceptable toxicity or two years. Kaplan-Meier estimates of overall survival (OS) and progression-free survival (PFS) were calculated. OS and PFS were based on immune-related response criteria by investigator assessment (data cut-off, January 31, 2023). Results: From May 2019 to Jan 2021, CCICC-002 enrolled 33 patients（19 squamous, 14 non-squamous NCSLC; 1 patient was excluded because the second biopsy revealed EGFR mutation) aged 46-73 years with median follow-up was 31.4 months (range, 7.6-44.4 months). Estimated 3-year OS was 51.8% in all patients; median OS was not reached (95% CI, 26.6 months-not reached) in all patients. In subgroups, median OS was 27.6 months (95% CI, 13.4 months-not reached) in squamous NCSLC and not reached (95% CI, 29.9 months-not reached) in non-squamous NCSLC, respectively. Median OS was not reached (95% CI, 27.6 months-not reached) in PD-L1 positive patients and 28.3 months (95% CI, 15.6 months-not reached) in PD-L1 negative patients, respectively. Estimated 3-year PFS rate was 27.5% and median PFS was 17.9 months (95% CI, 8.2-26.5 months) in all patients. Median PFS was 17.3 months (95% CI, 5.0-24.0 months) in squamous NCSLC and 22.4 months (95% CI, 5.7 months-not reached) in non-squamous NCSLC, respectively. Median response duration was 18.7 months (95% CI, 10.1-27.6 months). 30.3% of patients were ongoing at data cut-off, and the longest response was ongoing at 41.3 months. 1 of the 5 CMR (complete metabolic response by PET-CT) patients experienced disease progression during observation. Treatment-related AEs (TRAEs) occurred in 94.0% of patients and resulted in study discontinuation in 7.8%, and 15.2% experienced grade 3/4 TRAE. Conclusions: This long-term analysis of CCICC-002 represents the longest follow-up for CIK to date and confirms the durable antitumor activity and tolerability of CIK cells therapy in combination with Sintilimab plus chemotherapy in advanced NCSLC. Further studies are warranted to confirm these preliminary results. Clinical trial information: NCT03987867 .

A phase 2 study of modified chemotherapy plus pembrolizumab as perioperative therapy for stage II/IIIA esophageal squamous cell carcinoma.

e16081 Background: Immunotherapy plus chemotherapy has shown benefits for locally advanced esophageal squamous cell carcinoma (ESCC). However, the optimal dose, administration interval, and sequence between chemotherapy and immune checkpoint inhibitor are still elusive. In this study, we prospectively analyzed the efficacy and safety of modified chemotherapy followed by anti-programmed cell death protein 1 as perioperative therapy for stage II/IIIA ESCC. Methods: Patients with stage II/IIIA esophageal squamous cell carcinoma were eligible for this study. The patients were treated with 2 cycles of attenuated nab-paclitaxel and cisplatin (180-220mg/m2 for nab-paclitaxel, 60 mg/m2 for cisplatin) on day one and pembrolizumab (200 mg for patients weighted ≥60kg or 100 mg for patients weighted &lt;60kg) delayed on day five every 3 weeks. Subsequently, the patients received surgery four to six weeks after the second cycle treatment followed by 2 more cycles of treatments. The primary endpoints were major pathological response rate (MPR), and the second endpoints were pathological complete response rate (pCR), DFS, safety, R0 resection rate, and OS. The last follow-up time was January 31st, 2023. Results: A total of 23 patients were enrolled in our study and received whole 4 cycles of perioperative treatment. Of the whole patients, the mean age was 57.5. The median follow-up time was 19.2 months (range: 4.1-30.1). All patients underwent surgery and received R0 resection after 2 cycles of neoadjuvant attenuated chemotherapy plus delayed pembrolizumab. Down-stage was achieved in 9 of 21 (42.8%) patients with confirmed stage pre- and post- surgery. The MPR rate was 43.5%, and pCR rate was 26.1%. Up to the last follow-up, 1 patient reported death due to brain metastases, and 4 patients experienced disease progression. The median DFS and OS were not reached. The rates of one-year DFS and OS were 88.2% (15/17) and 94.4% (17/18) respectively. 21 patients (95.5%) reported treatment-related adverse events (TRAEs), most of which were grade 1-2. Two patients reported grade 3 leukopenia, and 1 patient reported grade 4 elevated transaminases and discontinued immunotherapy after surgery. The most common TRAEs were nausea (59.1%), rash (36.4%), asthenia or fatigue (31.8%), and leukopenia (27.3%). Conclusions: Our study suggested that modified nab-paclitaxel and cisplatin followed by delayed pembrolizumab as perioperative treatment was effective and well tolerated for locally advanced ESCC. Clinical trial information: ChiCTR2000034925 . [Table: see text]

Progression of atherosclerotic plaque determined by computed tomography angiography: a practical CCTA-based SCORE

Abstract Funding Acknowledgements Type of funding sources: None. Background Currently, no recommendations are endorsed by the different scientific societies on the clinical use of repeated coronary computed tomography angiography (CCTA) in patients with non-obstructive coronary artery disease (CAD). Purpose The aim of this study was to develop and validate a practical and simple CCTA risk score to predict medium-term disease progression in symptomatic patients at low-to-intermediate probability of CAD. Methods Six hundred forty-six [430 (derivation cohort) and 216 (validation cohort)] symptomatic patients with two repeated, clinically indicated CCTA scans, non-obstructive stenosis, and absence of high-risk plaque at baseline CCTA were included. Disease progression was defined as the new occurrence of obstructive CAD (stenosis≥50%) and/or high-risk plaque features at follow-up CCTA. Results In the derivation cohort a total of 167 (27%) patients experienced disease progression. Hazard ratios for disease progression derived from multivariable Cox proportional hazard model were as follows: 1.8 (95% confidence interval: 1.1–2.8) for active smoking, 1.2 (1.1–1.3) for segment involvement score, 0.45 (0.29–0.69) for calcified plaque (vs. non-calcified plaque), 2.7 (1.8–4.0) for stenosis 25–49% (vs. stenosis &amp;lt;25%), and 1.6 (1.1–2.4) for left main or proximal left anterior descending coronary artery location. The C-statistic of the derived score was 0.69 (0.63–0.74) and 0.62 (0.54–0.71) in the derivation and validation cohorts, respectively. Figure shows 2 explicative cases. Conclusions The new CCTA-based risk score is a simple and practical tool which can predict mid-term CAD progression in symptomatic patients with non-obstructive CAD.

Oral NRC-2694-A in combination with paclitaxel as therapy for recurrent and/or metastatic head and neck squamous cell carcinoma (R/M-HNSCC) that progressed on or after an immune checkpoint inhibitor (ICI): A multi-center, single-arm, phase 2 trial.

TPS6108 Background: HNSCC is the seventh most common cancer worldwide. Patients with R/M disease have limited treatment options and a poor prognosis. The USFDA has approved two ICI agents to treat R/M-HNSCC: pembrolizumab given as monotherapy or with platinum-based chemotherapy for first-line treatment of R/M disease and nivolumab (or pembrolizumab) monotherapy for treatment of disease that progressed on or after platinum-containing chemotherapy. In each setting, the ICI improved overall survival (OS); however, the absolute magnitude of the OS benefit was modest and most patients experienced disease progression within one year. There are no agents with regulatory agency-approval that are used to treat R/M-HNSCC that progressed on or after an ICI. Drugs commonly used in this setting have limited activity and include cetuximab (an epidermal growth factor receptor [EGFR] inhibitor), paclitaxel, docetaxel, a platinum, or 5-fluorouracil. Hence, there is an important unmet medical need to develop more effective treatments for R/M-HNSCC that progressed on or after an ICI. NRC-2694-A is an orally administered EGFR tyrosine kinase inhibitor, discovered and developed by NATCO Pharma Ltd., India. Based on the responses from Phase-I and Phase-II trials of NRC-2694-A in India, NAT2694US study is designed to evaluate the safety and efficacy of Oral NRC-2694-A in combination with paclitaxel in patients with R/M-HNSCC, who progressed on or after ICI therapy. Methods: NAT2694US is a multi-center, single-arm, Phase 2 study (NCI ClinicalTrials.gov Identifier: NCT05283226) with an estimated enrolment of 46 patients. Eligible patients are &gt;18 years of age with an ECOG performance status of 0-2 and histologically confirmed unresectable, measurable R/M-HNSCC (of the oral cavity, oropharynx, hypopharynx, and larynx), radiological disease progression on or after ICI therapy, and no prior taxane for R/M disease. Patients receive 300 mg of oral NRC-2694-A once daily and 175 mg/m² of paclitaxel IV infusion once every 21-day cycle for 6 cycles or more. Tumor response assessment with CT/MRI scans is performed every 6 weeks. The primary endpoint is objective response rate (ORR) using RECIST v1.1 performed by the investigator. The study uses a Simon’s 2-stage design with ORR H0: 30% and H1: 50% using a one-sided Type-1 error rate = 0.05). In Stage 1, fifteen patients are to be enrolled for tumor assessment. If objective response is observed in at least 6 of these 15 patients, then Stage 2 would be opened with the inclusion of 31 additional patients, leading to a total enrolment of 46 patients. The observation of objective response in at least 19 of 46 patients would reject the null hypothesis in favour of the alternative hypothesis. Enrolment to the NAT2694US trial is currently ongoing in USA. Clinical trial information: NCT05283226 .

A combination of niraparib plus anlotinib in patients with platinum-resistant ovarian clear cell carcinoma: Results of a single-arm phase II study (CC-ANNIE study).

e17552 Background: Ovarian clear cell carcinoma (OCCC) is a histological subtype of epithelial ovarian cancer with distinct biological and molecular characteristics. Patients with platinum-resistant OCCC have a poor prognosis and their treatment represents a significant unmet medical need. Studies have suggested potential efficacy of targeting DNA damage response pathways and inhibition of angiogenesis in OCCC. We hypothesised that patients with platinum-resistant OCCC might benefit from a combination of the poly (ADP-ribose) polymerase (PARP) inhibitor niraparib and the anti-angiogenic agent anlotinib. Methods: This was a phase II, single-arm, two-stage study with a Simon’s two-stage optimal design. The trial could continue to stage 2 if ≥1 responses were observed in the first 6 patients. Eligible patients had histologically confirmed OCCC that was platinum resistant, defined as progression within 6 months after their most recent platinum-based chemotherapy. Use of prior bevacizumab was permitted but prior PARP inhibitor or tyrosine kinase inhibitor treatments were not. Patients received niraparib (300 mg/day or 200 mg/day [baseline body weight &lt; 77 kg, platelet count &lt; 150,000/μL], orally) plus anlotinib (10 mg/day, orally, 2 weeks on and 1 week off, every 3 weeks) until disease progression or intolerable toxicity. The primary endpoint was objective response rate (ORR) assessed by investigators according to the RECIST V.1.1. Secondary endpoints included disease control rate (DCR), time to response (TOR), duration of response (DOR), safety and investigator-assessed progression-free survival (PFS) and overall survival (OS). Results: Between January 2022 and August 2022, 6 eligible patients were enrolled and included in the analyses. The median duration of treatment was 9.8 (range, 6.5 to 19.0) weeks. Of the 6 patients, 0 patients (0%) achieved an objective response, resulting in a confirmed ORR of 0%. The DCR was 50% (0 complete response, 0 partial response, 3 stable disease). With a median follow-up time of 7.5 (range, 3.5 to 10.0) months, all patients experienced disease progression, with a median PFS of 12.0 (95% confidence interval [CI], 3.6 to 20.4) weeks. Frequent treatment-related adverse events (AEs) included hypertension (33.3%), thrombocytopenia (33.3%), and hand-foot syndrome (16.6%). Conclusions: The phase 2 CC-ANNIE study did not meet the primary efficacy endpoint. The combination of niraparib and anlotinib did not show activity in patients with platinum-resistant OCCC. Clinical trial information: NCT05130515 .

Timing of disease progression and impact on survival in Swedish mantle cell lymphoma patients—a novel illness‐death model study

Background: In mantle cell lymphoma (MCL), time to relapse is a critical factor, and patients experiencing disease progression within 24 months from treatment start (POD24) have inferior survival. However, the cut-off at 24 months is arbitrary and potentially overly simplified. We aimed to quantify the impact of the timing of disease progression on overall survival, stratified by the most common first-line treatment concepts (Nordic-MCL, R-Bendamustin, and R-CHOP). Methods: Using the population-based Swedish lymphoma register, we identified all systemically treated MCL patients diagnosed between 2006 and 2018. We supplemented this with information on progression and relapse from medical chart reviews through 2022. Patients were categorized based on first-line treatment (Nordic MCL regimen, R-Bendamustin, R-CHOP, and others). POD was defined as a lack of response to primary therapy (progressive disease [PD]) or an initial response followed by a relapse. To assess the impact of POD timing on survival, we used an illness-death model with transition rates estimated using flexible parametric survival models to predict the five-year overall survival (OS) conditional on either being progression-free or experiencing POD as a smooth function of time since primary treatment. Results: A total of 1193 patients receiving systemic treatment were included. The median age at diagnosis was 70 years, and patients were followed for a median of 4 years (range 0–16 years, alive patients, six years). 33% of patients received R-Bendamustin (n = 387, median age 75 years), 30% received the Nordic MCL regimen (n = 351, median age 62 years), and 23% received R-CHOP (n = 276, median age 72 years). Almost half of the patients (48%, n = 571) experienced POD during follow-up. The five-year OS from treatment start was 47%, and progression-free survival was 32%. Among patients treated in the first line with either R-Bendamustin or the Nordic MCL protocol, those with a POD had substantially lower 5-year OS compared to patients who remained progression-free, also for POD occurring up to six years after primary treatment. For patients treated with R-CHOP, the impact of POD was largest if it occurred within 2–3 years after first-line therapy. Keyword: Aggressive B-cell non-Hodgkin lymphoma No conflicts of interests pertinent to the abstract.

Use of real-world evidence to benchmark clinical trial results: A case study in von Hippel-Lindau (VHL) disease.

4531 Background: Data from a natural history study can be used to benchmark results from single arm trials with comparable ascertainment of exposures and outcomes. Despite limitations of externally controlled trials, natural history study data can provide important information, especially when clinical trial results provide compelling evidence of change in the established progression of disease. Such results could include partial or complete response for patients receiving drug in a disease where spontaneous regression is not observed. The aim was to conduct a natural history study to benchmark results of a Phase 2 single-arm trial (LITESPARK [LS]-004) for a new HIF-2a inhibitor (belzutifan) using comparable RECIST-based study endpoints. After a median follow-up of 37.8 months, the objective response rate (ORR) for patients with renal cell carcinoma (RCC) in LS-004 was 64.0% (95% CI: 50.6 to 75.8). Methods: A study of existing electronic medical records was conducted for VHL patients with disease-associated RCC undergoing active surveillance at the US National Cancer Institute. VHL patients with ≥1 cm solid RCC, confirmed by independent review, were followed until death or last encounter. Additional LS-004 exclusion criteria were applied to define the natural history study cohort: ≥3.0 cm tumor and procedure performed within 60 days, prior systemic oncologic therapy, and metastasis prior the index date. The index date was the date of the earliest radiology report with measurable disease during the study window (July 2004 - June 2020). An analysis of radiographic outcomes was performed according to RECIST V1.1 for patients with ≥3 scans prior to last encounter, death, or renal therapy using an imaging charter similar to LS-004. Adjudication of best overall response (BOR) was performed if there was discordance between assessments by the two independent radiologists. Results: The natural history study population included 244 VHL patients (100% genetic confirmation; 55% male; median age: 41 years, median follow-up: 10 years). The median size of largest RCC tumor diameter at baseline was 2.5 cm (IQR: 1.9, 3.1), and 76% of patients had ≥1 surgery after the index date. Among patients with ≥3 scans (n=178/244), the confirmed real-world ORR within 5 years of follow-up was 1.8% (95% CI: 0.4%, 5.2%), all with partial response. The real-world BOR was progressive disease and stable disease for 22% and 74% of patients, respectively. Within 5 years, 80% of patients had disease progression. Conclusions: Using similar trial endpoints, this natural history study demonstrates that spontaneous regression of RCC solid tumors is unlikely for patients with VHL undergoing active surveillance in the absence of therapy, and most patients experience disease progression. These findings help contextualize the antitumor activity and efficacy of belzutifan in the treatment of patients with VHL disease-associated RCC.

PERIPHERAL T CELL LYMPHOMA (PTCL) AND TREATMENT OUT‐COME SINGLE CENTRE RETROSPECTIVE STUDY

Introduction: Mature T-cell lymphomas comprise 15% to 20% of all aggressive non-Hodgkin lymphomas (NHL) and 5% to 10% of all NHLs. Compared to their B-cell counterparts, PTCLs remain largely unexplored and the optimal treatment ill-defined due to disease rarity and biological heterogeneity. CHOP-type chemotherapy has been the mainstay of therapy for PTCL with some exception in NK/T cell lymphoma, but with the notable exception of ALK-positive ALCL, outcome has been uniformly disappointing3-5. For the main nodal PTCLs (AITL, PTCL-NOS, and ALK− ALCL), the 2- and 5-year progression-free survival (PFS) is approximately 35% and 25%, and the 2- and 5-year overall survival (OS) is 45% and 35%, respectively6-8. Progressions/relapses of PTCLs are frequent (approximately 70% of patients), occur most often early (during the first year after initial diagnosis), and have a poor outcome, with a median OS of approximately 6 months 9-11. Methods: Patients were identified through pathology database and informed consent obtained. Patient’s demographic characteristics, clinical features, initial / subsequent treatment and survival were analysed. Data cut-off was 31/01/2023. Results: Twenty-seven patients were included in this study, with male predominance (70%), the median age was 69 years (Rang 17-84 years) and the majority with advanced disease (67%). The common histology subtype was ALCL in 10 patients (37%) (Alk-Neg =7 & Alk-Pos =3) followed by PTCL in 9 patients (33%). While EATL, AITL subtypes were reported in 5(18%), 3(11%) patients respectively. Chemotherapy was the main initial treatment modality in our cohort (26 patients / 96%) (CHOP based /19 patients, CHOEP in 4 patients, and GDP based /3 patients) and 1patient (4%) was not suitable for any therapy. Complete response (CR) was achieved in 16 patients (59%) and 8 patients (30%) subsequently relapsed, while other treated patients (10/37%) experienced disease progression. At relapse GDP and Brentuximab Vedotin therapy were used for in 8 and 3 patients respectively resulted in CR in 2 patients and progression disease in the reminder. Autologous bone marrow transplant consolidation was used in 3 patients (10%), and radiotherapy was used in 5patients (15%). At time of study data analysis (31/01/2023), 8 patients (30%) were still alive and 19 patient (70%) had died mostly lymphoma related death (18 patients). Keywords: Aggressive T-cell non-Hodgkin lymphoma, Pathology and Classification of Lymphomas No conflicts of interests pertinent to the abstract.

Identification of prognostic biomarkers in plasma of patients with metastatic urothelial carcinoma (mUC).

e16564 Background: Performance status and visceral metastasis before first-line chemotherapy based on cisplatin (CDDP) predict survival of subjects with mUC. The objective of this study was to explore the prognostic value of selected plasma biomarkers. Methods: We have evaluated the samples from 86 mUC subjects (64.0% males). Performance status of ECOG 2 and visceral metastasis were present in 39.5% and 50.0% cases, respectively. The MILLIPLEX panels were used for determination of 51 biomarkers in plasma taken from patients before systemic therapy initiation. Study population was dichotomized into high and low groups by median for each parameter. Progression-free survival (PFS) and overall survival (OS) were estimated by the Kaplan-Meier method and compared with the log-rank test. Multivariate analysis was carried out by the Cox regression model. Results: At median follow-up of 8.6 months (6.4-10.1), 95.3% of patients experienced disease progression and died. Better PFS was associated with low levels of nine biomarkers: IL-1RA (HR 0.65, P=0.0425), IL-6 (HR 0.52, P=0.002), IL-8 (HR 0.46, P=0.0002), IL-10 (HR 0.49, P=0.0004), IL-15 (HR 0.61, P=0.0198), IL-22 (HR 0.45, P=0.0043), MCP-1 (HR 0.59, P=0.0147), M-CSF (HR 0.59, P=0.0119), and VEGF-A (HR 0.64, P=0.0392). OS was significantly better in patients with low levels of G-CSF (HR 0.42, P=0.047), IL-1RA (HR 0.63, P=0.0314), IL-2 (HR 0.61, P=0.0249), IL-6 (HR 0.47, P=0.004), IL-8 (HR 0.44, P=0.0001), IL-10 (HR 0.43, P&lt;0.0001), IL-15 (HR 0.53, P=0.0026), IL-22 (HR 0.47, P=0.0065), IL-27 (HR 0.63, P=0.0343), MCP-1 (HR 0.59, P=0.0134), M-CSF (HR 0.55, P=0.0042), TNFα (HR 0.53, P=0.0024), and VEGF-A (HR 0.59, P=0.0124). The independent prognostic values of IL-6, IL-10, MCP-1, M-CSF, and TNFα were confirmed in a multivariate analysis. Conclusions: In this study, we have proved that selected plasma biomarkers may have a prognostic value in mUC patients. Further research is required to understand their role as the biomarkers, but also potentially treatable pathogenic factors for mUC development. This research was funded by grant of the Integrated Infrastructure Operational Program, ITMS: 313011AFG5, co-financed by the European Regional Development Fund &amp; OncoReSearch, Slovakia.

Response to subsequent platinum-based chemotherapy post PARP inhibitor in recurrent epithelial ovarian cancer.

5578 Background: Maintenance therapy with PARP inhibitors (PARPi) can increase progression free survival (PFS) for recurrent or metastatic platinum-sensitive epithelial ovarian cancer (EOC). Little is known about disease trajectory following treatment with these agents, though some evidence suggests a decreased response to subsequent platinum-based chemotherapy. This retrospective cohort study assessed real-world response rates to platinum-based chemotherapy for recurrent high grade EOC following treatment with a PARPi. Methods: All patients prescribed a PARPi as maintenance therapy for recurrent or metastatic EOC at the Ottawa Regional Cancer Center (ORCC) from September 2017 to May 2022 were included. PFS following penultimate therapy (line of therapy preceding PARPi initiation) as well as the PFS following subsequent platinum-based chemotherapy in patients with disease progression more than 6 months after penultimate therapy were calculated. Incidence of platinum resistance in patients with disease progression following PARPi therapy was determined. Results: 91 patients were included in the analysis including 54 patients on niraparib and 36 patients on olaparib. Follow-up after initiation of PARPi ranged from 4.6 months to 62.0 months with a median of 16.3 months. 54 (59.3%) of patients experienced disease progression after initiation of PARPi therapy, including 10 (11.0%) who progressed within 6 months of their penultimate therapy. Of the 44 patients who experienced disease progression more than 6 months following penultimate therapy, 32 (72.7%) were rechallenged with platinum-based chemotherapy. Of these, 16 (50.0%) experienced further disease progression with 14 (43.8%) progressing within 6 months of their platinum rechallenge. Median PFS following platinum rechallenge was 4.4 months (from 0.8 months to 34.9 months), significantly lower than previous reports. Conclusions: Patients who experienced disease progression following PARPi therapy showed a poor response to subsequent platinum-based chemotherapy, even when progression occurred more than 6 months after completion of their penultimate platinum-based chemotherapy. This supports the theory that PARPi resistance may be a surrogate for platinum resistance and raises concern for possible contribution of PARPi in the induction of platinum resistance in recurrent EOC.