Disease Progression In Patients Research Articles

Plasma lipidomics profiling in predicting the chemo-immunotherapy response in advanced non-small cell lung cancer.

Advanced non-small cell lung cancer (NSCLC) presents significant treatment challenges, with chemo-immunotherapy emerging as a promising approach. This study explores the potential of lipidomic biomarkers to predict responses to chemo-immunotherapy in advanced non-small cell lung cancer (NSCLC) patients. A prospective analysis was conducted on 68 NSCLC patients undergoing chemo-immunotherapy, divided into disease control (DC) and progressive disease (PD) groups based on treatment response. Pre-treatment serum samples were subjected to lipidomic profiling using liquid chromatography-mass spectrometry (LC-MS). Key predictive lipids (biomarkers) were identified through projection to latent structures discriminant analysis. A biomarker combined model and a clinical combined model were developed to enhance the prediction accuracy. The predictive performances of the clinical combined model in different histological subtypes were also performed. Six lipids were identified as the key lipids. The expression levels of PC(16:0/18:2), PC(16:0/18:1), PC(16:0/18:0), CE(20:1), and PC(14:0/18:1) were significantly up-regulated. While the expression level of TAG56:7-FA18:2 was significantly down-regulated. The biomarker combined model demonstrated a receiver operating characteristic (ROC) curve of 0.85 (95% CI: 0.75-0.95) in differentiating the PD from the DC. The clinical combined model exhibited an AUC of 0.87 (95% CI: 0.79-0.96) in differentiating the PD from the DC. The clinical combined model demonstrated good discriminability in DC and PD patients in different histological subtypes with the AUC of 0.78 (95% CI: 0.62-0.96), 0.79 (95% CI: 0.64-0.94), and 0.86 (95% CI: 0.52-1.00) in squamous cell carcinoma, large cell carcinoma, and adenocarcinoma subtype, respectively. Pathway analysis revealed the metabolisms of linoleic acid, alpha-linolenic acid, glycerolipid, arachidonic acid, glycerophospholipid, and steroid were implicated in the chemo-immunotherapy response in advanced NSCLC. Lipidomic profiling presents a highly accurate method for predicting responses to chemo-immunotherapy in patients with advanced NSCLC, offering a potential avenue for personalized treatment strategies.

First-in-class PD-1/IL-2 bispecific antibody fusion protein IBI363 in patients with advanced melanoma: Safety and efficacy results from a phase I study.

9562 Background: Despite great success of immunotherapy (IO) in advanced melanoma, there remains unmet clinical needs for IO resistant and cold tumors. IBI363 is a first-in-class PD-1/IL-2α-bias bispecific antibody fusion protein which could block PD-1 checkpoint and activate α-bias IL-2 to rejuvenate exhausted tumor-specific T cells. Herein, we report updated results from the phase I study to evaluate safety and efficacy of IBI363 in pts with advanced melanoma. Methods: Eligible pts with advanced melanoma who failed or intolerant to standard therapy were enrolled to receive IBI363 intravenously at different dose levels ranging from 100-2000 μg/kg QW/Q2W/Q3W. Primary objective of the study was safety. Secondary objective was efficacy assessed by investigator per RECIST v1.1 including objective response rate (ORR), disease control rate (DCR), duration of response (DoR) and progression free survival (PFS). Results: As of January 11, 2024, 67 pts were enrolled (females: 55.2%, median age: 59.0 years, ECOG PS 1: 74.6%, prior treatment lines ≥2: 59.7%, prior IO: 89.6%). There were 17 pts with cutaneous melanoma, 22 pts with acral melanoma, 25 pts with mucosal melanoma and 3 pts with unknown primary melanoma. The median treatment duration was 12.0 weeks (range: 2.0-43.6) with 38 pts (56.7%) still on treatment. Most comment reason for end of treatment was disease progression in 25 pts (37.3%). All pts were included in safety analysis. Treatment-emergent adverse events (TEAEs) occurred in 63 (94.0%) pts. Grade ≥3 TEAEs and TRAEs occurred in 16 (23.9%) and 12 (17.9%) pts. Common TEAEs (≥20%) were arthralgia (34.3%), hyperthyroidism (29.9%), anemia (25.4%). TEAE leading to treatment discontinuation occurred in 1 (1.5%) pt.No pts had TEAEs leading to death. Pts with at least 1 post-baseline tumor assessment were included in efficacy evaluable set. In all evaluable pts (n=57), the best overall response was partial response (PR) in 16 pts, stable disease (SD) in 25 pts and progressive disease (PD) in 16 pts. The overall ORR was 28.1% (95%CI: 17.0-41.5%) and DCR was 71.9% (95%CI: 58.5-83.0). In pts had prior IO (n=52), ORR was 21.2% (95%CI: 11.1-34.7) and DCR was 67.3% (95%CI: 52.9-79.7). In 1 mg/kg Q2W pts had prior IO (n=25), ORR was 32.0% (95%CI: 14.9-53.5) and DCR was 80.0% (95%CI: 59.3-93.2). The DoR and PFS data were immature at the time of analysis. Biomarker analysis in baseline tumor region observed significantly higher CD8 T cell infiltration (measured by cell positivity and density) in PR/SD patients than PD patients (p<0.05). More updated data on safety and efficacy will be presented at the meeting. Conclusions: In pts with advanced melanoma, IBI363 showed encouraging efficacy in different tumor subtypes and in pts wit prior IO. The safety profiles were acceptable and manageable. Further clinical development of IBI363 in melanoma are ongoing both in China and overseas. Clinical trial information: NCT05460767 .

Association of complementing circulating tumor DNA and circulating tumor cells load on stable and progressive disease in treated patients.

3062 Background: Post curative-intent surgery and therapy, the presence of circulating tumor DNA (ctDNA) load represents Minimal Residual Disease (MRD). Conversely, presence of Circulating Tumor Cells (CTCs) in I-II cancer stage or even in disease free survival (DFS) patients indicates occult Cellular Residual Disease (CRD) with undetectable micro-metastasis. Thus these complementary biomarkers undergoing treatment are the indicators of non-responsiveness outcome suggesting the treatment modifications. Methods: Retrospectively, we monitored a cohort of 46 cancer patients for MRD using ctDNA and CTCs- treated or undergoing treatment (e.g. lung, breast, colon, HNC (n = 14, 7, 6, 4, respectively). OncoMonitor test detected single nucleotide variation (SNVs), small insertions and deletions (INDELs), copy number variations (CNVs), and translocations (fusions). Libraries were prepared using a hybridization-capture method covering 1000 targets with mean sequencing depth 5000X on Illumina Nextseq 2000 in a pair-end mode (150 x2). Variant calling was performed using a proprietary bioinformatics pipeline iCare. CTCs were isolated using the OncoDiscover platform possessing anti EpCAM antibody based immunomagnetic system per 1.5 mL blood. CTCs were confirmed with CK18+, PD-L1 and CD45 using a motorized fluorescence microscope. Results: From ctDNA, 47.82% (n = 22) of patients identified with at least 1 actionable genomic finding. 13.04% (n = 6) patients showed EGFR driver mutations. Also, 19.56% (n = 9) patients were identified with either EGFR driver/KRAS/PI3K passenger mutations with 4.34% (n = 2) identified with ALK-EML4 fusion. The average ctDNA load obtained in patients with progressive disease (n = 26) was 8.2 molecules per 1mL of plasma. At least 1 CTC was detected in 61.53% (n = 16) of progressive disease patients with the highest of 4 CTCs identified in 7.69% (n = 2) of patients. Only 30% (n = 6) of patients with stable disease were identified with at least 1 genomic finding from a total of 20 patients upon ctDNA analysis with an average ctDNA load of 2.2 molecules per 1mL of plasma. Patients with clinically progressive disease showed ctDNA load ~4 fold higher than in patients with stable disease upon treatment. No patients were identified with 4 CTC in the stable disease cohort as opposed to 7.69% in progressive disease patients upon treatment. Conclusions: We observed ctDNA and CTCs complementing MRD status, even post curative-intent surgery and therapy with prophecy for such patients likely to progress. Our findings are strongly indicative of positive correlation between ctDNA load, number of CTC detected, and disease progression from radiological findings for practical and clinical decisions. More studies in this direction are imperative to attain the follow ups for better clinical outcome.

METRADS-P vs. RECIST/PCWG criteria to detect disease progression in metastatic castration-resistant prostate cancer (mCRPC).

5070 Background: Radiographic Progression-free survival (rPFS) derived from Computer Tomography (CT) and Bone Scan (BS) using Prostate Cancer Working Group (PCWG) criteria is utilized as an intermediate clinical endpoint for overall survival (OS) benefit in mCRPC. Whole Body MRI (WBMRI) is emerging as a potentially superior response biomarker, allowing a more accurate assessment of bone marrow and soft tissue disease. We have now compared the performance of previously reported WBMRI criteria (MET-RADS-P) with PCWG criteria as a response biomarker for mCRPC, and this with overall survival (OS). Methods: We retrospectively analysed imaging data from mCRPC patients that 1) discontinued therapy based on PCWG criteria; 2) had contemporaneous WBMRI, CT, and BS at time-points according to PCWG. Soft tissue lesions were classified according to RECIST1.1 both on CT and WBMRI; bone lesions were classified on BS using PCWG criteria as non-PD (non-progressive disease), PD-U (PD unknown) & PD (progressive disease) and on WBMRI using MET-RADS-P as non–PD (subclassified as partial response-PR & stable disease-SD) & PD, for each imaging time-point. We calculated % agreement between MET-RADS-P and PCWG across all time-points. Median PFS as per PCWG (rPFS) and METRADS-P (mPFS) and median OS according to METRADS-P response at 12 weeks was estimated by Kaplan Meier. Results: 100 cases (91 subjects received 100 lines of treatment, 100 baseline imaging & 216 follow-up imaging assessments). For soft tissue disease, RECIST 1.1 and WBMRI assessments were concordant at 201 of 216 time-points (93.1%); the discordance was related to superior detection of local disease and liver metastases on WBMRI. Bone metastases assessments showed agreement in 37.5% time-points, with details as follows (% over BS category): 1) Negative BS (13 time-points): WBMRI 69.2% negative, 15.4% PR, 15.4% as PD; 2) Non-PD BS (154 time-points): WBMRI non-PD 51% (34.4% PR, 17.5% SD), 48.1% PD; 3) PD-U BS (40 time-points): WBMRI PD 90%; Non-PD 10% (1pt FLARE & 3pt with subsequent concordant PD). At time of PD-U, 30 out of 40 pt (75%) discontinued treatment due to RECIST PD (24/40) & clinical progression (6/40). 4) PD confirmatory BS (9 time-points) : WBMRI 100%PD. Median rPFS by PCWG was 4.9 months (m) (95%CI: 3.8-5.7); the median mPFS by MET-RADS-P was 2.8 months (2.6-3.9), with overall progression rate of 70% and 94% respectively. Non-PD by WBMRI at 12-weeks associated with longer OS when compared with PD by MRI (median OS: 17.9m (14.2-22.6) vs 14.4m (9.6-17.0) (crude log-rank test 0.0059). Conclusions: Regarding soft-tissue disease, MET-RADS-P detects progression earlier than RECIST in 4.2% time-points, while for bone metastases it detects progression earlier than PCWG at 51.9% of timepoints. WBMRI can better classify BS non-PD patients in PR, SD and PD. Response evaluation based on WBMRI is a prognostic factor in mCRPC.

Long-term remission and survival in patients with relapsed or refractory multiple myeloma after treatment with LCAR-B38M CAR T cells: 5-year follow-up of the LEGEND-2 trial

BackgroundThe autologous anti–B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T-cell therapy LCAR-B38M has been approved for the treatment of relapsed and refractory multiple myeloma in many countries across the world under the name ciltacabtagene autoleucel. LEGEND-2 was the first-in-human trial of LCAR-B38M and yielded deep and durable therapeutic responses. Here, we reported the outcomes in LEGEND-2 after a minimal 5-year follow-up.MethodsParticipants received an average dose of 0.5 × 106 cells/kg LCAR-B38M in split or single unfractionated infusions after cyclophosphamide-based lymphodepletion therapy. Investigator-assessed response, survival, safety and pharmacokinetics were evaluated.ResultsSeventy-four participants enrolled and had a median follow-up of 65.4 months. The 5-year progression-free survival (PFS) and overall survival (OS) rates were 21.0% and 49.1%, with progressive flattening of the survival curves over time. Patients with complete response (CR) had longer PFS and OS, with 5-year rates of 28.4% and 65.7%, respectively. Twelve patients (16.2%) remained relapse-free irrespective of baseline high-risk cytogenetic abnormality and all had normal humoral immunity reconstituted. An ongoing CR closely correlated with several prognostic baseline indices including favorable performance status, immunoglobulin G subtype, and absence of extramedullary disease, as well as a combination cyclophosphamide and fludarabine preconditioning strategy. Sixty-two (83.8%) suffered progressive disease (PD) and/or death; however, 61.1% of PD patients could well respond to subsequent therapies, among which, the proteasome inhibitor-based regimens benefited the most. Concerning the safety, hematologic and hepatic function recovery were not significantly different between non-PD and PD/Death groups. A low rate of second primary malignancy (5.4%) and no severe virus infection were observed. The patients who tested positive for COVID-19 merely presented self-limiting symptoms. In addition, a sustainable CAR T population of one case with persistent remission was delineated, which was enriched with indolently proliferative and lowly cytotoxic CD4/CD8 double-negative functional T lymphocytes.ConclusionsThese data, representing the longest follow-up of BCMA-redirected CAR T-cell therapy to date, demonstrate long-term remission and survival with LCAR-B38M for advanced myeloma.Trial registrationLEGEND-2 was registered under the trial numbers NCT03090659, ChiCTRONH-17012285.

Shoulder Proprioception: A Review.

The purpose of this review is to provide a comprehensive resource for shoulder proprioception assessment and its integration into clinical decision making as well as targeted rehabilitation protocols. Data for this review were acquired from peer-reviewed articles from computerized online databases, namely PubMed and Medline, published between 1906 and 2021. The development of digital/smart phone goniometers can improve shoulder joint range of motion (ROM) measurements and demonstrate comparable measurement accuracy to the universal standard goniometer. The inclinometer offers a portable and cost-effective method for measuring shoulder joint angles and arcs of motion in the vertical plane. Two types of dynamometers, the computerized isokinetic machine and the handheld hydraulic dynamometer, are reliable tools for objective shoulder rotator cuff strength assessment. Motion analysis systems are highly advanced modalities that create three-dimensional models of motion arcs using a series of cameras and reflective beads, offering unparalleled precision in shoulder proprioception measurement; however, they require time-consuming calibration and skilled operators. Advancements in wearable devices and compact mobile technology such as iPhone applications may make three-dimensional motion analysis more affordable and practical for outpatient settings in the future. The complex interplay between proprioception and shoulder dysfunction is not fully understood; however, shoulder proprioception can likely both contribute to and be caused by shoulder pathology. In patients with rotator cuff tears, glenohumeral osteoarthritis, and shoulder instability, clinicians can track proprioception to understand a patient's disease progression or response to treatment. Finally, rehabilitation programs targeting shoulder proprioception have shown promising initial results in restoring function and returning athletes to play.

Extended Follow-up and Resistance Mutations in CLL Patients Treated with Acalabrutinib

Background: Covalent Bruton tyrosine kinase inhibitor (cBTKi) is a standard treatment for chronic lymphocytic leukemia (CLL). Understanding of acquired resistance to cBTKi therapy has largely come from data on patients (pts) treated with the first-in-class cBTKi ibrutinib. Mutations in BTK C481 and to a lesser extent PLCG2 are frequently detected in ibrutinib-treated pts at the time of progressive disease (PD). In contrast, much less is known about genetic mechanisms of drug resistance in pts treated with next generation cBTKi acalabrutinib and zanubrutinib. A recent study identified 3 pts with BTK C481 mutations and no pts with PLCG2 mutations among 8 acalabrutinib-treated pts with progressive disease (PD) (Black, et al. Blood 2022). A second study found a kinase-dead BTK L528W mutation in 7/13 zanubrutinib-treated pts (Blombery, et al. Blood Adv 2022). Although cBTKi share the same mechanism of action by binding to BTK C481, the latter report discloses differences in clonal selection and underscores the need for further investigation in pts treated with next generation cBTKi. In a phase 2 study of acalabrutinib in pts with treatment naïve (TN) CLL or small lymphocytic lymphoma (SLL) with 17p deletion, or TP53 or NOTCH1 mutation, or relapsed/refractory (R/R) CLL/SLL regardless of cytogenetics or somatic mutations (Sun, et al. Blood 2020), we sought to understand clonal evolution during treatment. Methods: Peripheral blood mononuclear cells (PBMCs) were collected from 48 pts at baseline, after 6 months, then annually on treatment until PD. Current analysis includes 14 PD pts [excluding 3 Richter transformation (RT) pts] comprising 10 R/R and 4 TN CLL pts. Additionally, paired baseline and PD bone marrow (BM) from 6 pts and lymph node (LN) samples from 2 pts were included. Targeted next-generation sequencing of ~700 recurrently mutated genes in hematological malignancies (Collins, et al. Leuk Lymphoma. 2021) was performed using DNA isolated from CD19 + enriched cryopreserved PBMCs and BM aspirates, as well as fresh-frozen core LN biopsies. Filtered variants in putative CLL driver genes (Knisbacher, et al. Nat Genet. 2022) with variant allele frequencies (VAF) ≥1% for BTK and PLCG2, ≥5% for variants with known oncological significance, and ≥7.5% for all other variants were included in downstream analysis. Results: After a median follow-up of 6.5 years (IQR 2.9-6.3), 23/48 (48%) pts developed PD (20 CLL, 3 RT). PD occurred in 17/32 (53%) R/R pts and 6/16 (38%) TN pts. Median progression-free survival was reached at 6.0 years. Best response was complete remission in 2/20 (10%) pts and partial remission in 18/20 (90%) pts with CLL PD. IGHV was unmutated in all but one PD patient. At baseline, 34 CLL driver genes were mutated in 41/45 pts (91%; excluding 3 RT pts) with most mutations in NOTCH1, TP53, ATM, SF3B1, BIRC3, and NFKBIE. During acalabrutinib treatment but before PD, 14/45 pts (31%; 8 R/R and 6 TN) acquired mutations in 11 driver genes, most commonly in BRAF (n=4), CREBBP (n=4), and KMT2D (n=2). At the time of PD, 11/14 pts (79%) had newly acquired mutations in 4 genes, predominantly BTK (n=6) and PLCG2 (n=4). BTK C481 mutations (VAF 2-42%) were detected in 6/14 (43%; 4 R/R and 2 TN) pts and T474I mutation (VAF 4-46%) in 3/14 (21%; 1 R/R and 2 TN) pts. Paired BM samples in 2 pts and LN samples in 2 pts showed the same BTK mutations as PBMCs with similar VAFs. PLCG2 mutations (VAF 1-8%) were found in 4/14 (29%; 2 R/R and 2 TN) pts. BTK C481 co-occurred with BTK T474I in 3 pts, but on different sequencing reads suggesting independent subclones, and with a PLCG2 mutation in 1 pt. There have been no pts with BTK L528 mutations. In conclusion, mutations in BTK and PLCG2 are the predominant resistance mechanism to acalabrutinib. Among BTK mutations, C481 was the most common. All T474I mutations co-occurred with C481.

Clinical Characteristics of Long-Term Survivors Treated with BCMA CAR T Cell

Introduction Anti-BCMA(B-cell maturation antigen) CAR-T therapy, a novel and efficacious method for treating relapsed/refractory multiple myeloma (RRMM), has been approved and applied in clinics. Here, we report the survival analysis and clinical characteristics associated with long-term survivors (complete response at 18 months) after CAR-T cell therapy. Methods Between 1 January 2018 and 1 February 2023, 22 consecutive patients with relapsed/refractory MM were enrolled in a clinical trial of BCMA CAR T cells (registered at www.clinicaltrials.gov as #NCT04500431). This study was approved by the Tongji Hospital of Tongji University Ethics Committee, and written informed consent was provided by each patient. They all were treated with a single infusion of CAR-T cells. FC chemotherapy regimen was administered before transfusion. The median number of CAR-T cells transfused was 5.0 (range 4.0-6.6) ×10 6/kg. Long-term efficacy and related clinical characteristics were evaluated. Results In the 22 patients treated, the overall response rate was 77% (17 of 22). With a median follow-up of 24 months (range, 4-52), the median PFS were 17 months. The adverse events within 30 days after infusion were well tolerated. Toxic hematologic effects were the most common grade ≥3 events, including neutropenia (68%), anemia (54%), and thrombocytopenia (36%).Only 1 patient experienced grade 1 neurologic toxicity.No patients experienced severe infection within 30 days after infusion. Detailed patient baseline characteristics are described in Tables 1. During follow-up after CAR T-cell therapy, the complete response rate was 36.3%(8/22), 40.9(9/22) and 27.2(6/22) at 12 months, 18 months and 24 months, respectively. At 18 months, the patients achieved the highest complete response rate. Baseline characteristics, such as age, sex, isotype, ECOG, high-risk cytogenetics, prior lines of therapy, percentage of plasma blasts in bone marrow, serum monoclonal protein and extramedullary disease in the 9 complete response patients at 18 months were similar to other progressive disease 13 patients. However, the significant differences of International Staging system stage(p=0.034) and Durie-Salm staging system(p=0.002) at baseline were observed between the 9 complete response patients and 13 progressive disease patients at 18 months(Table 1). The International Staging system stage(area under curve 0.80) and Durie-Salm staging system(area under curve 0.86) predicted the outcome of patients at 18 months well. Durie-Salmon Staging system was published in 1975, which used commonly available clinical parameters including calcium, hemoglobin, bone lesions, creatinine level and serum or urine monoclonal protein. The ISS staging system was proposed in 2005 based on baseline serum levels of beta2-microglobulin (β2M) and albumin. And there was no statistically significant difference in the baseline serum levels of beta2-microglobulin, albumin, calcium, bone lesions and creatinine level between the 9 complete response patients and 13 progressive disease patients at 18 months. As figure 1 illustrates, the hemoglobin of 9 complete response patients was higher than that of 13 progressive disease patients with statistical significance at 9 time-points: PreFC(117.6±20.7 vs 94.6±23.6 , p = 0.028), D -4(113.6±15.9 vs 86.0±25.7 , p = 0.016), D -3(107.8±11.8 vs 84.6±23.0 , p = 0.027), D -2(117.6±20.7 vs 94.6±23.6 , p = 0.0009), D -1(111.0±19.9 vs 81.8±19.0 , p = 0.013), D0(107.1±20.4 vs 83.0±22.8 , p = 0.029), D1(107.7±19.1 vs 84.2±24.3 , p = 0.032), D4(104.1±14.9 vs 82.7±19.9 , p = 0.015), D5(103.4±19.1 vs 82.2±18.3 , p = 0.018). In the univariate Cox regression analysis, the hemoglobin at PreFC(hazard ration (HR) = 0.97; 95% confidence interval (CI): 0.95-1; p = 0.029), D -4(HR=0.96 ;95% CI:0.92-1, p = 0.012), D -3 (HR=0.97 ;95% CI:0.94-1, p = 0.029), D -2(HR=0.93 ;95% CI:0.89-1, p = 0.003), D -1(HR=0.97 ;95% CI:0.95-1, p = 0.047), D0(HR=0.97 ;95% CI:0.94-1, p = 0.038), D1(HR=0.97 ;95% CI:0.94-1, p = 0.044), D4(HR=0.95 ;95% CI:0.92-1, p = 0.01) and D5(HR=0.97 ;95% CI:0.94-1, p = 0.027) were relative factors of prognosis. Conclusions These long-term follow-up data in patients after BCMA CAR -T therapy suggest that baseline ISS ,DS staging and hemoglobin at 9 time-points display opposing association with long-term progression-free survival.

Modification of Lugano criteria by pre-infusion tumor kinetics improves early survival prediction for patients with lymphoma under chimeric antigen receptor T-cell therapy

BackgroundChimeric antigen receptor T-cell therapy (CART) is effective for patients with refractory or relapsed lymphoma with prolongation of survival. We aimed to improve the prediction of Lugano criteria for overall...

The prediction of early progressive disease in patients with hepatocellular carcinoma receiving atezolizumab plus bevacizumab.

The IMbrave 150 trial revealed the usefulness of atezolizumab plus bevacizumab therapy in patients with unresectable hepatocellular carcinoma (HCC), making it now considered the first-line systemic chemotherapy agent for HCC. The present study investigated factors associated with early tumor progression of atezolizumab plus bevacizumab in patients with advanced HCC in real-world clinical practice. A total of 184 HCC patients who received atezolizumab plus bevacizumab therapy were studied. We investigated the frequency of early progressive disease (e-PD; PD within 9 weeks) and analyzed the risk factors for e-PD. There were 47 patients (25.5%) diagnosed as e-PD. Patients with e-PD had a worse performance status (PS) and albumin-bilirubin (ALBI) and Child-Pugh (C-P) scores and a significantly higher rate of a systemic therapy than those with non-e-PD. A multivariate analysis showed that PS ≥1 (odds ratio [OR] = 4.5, 95% confidence interval [CI] = 1.9-10, p < 0.001), ALBI score ≥-2.30 (OR = 2.1, 95% CI = 1.0-4.5, p = 0.044) and the history of a systemic therapy (OR = 3.0, 95% CI = 1.4-6.4, p = 0.0038) were significant and independent determinants of e-PD. When examining the liver function trends in e-PD patients, the ALBI scores at 3 and 6 weeks after starting therapy were significantly higher than before the treatment (p < 0.001). The liver function and systemic therapy are useful predictors of e-PD in HCC patients treated with atezolizumab plus bevacizumab in real-world clinical practice.

A certified de-identification system for all clinical text documents for information extraction at scale.

Clinical notes are a veritable treasure trove of information on a patient's disease progression, medical history, and treatment plans, yet are locked in secured databases accessible for research only after extensive ethics review. Removing personally identifying and protected health information (PII/PHI) from the records can reduce the need for additional Institutional Review Boards (IRB) reviews. In this project, our goals were to: (1) develop a robust and scalable clinical text de-identification pipeline that is compliant with the Health Insurance Portability and Accountability Act (HIPAA) Privacy Rule for de-identification standards and (2) share routinely updated de-identified clinical notes with researchers. Building on our open-source de-identification software called Philter, we added features to: (1) make the algorithm and the de-identified data HIPAA compliant, which also implies type 2 error-free redaction, as certified via external audit; (2) reduce over-redaction errors; and (3) normalize and shift date PHI. We also established a streamlined de-identification pipeline using MongoDB to automatically extract clinical notes and provide truly de-identified notes to researchers with periodic monthly refreshes at our institution. To the best of our knowledge, the Philter V1.0 pipeline is currently the first and only certified, de-identified redaction pipeline that makes clinical notes available to researchers for nonhuman subjects' research, without further IRB approval needed. To date, we have made over 130 million certified de-identified clinical notes available to over 600 UCSF researchers. These notes were collected over the past 40 years, and represent data from 2757016 UCSF patients.

#3390 ADPKD PREDICTOR: A CLOUD-BASED PROGNOSTIC TOOL FOR AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE

Abstract Background and Aims ADPKD is a progressively debilitating genetic disease characterized by the growth of numerous cysts in the kidneys, leading eventually to end-stage renal disease. Total Kidney Volume (TKV) is accepted by FDA and EMA as a prognostic biomarker and quantitative predictor of kidney function decline, and is currently used to select patients to receive Tolvaptan treatment. However, TKV calculation from manual tracing of medical images is labor-intensive; for better accuracy, current available methods involve the injection of an iodinated contrast medium for CT scan, with important limitations in patients with impaired renal function. We developed ADPKD Predictor, a user-friendly cloud-based tool for fast and accurate estimation of disease classification and progression, based on automated kidney and cysts segmentation from MRI data. Method An online tool was designed on Microsoft Azure Cloud to automatize the set-up and running of a previously developed algorithm implemented in MATLAB to automatically detect kidneys and cysts contours from MRI data (T2-weighted turbo-spin-echo SPIR), based on advanced image processing techniques [1]. Through the web interface, the user is requested to upload the MRI data and select one point inside kidney's parenchyma in the central slice (Figure 1). Then, TKV is automatically calculated and eGFR based on CKD-EPI equation, ADPKD Imaging Classification and future eGFR [2], estimated Tolvaptan treatment effect [3], and GFR Category based on KDIGO CKD staging system are obtained (Figure 2). The MRI dataset is anonymized before upload to the cloud; data and results are stored in a secure and reliable environment controlled by the user. Results The proposed solution is very fast and precise compared to manual segmentation of medical images (absolute mean error 2.4% ± 2.7%) [1]. Moreover, it is faster and more accurate than the commonly used ellipsoid-based method, resulting in a manifold reduction of misclassification error (2.5%) [1] and therefore potential therapeutic consequences. Another advantage is its usability, with no specific computational expertise, numerical software or dedicated hardware required, since all computations are run remotely in the cloud. Conclusion ADPKD Predictor provides a fast and reproducible assessment of risk classification and disease progression, based on precise morphologic classification of the renal and cysts volume of patient. The proposed solution represents an extremely useful tool for researchers and clinicians to easily obtain an accurate estimation of risk classification potentially helping in a correct and effective stratification of patients, and monitor patient's disease progression, hence supporting a correct and effective therapy administration. Also, it would represent a great benefit for the patient, since the tool analyzes medical images obtained without the use of contrast medium.

Pyogenic Hepatic Abscess in an Immunocompetent Patient With Poor Oral Health and COVID-19 Infection.

Pyogenic hepatic abscess (PHA) is a collection of pus in the liver caused by bacterial infection of the liver parenchyma. PHA is more common in immunosuppressed individuals and those with diabetes mellitus, cancer, and liver transplant. We present a rare case of PHA with Fusobacterium nucleatum in an immunocompetent patient with poor oral health, history of diverticulitis, and recent COVID-19 infection whose only symptoms were chest pain and a 4-week history of fever and malaise. The source of infection in this patient was likely dental caries and periodontal disease, with COVID-19 infection playing a role as a red herring in this patient's disease progression, delaying diagnosis. Diagnosis and treatment of PHA must be prompt with drainage and empiric anaerobic coverage followed by a more tailored antibiotic regimen if indicated by culture and further drainage if indicated by computed tomography.

Sequential therapies after atezolizumab plus bevacizumab or lenvatinib first-line treatments in hepatocellular carcinoma patients

IntroductionThe aim of this retrospective proof-of-concept study was to compare different second-line treatments for patients with hepatocellular carcinoma and progressive disease (PD) after first-line lenvatinib or atezolizumab plus bevacizumab. Materials and methodsA total of 1381 patients had PD at first-line therapy. 917 patients received lenvatinib as first-line treatment, and 464 patients atezolizumab plus bevacizumab as first-line. Results49.6% of PD patients received a second-line therapy without any statistical difference in overall survival (OS) between lenvatinib (20.6months) and atezolizumab plus bevacizumab first-line (15.7months; p = 0.12; hazard ratio [HR]= 0.80). After lenvatinib first-line, there wasn’t any statistical difference between second-line therapy subgroups (p = 0.27; sorafenib HR: 1; immunotherapy HR: 0.69; other therapies HR: 0.85). Patients who underwent trans-arterial chemo-embolization (TACE) had a significative longer OS than patients who received sorafenib (24.7 versus 15.8months, p < 0.01; HR=0.64). After atezolizumab plus bevacizumab first-line, there was a statistical difference between second-line therapy subgroups (p < 0.01; sorafenib HR: 1; lenvatinib HR: 0.50; cabozantinib HR: 1.29; other therapies HR: 0.54). Patients who received lenvatinib (17.0months) and those who underwent TACE (15.9months) had a significative longer OS than patients treated with sorafenib (14.2months; respectively, p = 0.01; HR=0.45, and p < 0.05; HR=0.46). ConclusionApproximately half of patients receiving first-line lenvatinib or atezolizumab plus bevacizumab access second-line treatment. Our data suggest that in patients progressed to atezolizumab plus bevacizumab, the systemic therapy able to achieve the longest survival is lenvatinib, while in patients progressed to lenvatinib, the systemic therapy able to achieve the longest survival is immunotherapy.

Molecular predictors and immunomodulatory role of dual checkpoint inhibitor blockade using ipilimumab/nivolumab in patients with extensive stage small cell lung cancer.

8597 Background: Small cell lung cancer (SCLC) is an aggressive neuroendocrine carcinoma with poor prognosis. In extensive stage patients, frontline treatment with chemoimmunotherapy shows modest clinical benefit. However, the biological impact of immunotherapy in SCLC is poorly understood with no clear predictive biomarkers to guide patient selection in this setting. Methods: We collected paired baseline (pre-treatment), on-treatment (week 4), and progression biopsies from patients with relapsed advanced-stage SCLC treated with combination nivolumab (nivo) and ipilimumab (ipi) in a single-arm, phase 2 clinical trial (NCT03670056). Nivo 1 mg/kg and ipi 3 mg/kg were administered every 3 weeks for 4 cycles, followed by nivo maintenance until progressive disease (PD) by RECIST 1.1 or treatment-limiting toxicity. Paired pre/on-treatment samples were available from 16/22 patients, as well as 3 biopsies at progression. The tumor samples were studied using whole exome DNA sequencing (including germline DNA) and RNA-sequencing coupled to Ocean Genomics TxomeAI data analysis pipeline. Results: 6/11 evaluable patients had PD; 5 patients showed clinical activity of treatment (3 with stable disease, 2 with partial response). The frequency of deleterious mutations in TP53 and RB1 was 91% and 64%, respectively. Mutations in HLA-A were more common in baseline samples from patients with PD than those with clinical activity. New TP53 and PLEC mutations were found 4 of 6 patients with PD in week 4 samples vs baseline. The baseline tumor mutational burden was not associated with treatment sensitivity and prominently increased in week 4 biopsies of PD patients. All four molecular SCLC transcriptomic subtypes based on the expression of ASCL1, NEUROD1, and POU2F3 were present in the trial with SCLC-A being the most common (9/16 cases). All patients with clinical activity to ipi/nivo were of SCLC-A subtype. 2/16 of cases showed a different molecular subtype after 4 weeks of treatment: one case with SCLC-N switched to SCLC-A and another case converted from SCLC-A to SCLC-N. Comparison of baseline and on-treatment samples showed upregulation of transcripts associated with T-cell activation and PD-1 signaling. In the 3 biopsies at progression, transcriptomic changes included reduction of neutrophil degranulation, type 1/2 interferon and signatures, as well as down-regulation of β-2 microglobulin, while cell cycle and mitotic prophase pathways were overexpressed. Conclusions: Dual checkpoint blockade using nivo/ipi has a prominent immunomodulatory role in extensive stage SCLC characterized by increased local adaptive immune responses, reduced HLA class-I antigen presentation and change in the molecular subtype in a subset of cases. We identified genomic features associated with treatment sensitivity/resistance. Clinical trial information: NCT03670056 .

Treatment Strategy for Ultra-High-Risk Multiple Myelomas with Chromosomal Aberrations Considering Minimal Residual Disease Status and Bone Marrow Microenvironment.

Despite the development of anti-myeloma therapeutics, such as proteasome inhibitors, immunomodulatory drugs, anti-CD38 monoclonal antibodies, and autologous stem cell transplantation (ASCT), multiple myeloma remains incurable. A trial treatment combining four drugs-daratumumab, carfilzomib, lenalidomide, and dexamethasone-followed by ASCT frequently results in minimal residual disease (MRD) negativity and prevents progressive disease in patients with standard- and high-risk cytogenetics; however, it is insufficient to overcome the poor outcomes in patients with ultra-high-risk chromosomal aberration (UHRCA). In fact, MRD status in autografts can predict clinical outcomes after ASCT. Therefore, the current treatment strategy might be insufficient to overcome the negative impact of UHRCA in patients with MRD positivity after the four-drug induction therapy. High-risk myeloma cells lead to poor clinical outcomes not only by aggressive myeloma behavior but also via the generation of a poor bone marrow microenvironment. Meanwhile, the immune microenvironment effectively suppresses myeloma cells with a low frequency of high-risk cytogenetic abnormalities in early-stage myeloma compared to late-stage myeloma. Therefore, early intervention might be key to improving clinical outcomes in myeloma patients. The purpose of this review is to improve clinical outcomes in patients with UHRCA by considering MRD assessment results and improvement of the microenvironment.

Abstract 5743: Reprogramming myeloid cells by JAK inhibition to enhance checkpoint blockade immunotherapy

Abstract Background: Checkpoint inhibitors have achieved a wide adoption for treatment of advanced cancer, but the majority of patients fail to respond. Among the underlying causes are redundant mechanisms driving cytotoxic lymphocyte dysfunction. Motivated by the discovery of JAK inhibitors as hit compounds in a screen for the reversal of T cell exhaustion, this study investigates the hypothesis that JAK inhibition could enhance the efficacy of checkpoint inhibitors. Methods: Murine immunocompetent models of cancer were utilized (A20, EL4, LLC1, MC38). The combination therapy of systemic treatment with the JAK inhibitor ruxolitinib with anti-PD1 + anti-CTLA4 was evaluated for efficacy and biomarkers compared to checkpoint inhibitors (ICI) alone. Tumor-infiltrating, blood and lymphoid organ immune cells were phenotyped using single-cell transcriptomics, functional assays and flow cytometry. The combination therapy was clinically tested in an investigator-initiated Phase I/II clinical trial of ruxolitinib with nivolumab in relapsed or refractory Hodgkin lymphoma (NCT03681561). Patients who previously failed to respond to ICI received ruxolitinib for 1 week then nivolumab every 4 weeks concurrent with ruxolitinib twice daily. Peripheral blood was collected at baseline, 1 week after ruxolitinib and 4 weeks after 1st nivolumab dose. Hematologic and transcriptomic analyses were performed on peripheral blood samples. Results: The ruxolitinib + ICI combination was superior to ICI in 3/4 of the tumor models examined in controlling tumor growth. Tumor sizes were reduced by &amp;gt;50% in the MC38 (mean volume 123.1 vs 283.2 mm3, ICI + rux vs ICI, respectively, n=9 per group, ANOVA p=0.0094), LLC1 and A20 models (survival hazard ratio 0.24, ICI + rux vs ICI, n=8 per group, p=0.048). Remarkably, we observed a broad shift of tumor monocytes and granulocytes from a suppressive into an immunostimulatory state characterized by the expression of MHC molecules and the ability to stimulate T cell proliferation. Hodgkin lymphoma patients in the ruxolitinib with nivolumab trial exhibited an interim disease control rate of 76% (13/17). Ruxolitinib treatment in these patients did not impair T cell cytokine production but significantly reduced the neutrophil-to-lymphocyte ratio (NLR, mean difference -0.82, n=14, p=0.0023) and the expression of myeloid derived suppressor cell markers in monocytes (normalized enrichment score -1.74, n=14, q&amp;lt;0.001) compared to pre-treatment. The reduction in NLR was significantly greater in complete responders than in progressive disease patients (mean -2.6 vs -0.58, respectively, p=0.023). Conclusions: The combination of ruxolitinib with ICI was effective in preclinical models of cancer and in a Phase I/II Hodgkin lymphoma clinical trial. Unexpectedly, JAK inhibitor-mediated reprogramming of myeloid cells and the associated enhanced T cell activity may be important for the observed efficacy. Citation Format: Jaroslav Zak, Isaraphorn Pratumchai, Brett S. Marro, Kristi L. Marquardt, Michael B. Oldstone, Judith A. Varner, Veronika Bachanova, John R. Teijaro. Reprogramming myeloid cells by JAK inhibition to enhance checkpoint blockade immunotherapy. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5743.

Abstract 6683: Genetic alterations of circulating tumor DNA in advanced pancreatic cancer patients receiving 5-fluorouracil based chemotherapy

Abstract Background: Pancreatic cancer remains one of the most devastating malignancies due to lack of target therapeutic options for advanced disease. Liquid biopsy which analyzes tumor-related biomarkers in blood, has emerged as an innovative technology. The aim of this study was to identify circulating tumor DNA (ctDNA) mutations in pancreatic adenocarcinoma(PDAC) patients using multi-gene panels. Methods: Total of 45 patients (27 male, median age 63 years) blood samples were obtained at baseline then follow-up after 2 months samples were acquired in 16 patients at National Cancer Center, Korea from November 2021 to April 2022. CtDNA were analyzed by next-generation-sequencing (NGS) panel of 118 genes and the varient allele frequency (VAF) of detected genes were analyzed. Then the association between outcomes of 5FU treated response and survival (overall survival and progression-free survival; OS and PFS) and VAF reduction at follow-up were analyzed. Results: Total of 35 genes with 114 genetic alterations were detected and frequent mutations were as follows: KRAS (29.9%), TP53 (14.9%), GNAS(4.4%), SMAD4(4.4%), AR(3.5%), RNF434(3.5%), ATM(3.5%), BRCA2(2.6%) and PIK3CA(2.6%). The mean VAF level considering all pathogenic variants of 45 patients was 8.9%(range, 0 - 87.2) including 8 patients who were not detected ctDNA mutations in baseline, and the mean VAF was 4.2% (0 - 50.0) at follow-up in 16 patients. With association of clinical response, patients with partial response (PR) and stable disease (SD) were decreased VAF from 11% at baseline to 10% after 2 months, and three (60%) of patients showed clearance of ctDNA. Progressive disease (PD) patients were also decreased VAF 67% after 2 months, however, clearance of ctDNA was only observed in one patient (12.5%). Reduction of ctDNA more than 50% were associated with longer survival as PFS (&amp;gt; 50% reduction groups vs. no reduction group; 5 vs. 3 months, p value=0.903, OS (undefined vs. 6 months, p value =0.180). Conclusions: This study showed most common mutation was KRAS with several other mutations of ctDNA in PDAC, and outcomes represented association with ctDNA. Citation Format: SooBeen Heo, Sunhwa Park, Jung Won Chun, Yun-Hee Kim, Jun-Kyu Kang, Hwang-Phill Kim, Sang Myung Woo, Sun-Young Kong. Genetic alterations of circulating tumor DNA in advanced pancreatic cancer patients receiving 5-fluorouracil based chemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6683.

Abstract 4385: Unprecedented tumor: immune interaction–clinical and drug-development implications

Abstract Background: Classic therapeutic (RX) oncology principles demand radiographic response or durable stable disease as surrogates of overall survival (OS) prolongation, the ultimate metric of Rx benefit. Progressive disease (PD), however, is an undisputed indication of treatment failure. Immune Oncology (IO) trials reporting individual patient outcomes using swimmers' plot (SP) suggest substantial OS subsequent to PD, unprecedented pre-IO. Hypothesis: Unrecognized phenomenon of OS benefit in the setting of radiographic PD, is tissue-agnostic and prevalent (&amp;gt;15%). Methods: We conducted a retrospective review of IO monotherapy trials in 3 cancers if SP were reported. Percentage of PD patients (Pts) surviving beyond defined time landmarks is reported (Table). Results: Realizing that 3rd or subsequent Rx lines rarely provide &amp;gt; 6 months OS duration in most cancers, our results indicate that 2/3rd of IO-treated pts, regardless of histology, or line of therapy are performing significantly better than expected; 1/3rd surviving &amp;gt; 1 year beyond PD. Discussion: In IO, radiographic bulk may increase despite undeniable OS benefit (in years). We likely underestimated this phenomenon since pts with PD at 1st assessment aren't included in the SP, and with longer follow up, OS of PD pts is likely to improve with longer time to manifest it. This phenomenon–we term 'Disguised Responders' (DRs)–challenges an oncology principal. DRs needs to be considered by clinicians and future drug developers to accurately identify putative novel drugs. A plausible mechanism of DRs posits that 'virulence' of a given subclone, regardless of size or bulk, dictates Rx outcome. Virulence may operate through cachexia-induction, propensity to metastasize or metabolic adaptability, to name a few. Novel experimental approaches are desperately awaited to probe and measure virulence of different tumor subclones in future drug evaluations. Table 1. Clinical Trials of IO Monotherapy Number and (%) of pts surviving beyond clinical PD (months) Tumor Rx Line 1st Author/Yr N PD (n) &amp;lt;6 6-11 12-23 24-35 36-47 &amp;gt; 48 NSCLC* 2nd + Topalian ''19 22 12 1 2 4 1 4 1st + Fredinandus ''21 45 2 1 1 1st + Kim ''22 139 22 13 5 3 N/A Bilger ''22 18 10 3 4 3 2nd Dart ''21 7 3 2 1 2nd + Tozuka (MR) ''20 11 11 4 6 1 2nd + Tozuka (PD) ''20 51 51 29 12 7 2 1 2nd + Waterhouse ''20 39 38 16 14 4 4 Subtotal 332 149 63 (42%) 44 (30%) 28 (18%) 4 (3%) 5 (3%) 4 (3%) Melanoma 1st + Warburton ''20 70 13 1 4 3 4 1 2nd + Topalian ''19 34 21 1 2 10 4 4 2nd + Weber ''15 38 4 2 1 1 2nd + Dimitriou ''21 125 9 3 4 2 Subtotal 267 47 3 (6%) 8 (17%) 10 (21%) 17 (36%) 5 (11%) 4 (8.5%) RCC** 2nd + Topalian 19'' 10 7 1 1 2 3 7 15% 15% 30% 42% Total 609 203 33% 25% 15% 10% 6% 5.4% *Non-small cell lung cancer. ** Renal Cell Carcinoma Citation Format: Farah Mazahreh, Liyan Mazahreh, Brad Fugere, Ahmad Mazin Safar. Unprecedented tumor: immune interaction–clinical and drug-development implications. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4385.

Tumor-Naïve Circulating Tumor DNA as an Early Response Biomarker for Patients Treated With Immunotherapy in Early Phase Clinical Trials.

To evaluate early circulating tumor DNA (ctDNA) kinetics using a tumor-naïve assay and correlate it with clinical outcomes in early phase immunotherapy (IO) trials. Plasma samples were analyzed using a 425-gene next-generation sequencing panel at baseline and before cycle 2 (3-4 weeks) in patients with advanced solid tumors treated with investigational IO agents. Variant allele frequency (VAF) for mutations in each gene, mean VAF (mVAF) from all mutations, and change in mVAF between both time points were calculated. Hyperprogression (HyperPD) was measured using Matos and Caramella criteria. A total of 162 plasma samples were collected from 81 patients with 27 different tumor types. Patients were treated in 37 different IO phase I/II trials, 72% of which involved a PD-1/PD-L1 inhibitor. ctDNA was detected in 122 plasma samples (75.3%). A decrease in mVAF from baseline to precycle 2 was observed in 24 patients (37.5%) and was associated with longer progression-free survival (hazard ratio [HR], 0.43; 95% CI, 0.24 to 0.77; P < .01) and overall survival (HR, 0.54; 95% CI, 0.3 to 0.96; P = .03) compared with an increase. These differences were more marked if there was a >50% decrease in mVAF for both progression-free survival (HR, 0.29; 95% CI, 0.13 to 0.62; P < .001) and overall survival (HR, 0.23; 95% CI, 0.09 to 0.6; P = .001). No differences in mVAF changes were observed between the HyperPD and progressive disease patients. A decrease in ctDNA within 4 weeks of treatment was associated with treatment outcomes in patients in early phase IO trials. Tumor-naïve ctDNA assays may be useful for identifying early treatment benefits in phase I/II IO trials.