First-line Immunochemotherapy Research Articles

Association between sarcopenia, clinical outcomes, and survival in patients with extensive-stage small cell lung cancer treated with first-line immunochemotherapy: a prospective cohort study

Association between sarcopenia, clinical outcomes, and survival in patients with extensive-stage small cell lung cancer treated with first-line immunochemotherapy: a prospective cohort study

139P Multimodal prognosis modeling of advanced NSCLC treated with first-line immunochemotherapy: Integrating genomic and microenvironmental data

139P Multimodal prognosis modeling of advanced NSCLC treated with first-line immunochemotherapy: Integrating genomic and microenvironmental data

Lymphocyte recovery after bendamustine therapy in patients with mantle cell lymphoma. Results of a retrospective analysis and prognostic impact in the CAR-T era.

Bendamustine in combination with rituximab (BR) or with rituximab and cytarabine (R-BAC) is the standard first-line immunochemotherapy in mantle cell lymphoma (MCL) for elderly patients and patients ineligible for intensive regimens or autologous transplantation. As bendamustine causes prolonged lymphopenia and the literature lacks evidence of its persistence in patients with MCL, this retrospective analysis aims to estimate the lymphocyte recovery time, also in view of potential immunotherapy with CAR-T cells. Data were collected from 44 consecutive MCL patients who received bendamustine (BR or R-BAC) as first-line therapy at the Hematology Unit of Sapienza University Hospital between May 2011 and April 2022. Twenty patients (45%) were treated with R-BAC and 24 (55%) with BR. At baseline, the median lymphocyte count was 1795/µl (range: 370-11730/µL). One month after the end of therapy, it was 450/µl (range: 50-3300/µl) and 3 months after 768/µl (range: 260-1650/µl). After 6 and 9 months, we observed a gradual increase in median lymphocyte count of 900/µl (range: 370-2560/µl and 130-2770/µl, respectively). After 12 months median lymphocyte count was 1256/µl (range: 240-4140/µl). Median lymphocyte count at 1, 3, 6, and 9 months post-treatment was significantly lower than baseline but showed recovery by the 12 months. This finding is crucial for MCL patients considering CAR-T cell therapy, suggesting a minimum 9-month interval between bendamustine administration and leukapheresis.

Association Between Sarcopenia, Clinical Outcomes, and Survival in Patients with Extensive-Stage Small Cell Lung Cancer Treated with First-Line Immunochemotherapy: A Prospective Cohort Study.

To investigate the association between sarcopenia, short-term efficacy, and long-term survival in patients with extensive small-cell lung cancer (SCLC) treated with standard first-line immunochemotherapy. A total of 63 patients initially diagnosed with extensive-stage small cell lung cancer were enrolled in the prospective study from December 1, 2020 to December 31, 2022. The clinical characteristics, body composition, blood test results, and image data were obtained before treatment. Patients were divided into sarcopenia and non-sarcopenia groups according to the diagnostic criteria of the Asian Sarcopenia Working Group 2019. The primary outcome was overall survival (OS) and comprehensive survival analyses were performed. Secondary outcomes included short-term efficacy and adverse events associated with first-line immunochemotherapy. The median age of the 63 patients enrolled in our study was 63.0 years (40-80 years). The incidence of sarcopenia was 19.0% (12/63) in patients with extensive SCLC. Compared with non-sarcopenia patients, extensive-stage SCLC patients with sarcopenia were significantly older (69.0 vs. 62.0, P = 0.017), and had lower body mass index (BMI) (20.29 vs. 24.27, P < 0.001), hand grip strength (HGS) (20.42 vs. 30.75, P < 0.001), and albumin (35.9 vs. 41.40, P < 0.001). The objective response rate after two cycles of standard first-line immunochemotherapy in the sarcopenia group was lower than in the non-sarcopenia group (30.0 vs. 78.9%, P = 0.012). There was no significant difference in chemotherapy-related hematological toxicity between the two groups. During a median follow-up of 15 months (3-33 months), patients with extensive SCLC had a median OS of 24 months, with 1-year survival of 75% and 2-year survival of 52%, respectively. Compared to non-sarcopenia patients, the median OS in the sarcopenia group was significantly shorter (9 vs. 24 months, P = 0.0014). Multivariate Cox analysis showed that sarcopenia was an independent risk factor for OS in patients with extensive SCLC (HR = 4.993, 95%CI = 1.106-22.538, P = 0.037). Patients with Extensive SCLC and sarcopenia had worse clinical outcomes and shorter OS. Sarcopenia is a prognostic factor affecting first-line treatment efficacy and long-term survival of patients with SCLC in the era of immunotherapy.

Plasma extracellular vesicle long RNA profiling identifies a predictive signature for immunochemotherapy efficacy in lung squamous cell carcinoma.

The introduction of Immune Checkpoint Inhibitors (ICIs) has marked a paradigm shift in treating Lung Squamous Cell Carcinoma (LUSC), emphasizing the urgent need for precise molecular biomarkers to reliably forecast therapeutic efficacy. This study aims to identify potential biomarkers for immunochemotherapy efficacy by focusing on plasma extracellular vesicle (EV)-derived long RNAs (exLRs). We enrolled 78 advanced LUSC patients undergoing first-line immunochemotherapy. Plasma samples were collected, and exLR sequencing was conducted to establish baseline profiles. A retrospective analysis was performed on 42 patients to identify differentially expressed exLRs. Further validation of the top differentially expressed exLRs was conducted using quantitative reverse transcription PCR (qRT-PCR). Univariate Cox analysis was applied to determine the prognostic significance of these exLRs. Based on these findings, we developed a predictive signature (p-Signature). In the retrospective analysis of 42 patients, we identified 460 differentially expressed exLRs, with pathways related to leukocyte migration notably enriched among non-responders. Univariate Cox analysis revealed 45 exLRs with prognostic significance. The top 6 protein-coding exLRs were validated using qRT-PCR, identifying CXCL8, SSH3, and SDHAF1 as differentially expressed between responders and non-responders. The p-Signature, comprising these three exLRs, demonstrated high accuracy in distinguishing responders from non-responders, with an Area Under the Curve (AUC) of 0.904 in the retrospective cohort and 0.812 in the prospective cohort. This study highlighted the potential of plasma exLR profiles in predicting LUSC treatment efficacy. Intriguingly, lower p-Signature scores were associated with increased abundance of activated CD4+ and CD8+ T cells, indicating a more robust immune environment. These findings suggest that the p-Signature could serve as a valuable tool in guiding personalized and effective therapeutic strategies for LUSC.

Прогностическое значение цитотоксических CD8-позитивных Т-лимфоцитов реактивного микроокружения опухоли при диффузной В-крупноклеточной лимфоме

AIM. To assess the prognostic value of cytotoxic CD8-positive Т-lymphocytes of the reactive tumor microenvironment in diffuse large B-cell lymphoma (DLBCL). MATERIALS &amp; METHODS. The study enrolled 124 patients with newly diagnosed DLBCL. All patients received the standard R-CHOP first-line immunochemotherapy. Immunochemistry and morphometry were used to assess the relative count of CD8-positive Т-lymphocytes in the biopsy samples of lymph nodes or other tumor tissues. In each biopsy sample, 20 fields of view were analyzed to assess the mean relative count of CD8-positive Т-lymphocytes in the reactive tumor microenvironment. Т-cells were counted by double-blind technique. Patients were aged 23–80 years (median 59 years); there were 62 women and 62 men. RESULTS. Obtained by ROC-analysis, the threshold value of the CD8-positive Т-lymphocyte count in the reactive tumor microenvironment was 13 %. The subthreshold relative count of cytotoxic CD8-positive Т-lymphocytes (≤ 13 %) was associated with extranodal lesions in DLBCL patients as well as with the lack of complete response to the R-CHOP first-line therapy and worse progression-free (PFS) and overall survival (OS) rates. In the group with the above-threshold (&gt; 13 %) count of CD8-positive Т-lymphocyte, the 5-year PFS was 60 % (median not reached), in the group with the subthreshold count it was 45.3 % (median 39 months; p = 0.036); the 5-year OS was 78.3 % (median not reached) and 45.3 % (median 40 months) in the groups with the above- and subthreshold CD8+ T-cell counts, respectively (p = 0.001). CONCLUSION. The results of the present study clearly indicate the need to assess the count of cytotoxic CD8-positive Т-lymphocytes of the reactive tumor microenvironment in DLBCL patients as early as on diagnosis verification. It is likely that this approach will allow clinicians to more accurately predict the course of DLBCL.

Lisocabtagene maraleucel in follicular lymphoma: the phase 2 TRANSCEND FL study

An unmet need exists for patients with relapsed/refractory (R/R) follicular lymphoma (FL) and high-risk disease features, such as progression of disease within 24 months (POD24) from first-line immunochemotherapy or disease refractory to both CD20-targeting agent and alkylator (double refractory), due to no established standard of care and poor outcomes. Chimeric antigen receptor (CAR) T cell therapy is an option in R/R FL after two or more lines of prior systemic therapy, but there is no consensus on its optimal timing in the disease course of FL, and there are no data in second-line (2L) treatment of patients with high-risk features. Lisocabtagene maraleucel (liso-cel) is an autologous, CD19-directed, 4-1BB CAR T cell product. The phase 2 TRANSCEND FL study evaluated liso-cel in patients with R/R FL, including 2L patients who all had POD24 from diagnosis after treatment with anti-CD20 antibody and alkylator ≤6 months of FL diagnosis and/or met modified Groupe d’Etude des Lymphomes Folliculaires criteria. Primary/key secondary endpoints were independent review committee–assessed overall response rate (ORR)/complete response (CR) rate. At data cutoff, 130 patients had received liso-cel (median follow-up, 18.9 months). Primary/key secondary endpoints were met. In third-line or later FL (n = 101), ORR was 97% (95% confidence interval (CI): 91.6‒99.4), and CR rate was 94% (95% CI: 87.5‒97.8). In 2L FL (n = 23), ORR was 96% (95% CI: 78.1‒99.9); all responders achieved CR. Cytokine release syndrome occurred in 58% of patients (grade ≥3, 1%); neurological events occurred in 15% of patients (grade ≥3, 2%). Liso-cel demonstrated efficacy and safety in patients with R/R FL, including high-risk 2L FL. ClinicalTrials.gov identifier: NCT04245839.

Impact of timing of immunotherapy in survival among patients with advanced lung adenocarcinoma treated with first-line immunochemotherapy: A propensity score matching.

e20560 Background: Immunochemotherapy combinations have been the mainstream first-line standard treatment of advanced non-small cell lung cancer (NSCLC), wherein concurrent chemotherapy and immunotherapy are conventionally fixed to an established dosing regimen. Few studies had suggested the remarkable impact of the timing of immunotherapy on immunochemotherapy combined therapy. However, this issue has not been addressed in advanced NSCLC cohort. Methods: This study was a retrospective analysis of 532 patients with advanced lung adenocarcinoma (LUAD) without EGFR/ALK mutations who underwent immunochemotherapy as first-line systemic treatment between June 2018 to June 2022 at 3 facilities. Patients were divided into two groups (induced and non-induced) according to the different timing of immunotherapy in combined therapy, which defined induced as receiving 1 or more cycles of full-dose chemotherapy alone before concurrent immunochemotherapy. The bias between induced and non-induced groups was minimized with Propensity Score Matching (PSM). Patients outcomes, including progression-free survival (PFS) and overall survival (OS), were compared between the two groups by Kaplan-Meier survival curves and Cox regression analyses. Results: Survival analysis showed that both PFS and OS of the induced chemotherapy group patients were significantly longer than that of non-induced group (PFS: 14.63 months vs. 10.13 months, p = 0.004; OS: Not reached vs. 20.27 months, p = 0.0013). In the COX regression, after adjusting for confounders, induction chemotherapy was found to be a remarkable favorable factor for both PFS and OS (PFS: HR = 0.73, p= 0.018; OS: HR = 0.69, p= 0.034). After pretreatment features and treatment parameters were included in PSM, 104 patients were identified in each groups with matched characteristics, and moreover, the results of survival analysis remained consistent and showed significant difference between induced and non-induced group (PFS: 14.63 months vs. 10.23 months, p = 0.029; HR = 0.71, p= 0.030. OS: Not reached vs 18.27 months, p = 0.0013; HR = 0.52, p= 0.002). Conclusions: For advanced LUAD patients treated with first-line immunochemotherapy combinations, the timing of immunotherapy had significant impact on prognosis, which suggested notable benefit of induction chemotherapy before concurrent immunochemotherapy.

Immune checkpoint inhibitor retreatment in second-line treatment of esophageal cancer: A real-world study.

e16034 Background: Immunotherapy combined with chemotherapy has been recommended in several guidelines and consensus for the first-line treatment of advanced esophageal cancer(EC), but it is controversial whether to continue immune checkpoint inhibitors (ICIs) after the progress of first-line immunotherapy. Methods: This was a single-center, retrospective, observational, real-world study to collect general conditions and clinical data of EC patients hospitalized in the First Affiliated Hospital of Henan University of Science and Technology between February 2020 and December 2023. All patients received programmed cell death protein 1 (PD-1) or its ligand (PD-L1) inhibitor combination therapy in the first-line and received at least two cycles of PD-1/PD-L1 inhibitor-based therapy in the second-line setting after progression. We evaluated the efficacy and safety including overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), grade 3-5 treatment-related adverse effects (TRAE) and immune-related adverse events (irAEs). We also evaluated the relationship between clinical features and outcomes using univariate and multivariate analyses. Results: We enrolled 214 patients, with a median age 67.9 (47 – 87) years, male sex 66.8%, 201(93.9%) ESCC and 11(5.1%) EAC. In all patients, the mOS and mPFS were 9.6 (95%CI 9.1-10.1) months and 4.4 (95%CI 4.1-4.7) months; The ORR was 33.2%, DCR was 65.9%. 162 (75.7%) patients treated with immunochemotherapy(I+C), 37 (17.3%) patients received immunotherapy combined with anti-angiogenic drugs(I+A) and 15 (7.0%) patients treated with immunotherapy combined with chemotherapy and anti-angiogenic drugs(I+C+A). The mOS were 9.1 (95% CI 8.4 – 9.8) months, 10.0 (95% CI 8.7 – 11.3) months and 11.5 (95% CI 10.7 – 12.3) months, respectively. The mPFS were 4.3m (95%CI 4.0-4.6) months, 4.3 (95%CI 4.0-14.6) months and 6.0 (95%CI 4.2-6.4) months. mPFS and mOS did not have significant difference between these groups. Univariate and multivariate analyses showed that PFS more than 6 months on first-line therapy was an independent prognostic factor for PFS and OS in second-line therapy. The incidence of grade ≥ 3 TRAEs and irAEs were 25.7% and 5.6%. No treatment-related deaths occurred. Conclusions: This real-world data showed PD-1 or PD-L1 inhibitors retreatment might have good efficacy and manageable safety in EC patients who progress after first-line immunochemotherapy. [Table: see text]

First-line immunochemotherapy modulates peripheral immune landscape in advanced gastric cancer and gastroesophageal junction cancer (GC/GEJC): Prediction of response to combination therapy.

e14540 Background: The use of immunochemotherapy has brought about a change in the treatment of advanced or metastatic GC/GEJC, but only a subset of patients could benefit substantially. Therefore, seeking efficacious biomarkers to identify favorable populations for the regimen is imperative. This study aims to explore predictive markers and potential mechanism of combination therapy for GC/GEJC in real-world settings based on blood proteomic biopsy. Methods: This is a prospective, single-center trial in which all patients are adults with advanced or metastatic GC/GEJC confirmed by pathology or imaging. 30 eligible patients will receive PD-1 mab (sintilimab/nivolumab (NIVO) Q3W) and chemotherapy (SOX/XELOX Q3W) regardless of programmed death ligand-1 status. Blood samples were collected before treatment and after every two treatment cycles for Olink Target 96 IO analysis. CT scans were performed after every two cycles and will be categorized as responding (complete response plus primary response) or non-responding (progress disease plus stable disease) according to RECIST 1.1. Results: As of January 17, 2024, a total of 21 patients were enrolled. Eight of these patients received 16 samples before and after treatment, with 4 each of the 8 patients responding and non-responding. By analyzing the baseline samples comparing the responding and non-responding groups, it was found that patients in the responding group had lower expression of serum PD-L1 (sPD-L1) ( p=0.015). In the post-treatment samples, angiopoietin 1 was found to be poorly expressed in the responding patients ( p&lt;0.001). In contrast, high expression of angiopoietin 2 in post-treatment blood samples was more pronounced in non-responders compared to pre-treatment ( p=0.020). Additionally, we observed that immunotherapy can modify the immune microenvironment by up-regulating the T cell receptor signaling and NK cell-mediated toxic effects pathways. These pathways may be potential targets for treatment. Conclusions: In summary, low sPD-L1 level before treatment may be a predictive biomarker for better efficacy of immuno-combination chemotherapy in advanced GC/GEJC; whereas elevation of angiopoietin after treatment predicts poor efficacy and suggests that antiangiogenic therapy may subsequently be added in non-responding patients. We are further recruiting more patients to obtain more accurate conclusions. Clinical trial information: ChiCTR2300078000 .

First-line sintilimab combined with platinum-based chemotherapy in extensive stage small cell lung cancer: A phase II study and post-hoc biomarker analysis.

e20127 Background: Immune checkpoint inhibitors (ICIs) combined with etoposide and platinum-based chemotherapy improves prognosis of patients with extensive-stage small-cell lung cancer (ES-SCLC). However, nearly 40% of patients do not benefit from Immunochemotherapy. Herein, this phase II study of first-line immunochemotherapy was conducted aiming to investigate potential biomarkers associated with therapeutic efficacy. Methods: A multi-center, single-arm, prospective phase II trial (ChiCTR2000038354) was designed and conducted to evaluate the efficacy and safety of sintilimab combined with platinum-based chemotherapy in patients with ES-SCLC who had not previously received treatment. The primary endpoint of this study is progression-free survival (PFS), with patients being defined as disease progression according to RECIST 1.1. Pre-treatment FFPE samples were analyzed using whole exome sequencing (WES) and whole transcriptome sequencing (WTS) to investigate biomarkers. Results: A total of 44 patients were included in the study, with a median follow-up of 10 months and a median PFS of 7.57 months. 8 patients with a PFS greater than 6 months were defined as the responder group (R group) and 5 patients with a PFS less than 6 months belonged to the non-responder group (NR group). WES and WTS were performed on the pre-treatment samples of these 13 patients. WES results revealed mutation frequencies of TP53 (69%), RB1 (31%) and FAT1 (31%) aligning with prior research. Significantly, ZFHX4 mutations correlated with R group (p = 0.05). Genomic instability, as defined by Homologous Recombination Deficiency (HRD) scores, displayed higher scores in NR group than in R group (p = 0.023), which suggests potential benefits of PARP inhibition in the NR group. WTS data revealed that higher M2/M1 macrophage ratio (p = 0.028) in NR group. Additionally, the NR group demonstrated significant VEGFA overexpression. Besides, NOTCH-signaling (p = 0.034), KRAS-signaling-DN (p&lt;0.001), Angiogenesis (p&lt;0.001) and EMT (p&lt;0.001) pathway were also enriched in NR group. Conversely, M1 macrophages (p = 0.079), CD4+T cells (p = 0.093), Mast cells (p = 0.045), NK cells (p = 0.045) and neutrophils (p = 0.06) was higher in R group. Conclusions: This study highlights genomic instability as well as activation of cancer hallmarks such as angiogenesis, EMT may result the resistance to immunotherapy in ES-SCLC patients. These findings may shed light on combinational strategy overcoming therapeutic resistance. Clinical trial information: ChiCTR2000038354.

Prognostic relevance of circulating lymphoma cells at diagnosis in newly diagnosed follicular lymphoma patients.

Follicular lymphoma (FL) is the most common indolent B-cell non-Hodgkin lymphoma. Circulating lymphoma (CL) cells can be seen at diagnosis in some FL patients, however, previous studies evaluating this have shown mixed results. Therefore, we sought to evaluate the impact of CL at diagnosis on outcomes in patients with newly diagnosed FL using data from a single center. Patients were divided into CL+ and CL- based on immunophenotyping via peripheral blood (PB) flow cytometry. CL was defined as detectable clonally restricted B-cells that matched the actual or expected B-cell immunophenotype of FL. The primary endpoint was progression-free survival (PFS) after first-line treatment and secondary endpoints included overall response rate (ORR), overall survival (OS), diagnosis to treatment interval (DTI), progression of disease within 2years of diagnosis (POD24), and cumulative incidence of transformation between the two groups. Among the 541 patients with FL, 204 had PB flow cytometry performed at diagnosis, and after excluding patients not meeting the eligibility criteria, 147 cases remained with 24 (16%) CL+ at diagnosis. Patients in the CL+ group were younger (53 vs. 58years, p=0.02), had more extranodal involvement (83% vs. 44%, p<0.01), follicular lymphoma international prognostic index 3-5 (55% vs. 31%, p=0.01), and a higher proportion received first-line immunochemotherapy (75% vs. 43%, p=0.01) compared to the CL-group. The median PFS was not significantly different between CL+ (6.27years, 95% CI=3.61-NR) and CL- (6.61years, 95% CI=5.10-9.82) cohorts regardless of the first-line treatment or level of absolute PB CL cells. There was no significant difference in ORR, median OS, DTI, POD24, and cumulative incidence of transformation between the two groups. In our study, we found that the presence of CL cells at diagnosis in FL in the contemporary era did not impact outcomes and survival.

Combinational therapy of CAR T-cell and HDT/ASCT demonstrates impressive clinical efficacy and improved CAR T-cell behavior in relapsed/refractory large B-cell lymphoma

BackgroundApproximately two-thirds of patients with relapsed or refractory large B-cell lymphoma (R/R LBCL) do not respond to or relapse after anti-CD19 chimeric antigen receptor T (CAR T)-cell therapy, leading to...

First-line treatments for extensive-stage small-cell lung cancer with immune checkpoint inhibitors plus chemotherapy: a China-based cost-effectiveness analysis.

To determine the cost-effectiveness of imported immune checkpoint inhibitors (ICIs) such as atezolizumab and durvalumab, and domestic ICIs like serplulimab and adebrelimab, in combination with chemotherapy for extensive-stage small cell lung cancer (ES-SCLC) in China. Using a 21-day cycle length and a 20-year time horizon, a Markov model was established to compare the clinical and economic outcomes of five first-line ICIs plus chemotherapy versus chemotherapy alone, as well as against each other, from the perspective of the Chinese healthcare system. Transition probabilities were estimated by combining the results of the CAPSTONE-1 trial and a published network meta-analysis. Cost and health state utilities were collected from multiple sources. Both cost and effectiveness outcomes were discounted at a rate of 5% annually. The primary model output was incremental cost-effectiveness ratios (ICERs). A series of sensitivity analyses were preformed to assess the robustness of the model. In the base-case analysis, the addition of first-line ICIs to chemotherapy resulted in the ICERs ranged from $80,425.31/QALY to $812,415.46/QALY, which exceeded the willing-to-pay threshold set for the model. When comparing these first-line immunochemotherapy strategies, serplulimab plus chemotherapy had the highest QALYs of 1.51286 and the second lowest costs of $60,519.52, making it is the most cost-effective strategy. Our subgroup-level analysis yielded results that are consistent with the base-case analysis. The sensitivity analysis results confirmed the validity and reliability of the model. In China, the combination of fist-line ICIs plus chemotherapy were not considered cost-effective when compared to chemotherapy alone. However, when these fist-line immunochemotherapy strategies were compared with each other, first-line serplulimab plus chemotherapy consistently demonstrated superiority in terms of cost-effectiveness. Reducing the cost of serplulimab per 4.5 mg/kg would be a realistic step towards making first-line serplulimab plus chemotherapy more accessible and cost-effective.

Predictive progression outcomes and risk stratification in patients with recurrent or metastatic nasopharyngeal carcinoma who received first-line immunochemotherapy.

Progression after first-line immunochemotherapy (ICT) for recurrent or metastatic nasopharyngeal carcinoma (R/M NPC) is a clinical concern due to subsequent limited treatment options. This study firstly predicted the progress outcome. A cohort of 186 R/M NPC cases that received first-line ICT was included for developing a Cox regression model for progression-free survival (PFS) and risk stratification, which was verified by cross-validation. Discrimination and calibration were evaluated. Progression sites in risk groups was shown with a Sankey diagram. Baseline predictors including liver metastasis, trend of plasma Epstein-Barr virus DNA copies, lymphocyte-to-monocyte ratio, and level of platelet and lactate dehydrogenase were identified for model construction, which stratify the cohort into low, middle, and high-risk groups. The overall concordance index (C-index) was 0.67 (95% CI 0.62-0.73). The area under the curve (AUC) was 0.68 (95% CI 0.60-0.76), 0.74 (95% CI 0.66-0.82), 0.75 (95% CI 0.65-0.84) at predicting 12, 18, and 24months PFS, indicating a moderate accuracy. Cross-validation showed the model performance was robust. Compared with the low-risk group (median PFS: 24.4months, 95% CI 18.4months to not reached), the high-risk group (median PFS: 7.1months, 95% CI 6.4-10.1months; hazard risk: 7.4, 95% CI 4.4-12.4, p < 0.001) progressed with more liver metastasis after ICT resistance. It was the first study that described the risk factors and progression characteristics in R/M NPC patients who received first-line ICT, investigating the progression patterns, which was helpful to identify patients with different risks and help guide personalized interventions.

Comparison of different maintenance regimens following first-line immunochemotherapy for advanced non-small cell lung cancer.

Immunochemotherapy is the standard first-line treatment for non-small cell lung cancer (NSCLC). However, the ideal combination strategy and maintenance regimen remain uncertain. This study aims to compare the clinical efficacy of different first-line maintenance regimens for advanced EGFR/ALK (epidermal growth factor receptor/anaplastic lymphoma Kinase) negative NSCLC and explore the eligibility of chemo-free maintenance. We conducted a retrospective evaluation of 1,510 EGFR/ALK negative NSCLC patients who received immune checkpoint inhibitors (ICIs) treatment in our center from 2019 to 2021. Patients who had controlled disease after 2-6 cycles of first-line ICIs in combination with platinum-based doublet chemotherapy with or without anti-angiogenesis were included. Four maintenance regimens were analyzed: ICIs plus platinum-free chemotherapy with (group 1, I+C+A) or without anti-angiogenesis maintenance (group 2, I+C), single-agent ICIs maintenance (group 3, I) or ICIs plus anti-angiogenesis maintenance (group 4, I+A). For group 3-4, rechallenge with initial chemo-agents was given upon the first progression, those who achieved controlled disease were repeatedly followed by another chemo-free period. The primary outcome was progression-free survival (PFS). Notably, for group 3-4, PFS was characterized as the duration between treatment initiation and failure of rechallenge (last disease progression). In total, 140 eligible patients in the maintenance phase were analyzed, with 20, 40, 42, and 38 patients in groups 1 to 4, respectively, displaying comparable baselines. Median PFS was similar in the I+C+A maintenance group (22.6 months), I+C maintenance group (21.0 months), and I+A maintenance group (21.5 months), whereas PFS was inferior in group 4 with I maintenance alone (13.4 months). Median chemo-free duration were 6.3 months in I maintenance group, while 13.5 months in I+A maintenance group. During the maintenance period of group 1 to 4, 25%, 25%, 19%, and 42% of patients experienced partial response (PR) again, respectively. Fifty-five percent, 65%, 48% and 61% of patients sustained durable disease control at the end of follow-up. In group 4, 39% of patients received progressive disease (PD) and rechallenge initial chemo-agents. Fifty percent of patients achieved PR and resumed to chemo-free maintenance. We showed that following first-line immunochemotherapy, chemo-free maintenance by ICIs plus anti-angiogenesis and on-demand chemo-rechallenge provided comparable efficacy to chemo-on maintenance in terms of PFS, thus allowing the minimization of cytotoxic drugs without compromising therapeutic effectiveness. In addition, anti-angiogenesis is essential during chemo-free maintenance.

Circulating Tumor DNA Dynamics as Early Outcome Predictors for Lisocabtagene Maraleucel as Second-Line Therapy for Large B-Cell Lymphoma from the Phase 3 TRANSFORM Study

Background: While the prognostic value of MRD using ultrasensitive circulating tumor DNA (ctDNA) assays after first-line immunochemotherapy for DLBCL has been shown (Roschewski M, et al. Blood 2022;140[suppl 1]:785), its relevance to outcomes after second-line (2L) treatment with CD19-directed CAR T cell therapy remains unclear. The phase 3 TRANSFORM study (NCT03575351) showed statistically significant and clinically meaningful improvements in event-free survival (EFS), CR rate, and PFS for lisocabtagene maraleucel (liso-cel) compared with standard of care (SOC) for patients (pts) with primary refractory or early relapsed large B-cell lymphoma (LBCL) eligible for autologous HSCT (Kamdar M, et al. Lancet 2022; Abramson JS, et al. Blood 2023). Here, we report longitudinally measured ctDNA levels from TRANSFORM as a prospective measure of disease burden and describe the predictive value of ctDNA after 2L liso-cel therapy for LBCL. Methods: From the original randomized population (n = 184), 551 plasma samples from 160 pts (liso-cel, n = 79; SOC, n = 81) were used for ctDNA assessment in a blinded manner by Phased Variant (PV) Enrichment and Detection Sequencing (PhasED-Seq) at Foresight Diagnostics. Tumor-derived PVs were identified directly from baseline plasma samples taken at screening without use of tumor tissue; matched DNA from peripheral blood mononuclear cells was used to censor germline variants and clonal hematopoiesis. PVs were used to longitudinally assess ctDNA on the day of liso-cel infusion; at Day 15; and Months 1, 2, 3, and 12 after infusion. For the SOC arm, only pretreatment samples were evaluated. ctDNA levels were compared with baseline characteristics, responses by Lugano 2014 criteria, and EFS. Pts/samples were reported as having detectable MRD when ctDNA levels exceeded a detection threshold (≈1:10 6 cell-free DNA molecules) corresponding to 98% specificity. Results: PVs were identified from 136 of 160 pts (85%) with evaluable pretreatment samples from the liso-cel and SOC treatment arms. The remaining samples had lower disease burden (sum of product of diameters[SPD]; 13%) or failed quality check (2%). Pretreatment ctDNA levels varied widely (median [IQR]: 136 [35‒696] haploid genome equivalents/mL) and were correlated with disease indices portraying higher-risk disease, including stage ( P = 0.02), age-adjusted International Prognostic Index ( P &amp;lt; 0.0001), disease burden (SPD; P &amp;lt; 0.0001), and LDH ( P &amp;lt; 0.0001). Serial ctDNA levels were evaluated after liso-cel infusion in 63 pts. Achieving undetectable ctDNA was associated with achieving CR and longer EFS at all time points after liso-cel infusion. ctDNA levels decreased rapidly in pts who achieved CR at Month 3, with 50% (17/34) having undetectable ctDNA by Day 15 after liso-cel infusion. Conversely, 89% of pts (16/18) with PD at Month 3 still had detectable ctDNA at Day 15 with lower levels of ctDNA clearance. These results highlight significant enrichment of undetectable ctDNA observed as early as Day 15 after infusion between pts with Month 3 CR versus PD ( P = 0.006). ctDNA clearance in pts who achieved CR at Month 3 continued to deepen further over time, with undetectable ctDNA rates of 63%, 74%, and 86% at 1, 3, and 12 months after liso-cel infusion, respectively. Furthermore, most pts in CR by PET/CT had undetectable ctDNA at paired time points (71%), confirming that pts achieving CR also achieved durable molecular remission. In the cases with discordant CR and ctDNA results, detection of residual ctDNA was significantly prognostic for shorter EFS at all respective response assessments (fraction of CR cases with residual ctDNA at 1 month and Log-rank test P value for EFS: 47% [15/32], P = 0.011; 3 months: 26% [9/34], P = 0.025; 12 months: 13% [4/31], P = 0.003). Conclusions: Achieving undetectable ctDNA in the first 3 months and as early as 15 days after liso-cel infusion was significantly associated with durable clinical benefit. Conversely, detectable ctDNA captured relapse risk unmeasured by imaging. These results demonstrate the potential clinical value of ctDNA monitoring as a biomarker for disease surveillance and as an early predictor of clinical benefit of liso-cel treatment for LBCL, which could guide and accelerate future clinical trials.

Inhibition of glutaminase-1 in DLBCL potentiates venetoclax-induced antitumor activity by promoting oxidative stress

AbstractDiffuse large B-cell lymphoma (DLBCL) is the most common lymphoma in adults, but first-line immunochemotherapy fails to produce a durable response in about one-third of the patients. Because tumor cells often reprogram their metabolism, we investigated the importance of glutaminolysis, a pathway converting glutamine to generate energy and various metabolites, for the growth of DLBCL cells. Glutaminase-1 (GLS1) expression was robustly detected in DLBCL biopsy samples and cell lines. Both pharmacological inhibition and genetic knockdown of GLS1 induced cell death in DLBCL cells regardless of their subtype classification, whereas primary B cells remained unaffected. Interestingly, GLS1 inhibition resulted not only in reduced levels of intermediates of the tricarboxylic acid cycle but also in a strong mitochondrial accumulation of reactive oxygen species. Supplementation of DLBCL cells with α-ketoglutarate or with the antioxidant α-tocopherol mitigated oxidative stress and abrogated cell death upon GLS1 inhibition, indicating an essential role of glutaminolysis in the protection from oxidative stress. Furthermore, the combination of the GLS1 inhibitor CB-839 with the therapeutic BCL2 inhibitor ABT-199 not only induced massive reactive oxygen species (ROS) production but also exhibited highly synergistic cytotoxicity, suggesting that simultaneous targeting of GLS1 and BCL2 could represent a novel therapeutic strategy for patients with DLBCL.

Comparative analysis of using atezolizumab vs. durvalumab in combination with platinum-containing chemotherapy in adult patients with advanced small cell lung cancer

Background. In recent decades, a course of chemotherapy with etoposide (EP) and platinum preparations (сarboplatinum, CP) has been recommended as a standard first-line treatment option in patients with advanced small cell lung cancer (SCLC), but with the advent of new immunological drugs, immune checkpoint inhibitors, approaches to therapy have changed. Based on randomized clinical trials, courses combining traditional platinum-containing chemotherapy with inhibitors of programmed death-ligand 1 (PD-L1) atezolizumab (ATZ) or durvalumab (Durv) have been included in many clinical recommendations for oncologists.Objective: to evaluate the clinical and cost-effectiveness of using ATZ and Durv as first-line therapy in advanced SCLC adult patients within the Russian healthcare system.Material and methods. The model of treatment of advanced SCLC adult patients in conditions of the healthcare system of the Russian Federation included the most popular options for first-line immunochemotherapy: CP/EP + ATZ and CP/EP + Durv courses. Pharmacoeconomic cost-effectiveness analysis, sensitivity analysis of the selected model to changes in its initial parameters, budget impact analysis were carried out.Results. The total medical costs for CP/EP + ATZ course (2,310,546.07 rubles) were significantly lower than for the CP/EP + Durv course (4,081,833.98 rubles). With comparable costs for the treatment of complications (426,175.17 and 407,704.50 rubles, respectively), the cost of Durv exceeded ATZ by 94.8%. When conducting a cost-effectiveness analysis, the advantage was retained by the CP/EP + ATZ course, the cost-effectiveness ratios for which amounted to 187,849.27 rubles per month of patient's life and 444,335.78 rubles per month of patient's life without progression (for CP/EP + Durv, 316,421.24 and 800,359.60 rubles, respectively). When choosing the CP/ET + ATZ strategy, the savings will be 128,571.96 rubles per month of life and 356,023.82 rubles per month of life without progression. Sensitivity analysis demonstrated the stability of the developed model: to increase in the price of the CP/EP + ATZ course up to +68%; to decrease in overall survival with the course of CP/EP + ATZ up to –40%; to decrease in progression-free survival with the course of CP/EP + ATZ to –44%. Budget impact analysis showed that with a possible cohort size of 4,448 people an increase in the proportion of patients receiving CP/EP + ATZ course from 70% to 90% will reduce budget costs by 1,575,737,725.38 rubles per year, which will allow additional treatment of 681.9 advanced SCLC patients per year (+15.3%).Conclusion. The use of ATZ combined with standard platinum-containing chemotherapy in advanced SCLC adult patients as the first-line therapy is clinically and cost-effective strategy within the Russian healthcare system, as it allows to reduce therapy costs compared to Durv and treat more SCLC patients, which fully corresponds to the target indicators of the federal program “Oncology”.

Lenalidomide in Combination with Etoposide Induced Ferroptotic Cell Death in DLBCL

Background ： Relapse/refractory(R/R) DLBCL after first-line immunochemotherapy have unfavorable outcomes, treatment of which remains challenging. The combination of multiple drugs in the second-line regimen improves efficacy but also increases toxicity, often leading to treatment-related adverse events (AEs) or dose reduction/interruption. This study aims to explore the effects of lenalidomide in combination with ibrutinib in diffuse large B-cell lymphoma and investigate its potential mechanisms. Methods: 1. From February 2019 to June 2023, patients aged 60 and above who received R 2-ICE regimen were analyzed for the efficacy and AE of the second-line therapy. 2. Human DLBCL cell lines SU-DHL-4 and U2932 were screened using the CCK-8 assay to demonstrate the synergistic cytotoxic effect of different drugs on DLBCL cells. Subsequently, various experiments were conducted to investigate whether oxidative damage occurred and explore the underlying mechanisms . These experiments included measurement of intracellular iron levels, MDA assay, detection of H 2O 2 and ·OH levels, ROS assay, assessment of mitochondrial membrane potential, and Hoechst staining. 3. SCID mouse model with subcutaneous xenografts of SU-DHL-4 cells in the right thigh was established. Different chemotherapy regimens, including PBS, R 2, R 2-ICE, and R 2-E, were administered to the mice, and the tumor-inhibitory effects and in vivo toxicity (evaluated based on body weight) of these treatments were observed. Results: 1. A total of 19 patients aged 60 years and above with relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL) received the R2-ICE regimen as second-line chemotherapy. They completed at least 2 treatment cycles, and the therapeutic efficacy was evaluated. Short-term efficacy: Overall Response Rate (ORR) was 81% (43.75% Complete Response [CR], 37.5% Partial Response [PR]). Long-term efficacy: Median follow-up of 30 months, with 1-year Progression-Free Survival (PFS) of 42.9% and 2-year PFS of 32.1%. One-year Overall Survival (OS) was 75%, and 2-year OS was 37.5%（Figure1A-B）. 2. Through CCK-8 cell proliferation assay, it was observed that lenalidomide，carboplatin and etoposide exerted time- and dose-dependent inhibitory effects on SU-DHL-4 and U2932 cells. Different IC50 concentrations of these drugs were chosen after 48 hours of treatment, and lenalidomide was administered in combination with etoposide or carboplatin. By calculating the CCK-8 cell survival rate and drug synergy formula, it was determined that lenalidomide in combination with etoposide had a synergistic inhibitory effect on DLBCL cell lines. Further CCK-8 experiments showed that ferroptosis inhibitor Fer-1-treated cells partially resisted the cytotoxic effect of lenalidomide in combination with etoposide on DLBCL cells (all differences were statistically significant, Figure 1. C-E). These findings indicate that lenalidomide in combination with etoposide suppresses DLBCL proliferation via the ferroptosis pathway. 3. Experiments of SU-DHL-4 cells were divided into four groups：control，len, eto，len+eto. By performing intracellular iron content detection, MDA assay, H2O2 and ·OH level detection, ROS experiment, mitochondrial membrane potential detection, and Hoechst staining, it was demonstrated that lenalidomide in combination with etoposide induces intracellular accumulation of ROS through an iron-dependent Fenton reaction, leading to cell membrane and DNA damage and DLBCL cell death(Figure 2). 4. SU-DHL-4 pretreated with Fer-1, and the experiments were divided into four groups: control, control + Fer-1, len+eto, len+eto+ Fer-1. By performing experiment mentioned above demonstrated that Fer-1 could reverse the oxidative damage induced by lenalidomide in combination with etoposide（Figure 3）. 5.In in vivo experiments, chemotherapy administered with PBS, R 2, R 2-E, and R 2-ICE regimens showed that R 2-E and R 2-ICE had similar tumor-suppressive effects and R 2-E were lower toxicity（Figure 4）. Conclusion: Lenalidomide combined with etoposide enhances intracellular reactive oxygenlevels through the ferroptosis pathway, resulting in synergistic killing of DLBCL cells through lipid and DNA oxidation damage. In vivo experiments confirmed that R 2-E showed similar antitumor effects with R 2-ICE and had lower toxicity.