Trend For Overall Survival Research Articles

RADT-04. SEQUENCING OF CHECKPOINT INHIBITORS AND RADIOTHERAPY IN MELANOMA BRAIN METASTASES: A META-ANALYSIS OF COMPARATIVE STUDIES

Abstract OBJECTIVE Melanoma brain metastases significantly worsen prognosis, with incidence rates as high as 50%. While both immunotherapy and radiotherapy improve survival, the optimal sequencing remains undetermined. This meta-analysis aims to define the most effective treatment sequence for improving progression-free survival (PFS) and overall survival (OS). METHODS A review of the medical literature was conducted using online databases. Inclusion criteria consisted of English language, diagnosis of melanoma brain metastases, comparative studies of immune checkpoint inhibitors given before or after radiotherapy, and those that reported overall (OS) and progression-free (PFS) survival. Studies that reported mixed data that included concurrent immune checkpoint inhibitors with radiotherapy were excluded. A meta-analysis using the fixed effects and random effects models was conducted. RESULTS Our analysis included six retrospective studies encompassing 213 patients, with a median age of 62 years and follow-up of 22 months. The results indicate a clear disadvantage in PFS when immunotherapy precedes radiotherapy (HR=1.77; 95% CI 1.21-2.60; p=0.003; I2=13.5%). Similarly, initiating treatment with immune checkpoint inhibitors followed by radiotherapy showed a trend towards poorer OS compared to the reverse sequence, although this finding was of borderline significance (HR=1.39; 95%CI 0.97-1.99; p=0.07; I2=0%). CONCLUSIONS This meta-analysis, the first and largest to date, provides compelling evidence that initiating treatment with radiotherapy followed by immune checkpoint inhibitors significantly improves PFS with a trend for a better OS in patients with melanoma brain metastases. These findings suggest that radiotherapy should precede immunotherapy to optimize clinical outcomes in this patient population. Further research, particularly prospective studies, is necessary to confirm these results.

Survival outcomes of patients with gastric cancer treated with first-line nivolumab plus chemotherapy based on claudin 18.2 expression.

Claudin 18.2 has emerged as a viable therapeutic target in gastric cancer; however, its clinical relevance in the context of immune checkpoint inhibitor-based chemotherapy is not known. This study aimed to investigate the efficacy of nivolumab plus chemotherapy according to claudin 18.2 expression in patients with gastric cancer. This single-center study included patients with advanced gastric cancer who were treated with first-line nivolumab plus chemotherapy (n = 204) or chemotherapy alone (n = 183) whose claudin 18.2 immunohistochemistry results were available. Claudin 18.2 positivity (moderate-to-strong expression in ≥ 75% by the 43-14A clone) was analyzed in terms of efficacy outcomes. Among patients treated with nivolumab plus chemotherapy, 96 (47.1%) were assessed to have claudin 18.2-positive tumors. Between patients with claudin 18.2-positive and -negative tumors, objective response rate with nivolumab plus chemotherapy was comparable. Progression-free survival (PFS) and overall survival (OS) with nivolumab plus chemotherapy were comparable between those with claudin 18.2-positive and -negative tumors. For both subgroups with PD-L1 combined positive score ≥ 5 and < 5, PFS and OS with nivolumab plus chemotherapy were also comparable between patients with claudin 18.2-positive and -negative tumors. A consistent trend of favorable PFS and OS was observed with nivolumab plus chemotherapy compared to that of chemotherapy alone in both claudin 18.2-positive and -negative subgroups. The efficacy of nivolumab plus chemotherapy did not vary according to claudin 18.2 positivity. The clinical benefit of nivolumab plus chemotherapy over chemotherapy was consistently observed in claudin 18.2-positive and -negative gastric cancer cases.

Second-Line Fluoropyrimidine-Based Chemotherapy in Advanced Biliary Tract Cancer: A Meta-Analysis Based on Individual Patient-Level Data of Randomized Trials.

While fluoropyrimidine-based chemotherapy regimens are recommended second-line treatment for patients with advanced biliary tract cancer (BTC), there have been no studies comparing different regimens head-to-head. We performed individual patient-level meta-analysis based on data from the intention-to-treat population of the phase 2b NIFTY trial (liposomal irinotecan [nal-IRI] plus fluorouracil and leucovorin [5-FU/LV] vs. 5-FU/LV; NCT03542508) and the phase 2 FIReFOX trial (modified oxaliplatin plus 5-FU/LV [mFOLFOX] vs. modified irinotecan plus 5-FU/LV [mFOLFIRI]; NCT03464968). Pairwise log-rank tests and multivariable analysis using Cox proportional hazards modeling with shared frailty to account for the trial's effect were used to compare overall survival (OS) between regimens. A total of 277 patients were included. The nal-IRI plus 5-FU/LV group (n=88) showed significantly better OS compared to the mFOLFOX group (n=49, pairwise log-rank, p=0.02), and mFOLFIRI group (n=50, p =0.03). Multivariable analysis showed consistent trends in OS with adjusted hazard ratios of 1.39 (mFOLFOX vs nal-IRI plus 5-FU/LV, 95% CI 0.93-2.07, p=0.11) and 1.36 (mFOLFIRI vs nal-IRI plus 5-FU/LV, 95% CI 0.92-2.03, p=0.13), respectively. Compared to the 5-FU/LV group, the mFOLFOX group and the mFOLFIRI group did not show differences in terms of OS (pairwise log-rank p=0.83 and p=0.58, respectively). The nal-IRI plus 5-FU/LV group experienced more frequent diarrhea, while the mFOLFOX group experienced peripheral neuropathy. Nal-IRI plus 5-FU/LV showed favorable survival outcomes compared to mFOLFOX, mFOLFIRI, or 5-FU/LV. The safety profiles of these regimens should be considered along with efficacy.

Overall Survival in Real-World Patients with Unresectable Hepatocellular Carcinoma Receiving Atezolizumab Plus Bevacizumab Versus Sorafenib or Lenvatinib as First-Line Therapy: Findings from the National Veterans Health Administration Database.

Background/Objectives: This study evaluated comparative overall survival (OS) of United States veterans with unresectable hepatocellular carcinoma (uHCC) receiving first-line (1L) atezolizumab plus bevacizumab vs. sorafenib or lenvatinib, overall and across racial and ethnic groups. Methods: In this retrospective study, patients with uHCC who initiated atezolizumab plus bevacizumab (post-2020) or sorafenib or lenvatinib (post-2018) were identified from the Veterans Health Administration National Corporate Data Warehouse (1 January 2017-31 December 2022). Patient characteristics were evaluated in the year prior to 1L treatment initiation. Kaplan-Meier and multivariable Cox regression methods were used to compare OS starting from treatment between cohorts, both overall and by race and ethnicity. Results: Among the 1874 patients included, 405 (21.6%) received 1L atezolizumab plus bevacizumab, 1016 (54.2%) received sorafenib, and 453 (24.2%) received lenvatinib, with a median follow-up time of 8.5, 7.6, and 8.2 months, respectively. Overall, patients receiving atezolizumab plus bevacizumab had longer unadjusted median OS (12.8 [95% CI: 10.6, 17.1] months) than patients receiving sorafenib (8.0 [7.1, 8.6] months) or lenvatinib (9.5 [7.8, 11.4] months; both log-rank p < 0.001). After adjustment, atezolizumab plus bevacizumab was associated with a reduced risk of death by 30% vs. sorafenib (adjusted HR: 0.70 [95% CI: 0.60, 0.82]) and by 26% vs. lenvatinib (0.74 [0.62, 0.88]; both p < 0.001). OS trends in the White, Black, and Hispanic patient cohorts were consistent with that of the overall population. Conclusions: Atezolizumab plus bevacizumab was associated with improved survival outcomes compared with sorafenib and lenvatinib in patients with uHCC, both overall and across racial and ethnic subgroups.

Dissecting the Significance of Acid Phosphatase 1 Gene Alterations in Prostate Cancer.

The acid phosphatase 1 (ACP1) gene encodes low-molecular-weight protein tyrosine phosphatase, which is overexpressed in prostate cancer (PC) and a potential therapeutic target. We analyzed ACP1 expression in primary/metastatic PC and its association with molecular profiles and clinical outcomes. NextGen sequencing of DNA (592-gene/whole-exome sequencing)/RNA(whole-transcriptome sequencing) was performed for 5,028 specimens. ACP1-High/ACP1-Low expression was defined as quartile (Q4/1) of RNA transcripts per million (TPM). DNA mutational profiles were analyzed for ACP1-quartile-stratified samples. Gene set enrichment analysis was used for Hallmark collection of pathways. PD-L1+(≥2+, ≥5%; SP142) was tested by immunohistochemistry. Tumor microenvironment's (TME) immune cell fractions were estimated by RNA deconvolution/quanTIseq. Overall survival (OS) was assessed from initial diagnosis/treatment initiation to death/last follow-up. We included 3,058 (60.8%) samples from the prostate, 634 (12.6%) from lymph node metastases (LNMs), and 1,307 (26.0%) from distant metastases (DMs). ACP1 expression was higher in LNM/DM than prostate (49.8/47.9 v 44.1 TPM; P < .0001). TP53 mutations were enriched in ACP1-Q4 (37.9%[Q4] v 27.0%[Q1]; P < .001) among prostate samples. Pathways associated with cell cycle regulation and oxidative phosphorylation were enriched in ACP1-Q4, whereas epithelial-mesenchymal transition and tumor necrosis factor-alpha signaling via nuclear factor kappa-light-chain-enhancer of activated B-cell pathways were enriched in ACP1-Q1. Neuroendocrine and androgen receptor signaling was increased in ACP1-Q4. M2 macrophages and natural killer cell fractions were increased, whereas T cells and M1 macrophages were decreased in ACP1-Q4. While OS differences between ACP1-Q1/Q4 were not statistically significant, there was a trend for worse OS among ACP1-Q4 prostate samples (Q4 v Q1: hazard ratio [HR], 1.19 [95% CI, 0.99 to 1.42]; P = .06) and DM (HR, 1.12 [95% CI, 0.93 to 1.36]; P = .22) but not LNM (HR, 0.98 [95% CI, 0.74 to 1.29]; P = .87). ACP1-High tumors exhibit a distinct molecular profile and cold TME, highlighting ACP1's potential role in PC pathogenesis and novel therapeutic targeting.

Tertiary lymphoid structures' pattern and prognostic value in primary adenocarcinoma of jejunum and ileum.

To date, there have been no reports on tertiary lymphoid structures (TLS) in primary adenocarcinoma of jejunum and ileum. In this study, we employed digital pathology image analysis software to classify and quantify TLS, and evaluated the maturity of TLS using immunohistochemistry. Molecular genetics and immunotherapy biomarker detection were performed using next-generation sequencing technology, such as tumor mutational burden (TMB) and microsatellite instability (MSI). The aim of this study was to investigate the presence, location, maturity, association with immunotherapy biomarkers, and prognostic value of TLS in primary adenocarcinoma of jejunum and ileum. Compared to secondary follicle-like TLS (SFL-TLS), intra-tumoral TLS (IT-TLS) were more likely to manifest as early TLS (E-TLS) (P = 0.007). Compared to IT-TLS, SFL-TLS had a higher propensity to occur at the invasive margin(IM) (P = 0.032) and showed a trend towards being more prevalent at the tumor periphery (P = 0.057). In terms of immunotherapy biomarkers, there was a higher trend of IM-TLS density in PD-L1(22C3) score CPS < 1 group compared to PD-L1(22C3) score CPS ≥ 1 group (P = 0.071). TMB-H was significantly associated with MSI-H (P = 0.040). Univariate survival analysis demonstrated a correlation between high SFL-TLS group and prolonged disease free survival (DFS) (P = 0.047). There was also a trend towards prolonged DFS in the E-TLS-high group compared to the E-TLS-low group (P = 0.069). The peri-tumoral TLS (PT-TLS)-high group showed a trend of prolonged overall survival (OS) compared to the PT-TLS-low group (P = 0.090). In conclusion, the majority of TLS were located at the invasive margin and tumor periphery, predominantly consisting of mature TLS, while IT-TLS were mainly immature. Notably, TMB was closely associated with MSI and PD-L1, indicating potential predictive value for immunotherapy in primary adenocarcinoma of jejunum and ileum.

Patient-reported outcomes in the subpopulation of patients with mismatch repair-deficient/microsatellite instability-high primary advanced or recurrent endometrial cancer treated with dostarlimab plus chemotherapy compared with chemotherapy alone in the ENGOT-EN6-NSGO/GOG3031/RUBY trial

ObjectiveIn the ENGOT-EN6-NSGO/GOG3031/RUBY trial, dostarlimab+carboplatin–paclitaxel demonstrated significant improvement in progression free survival and a positive trend in overall survival compared with placebo+carboplatin–paclitaxel, with manageable toxicity, in patients with primary advanced...

Long-Term Survival and Immune Reconstitution of Donor-Derived Chimeric Antigen Receptor T-Cell Therapy for Childhood Molecular Relapse of B-Cell Acute Lymphoblastic Leukemia After Allogeneic Hematopoietic Stem Cell Transplantation

Measurable residual disease (MRD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an independent risk factor for relapse in patients with acute lymphoblastic leukemia (ALL). This study aimed to assess the efficacy, safety, and immune reconstitution of chimeric antigen receptor T-cell (CAR-T) therapy in patients with molecular relapse after allo-HSCT. Eleven patients with molecular relapse of B-cell-ALL who underwent CAR-T therapy after allo-HSCT were enrolled. The rate of MRD negativity after a month of CAR-T infusion was 81.8%. Patients who bridged to second-HSCT after CAR-T therapy (n = 3) showed a trend of higher 3-year leukemia-free survival and 3-year overall survival than those who did not (n = 8; 100% vs. 75.0%; 95% CI, 45.0–104.9%; p = 0.370). No treatment-related mortalities were observed. Among patients who did not bridge to second-HSCT and remained in complete remission until the last follow-up (n = 6), five of them had not recovered normal immunoglobulin concentrations with a median follow-up of 43 months. CAR-T therapy may be a safe and effective treatment strategy to improve survival after allo-HSCT; however, the problem of prolonged hypogammaglobulinemia in patients who do not bridge to second-HSCT is worth noting.

Monitoring Overall Survival in Pivotal Trials in Indolent Cancers

Indolent cancers are characterized by lengthy overall survival (OS) times. Therefore, powering a clinical trial to provide definitive assessment of the effects of an experimental intervention on OS in a reasonable timeframe is generally infeasible. Instead, the primary outcome in many pivotal trials is an intermediate clinical response such as progression-free survival. In several recently reported pivotal trials of interventions for indolent cancers that yielded promising results on an intermediate outcome, however, more mature data or post-approval trials showed concerning OS trends. These problematic results have prompted a keen interest in quantitative approaches for monitoring OS that can support regulatory decision-making related to the risk of an unacceptably large detrimental effect on OS. The US Food and Drug Administration, the American Association for Cancer Research, and the American Statistical Association recently organized a one-day multi-stakeholder workshop entitled “Overall Survival in Oncology Clinical Trials.” In this article, we propose OS monitoring guidelines tailored for the setting of indolent cancers. Our pragmatic approach is modeled, in part, on the monitoring guidelines the FDA has used in cardiovascular safety trials conducted in Type 2 Diabetes Mellitus. We illustrate proposals through application to several examples informed by actual case studies.

Real-World Data with CDK4/6 Inhibitors-A Single Center Experience from Croatia.

There are limited real-world data (RWD) regarding the use of cyclin-dependent kinase (CDK) 4/6 inhibitors in western Balkan. The aim of our study was thus to analyze factors influencing progression-free survival (PFS) and overall survival (OS), along with the differences in adverse effects of CDK 4/6 therapy in a tertiary healthcare center in Croatia. We evaluated medical and demographic data for 163 consecutive patients with metastatic breast cancer treated with CDK4/6 inhibitors for at least one month, from October 2018, after the drug became available in Croatia. Eligible patients in our study were those patients who were treated with palbociclib, ribociclib, or abemaciclib. The median PFS of CDK4/6 inhibitors treatment was 2.2 years (95% CI 1.8-3.3), with the longest ongoing treatment for 5.4 years. Treatment with CDK4/6 inhibitors in the first line was associated with a longer PFS compared to the second line or beyond (HR 0.50, 95% CI 0.3-0.9), and patients without liver metastasis exhibited longer survival compared to patients with liver metastasis (HR 0.46, 95% CI 0.2-0.8) (both p < 0.05). Regarding the choice of CDK4/6 inhibitors, ribociclib exhibited longer PFS compared to palbociclib (HR 0.49, 95% CI 0.29-0.82) (p = 0.0032), although the effect was not statistically significant when separating patients who were treated with CDK4/6 inhibitors in the first-line (HR 0.59, 95% CI 0.29-1.2), or second- or later-line therapy (0.49, 95% CI 0.15-1.55); the trend was present in both lines, however. The presence of liver metastasis (p = 0.04), initial luminal A grade (p = 0.039), and time to metastasis up to 5 years from the initial cancer (p = 0.002) were the only factors that remained statistically significant for PFS in multivariate analysis. Median OS since the diagnosis of metastatic disease was 4.5 years (95% CI 3.9-6.3), median OS since the start of CDK4/6 inhibitors treatment was 3.7 years (95% CI 3.4-4.4), while median OS from initial cancer diagnosis was 15.8 years (95% CI 13.8-18.3). There was no difference in OS based on the choice of CDK4/6 inhibitor (p = 0.44) or the adjuvant hormonal therapy (p = 0.12), although a nonsignificant trend for better OS with ribociclib was present for both regardless of whether it was in first- or second/later-line therapies (p > 0.05). In a multivariate analysis, only the presence of liver metastasis (p = 0.0003) and time to metastasis under 5 years from primary breast cancer (p = 0.03) were associated with a worse OS. Our study provides the RWD with the use of CDK4/6 inhibitors in the treatment of metastatic HR+/HER2- breast cancer. To our best knowledge, there are limited RWD regarding CDK 4/6 inhibitors use in western Balkan; thus, our study provides valuable data from everyday clinical practice for this region of Europe, bridging the gap between randomized clinical trials and clinical reality in western Balkan.

Combination Therapy of Atezolizumab, Bevacizumab, Carboplatin, and Paclitaxel for Metastatic Non-squamous Non-small Cell Lung Cancer With Epidermal Growth Factor Receptor (EGFR)-Tyrosine Kinase Inhibitor Resistance and EGFR Mutations.

Atezolizumab, bevacizumab, carboplatin, and paclitaxel (ABCP) combination therapyhas a potential efficacy in a specific subset of non-squamous non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations following tyrosine kinase inhibitor (TKI) treatment. However, there is a dearth of investigations on the effectiveness of ABCP therapy as the primary outcome of EGFR-TKI use. A single-center retrospective analysis was performed on 24 cases of stage IV EGFR-positive non-squamous NSCLC patients who received one or more lines of EGFR-TKItherapy and subsequently initiated ABCP therapy within the timeframe of April 1, 2019, to April 30, 2023. This study assessed overall survival and progression-free survival associated with ABCP therapy, further analyzing the overall survival data based on EGFR subgroups. The mean age of the cohort was 65 ± 9 years with 14 females (58%). The performance status (PS) was recorded as 0 in 13 out of 24 patients (54%) and 1 in 11 out of 24 patients (46%). Thirteen (54%) patients had a history of smoking. Adenocarcinoma histology was prevalent in all cases. The EGFR mutations included Ex19del in 14 patients (58%) and L858R in 10 (42%) patients. At ABCP therapy initiation, liver metastases were evident in three cases (13%) and brain metastases in eight (33%). Programmed death ligand 1 (22C3) expression levels varied, with <1%, 1-49%, and ≥50% observed in five, 11, and five cases, respectively, while data were missing for three cases. The median follow-up duration was 14.1 months, with median overall survival estimated at 23.6 months (95% CI: 14.5 months - not reached) and median progression-free survival at 5.6 months (95% CI: 4.9-11.5 months). The EGFR L858R mutation showed a favorable trend in overall survival compared with the EGFR Ex19del mutation (not evaluated vs. 23.6 months). ABCP therapy for EGFR-positive non-squamous NSCLC is a promising option, similar to immune checkpoint inhibitor-free platinum-based combination therapy. Therefore, prospective trials are necessary to confirm the efficacy of these treatments.

Chronic Myeloid Leukemia in Bulgaria in the New Millennium: Identification of Directions for Improvement in Management and Outcomes Reporting

Background: In the last two decades, tyrosine kinase inhibitors (TKIs) and advances in molecular diagnostics have revolutionized management and long-term clinical outcomes in chronic myeloid leukemia (CML). Real-world data from different countries allow for the identification of country-specific issues in the clinical management and development of specific plans for improvement. Here, we aimed to analyze the trend in overall survival in Bulgarian CML patients since 2000. Methods: We retrieved publicly available Bulgarian CML data from several sources such as the Bulgarian National Cancer Registry, Bulgarian National Statistical Institute, and National Health Insurance Fund since 2000. We used the retrieved data of a total of 1513 Bulgarian CML patients to describe the trends in overall survival (OS), conditional overall survival, life expectancy, and life years lost over five time periods. We also described the trends in healthcare expenditures for TKIs and CML patients’ coverage with TKIs since 2014. Results: In both uni- and multivariate models, we found a constant increase in OS over the three 5-year periods until 2014. The period 2015–2019 was not associated with an additional increase in OS. Identical dynamics in the improvement in life expectancy (LE) and in life years lost (LYLs) was observed. Additionally, conditional 5-year survival did not improve during 2015–2019 in comparison to 2010–2014. Population-level data did not show consistent changes in the documented number of deaths due to CML since 2013. The period after 2013 is marked by a constant increase in the annual expenditures for TKIs, reaching to about 2.0 EUR/capita. The number of patients who received at least one TKI also increased during that period. Conclusions: After the initial significant improvement in the clinical outcomes for Bulgarian CML patients until 2014, subsequent periods did not bring further benefit in spite of the improved coverage with second- and third-line TKIs. Multiple factors may contribute to these suboptimal outcomes. Therefore, one can propose several additional measures at the country level, which could lead to additional improvement in the OS of Bulgarian CML patients.

Evaluation of serum mid-infrared spectroscopy as new prognostic marker for first-line bevacizumab-based chemotherapy in metastatic colorectal cancer

Background and aimsBevacizumab-based chemotherapy is a recommended first-line treatment for metastatic colorectal cancer (mCRC). Robust biomarkers with clinical practice applicability have not been identified for patients with this treatment. We aimed to evaluate the prognostic yield of serum mid-infrared spectroscopy (MIRS) on patients receiving first-line bevacizumab-based chemotherapy for mCRC. MethodsWe conducted an ancillary analysis from a multicentre prospective study (NCT00489697). All baseline serums were screened by attenuated total reflection method. Principal component analysis and unsupervised k-mean partitioning methods were performed blinded to all patients’ data. Endpoints were progression-free survival (PFS) and overall survival (OS). ResultsFrom the 108 included patients, MIRS discriminated two prognostic groups. First group patients had significantly lower body mass index (p = 0.026) and albumin levels (p < 0.001), and higher levels of angiogenic markers, lactate dehydrogenase and carcinoembryonic antigen (p < 0.001). In univariate analysis, their OS and PFS were shorter with respective medians: 17.6 vs 27.9 months (p = 0.02) and 8.7 vs 11.3 months (p = 0.03). In multivariate analysis, PFS was significantly shorter (HR = 1.74, p = 0.025) with a similar trend for OS (HR = 1.69, p = 0.061). ConclusionBy metabolomic fingerprinting, MIRS proves to be a promising prognostic tool for patients receiving first-line bevacizumab-based chemotherapy for mCRC.

Improved survival with immunotherapy for microsatellite unstable colorectal cancer with peritoneal metastases.

KEYNOTE-177 demonstrated that immunotherapy was superior to chemotherapy for microsatellite-instability-high(MSI-high) metastatic colorectal cancer. Colorectal cancer with peritoneal metastases (CRPM) has a poorer prognosis than other metastatic sites, with an unclear role of immunotherapy. We evaluated trends in immunotherapy use and overall survival (OS). Patients with CRPM and MSI testing were identified in the National Cancer Database (2016-2020). We evaluated immunotherapy use by year and associated patient/hospital factors. OS was compared for immunotherapy versus chemotherapy, cytoreductive surgery (CRS), and immunotherapy plus CRS. Among 15 322 CRPM patients, 7072 (46.2%) patients had documented MSI testing, with 819 (11.6%) MSI-high. Ninety-eightMSI-high patients received immunotherapy alone (12.3%), increasing from 0% in 2016to 19.1% in 2020 (p < 0.01). On multivariable analysis, only higher comorbidity was associated with immunotherapy (OR: 2.83 [1.22-6.52]). Two-year OS with immunotherapy versus chemotherapy was 64.2% versus 54.1% (p < 0.05). In patients receiving CRS plus systemic therapy (N = 96), 2-year OS was 68.4%. Among patients who underwent immunotherapy and CRS versus immunotherapy alone, 2-year OS was 80.0% versus 60.0% (p = 0.14). Immunotherapy was associated with significantly better survival compared to chemotherapy in MSI-high CRPM. Two-year OS with systemic + CRS was 68.4%. Despite its role in guiding treatment, MSI testing remains low for these patients.

Autologous transplant vs. CAR-T therapy in patients with DLBCL treated while in complete remission

In patients with relapsed DLBCL in complete remission (CR), autologous hematopoietic cell transplantation (auto-HCT) and CAR-T therapy are both effective, but it is unknown which modality provides superior outcomes. We compared the efficacy of auto-HCT vs. CAR-T in patients with DLBCL in a CR. A retrospective observational study comparing auto-HCT (2015–2021) vs. CAR-T (2018–2021) using the Center for International Blood & Marrow Transplant Research registry. Median follow-up was 49.7 months for the auto-HCT and 24.7 months for the CAR-T cohort. Patients ages 18 and 75 with a diagnosis of DLBCL were included if they received auto-HCT (n = 281) or commercial CAR-T (n = 79) while in a CR. Patients undergoing auto-HCT with only one prior therapy line and CAR-T patients with a previous history of auto-HCT treatment were excluded. Endpoints included Progression-free survival (PFS), relapse rate, non-relapse mortality (NRM) and overall survival (OS). In univariate analysis, treatment with auto-HCT was associated with a higher rate of 2-year PFS (66.2% vs. 47.8%; p < 0.001), a lower 2-year cumulative incidence of relapse (27.8% vs. 48% ; p < 0.001), and a superior 2-year OS (78.9% vs. 65.6%; p = 0.037). In patients with early (within 12 months) treatment failure, auto-HCT was associated with a superior 2-year PFS (70.9% vs. 48.3% ; p < 0.001), lower 2-year cumulative incidence of relapse (22.8% vs. 45.9% ; p < 0.001) and trend for higher 2-year OS (82.4% vs. 66.1% ; p = 0.076). In the multivariable analysis, treatment with auto-HCT was associated with a superior PFS (hazard ratio 1.83; p = 0.0011) and lower incidence of relapse (hazard ratio 2.18; p < 0.0001) compared to CAR-T. In patients with relapsed LBCL who achieve a CR, treatment with auto-HCT is associated with improved clinical outcomes compared to CAR-T. These data support the consideration of auto-HCT in select patients with LBCL achieving a CR in the relapsed setting.

Outcomes of therapeutic plasma exchange for the treatment of patients with multiple myeloma cast nephropathy.

Current treatment guidelines of myeloma cast nephropathy (MCN) recommend the institution of plasma cell-directed therapy and consideration of therapeutic plasma exchange (TPE), with the goal of rapid reduction of the serum free light chain (sFLC). However, the role of TPE continues to remain a subject of debate. The goal of this retrospective bi-institutional study was to evaluate the clinical outcomes of TPE in combination with systemic therapy. Eighty patients were included in this analysis, of whom 72.5% had ≥50% drop in their initial involved sFLC. At 3months from TPE initiation, the overall hematologic response rate (ORR) was 67.5% with a very good partial response or better (≥VGPR) rate of 40%. At 6months, ORR was 57.5%, with ≥VGPR rate of 49%. The renal response rate at 3 and 6months was 47.5% and 43.75%, respectively; the overall renal response rate was 48.75%. On multivariable analysis, every one unit increase in baseline creatinine (odds ratio [OR] 0.76, p=0.006), and achievement of ≥VGPR (OR 21.7 p<0.0001) were significantly associated with renal response. Also, a ≥50% drop in sFLC was favorably associated with renal response (OR 3.39, p=0.09). With a median follow-up of 36.4months, the median overall survival (OS) was 11months. On multivariable analysis, achievement of renal response (hazard ratio [HR]0.3, p<0.0001) and newly diagnosed disease (NDMM; HR 0.43, p=0.0055) were associated with improved OS. Among NDMM patients, those treated with daratumumab-based regimens had a trend for better OS (p=0.15), compared to other regimens, but the difference was not significant. At the end of follow-up, an estimated 40.4% of patients who were on dialysis were able to become dialysis independent. In conclusion, our study highlights the poor survival of patients with MCN. Achievement of early renal response is crucial for prolonged OS, with daratumumab-based therapies showing promise.

SURG-07. A PHASE I STUDY EXAMINING THE FEASIBILITY OF INTERMITTENT CONVECTION-ENHANCED DELIVERY (CED) OF MTX110 FOR THE TREATMENT OF CHILDREN WITH NEWLY DIAGNOSED DIFFUSE MIDLINE GLIOMAS

Abstract BACKGROUND Histone deacetylase inhibitors have been found preclinically to be among the most active agents against Diffuse Midline Gliomas (DMGs), however, they are clinically ineffective with systemic delivery due to low blood brain barrier penetration and systemic toxicity. Using an implantable subcutaneous pump connected with a catheter directly implanted into the pons we have conducted a phase I, 3 + 3 dose escalation study to investigate the safety and feasibility of repeated infusions of MTX110 (Biodexa Ltd), a water-soluble formulation of panobinostat, via CED. METHODS Eligible patents were between 3 and 18 years of age with newly diagnosed DMG following radiation therapy, without evidence of hemorrhage or cyst in the tumor, and having normal organ function. First, patients underwent tumor biopsy and device implantation, then received two 48-hour-infusion pulses 7 days apart. Three dose levels of MTX110 infusions (30, 60, 90 mcM) were studied. The infusion pump was prefilled with MTX110 (and gadolinium for co-infusion as a contrast agent), which was then administered using the wireless N’Vision clinical programmer at a rate of 0.2 mL/hr. RESULTS Nine patients were treated in the study (30 mcM group, n=3; 60 mcM group, n=4; 90 mcM group, n=2). All patients had an H3K27M mutated tumor. All but one patient had adequate tumor coverage with the infusate. One patient suffered a severe adverse event related to the infusion and tumor anatomy. Four patients had Grade 2 transient neurological deficits related to biopsy (n=1) or infusion (n=3). We observed one objective response. Median PFS was 10 months from diagnosis (range 8 to 20 months) while median OS was 16.5 months (range 12 to 35 months). CONCLUSIONS The study has demonstrated safety and feasibility of repeated infusions of MTX110 via CED in DMG patients with a favorable trend in overall survival warranting further trials with higher number of infusion pulses.

IMpower010: Final disease-free survival (DFS) and second overall survival (OS) interim results after ≥5 years of follow up of a phase III study of adjuvant atezolizumab vs best supportive care in resected stage IB-IIIA non-small cell lung cancer (NSCLC).

LBA8035 Background: IMpower010 (NCT02486718) met its primary endpoint of significant DFS improvement with atezo vs BSC after adj chemotherapy in resected NSCLC in the PD-L1 TC ≥1% and all-randomized stage II-IIIA populations, leading to worldwide approval of adj atezo for PD-L1 TC ≥1% or PD-L1 TC ≥50% stage II-IIIA NSCLC. At OS IA1, a trend favoring atezo was seen in the PD-L1 TC ≥1% stage II-IIIA population. Here we report findings from the DFS FA and OS IA2. Methods: The IMpower010 study design has been previously described (Felip et al, Lancet 2021). The primary DFS and secondary OS endpoints were tested hierarchically: DFS in the PD-L1 TC ≥1% (SP263) stage II-IIIA, then in the all-randomized stage II-IIIA, and then in the intent-to-treat (ITT; stage IB-IIIA) populations, followed by OS in the ITT population. Secondary endpoints included 3- and 5-y DFS and DFS in the PD-L1 TC ≥50% (SP263) stage II-IIIA population. OS in the ITT population could only be formally tested if the significance boundary for DFS in that population was crossed. Results: At the DFS FA and OS IA2 (clinical cutoff date: Jan 26, 2024), with a minimum follow-up of 60 mo, DFS and OS for the PD-L1 TC ≥1% and TC ≥50% stage II-IIIA populations were consistent with previously observed benefit; the difference in median (m) DFS between arms in the PD-L1 TC ≥1% population was 31.2 mo (Table). In the ITT population, the significance boundary for DFS was not crossed and OS was similar between arms, although data were immature. The safety profile of atezo was consistent with prior analyses. Conclusions: These results provide the first cancer immunotherapy data with ≥5 y of follow-up from a Phase III study in resectable NSCLC. Although the statistical boundary for the ITT population was not crossed, DFS benefit with adj atezo continues to translate into a positive OS trend vs BSC in the PD-L1 TC ≥1% and TC ≥50% stage II-IIIA populations. These results further support the use of adj atezo in PD-L1–selected populations. Clinical trial information: NCT02486718 . [Table: see text]

Results from the randomized phase 3 DREAMM-8 study of belantamab mafodotin plus pomalidomide and dexamethasone (BPd) vs pomalidomide plus bortezomib and dexamethasone (PVd) in relapsed/refractory multiple myeloma (RRMM).

LBA105 Background: Use of triplet/quadruplet therapies for 1L MM raises the need for novel combinations at first relapse, which belantamab mafodotin (belamaf) combos may address. In DREAMM-7, BVd led to a significant improvement in progression-free survival (PFS) and a strong trend in improved overall survival (OS) vs daratumumab-Vd in patients (pts) with ≥1 prior therapy. We report results from DREAMM-8 (NCT04484623), which tested a different belamaf combo (BPd) and met its primary endpoint of independent review committee–assessed PFS at a prespecified interim analysis. Methods: DREAMM-8 is a phase 3, open-label, randomized, multicenter trial evaluating the efficacy and safety of BPd vs PVd in RRMM pts who received ≥1 prior line of therapy (LoT), including lenalidomide. Pts were randomly assigned 1:1 to BPd (28-d cycles): belamaf 2.5 mg/kg IV (D1, C1), 1.9 mg/kg (D1, C2+) + pom 4 mg (D1-21, all C) + dex 40 mg (D1, QW, all C), or PVd (21-d cycles): pom 4 mg (D1-14, all C) + bortezomib 1.3 mg/m2 SC (D1, 4, 8, 11 [C1-8]; and D1, 8 [C9+]) + dex 20 mg (day of and 1 day after bortezomib dose). Results: 155 pts were randomly assigned to BPd and 147 to PVd. With a median (range) follow-up of 21.78 mo (0.03-39.23), median PFS (95% CI) was not reached (NR; 20.6-NR) with BPd vs 12.7 mo (9.1-18.5) with PVd (HR, 0.52; 95% CI, 0.37-0.73; P&lt;0.001). 12-month PFS rate (95% CI) was 71% (63-78%) with BPd vs 51% (42-60%) with PVd. ORR (95% CI) was 77% (70.0-83.7%) with BPd vs 72% (64.1-79.2%) with PVd; rate of complete response or better (95% CI) was 40% (32.2-48.2%) with BPd vs 16% (10.7-23.3%) with PVd. Median duration of response (95% CI) was NR (24.9-NR) with BPd vs 17.5 mo (12.1-26.4) with PVd. A positive trend favoring BPd was seen for OS (HR, 0.77; 95% CI, 0.53-1.14); follow up for OS is ongoing. Adverse events (AEs) were reported in &gt;99% and 96% of pts in the BPd and PVd arms, respectively. Of pts treated with BPd, 89% had ocular AEs (CTCAE grade 3/4, 43%) vs 30% (grade 3/4, 2%) in the PVd arm. AEs were generally manageable, and broadly consistent with known safety profile of individual agents. Conclusions: The DREAMM-8 study demonstrated a statistically significant and clinically meaningful PFS benefit with BPd vs PVd in RRMM with &gt;1 prior LoT. BPd also led to deeper and more durable responses, showed a favorable OS trend, and had a manageable safety profile. Clinical trial information: NCT04484623 . [Table: see text]

PD-1 inhibitor plus concurrent chemoradiotherapy for high-risk locally advanced cervical cancer.

Aim: The prognosis of high-risk, locally advanced cervical cancer (LACC) remains poor following concurrent chemoradiotherapy (CCRT). We investigated whether the effect of CCRT can be enhanced by programmed cell death protein 1 (PD-1) inhibitor.Methods: A retrospective cohort study wasconducted to compare the efficacy and safety of CCRT group (n=82) and PD-1 inhibitor plus CCRT group (n=70).Results: Compared with the CCRT group, the PD-1 inhibitor plus CCRT group had significantly higher objective response rate, median progression-free survival, leukopeniaand fatigue. The addition of PD-1 inhibitor to CCRT showed a favorable trend in overall survival without statistical significance.Conclusion: PD-1 inhibitor plus CCRT presented a significant survival benefit and a manageable safety profile in high-risk LACC.