Estimated Median Overall Survival Research Articles

Triple combination of vemurafenib, cobimetinib, and atezolizumab in real clinical practice in the Russian Federation: results of the A1 cohort of the ISABELLA study.

Among several treatment options for BRAF-mutant metastatic melanoma, a combination of BRAF inhibitor, MEK inhibitor, and anti-PDL1 antibody seems to be a new emergent approach recently registered in the Russian Federation. It is still not clear which patient population benefits more from this simultaneous use of three drugs instead of its sequencing. This study aimed to evaluate patients' characteristics treated in real practice in 14 Russian regions by triple combination and to analyze their outcomes depending on biomarkers (PD-L1 expression). This was a part (cohort A1) of a prospective non-interventional study of clinical outcomes and biomarkers in patients with skin melanoma. Patients were included in cohort A1 if combination treatment with vemurafenib (vem) + cobimetinib (cobi) + atezolizumab (atezo) was initiated no earlier than 12 weeks (84 days) prior to written informed consent to participate in this study. The index event was the initiation of therapy with all three drugs vem + cobi + atezo (i.e., triple combination). The primary efficacy endpoint of the study was the 24-month overall survival (OS), defined as the time from the index date to the date of death from any cause. If the patient did not experience an event, the OS will be censored at the date of the last contact. Objective response rate (ORR), duration of response (DoR), and progression-free survival (PFS) in the Intention to treat (ITT) population, in biomarker positive population, and in population with brain metastases were also evaluated. Quality of life questionnaires were pre-planned by protocol if it was a part of routine practice. Adverse events were also collected. Between March 2021 and May 2023, 59 patients were enrolled in 19 centers from 14 regions of Russia. Thirty-one of 59 (52.4%) patients had central nervous system metastases, and 18 of 31 (58.4%) were symptomatic. Forty of 59 patients (68%) received the triple combination as the first-line treatment. The median follow-up period was 16.83 [95% confidence interval (CI) 13.8-19.8] months. The mean duration of therapy with this regimen was 9.95 months (95% CI 7.48-13.8). ORR was 55.1%; progression as the best outcome was seen in 16.3%. The median DoR was 12.95 months (95% CI 11.0-14.8 months), with a median of 20.3 months (95% CI 9.1-31.5 months) when triple therapy was administered in the first-line treatment. In patients with brain metastases (N = 31), ORR was 45.1%; the median DoR was 12.95 (95% CI 11.0-14.8 months). The median PFS in the entire population was 13.6 months (95% CI 8.6-18.6); the 24-month PFS was 22%. The estimated median OS in the entire population was 15.8 months (95% CI NA); 24-month OS was 45% (95% CI 0.32-0.64). In multivariate Cox regression model, biomarkers of interest [lactate dehydrogenase, Programmed cell death ligand-1 (PD-L1)] did not have statistically significant impact on PFS, OS, or DoR probably due to high data missing rate. No unexpected adverse events were reported. Grades 3-4 AEs were seen in 23 of 59 patients (38%) with most common were skin and liver toxicity. Triple combination of atezolizumab, vemurafenib, and cobimetinib had proven its efficacy and tolerability in real settings. No impact of potential predictive biomarkers was seen (NCT05402059).

First-line zorifertinib for EGFR-mutant non-small cell lung cancer with central nervous system metastases: The phase 3 EVEREST trial.

Zorifertinib (AZD3759), an epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) with high blood-brain barrier penetration capability, demonstrated promising intracranial and systemic antitumor activity in phase 1 and 2 studies in central nervous system (CNS)-metastatic patients. In this phase 3 EVEREST trial (ClinicalTrials.gov: NCT03653546), patients with EGFR-sensitizing mutations, advanced treatment-naive non-small cell lung cancer (NSCLC), and non-irradiated symptomatic or asymptomatic CNS metastases were randomized (1:1) to zorifertinib or first-generation EGFR-TKI (gefitinib or erlotinib; control). The primary endpoint was blinded independent central review (BICR)-assessed progression-free survival (PFS) per RECIST1.1. Overall, 439 patients were randomized (zorifertinib n= 220; control n= 219). Most patients had the EGFR L858R mutation (55%) or >3 CNS lesions (54%). Median PFS was significantly longer with zorifertinib versus control (9.6 versus 6.9months; hazard ratio [HR], 0.719; 95% confidence interval [CI], 0.580-0.893; p= 0.0024). Zorifertinib significantly prolonged intracranial PFS versus control (BICR per modified RECIST1.1: HR, 0.467; 95% CI, 0.352-0.619; investigator per RANO-BM: HR, 0.627; 95% CI, 0.466-0.844). Overall survival (OS) was immature; the estimated median OS was 37.3months with zorifertinib and 31.8months with control (HR, 0.833; 95% CI, 0.524-1.283) in patients subsequently treated with third-generation EGFR-TKIs. Safety profiles were consistent with previously reported data for zorifertinib. Zorifertinib significantly improved systemic and intracranial PFS versus first-generation EGFR-TKIs; adverse events were manageable. Sequential use of zorifertinib and third-generation EGFR-TKIs showed the potential to prolong patients' survival. The results favor zorifertinib as a novel, well-validated first-line option for CNS-metastatic patients with EGFR-mutant NSCLC. This work was funded by Alpha Biopharma (Jiangsu) Co., Ltd., China.

Escalated-dose radiotherapy for unresected locally advanced pancreatic cancer: Patterns of care and survival in the United States.

With locally advanced pancreatic cancer (LAPC), uncontrolled local tumor growth frequently leads to mortality. Advancements in radiotherapy (RT) techniques have enabled conformal delivery of escalated-dose RT (EDR), which may have potential local control and overall survival (OS) benefits based on retrospective and early prospective studies. With evidence for EDR emerging, we characterized the adoption of EDR across the United States and its associated outcomes. We searched the National Cancer Database for nonsurgically managed LAPC patients diagnosed between 2004 and 2019. Pancreas-directed RT with biologically effective doses (BED10) ≥39 and ≤70 Gy was labeled conventional-dose RT (CDR), and BED10 >70 and ≤132 Gy was labeled EDR. We identified associations of EDR and OS using logistic and Cox regressions, respectively. Among the definitive therapy subset (n = 54,115) of the entire study cohort (n = 91,493), the most common treatments were chemotherapy alone (69%), chemotherapy and radiation (29%), and RT alone (2%). For the radiation therapy subset (n = 16,978), use of pancreas-directed RT remained between 13% and 17% over the study period (ptrend > 0.999). Using multivariable logistic regression, treatment at an academic/research facility (adjusted odds ratio [aOR] 1.46, p < 0.001) and treatment between 2016 and 2019 (aOR 2.54, p < 0.001) were associated with greater receipt of EDR, whereas use of chemotherapy (aOR 0.60, p < 0.001) was associated with less receipt. Median OS estimates for EDR and CDR were 14.5 months and 13.0 months (p < 0.0001), respectively. For radiation therapy subset patients with available survival data (n = 13,579), multivariable Cox regression correlated EDR (adjusted hazard ratio 0.85, 95% confidence interval 0.80-0.91; p < 0.001) with longer OS versus CDR. Utilization of EDR has increased since 2016, but overall utilization of RT for LAPC has remained at less than one in five patients for almost two decades. These real-world results additionally provide an estimate of effect size of EDR for future prospective trials.

The survival outcome differs between left-sided colon cancer and middle/low rectal cancer after colorectal hepatic metastasectomy

BackgroundThe clinical outcomes between left-sided colon cancer and middle/low rectal cancer seem to be different. This study aimed to examine the effect of primary tumor location regarding the left-sided colon and middle/low rectum on the overall survival (OS) of patients who underwent colorectal hepatic metastasectomy. MethodsPatients who underwent colorectal hepatic metastasectomy were retrospectively enrolled. Patients were classified into 2 groups according to the primary tumor location (left-sided colon and middle/low rectum). Categorical variables were compared using the chi-square test or Fisher exact test, and continuous variables were analyzed using the Student t test. Survival was analyzed using the Kaplan-Meier method and log-rank test. The prognostic factors were analyzed by univariate and multivariate analyses using Cox proportional hazards regression models. ResultsOverall, 365 patients were enrolled. Patients with left-sided colon cancer had significantly better OS than those with middle/low rectal cancer (hazard ratio [HR], 0.725; P = .018), with median OS estimates of 48 and 38 months, respectively. In the subgroup analysis of RAS mutations, patients with left-sided colon cancer had significantly prolonged OS compared with those with middle/low rectum cancer (HR, 0.608; P = .034), with median OS estimates of 49 and 26 months, respectively. This observation was limited to patients with RAS mutations. ConclusionAccording to our findings, patients with middle/low rectal cancer had poorer survival outcome and should not be categorized together with patients with left-sided colon cancer in terms of OS after colorectal hepatic metastasectomy.

Treatment Outcomes of Stereotactic Ablative Body Radiotherapy on Extra-cranial Oligometastatic and Oligoprogressive Breast Cancer: Mature Results from a Single Institution Experience

AimsEvidence shows stereotactic ablative body radiotherapy (SABR) is used as a non-invasive ablative therapy in the treatment of multisite oligometastatic (OM) and oligoprogressive (OP) diseases originating from metastatic breast cancer. This study aims to report the treatment outcomes and to investigate what factors that are prognostic in terms of local control, progression-free survival (PFS) and overall survival (OS) in patients receiving SABR for extracranial OM and OP diseases originating from metastatic breast cancer. Materials and methodsA retrospective review on treatment records of patients with OM and OP from metastatic breast cancer who underwent SABR at a single was carried out. SABR was performed with daily image-guided radiotherapy (IGRT) using a dedicated robotic SABR machine. Local control, PFS and OS were calculated using Kaplan-Meier statistics and the post-treatment toxicity data was scored following the CTCAE v4.0 protocol. Univariate and multivariate Cox regression tests were used in the subgroup analysis of prognostic factors on PFS and OS including patients’ age, types of follow-up imaging (staging CT only vs whole-body MR/PET), metastases status (OM vs OP), primary breast cancer tumour grade, hormone receptors (ER/PR/HER2) status, change of systemic treatments at SABR, number of metastases, SABR treatment sites and doses. Results56 metastatic breast cancer patients (38 patients with OM and 18 patients with OP) were involved in this retrospective review. The median follow-up was 35.6 months (range 4.0–132.9 months). The estimated local control at 1 , 2 and 5 years were 90.9%, 88.7% and 88.7%, respectively. The estimated median PFS was 19.2 months (95%CI 10.3–28.1 months); the PFS at 1, 2 and 5 years were 63.3%, 44.4% and 33.2%. The estimated OS at 1, 2 and 5 years were 98.0%, 91.9% and 74.3%, respectively with the estimated median OS of 105.1 months (95%CI 51.5–158.7 months). The vast majority of patients tolerated the treatment well with the commonest acute side effects as grade 1 fatigue. There were no statistically significant factors found in OS regression analysis. The types of follow-up imaging, metastases status, oestrogen receptor status, and number of metastases for SABR were statistically significant factors (p < 0.05) in the multivariate Cox regression analysis on PFS. ConclusionThere are limited studies published on the efficacy and post-treatment toxicities of metastatic breast cancer OM and OP SABR with adequate length of follow-up. This study confirmed that SABR was a safe, non-invasive treatment option for patients with extracranial OM and OP diseases originated from primary breast cancer in terms of the acceptable post-treatment toxicities.

Body composition measurements and clinical outcomes in patients with resectable pancreatic adenocarcinoma – analysis from SWOG S1505

Sarcopenic obesity and muscle attenuation have been associated with survival in patients with borderline resectable and advanced pancreatic ductal adenocarcinoma (PDA); however, these relationships are unknown for patients with resectable PDA. This study examined the associations between skeletal muscle and adipose tissue as measured on baseline computed tomography (CT) and the overall survival (OS) of participants with resectable PDA in a secondary analysis of the Southwest Oncology Group S1505 clinical trial (identifier: NCT02562716). The S1505 phase II clinical trial enrolled patients with resectable PDA who were randomized to receive modified FOLFIRINOX or gemcitabine and nab-paclitaxel as perioperative chemotherapy, followed by surgical resection. Baseline axial CT images at the L3 level were analyzed with externally validated software, and measurements were recorded for skeletal muscle area and skeletal muscle density, visceral adipose tissue area (VATA) and density, and subcutaneous adipose tissue area and density. The relationships between CT metrics and OS were analyzed using Cox regression models, with adjustment for baseline participant characteristics. Of 98 eligible participants with available baseline abdominal CT, 8 were excluded because of imaging quality (eg, orthopedic hardware), resulting in 90 evaluable cases: 51 men (57.0%; mean age, 63.2 years [SD, 8.5]; mean body mass index [BMI], 29.3kg/m2 [SD, 6.4]), 80 White (89.0%), 6 Black (7.0%), and 4 unknown race (4.0%). Sarcopenia was present in 32 participants (35.9%), and sarcopenic obesity was present in 10 participants (11.2%). Univariable analyses for the 6 variables of interest indicated that the standardized mean difference (hazard ratio [HR], 0.75; 95% CI, 0.57-0.98; P=.04) was statistically significantly associated with OS. In models adjusted for sex, race, age, BMI, performance score, contrast use, sarcopenia, and sarcopenic obesity, VATA was statistically significantly associated with OS (HR, 1.58; 95% CI, 1.00-2.51; P=.05). No difference was observed in OS between participants according to sarcopenic obesity or sarcopenia categories. The median OS estimates were 25.1 months for participants without sarcopenic obesity, 18.6 months for participants with sarcopenic obesity, 23.6 months for participants without sarcopenia, and 27.9 months for participants with sarcopenia. This was the first study to systematically evaluate body composition parameters in a prospective multicenter trial of patients with resectable PDA who received perioperative chemotherapy. Visceral adipose tissue was associated with survival; however, there was no association between OS and sarcopenia or sarcopenic obesity. Further studies should evaluate these findings in more detail.

Venetoclax Combined with Azacitidine Was Effective and Safe for Relapsed/Refractory T-Cell Acute Lymphoblastic Leukemia/ Lymphoblastic Lymphoma: Preliminary Results of a Phase 2, Multicenter Trial

Introduction: Relapsed/refractory T-cell acute lymphoblastic leukemia/lymphoblastic lymphoma (R/R T-ALL/LBL) is highly heterogeneous. The available salvage treatment options for relapsed patients showed remission rates of less than 50% and a 5-year overall survival (OS) rate of less than 25%. Venetoclax, a Bcl-2 inhibitor, in combination with azacitidine, has demonstrated a high remission rate in 5 patients with R/R T-ALL/LBL in our previous report. Here, we report the interim analysis of a phase 2 study (NCT05149378) for the treatment of venetoclax combined with azacitidine for R/R T-ALL/LBL. Methods: From November 2021 to May 2023, a total of 18 R/R T-ALL/LBL patients were enrolled in the study. Among them, 11 were male and 7 were female. These patients were from seven hospitals, including the central hospital of the First Affiliated Hospital of Soochow University. All patients received salvage treatment with venetoclax (orally, 100mg on day 1, 200mg on day 2, and 400mg on days 3-21) and azacitidine（75mg/m 2/d on days 1-7, subcutaneously). Bone marrow evaluation was performed after the blood cell count recovery or within 42 days since the initiation of the treatment. Results: Among the 18 patients enrolled, 8 were diagnosed with T-ALL, 7 with ETP-ALL, and 3 with T-LBL (Table). 5/18 patients were relapsed T-ALL/LBL, 13/18 patients were refractory to previous treatments. The median age of the patients was 39 years (range: 30-53). After 1-2 courses of venetoclax in combination with azacitidine regimen. 4 (22.2%) achieved CR, 1 patient (5.6%) achieved CRh, 9 (50.0%) patients achieved CRi and 2 (11.1%) achieved MLFS. The overall response rate was 88.9%. With a median follow-up time of 24.1 months (95% CI: 6.8-41.4), the estimated median OS was 24.1 months (95% CI: 6.8-41.4) (Figure a) and the median relapse-free survival was 14.0 (95% CI: 3.8-24.2) months (Figure b). After the treatment, 12/18 (66.7%) patients underwent allogeneic hematopoietic stem cell transplantation. Five patients experienced relapse between 6 to 19 months after the venetoclax and azacitidine treatment. Four patients died because of relapse after the regimen, two patients died because of COVID-19. Grade 3 or higher treatment-related hematologic AE included neutropenia (15/18, 83.3%), anemia (6/18, 33.3%), and thrombocytopenia (4/18, 22.2%). Treatment-related non-hematologic AE included infections (6/18, 33.3%. 4 patients developed pneumonia, 1 patient had perianal infection, 1 patient developed sepsis), elevation of ALT and AST (5/18, 27.8%), and renal function impairment (2/18, 11.1%). There was no other grade 3 or higher non-hematologic AE and no treatment-related death was observed. Conclusion: Our results showed that venetoclax in combination with azacitidine was an effective salvage regimen for R/R T-ALL/LBL patients. The benefit of this regimen for distinct cytogenetic groups in R/R T-ALL/LBL needs to be analyzed in more cases.

Outcomes of Salvage VDT-PACE-like Regimens in Relapsed-Refractory Multiple Myeloma: 10-Year Experience of a Large Academic Institution

Introduction: Rapidly evolving therapies for multiple myeloma (MM) have drastically changed the treatment landscape over the last decade. Despite the introduction of novel agents into clinical practice, MM remains challenging to treat in the setting of aggressive relapse and/or multi-refractory disease, accompanied by high tumor burden and extramedullary sites. Intensive chemotherapy with VDT-PACE (bortezomib, dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, etoposide)-like regimens may be used for a limited number of cycles as a bridging regimen to quickly achieve cytoreduction. This study aimed to evaluate outcomes of patients treated with VDT-PACE-like regimens (VPRs) for relapsed-refractory MM (RRMM) at our center. Methods: We retrospectively analyzed medical records of patients with RRMM who were treated with VPRs at our institution between 1/1/2013 and 6/1/2023. Responses including complete response (CR), very good partial response (VGPR), partial response (PR) and minimal response (MR) were measured according to the International Myeloma Working Group (IMWG) criteria. Baseline characteristics were outlined by descriptive analysis. Kaplan-Meier method was used for progression free survival (PFS), and overall survival (OS) calculations. Patients were censored in PFS analysis if they started another therapy before progression. Results: A total of 93 patients with RRMM were included in this analysis. Median age was 59 (range 42-84) years, 41% were female and 82% were White. The median number of prior lines of therapy was 6 (range 1-17) and median percentage of bone marrow plasma cells prior to VPRs initiation was 70%. Of the entire cohort, 60% of patients had high risk cytogenetics and 27% had plasma cell leukemia; other baseline patient and disease characteristics are summarized in Table 1. Patients received a median of 1 cycle (range 1-4) of VPRs; 37% received &amp;gt;2 cycles of treatment. After completion of cycle 1, VGPR or better, PR, and MR were achieved in 25 (27%), 30 (32%) and 11 (12%) patients, respectively. The estimated median PFS was 4 months (95% Cl, 2.8 - not reached [NR]) and the estimated median OS was 7 months (95% Cl, 5-8) from VPRs initiation (Figure 1). Among the 72 patients who received further treatment post VPRs completion, 19% underwent autologous hematopoietic cell transplant (AHCT), 70% were switched to another plasma cell-directed therapy, and 11% received chimeric antigen receptor T (CAR T)-cell therapy as the next line of therapy. The remaining 21 patients were transitioned to hospice immediately following VPRs, or died prior to receiving next line of therapy due to disease progression. Thirty-eight patients (41%) were readmitted after cycle 1 due to complications; median number of readmissions was 1 (range 1-4), and median cumulative duration of inpatient hospital stay was 7.5 (range 1-42) days. Severe neutropenia (defined as neutrophilic count &amp;lt;500 x10 9/L) and severe thrombocytopenia (defined as platelet count &amp;lt;25 x10 9/L) were seen in 57 (61%) and 43 (46%) patients, respectively after cycle 1, and 28 (30%) patients developed neutropenic fever. Conclusion: VPRs are feasible salvage treatment options in RRMM patients with aggressive and multi agent-refractory disease. Most patients responded to VPRs bridge therapy and were able to transition to autologous hematopoietic cell transplant, CAR T-cell therapy or other less toxic plasma-cell directed regimens. Despite that, the median overall survival of the entire cohort was short indicating that VPRs might not be able to reverse the poor prognosis of highly aggressive RRMM disease.

Clinical, Cytogenetic and Molecular Characterization of a 96 MDS and AML Cohort with TP53 Mutation

Introduction The last European LeukamiaNet (ELN) recommendations (Döhner H. et al. Blood. 2022) and the International Consensus Classification (ICC, Hasserjian R.P. et al. Virchows Arch. 2023) described a new entity, called myelodysplastic syndrome (MDS)/ acute myeloid leukemia (AML) with TP53 mutation ( TP53mut), comprising high-risk MDS with an excess of bone marrow blasts cells (more than 10%) and a TP53 mutation (variant allele frequency VAF ≥ 10%). They suggested that MDS and AML represent a biologic continuum rather than two distinct diseases separated by a blast cutoff. Among teams who worked on that topic, T. Grob et al. ( Blood. 2022) studied the molecular characterization of high-risk AML and MDS with TP53mut and suggested that these two types of pathologies should be considered as a single entity, with no difference in molecular characteristics or survival. In this study, we describe the clinical, cytogenetic, and molecular characteristics of a cohort of 96 MDS and AMLs with TP53mut. Patients and methods We included all the patients with AML, MDS/AML, MDS with increased blasts (MDS-IB1) and MDS-low blast (MDS-LB) with at least one TP53mut (VAF ≥ 1%) received between Aug. 2020 and Dec. 2022 at the Institut Paoli-Calmettes (IPC, Marseille, France). Clinical and biological data were extracted retrospectively from the AML IPC database. Morphologic and cytogenetic data were analyzed by standard techniques. NGS was performed using a custom targeted panel of 60 genes (Custom Myeloid Lymphoid Solution, SOPHIA GENETICS). Results We registered 96 patients with a TP53 mutation (VAF ≥ 1%), divided into AML (n=60), MDS/AML (n=14), MDS-IB1 (n=12) and MDS-LB (n=10). Median age was 71 (range, 28-88). Thirty-eight patients had been treated for a prior solid malignancy and 26 patients had a history of myeloid malignancy. TP53mut was detected at diagnosis for 85 patients and at relapse or during follow-up for 12 patients (no NGS data available at diagnosis). We detected 142 mutations in the TP53 gene, mostly missense (73%) between exon 4 and exon 11 with a median VAF of 39% (Figure 1). We found 3 hotspots mutations in positions 273, 248 and 220 with respectively 9, 9 and 8 mutations. Biallelic status (presence of ≥ 2 mutations or a mutation + a deletion) was found in 66 patients (69%). Karyotypes were available for 95 patients. The karyotype was abnormal in 88% of cases, complex in 71% and unfavorable in 80% of cases according to ELN classification or Revised International Prognostic Scoring System (R-IPSS). Complete NGS analysis revealed at least one mutation in 59 of the other genes of the panel in 67 patients (70%), the most frequent being DNMT3A (22%), TET2 (17%), ASXL1 (13%) and PPM1D (11%) (Figure 2). In our cohort of TP53mut LB-MDS (n=10), we found that 9/10 patients had co-mutations in DNMT3A (n=4) , TET2 (n=6) and PPM1D (n=2) genes, 7/10 with biallelic status and 3/10 with complex karyotype. AML and MDS/AML patients with TP53mut detected at diagnosis (n=65) were treated with intensive chemotherapy (n=13), VEN-AZA (n=26), non-intensive therapy (n=14) or best supportive care (BSC, n=12). Seventeen patients were treated with allogeneic stem-cell transplantation (ASCT). With a median follow-up (FU) of 13 months, median overall survival (OS) of the whole cohort was 7 months (ranges, 1-41). Median OS in the AML and MDS/AML group was 6 months (ranges, 1-41). Patients treated with non-intensive approach had the longest median OS (15 months) compared to patients treated with intensive chemotherapy and VEN-based approaches (8 and 6 months, respectively) and patients treated with BSC (1 month, p=0.02). Patients with MDS-IB1 and MDS-LB had 11-months median OS (ranges, 1-28). The four patients treated with upfront ASCT were still alive at the last FU date and have an estimated median OS of 18.5 months (ranges, 6-26). Conclusion Our data confirm that MDS and AML with TP53 mutation are frequently associated with complex karyotypes and have a poor prognosis. nterestingly we identified mutations in PPM1D gene, involved in TP53 pathway, in 11% of cases. Patients with AML or MDS/AML treated with non-intensive approach seem to have the longest OS (15 months). Patients with MDS-IB1 or MDS-LB treated with upfront ASCT seem to have a prolonged OS (18.5 months). Clinical, functional and mechanistic studies are required to complete these findings.

Outcomes of BCMA-Directed Chimeric Antigen Receptor T-Cell (CART) Therapy in Patients with Relapse-Refractory Multiple Myeloma with Extramedullary Disease

Background: Presence of extramedullary disease (EMD) is associated with poor outcomes for patients with relapsed-refractory multiple myeloma (RRMM) and has been identified as a major risk factor for early progression (≤ 3 months) after CAR T-cell therapy. Idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel) are B-cell maturation antigen (BCMA) targeting CAR T-cell therapies approved for patients with RRMM who have received ≥4 prior lines of therapy (LOT). This is a multicenter retrospective study on the real-world safety and efficacy of commercially available ide-cel and cilta-cel in heavily pretreated RRMM patients with EMD. Methods: Three U.S. academic centers, part of the U.S. Myeloma Innovations Research Collaborative (USMIRC), contributed data to this analysis, which included patients with RRMM who had received an ide-cel or cilta-cel infusion ≥30 days prior to data-cut off (7/1/2023). Baseline patient characteristics were outlined by descriptive analyses. Responses including overall response (ORR), and complete response or better (≥CR) rates were evaluated using the International Myeloma Working Group (IMWG) criteria. Statistical analysis was done with the Fisher's exact test and Kaplan Meier method for progression free (PFS) and overall survival (OS) calculations. Results: A total of 132 patients who received commercial (standard of care) BCMA-directed CAR T-cell therapy between 5/1/2021 and 5/30/2023 were included in this study. Out of these, 64 (48%) patients had a previous history or existing EMD prior to CART infusion. Table 1 summarizes the main patient characteristics and outcomes stratified as EMD and non-EMD groups. Both groups had comparable baseline patient and disease characteristics including median age, ECOG performance status, median bone marrow plasma cell percentage, high-risk cytogenetics, number of prior LOT, refractoriness status prior to CART and type of CAR T-cell product received. CART-related toxicities were comparable between the EMD and the non EMD groups. Cytokine release syndrome (CRS) was seen in 73% (≥ grade 3: 5%) of EMD patients vs 79% (≥ grade 3: 4%) of non-EMD patients (p=0.79). Likewise, immune effector cell-associated neurotoxicity syndrome (ICANS) was noted in 28% (≥ grade 3: 5%) of EMD patients vs 32% (≥ grade 3: 9%) of non-EMD patients (p=0.72). Infections were seen in 39% of the EMD group vs 28% of the non-EMD group (p=0.38). Response rates were also similar between the EMD vs non EMD cohorts: ORR 78% vs 96% (p=0.44); and ≥CR rate 42% vs 51% (p=0.54), respectively. With a median follow up of 7.2 (range 0.5-22.8) months for the entire patient cohort, the estimated median PFS was inferior for the EMD group (6.5 months [95% CI, 5.1-9.6]) compared to the non-EMD group (9.8 months [95% CI, 8.2-16.4]) (p=0.017) (Figure 1). At the time of data cut-off, 43 patients had died, 77% from disease progression, 11.5% from CART-related complications and 11.5% from unrelated causes. The estimated median OS was significantly worse for the EMD group (12.9 months [95% CI, 9.5-NA]) compared to the non-EMD group (19.4 months [95% CI, 1.2-NA]) (p=0.031). Conclusions: This is the largest multicenter retrospective study delineating the real-world outcomes of ide-cel and cilta-cel CAR T-cell therapies in RRMM patients with the high-risk disease feature of EMD. Based on our results, patients with prior history or presence of existing EMD at the time of CART infusion did not have any excessive treatment-related toxicities. However, these patients did experience shorter PFS and OS compared to patients without EMD highlighting the presence of EMD as a risk factor for poor outcomes after CART. Therefore, this group of patients should be considered for pre- and post-CART risk mitigation strategies aiming to prevent disease progression and improve survival outcomes.

Real World Results of Brexucabtagene Autoleucel for Patients with Relapsed/Refractory Mantle Cell Lymphoma - First German/Swiss Analysis

Background: Chimeric antigen receptor T-cells have revolutionized treatment in many B-cell neoplasias. In MCL, brexucabtagene autoleucel (brexu-cel) has been the first product approved based on results of the ZUMA-2 trial for patients failing prior chemoimmunotherapy and BTK-inhibitor. However, in ZUMA-2, strict criteria have been used for patient selection, e.g. no use of intensive bridging/holding treatment was allowed, excluding patients with high treatment needs. In contrast to this, in the real-world scenario patient selection is much more diverse questioning whether the results of controlled trials can be reproduced in the regular treatment landscape. In this intent, we have analyzed the results obtained with brexu-cel as standard-of-care treatment (SOC) of r/r MCL in Germany and Switzerland. Patients/methods: Eligible for this first analysis of an ongoing registry study were all German and Swiss patients with r/r MCL who have been treated with SOC brexu-cel since 09/2020 and were registered with the German Stem Cell Registry (DRST) and the Registry of the European Mantle Cell lymphoma (EMCL), respectively. Of note, some patients have received more than one CAR-T-treatment. Data were analyzed for patient and disease characteristics, prior treatment history, response to treatment, and complications as well as post treatment outcomes. Due to the character of this analysis based on real world data, with heterogeneous surveillance strategies we have used primarily time to next treatment (TTNT) instead of progression-free survival, due to the potential biases for the latter. While still adding patients to the analysis, an additional follow-up data cut is planned 10/2023. Results: 111 patients have been identified: median age at diagnosis was 64.3 years (range 42.3-79.5; 19/99 patients ≥ 70), 18% female (not known (nk) 2.7%); ethnicity 66.7% Caucasian (nk 30.6%). Disease characteristics: 80/88 had stage 3/4 (91%), histology was classical in 34/57 cases (60%) and blastoid in 19/57 (33%), respectively. MIPI score was low 14/53 (26%), intermediate 17 (32%), high 21 (40%). TP53 alteration was present in 13/58 (22%), Ki67-expression was ≤ 30% in 18/50 (36%). TTNT for last treatment preceding CAR-T-treatment was 7.7 months. Overall survival (OS) for the entire patient population from diagnosis was 12.8 years. Preceding CAR-T, median number of treatments was 3 (range 1-9), all patients had prior Rituximab and Ibrutinib, 62 patients (56%) had received autologous stem cell transplantation (SCT) and 11 patients had received an allogeneic SCT. Median age at this time point was 68.1 years (range 49-82y). 50/110 patients were &amp;gt;70 years. Bridging treatment had been used in 88/112 (79%) preceding CAR. Based on investigator evaluation ORR was 86%, best response to CAR-T was CR in 47/76 patients (62%) and PR in 18/76 (24%). Time to death or new treatment after CAR-T was 8 months (mo) for patients ≤ 70y and 12 mo for patients &amp;gt; 70y. There was no difference for the number of prior lines (≤ 3 vs. &amp;gt; 3). The estimated median OS was 1.9 years. 26 patients have received at least 1 additional line of treatment after progression. Safety: Post-CAR CRS was seen in 95/114 (83%), Grade 1/2 77/95 (81%), Grade 3/4 (18%), Grade 5 (1%); ICANS was noted in 57/111 (51%), Grade 1/2 43/57 (75%), all other Grade 3/4. The rate of ICU admissions was 25/106 (24%). However, within 28 days after CAR-T-cell treatment 9/98 (9%) patients have died. Overall, in the post CAR-T-period 20 patients died of reasons other than progression: 4 CAR-related, 11 infections, 5 other/unknown. Discussion: In this real-world analysis, we could demonstrate, despite a more heterogeneous pre-treated patient population, a high overall and complete response rate. Median post CAR-T-cell survival was promising with 1.9 years. While CRS and ICANS risks seem to be comparable to trial data, the high non-relapse mortality (NRM) observed after SOC brexu-cel for r/r MCL is a concern and warrants refinement of anti-infectious surveillance and prophylaxis. Further work focusses on the identification of potential risk factors, e.g. using risk scores such as CAR-HAEMATOTOX, EASIX, and Severe4.

Golidocitinib in Treating Refractory or Relapsed Peripheral T- Cell Lymphoma: Full Analysis of the Multinational Pivotal Study Results (JACKPOT8)

Introduction: Golidocitinib is the first JAK1 selective inhibitor to enter into pivotal clinical development for the treatment of relapsed/refractory peripheral T cell lymphoma (r/r PTCL). Preliminary analysis of the JACKPOT8 study (NCT04105010) has shown promising antitumor efficacy and a manageable safety profile of golidocitinib. Here we reported the full analysis of the phase 2 multinational pivotal study JACKPOT8 Part B. Methods: This study enrolled r/r PTCL patients who had undergone at least one line of systemic therapies. All patients received golidocitinib at 150 mg once daily (QD) until disease progression or pre-defined discontinuation criteria were met. The primary endpoint was a CT-based objective response rate (ORR) assessed by an independent review committee (IRC) per Lugano 2014 criteria. Other efficacy endpoints included duration of response (DoR), progression-free survival (PFS), and overall survival (OS). The efficacy analysis set included patients whose pathological diagnosis of PTCL has been retrospectively confirmed by a central laboratory and who had at least one measurable lesion at the baseline assessed by IRC. The safety analysis set included all dosed patients. Results: A total of 88 efficacy evaluable patients with r/r PTCL were included in the analysis. The median age was 57.5 years, and the majority (64.8%) were male. The major pathological subtypes included PTCL NOS (56.8%), AITL (18.2%), and ALCL (11.4%). At the baseline, 54.5% of patients had ECOG PS of 1, 52.3% had elevated LDH levels, and 21.6% had bone marrow involvement. The median prior lines of therapies were two. All patients had been treated with chemotherapies, 50% had been treated with histone deacetylase inhibitors, and 10.2% had received CD30 targeted therapy. Per IRC assessment based on CT imaging, 39 patients achieved tumor response, with an ORR of 44.3% (95% CI: 33.7%, 55.3%), and 26 patients (29.5%) achieved complete response. The primary endpoint met the pre-defined target with statistical significance ( p &amp;lt; 0.0001). Tumor response was observed in various subtypes, irrespective of age, gender, baseline bone marrow involvement, and ECOG PS. With a median follow-up time of 10.4 months for DoR, 59% of responders were still event-free. The median DoR has not been reached, with an estimated 12-month DoR rate of 70.2%. With a median follow-up time of 9.6 months for PFS, the median PFS was 5.6 months. The longest PFS was 20 months, and the patient was still responding. Per investigator assessment, 34 patients achieved tumor response (ORR: 38.6%). The DoR and PFS by investigator assessment were similar to that of IRC assessed results. With a median follow-up time of 15.1 months for OS, approximately 60% of patients were still alive, with an estimated median OS of 19.2 months. A total of 112 patients were included in the safety analysis set. The median relative dose intensity was 100%. A total of 62 patients (55.4%) reported ≥ grade 3 treatment-emergent adverse events (TEAEs). The most common drug-related ≥ grade 3 TEAEs were hematological adverse events in nature, including neutropenia (25%), leukopenia (23.2%), and lymphopenia (18.8%). The majority of TEAEs were reversible and clinically manageable. Treatment-related AEs leading to dose interruption, reduction, and discontinuation were reported in 36.6%, 7.1%, and 8% of patients, respectively. Conclusions: This pivotal study met its primary objective, suggesting golidocitinib can be an effective treatment option with a manageable safety profile for patients with r/r PTCL. The updated data will be presented at the conference.

Modified Staging System for Waldenström Macroglobulinemia (MSS-WM): A Multi-Institutional Externally Validated Prognostic Model for Active/Symptomatic Waldenström Macroglobulinemia

Background: Waldenström Macroglobulinemia (WM) is an indolent lymphoma with heterogeneous outcomes. The recently developed, Revised International Prognostic Scoring System for WM (rIPSS-WM) did not examine the prognostic impact of MYD88L265P, a somatic alteration present in most patients with WM. Moreover, rIPSS-WM could only be partially validated in an external cohort. Here, we report the performance of rIPSS-WM and propose a refined prognostic model with external validation. Methods: We reviewed medical records of treatment-naïve patients with active WM consecutively seen at Mayo Clinic, Rochester (MCR) between 01/01/1996 and 12/31/2017. We applied the rIPSS-WM model in patients with data available for all required parameters, including age, serum beta-2 microglobulin (β2M), serum lactate dehydrogenase (LDH) and serum albumin at diagnosis to assess the prognostic utility of this model. We then identified the dichotomized clinical and laboratory parameters prognostic for overall survival (OS) by univariate analyses (UVA) in our cohort. The significant parameters were analyzed to independently predict OS in a multivariable analysis (MVA) and to create a prognostic model, which was subsequently validated in an independent multi-institutional cohort. Results: We identified 889 patients with active WM at MCR, with a median follow-up of 8.2 [95% confidence interval (CI): 7.5-9] years. The estimated median OS for this cohort was 10.6 (95%CI: 9.7-11.4) years. Patients with available data in this cohort for the validation of rIPSS-WM (n=241) were risk stratified into very low (n=46), low (n=64), intermediate (n=58), high (n=46) and very-high risk groups (n=27) per rIPSS-WM, with the respective 5-year OS rates of 96%, 76%, 72%, 77% and 32%, demonstrating overlapping survival curves for the low, intermediate and the high-risk groups. Because rIPSS-WM could not be validated, we used the data from the MCR cohort and identified age at diagnosis of active WM, LDH &amp;gt;upper limit of normal (ULN), β2M &amp;gt;3µg/mL and albumin &amp;lt;3.5g/dL as statistically significant prognostic markers for OS on UVA. Notably, the presence of MYD88 L265P did not impact OS [median 11.4 years (95%CI: 10.1-not reached (NR) for MYD88 L265P genotype (n=231) versus 10 years (95% CI: 8.1-NR) for MYD88 WT genotype (n=65); p=0.33]. On MVA, LDH &amp;gt;ULN (HR 2.34), serum albumin &amp;lt;3.5 g/dL (HR 1.5) and age groups 65-75 years (HR 1.4) and &amp;gt;75 years (HR 2.6) were independently prognostic. Based on comparable HRs, we assigned a score of 1 point each to serum albumin &amp;lt;3.5 g/dL and age group 66-75 years and similarly, 2 points each for age &amp;gt;75 years and serum LDH &amp;gt;ULN per their impact on OS. Patients with the composite scores of 0, 1 and 2 were categorized as low risk, low- intermediate risk and intermediate risk, respectively. Due to similar OS for the scores of 3 to 5, these were combined to form the high-risk group of our proposed model: Modified Staging System for WM (MSS-WM). The median OS was 14.6 years [95%CI: 9.1 years-NR] for low-risk (score 0, n=71, 21%), 11.2 years (95% CI: 9.1-15.2 years) for low-intermediate risk (score 1, n=110, 32%), 8.1 years (95% CI: 6.4-12.2) for intermediate risk (score 2, n=81, 24%) and 5.5 years (95 % CI: 3.9-11 years) for the high-risk group (score ≥3, n=79, 23%); p&amp;lt;0.0001. In this derivation cohort, the 5-year OS rate was 93%, 82%, 69% and 55% and 10-year OS rate was 60%, 53%, 45% and 30% for the low, low-intermediate, intermediate, and high-risk cohort, respectively ( Figure 1A). We also validated MSS-WM using competing risk analysis (p=0.001) and in the cohort of rituximab treated patients (p&amp;lt;0.0001). We then used data from an independent series of 335 treatment-naïve symptomatic patients from academic institutions (n=5) across the US and Europe for external validation of the MSS-WM model. The median follow-up for the validation cohort was 6.3 years (95% CI: 5.5-7.2 years). The 5-year OS was 93%, 90%, 75% and 57% and the estimated 10-year OS was 91%, 80%, 64% and 35% for the low risk (n= 86, 26%), low-intermediate (n=107, 32%), intermediate (n=86, 26%) and high-risk (n=59, 18%) cohorts, respectively (p&amp;lt;0.0001, Figure 1B). Conclusions: Our proposed model, MSS-WM, is a simple, clinically useful, externally validated model that reliably risk stratifies previously untreated patients with active WM into four groups that have distinct outcomes based on the composite scores derived from the patients' age, serum albumin and serum LDH at diagnosis.

Impact of “Cell-of-Origin” on Outcome after Axicabtagene-Ciloleucel CAR-T Cell Therapy in Relapsed/Refractory Aggressive Non-Hodgkin B-Cell Lymphomas

Introduction: Despite significant advances in characterizing aggressive B-cell non-Hodgkin lymphomas (aNHL) based on molecular and genetic signatures, the Hans algorithm, determined by immunohistochemistry, remains the most commonly used approach to differentiate aNHLs based on the cell-of-origin (COO) into germinal center B-cell (GCB) and non-GCB types. Although the Hans algorithm has demonstrated reliability as a predictor of better outcomes in newly diagnosed GCB cases, conflicting evidence has emerged, particularly in the relapsed/refractory (R/R) setting, and there are no definitive data about the impact of COO in patients (pts) receiving CAR-T cells. Thus, we conducted a retrospective analysis to evaluate the impact of COO extended to R/R aNHLs who underwent treatment with axicabtagene-ciloleucel (axi-cel). Methods: We retrospectively collected data from pts with R/R aNHLs treated with axi-cel at Fred Hutchinson Cancer Center between February 2018 and August 2022. The Hans algorithm, using CD10, BCL6 and MUM1 markers, was employed to stratify the pts into two cohorts: GCB and non-GCB. Paired biopsies of diagnosis and relapse before CAR-T eligibility were reviewed at our institution. Response to CAR-T was assessed at one month per Lugano PET/CT criteria. Univariate cox proportional hazard regression was used to estimate associations between baseline factors and outcomes. Statistically significant factors ( p&amp;lt;.05) in univariate analysis were further evaluated by multivariate analysis. Continuous variables were compared by Mann-Whitney U test and categorical variables by Fischer's exact test. Progression-free survival (PFS) was calculated from the date of CAR-T cell infusion to the date of death from any cause, disease progression or relapse. Overall survival (OS) was calculated from the date of CAR-T cell infusion to the date of death from any cause. Results: Sixty-four pts were included in this analysis, with an equal distribution of pts in the two cohorts: 32 with GCB subtype and 32 with non-GCB subtype. Baseline pts' characteristics and histology subtypes are listed in Table 1. Transformed follicular lymphoma and primary mediastinal B-cell lymphoma were not included in this analysis. The presence of bulky disease (defined as &amp;gt;5cm diameter) was higher in the GCB subtype (56% vs 22%, p&amp;lt;.001). Although primary refractory cases were more frequent in the GCB cohort (87.5 vs 66%), statistical significance was not reached (NR)( p=.07). The same proportion of pts received bridging therapy in the two groups (53% vs 53%, p=.99). Pts evaluable for response assessment were 62. Median time to best response was 29 days (range, 21-186) for GCB pts and 31 days (range, 22-182) for non-GCB pts ( p=.91). The overall response rate was 70% for GCBs (34.5% complete response [CR], 34.5% partial response [PR]) and 75% for non-GCBs (44% CR, 31% PR). After a median follow-up of 24.5 months (range, 9-121), comparable outcomes were observed for both the COO groups: despite the estimated median OS of 14 months (95% CI, 4.73-NR) for GCB vs 40 months (95% CI, 12.55-67.46) for non-GCB, we did not find any significant differences ( p=.73) (Figure 1A). Estimated median PFS was 10 months (95% confidence interval [CI], 3.5-16) for GCB and 11 months (95% CI, 0-24) for non-GCB ( p=.57) (Figure 1B). The 2-year OS and PFS were: GCB, 45% (95% CI, 30-69) and 44% (95% CI, 29-67) respectively; non-GCB, 55% (95% CI, 38-79) and 29% (95% CI, 16-55), respectively. Treatment-related toxicities did not differ between GCB and non-GCB, with cytokine-release syndrome rates of 97% vs 94% ( p=.99) and neurotoxicity rates of 53% vs 62.5% ( p=.61), respectively. The incidence of infectious complications was 25% vs 19% ( p=.76). On univariate analysis, the impact of COO on OS (HR=0.82, 95% CI 0.39-1.73, p=.60) and PFS (HR=1.18, 95% CI 0.61-2.28, p=.62) was undetermined. After adjusting for bulky disease, elevated LDH, absolute lymphocyte count≤1000/uL, performance status≥2, &amp;gt;2 lines of therapy and response status before axi-cel infusion, the impact of COO on OS (adjusted HR [aHR]=1.73, 95% CI 0.71-4.22, p=.23) and PFS (aHR=2.01, 95% CI 0.93-4.35, p=.08), remained undetermined. Conclusion: We could not confirm an association between COO, as determined by Hans algorithm, and outcomes in R/R aNHLs who received axi-cel at our center. Prospective analyses on larger datasets and other types of CAR-T products are needed.

Real-World Experience With CPX-351 Treatment for Acute Myeloid Leukemia in England: An Analysis From the National Cancer Registration and Analysis Service

BackgroundCPX-351 demonstrated improved overall survival (OS) versus conventional 3 + 7 daunorubicin/cytarabine chemotherapy in a registrational phase III study in older patients with newly diagnosed, high-risk secondary acute myeloid leukemia (AML). This retrospective, population-based cohort study aimed to describe and compare the characteristics and survival outcomes of younger (<60 years) versus older (≥60 years) patients with AML treated with CPX-351 in England. Patients and MethodsThe study included adults aged ≥18 years diagnosed with AML in England between January 2013 and March 2022, and treated with CPX-351 in routine clinical practice (patients who received CPX-351 in a clinical trial were excluded). Patient records were sourced from the population-level cancer analysis system database available through the National Cancer Registration and Analysis Service. ResultsOf 353 included patients, 104 (29.5%) were <60 years. With a median follow-up of 10.9 months from diagnosis, the estimated median OS was 12.9 months overall, 17.3 months for adults <60 years and 11.7 months for those ≥60 years. All-cause mortality by Day 30 from diagnosis was 6% overall, 4% for adults <60 years and 6% for those ≥60 years. Hematopoietic cell transplantation (HCT) was received by 54% of adults <60 years and 38% of those ≥60 years after CPX-351, with median OS landmarked from the HCT date not yet reached for either age subgroup. ConclusionThis study provides real-world survival outcomes data suggesting that CPX-351 is an effective treatment for both younger (<60 years) and older (≥60 years) adults with AML.

Pancreatic cancer associated ascites: Risk factors, outcomes, and management.

e16305 Background: Pancreatic ductal adenocarcinoma (PDAC) is associated with significant morbidity and mortality as most patients present with advanced disease. The development of ascites has been associated with poor outcomes and further characterization and contemporary management strategies are needed. Therefore, we performed a comprehensive analysis of PDAC patients with ascites, including clinical and biological data, to describe its incidence, associated clinical factors, and outcomes. Methods: Patients were prospectively consented and enrolled the Gastrointestinal Biobank (“GI-Bank”) at Cedars-Sinai Medical Center, which collected patient specimens, associated clinical data, and self-reported questionnaires. Data was consolidated using a standard software tool (Redcap). Statistical analysis was conducted using Excel and using Datatab.net software tools. Results: Of the 437 patients with PDAC, 182 (41.6%) developed ascites. Overall survival (OS) between ascites and non-ascites groups were significantly different by log-rank test (p = 0.001), and estimated median OS was 473 days (95% CI [407, 537]) in ascites patients versus 554 days [467, 678] in non-ascites patients. In Cox proportional hazards model analysis, ascites status, but not sex or race, was associated with decreased survival (HR 1.49, [1.18, 1.87]). Ascitic fluid data was obtained in 77 patients; 62 (80.5%) had SAAG &gt; 1.1; 14(22.6%) of SAAG &gt; 1.1 patients also had positive cytology. The estimated median OS from the diagnosis of ascites was 100 days [76, 128] and median time to puncture was 4 days. Estimated median time from first tap to death was 56 days [42, 95]. 90 (49.5%) were treated with diuretics and 41 (22.5%) were treated with PleurX catheter. Patients with ascites had a worse survival and were more likely to receive greater than one chemotherapy regimen. There was no relationship between ascites and receipt of surgery or radiation. Conclusions: The development of ascites in patients with pancreatic cancer is common and contributes to significant morbidity and mortality. The use of diuretics is lower than would be expected for patients with elevated SAAG. Prospective evaluation of management strategies is needed to improve this important clinical conundrum.

Real-world treatment patterns and outcomes for patients with advanced melanoma treated with immunotherapy or targeted therapy.

To identify real-world patterns of first line treatment, treatment sequence and outcomes for older adults diagnosed with advanced melanoma who received immunotherapy or targeted therapy. The study population included older adults (ages 65+) diagnosed with unresectable or metastatic melanoma between 2012 and 2017 and who received first line immunotherapy or targeted therapy. Using the linked surveillance, epidemiology, and end results-medicare data, we described patterns of first line treatment and treatment sequence through 2018. We used descriptive statistics to report patient and provider characteristics by first line treatment receipt and changes in first line therapy use over calendar time. We also described overall survival (OS) and time to treatment failure (TTF) by first line treatment using the Kaplan-Meier method. For patterns of treatment sequence, we reported commonly observed treatment switch patterns by treatment sub-category and calendar year. The analyses included 584 patients (mean age = 76.3 years). A majority (n = 502) received first line immunotherapy. There was a sustained increase in immunotherapy uptake, most notably from 2015 to 2016. The estimated median OS and TTF were longer with first line immunotherapy than with targeted therapy. Individuals treated with CTLA-4 + PD-1 inhibitors had the longest median OS (28.4 months). The most common treatment switch pattern was from a first line CTLA-4 inhibitor to a second line PD-1 inhibitor. Our findings inform understanding of treatment patterns of currently used immunotherapies and targeted therapies in older adults with advanced melanoma. Immunotherapy use has increased steadily with PD-1 inhibitors becoming a dominant treatment option since 2015.

Association of Brain Metastases With Survival in Patients With Limited or Stable Extracranial Disease

Intracranial metastatic disease (IMD) is a severe complication of cancer with profound prognostic implications. Patients with IMD in the setting of limited or stable extracranial disease (IMD-SE) may represent a unique and understudied subset of patients with IMD with superior prognosis. To evaluate overall survival (OS), progression-free survival (PFS), and intracranial PFS (iPFS) in patients with IMD-SE secondary to any primary cancer. Records were identified from MEDLINE, EMBASE, CENTRAL, and gray literature sources from inception to June 21, 2021. Studies in English reporting OS, PFS, or iPFS in patients with IMD-SE (defined as IMD and ≤2 extracranial metastatic sites) and no prior second-line chemotherapy or brain-directed therapy were selected. Author, year of publication, type of study, type of primary cancer, and outcome measures were extracted. Random-effects meta-analyses were performed to estimate effect sizes, and subgroup meta-analysis and metaregression were conducted to measure between-study differences in February 2022. The primary end point was OS described as hazard ratios (HRs) and medians for comparative and single-group studies, respectively. Secondary end points were PFS and iPFS. Overall, 68 studies (5325 patients) were included. IMD-SE was associated with longer OS (HR, 0.52; 95% CI, 0.39-0.70) and iPFS (HR, 0.63; 95% CI, 0.52-0.76) compared with IMD in the setting of progressive extracranial disease. The weighted median OS estimate for patients with IMD-SE was 17.9 months (95% CI, 16.4-22.0 months), and for patients with IMD-PE it was 8.0 months (95% CI, 7.2-12.8 months). Pooled median OS for all patients with IMD-SE was 20.9 months (95% CI, 16.35-25.98 months); for the subgroup with breast cancer it was 20.2 months (95% CI, 10.43-38.20 months), and for non-small cell lung cancer it was 27.5 months (95% CI, 18.27-49.66 months). Between-study heterogeneity for OS and iPFS were moderate (I2 = 56.5%) and low (I2 = 0%), respectively. In this systematic review and meta-analysis of patients with IMD-SE, limited systemic disease was associated with improved OS and iPFS. Future prospective trials should aim to collect granular information on the extent of extracranial disease to identify drivers of mortality and optimal treatment strategies in patients with brain metastases.

Dose-escalated pancreas radiotherapy for unresected pancreatic adenocarcinoma: Patterns of care and survival in the United States.

676 Background: Randomized trials have not shown an overall survival (OS) benefit to adding radiotherapy (RT) to chemotherapy for patients with locally advanced pancreatic adenocarcinoma (LAPC). However, trials such as LAP07 did not incorporate escalated-dose RT (EDR), which may confer longer survival. The adoption of EDR across the United States and associated outcomes are unknown. Methods: We queried the National Cancer Data Base for non-surgically managed patients with LAPC diagnosed between 2004 and 2019. RT with biologically effective doses (BED10) &gt; 70 and ≤ 200 Gy were labeled EDR and conventional-dose RT (CDR) for 39-70 Gy doses. Associations with receipt of EDR and with OS were identified using multivariate analysis (MVA) logistic and Cox regressions, respectively. Bonferroni corrections were applied. Cochran-Armitage and Mann-Kendall trend tests were performed to assess trends in use of RT. Results: Of 64,303 patients, the most common treatments were chemotherapy alone (CT) (71%), chemoradiation (CRT) (27%), and pancreas RT alone (2%). 18,970 patients received pancreas RT, of which 91% was CDR (median dose 50.4 Gy; median 28 fractions) and 9% was EDR (50 Gy; 5 fractions). Use of pancreas RT increased from 14% in 2004 to a peak of 18% in 2010, decreased to a nadir of 13% in 2016, and subsequently increased to 15% by 2019 ( Ptrend &lt; 0.001). EDR use increased from 7% in 2004 to 22% in 2019 ( Ptrend &lt; 0.0001). Median BED10 increased from 53 to 59 Gy ( Ptrend&lt; 0.001). Of patients receiving pancreas RT, use of intensity-modulated RT (IMRT) and stereotactic body RT (SBRT) respectively increased from 25% and 2% in 2004 to 60% and 27% in 2019, while use of 3-D conformal RT (3D-CRT) decreased from 64% to 9% ( Ptrend &lt; 0.02 for all comparisons). On MVA logistic regression, primary tumor location in the body/tail vs. head (aOR 1.22, 95% CI 1.07-1.40; P = 0.003) associated with greater EDR receipt, whereas T3-4 vs. T2 disease (aOR 0.81, CI 0.71-0.92; P = 0.002) associated with lesser receipt. At a median follow up of 59.1 months (CI 57.5-61.0), median OS estimates for CDR and EDR were 10.2 months (CI 10.1-10.3) and 13.3 months (CI 13.2-13.5; P &lt; 0.0001), respectively. On MVA Cox regression, N1 vs. N0 disease (HR 1.08, CI 1.06-1.10; P &lt; 0.001) correlated with higher risk of death, whereas CRT vs. CT (HR 0.83, CI 0.81-0.85; P &lt; 0.001) correlated with lower risk of death. Subset MVA of 14,634 CRT patients correlated higher RT dose—as both a categorical variable (EDR vs. CDR; HR 0.84, CI 0.79-0.90; P &lt; 0.001) and continuous variable (BED10; HR 0.994, CI 0.992-0.995; P &lt; 0.001)—with lower risk of death. Conclusions: Fewer than 1 in 6 patients with unresected LAPC received pancreas RT, despite a nominal increase in utilization in recent years. Although retrospective, these NCDB data suggest longer OS with the addition of RT for unresected LAPC, suggesting continued unmet need. EDR is associated with longer survival vs. CDR.

Survival of patients with mantle cell lymphoma in the rituximab era: Retrospective binational analysis between 2000 and 2020.

Mantle cell lymphoma (MCL) is a rare peripheral B-cell lymphoma characterised by eventual relapse and progression towards a more aggressive disease biology. With the introduction of rituximab- and cytarabine-based immunochemotherapy regimens, the prognosis of the disease has changed dramatically over the last two decades. To assess the real-world survival of patients with MCL, we used a population-based cohort of 564 patients with MCL who were diagnosed and treated between 2000 and 2020. Patient data were collected from seven Finnish treatment centres and one Spanish treatment centre. For the entire patient population, we report a 2-year overall survival (OS) rate of 77%, a 5-year OS of 58%, and a 10-year OS of 32%. The estimated median OS was 80 months after diagnosis. MCL is associated with increased mortality across the entire patient population. Additionally, we assessed the survival of patients after MCL relapse with the aim of establishing a cut-off point of prognostic significance. Based on our statistical analysis of survival after the first relapse, disease progression within 24 months of the initial diagnosis should be considered as a strong indicator of poor prognosis.