Increase In Median Overall Survival Research Articles

Progression-free survival as a surrogate endpoint for overall survival in patients with relapsed or refractory multiple myeloma.

The goal of the research was to assess the quantitative relationship between median progression-free survival (PFS) and median overall survival (OS) specifically among patients with relapsed/refractory multiple myeloma (RRMM) based on published randomized controlled trials (RCTs). Two bibliographic databases (PubMed and Embase, 1970-2017) were systematically searched for RCTs in RRMM that reported OS and PFS, followed by an updated search of studies published between 2010 and 2022 in 3 databases (Embase, MEDLINE, and EBM Reviews, 2010-2022). The association between median PFS and median OS was assessed using the nonparametric Spearman rank and parametric Pearson correlation coefficients. Subsequently, the quantitative relationship between PFS and OS was assessed using weighted least-squares regression adjusted for covariates including age, sex, and publication year. Study arms were weighted by the number of patients in each arm. A total of 31 RCTs (56 treatment arms, 10,450 patients with RRMM) were included in the analysis. The average median PFS and median OS were 7.1 months (SD 5.5) and 28.1 months (SD 11.8), respectively. The Spearman and Pearson correlation coefficients between median PFS and median OS were 0.80 (P < 0.0001) and 0.79 (P < 0.0001), respectively. In individual treatment arms of RRMM trials, each 1-month increase in median PFS was associated with a 1.72-month (95% CI 1.26-2.17) increase in median OS. Analysis of the relationship between PFS and OS incorporating more recent studies in RRMM further substantiates the use of PFS to predict OS in RRMM.

Outcomes and adverse events in older acute lymphoblastic Leukemia patients treated with a pediatric-inspired protocol with Pegylated or native Asparaginase

ABSTRACT This retrospective report presents the outcomes and adverse events (AEs) observed in 73 patients aged 60 years or older diagnosed with Philadelphia Chromosome-negative Acute Lymphoblastic Leukemia (Ph-negative ALL) treated with a pediatric-inspired protocol incorporating either Pegylated (PEG-ASP) or Native Asparaginase (EC-ASP). Notably, 61% of patients experienced AEs of Grade III-IV severity. The most prevalent AEs included thrombosis (35.6%), febrile neutropenia (38.4%), and transaminitis (34.2%). AEs did not translate into significant differences concerning overall survival, leukemia-free survival, or early mortality. Furthermore, we observed a reduction in early mortality rates (11% vs. 20%) and an increase in median overall survival (54 vs. 48 months) compared to our previous data. These findings suggest that the utilization of a pediatric-inspired chemotherapy protocol, with ASP, is an effective and well-tolerated therapeutic option for older patients with Ph-negative ALL. However, it emphasizes the importance of diligent monitoring and close follow-up throughout treatment.

Enhancing Patient Selection in Stage IIIA-IIIB NSCLC: Invasive Lymph Node Restaging after Neoadjuvant Therapy.

Restaging of mediastinal lymph nodes plays a crucial role in the multimodal treatment of stage IIIA Non-Small-Cell Lung Cancer (NSCLC). This study aimed to assess the impact of restaging using endobronchial ultrasound (EBUS), endoesophageal ultrasound (EUS), and transcervical extended mediastinal lymphadenectomy (TEMLA) after neoadjuvant chemotherapy (CHT) or chemoradiotherapy (CRT) on the 5-year overall survival (OS) of patients with NSCLC diagnosed with clinical stage IIIA-IIIB and metastatic ipsilateral mediastinal nodes (N2) who underwent radical pulmonary resections. Patients diagnosed with stage IIIA-IIIB NSCLC and N2 mediastinal nodes were included in this study. Restaging of mediastinal lymph nodes was performed using EBUS, EUS, and TEMLA. The patients were divided into two groups based on the restaging method: the TEMLA restaging group and the chest CT scan-only group. The primary outcome measure was the 5-year OS rate, and the secondary outcome measures included median OS and survival percentages. Statistical analysis, including the log-rank test, was conducted to assess the differences between the two groups. The TEMLA restaging group demonstrated significantly better overall survival compared to the chest CT scan-only group (log-rank test, p = 0.02). This was evident through a four-fold increase in median OS (59 vs. 14 months) and a higher 5-year OS rate of 55.9% (95% CI: 40.6-71.1) compared to 25.0% (95% CI: 13.7-36.3) in the chest CT scan-only group (p = 0.003). Invasive restaging of mediastinal lymph nodes improves the selection of patients with stage IIIA-IIIB (N2) NSCLC after neoadjuvant therapy. The use of EBUS, EUS, and TEMLA provides valuable information for identifying patients who may benefit from surgery by identifying N2 to N0-1 downstaging. These findings emphasize the importance of incorporating restaging procedures into the treatment decision-making process for NSCLC patients with mediastinal lymph node involvement.

Real-world progression in the survival of de novo Metastatic prostate cancer over the past decade

BackgroundThe impact of evolving treatment strategies for metastatic prostate cancer (mPCa) on real-world survival is not well understood. We analyzed changes in mPCa survival over the past decade and discussed the potential driving factors behind these changes. MethodsOur study involved 43,228 mPCa patients (2004–2020) from the SEER database, divided into 4 diagnostic periods. We used a multivariate Cox proportional hazards model to evaluate diagnostic periods' influence on overall mortality (OM) and prostate cancer-specific mortality (PSM), and calculated relative median survival improvements between adjacent periods. Subgroup analyses based on age and distant metastasis sites were conducted. ResultsPatients diagnosed in 2016 to 2020 experienced significantly reduced mortality risk compared to those in 2004 to 2007 (HR 0.64 for OM, HR 0.62 for CSM, both P < 0.001). The study period witnessed an absolute improvement in median overall survival (OS) and prostate cancer-specific survival (PCSS), 17 months (54.8%) and 25 months (67.6%) respectively. The most rapid relative survival improvement occurred post-2016, with a 29.7% increase in median OS and a 37.8% increase in PCSS compared to 2012 to 2015. There was a significant reduction in mortality risk throughout the study period in both age groups (age <75 and ≥75), but absolute survival gains were smaller in the older group (24 months [68.6%] vs. 8 months [32%] for OS, 36 months [90.0%] vs. 11 months [33.3%] for PCSS), with lower relative survival improvements after 2016 (37.2% vs. 17.9% for OS, 49% vs. 22.2% for PCSS). All metastasis site subgroups (except M1a) exhibited a significant reduction in mortality risk (all P < 0.001). Absolute survival improvements were 58 months (134.9%) for M1a, 16 months (50.0%) for M1b, and 17 months (54.8%) for M1c. ConclusionThe survival of mPCa have significantly improved over the past decade, although the progress is slower in elderly patients. Investigating the underlying reasons for survival differences among various patient profiles can further refine mPCa treatment strategies.

Second-Line Chimeric Antigen Receptor T-Cell Therapy in Diffuse Large B-Cell Lymphoma : A Cost-Effectiveness Analysis.

First-line treatment of diffuse large B-cell lymphoma (DLBCL) achieves durable remission in approximately 60% of patients. In relapsed or refractory disease, only about 20% achieve durable remission with salvage chemoimmunotherapy and consolidative autologous stem cell transplantation (ASCT). The ZUMA-7 (axicabtagene ciloleucel [axi-cel]) and TRANSFORM (lisocabtagene maraleucel [liso-cel]) trials demonstrated superior event-free survival (and, in ZUMA-7, overall survival) in primary-refractory or early-relapsed (high-risk) DLBCL with chimeric antigen receptor T-cell therapy (CAR-T) compared with salvage chemoimmunotherapy and consolidative ASCT; however, list prices for CAR-T exceed $400 000 per infusion. To determine the cost-effectiveness of second-line CAR-T versus salvage chemoimmunotherapy and consolidative ASCT. State-transition microsimulation model. ZUMA-7, TRANSFORM, other trials, and observational data. "High-risk" patients with DLBCL. Lifetime. Health care sector. Axi-cel or liso-cel versus ASCT. Incremental cost-effectiveness ratio (ICER) and incremental net monetary benefit (iNMB) in 2022 U.S. dollars per quality-adjusted life-year (QALY) for a willingness-to-pay (WTP) threshold of $200 000 per QALY. The increase in median overall survival was 4 months for axi-cel and 1 month for liso-cel. For axi-cel, the ICER was $684 225 per QALY and the iNMB was -$107 642. For liso-cel, the ICER was $1 171 909 per QALY and the iNMB was -$102 477. To be cost-effective with a WTP of $200 000, the cost of CAR-T would have to be reduced to $321 123 for axi-cel and $313 730 for liso-cel. Implementation in high-risk patients would increase U.S. health care spending by approximately $6.8 billion over a 5-year period. Differences in preinfusion bridging therapies precluded cross-trial comparisons. Neither second-line axi-cel nor liso-cel was cost-effective at a WTP of $200 000 per QALY. Clinical outcomes improved incrementally, but costs of CAR-T must be lowered substantially to enable cost-effectiveness. No research-specific funding.

Treatment Patterns and Outcomes of Patients with Acute Myeloid Leukemia (AML) from 2013 to 2022: A Connect ® Myeloid Registry Study

Introduction There has been a rapid evolution in diagnostic and management evaluation for AML, associated with the introduction of new therapies, some of which target specific mutations, over the past decade. The Connect ® Myeloid Registry (NCT01688011) is a multicenter, prospective, observational cohort study that began enrollment in December 2013 and represents a rich source of information to evaluate changes in disease course and outcomes over time in patients with myeloid diseases. We evaluated 10-year longitudinal data from patients with AML treated in real-world clinical practice at community and academic institutions to understand the evolution of diagnosis and treatment of patients with this myeloid condition. Methods Patients in the AML cohort were ≥ 55 years of age and newly diagnosed with AML according to the 2008 revised World Health Organization criteria and were grouped by year of diagnosis: 2013-2016 (Group 1; before commercial availability of numerous novel therapies including venetoclax, midostaurin, ivosidenib, enasidenib, gemtuzumab ozogamicin, and others), and 2017-2022 (Group 2; after availability of new therapies). Baseline demographic and clinical characteristics, treatment patterns, and outcomes were evaluated by group. Overall survival (OS) from the date of diagnosis was estimated by the Kaplan-Meier method. Results A total of 773 patients with AML (Group 1, n = 292; Group 2, n = 481) were assessed. Median (range) age was 70.0 years (55.0-91.0) in Group 1, and 71.0 years (55.0-97.0) in Group 2. Median OS was 11.0 months (95% confidence interval [CI]: 9.0-14.0) in Group 1, and 16.0 months (13.0-18.0) in Group 2 ( P = 0.039; Figure). A higher percentage of patients in Group 2 survived to 60 months compared with Group 1 ( Figure). Improved survival over time was primarily observed in patients &amp;lt; 75 years of age at diagnosis; median (95% CI) OS among patients &amp;lt; 75 years of age increased over time from 14.0 months (11.0-17.0) in Group 1 to 20.0 months (17.0-24.0) in Group 2 ( P = 0.022) but remained unchanged over time among patients ≥ 75 years of age (9.0 months [6.0-10.0] in Group 1; 9.0 months [6.0-13.0] in Group 2; P = NS). Rates of transplant increased significantly over time for younger patients; among those &amp;lt; 75 years of age at diagnosis, 45/201 (22%) in Group 1 received a transplant, compared with 99/318 (31%) in Group 2( P = 0.035). The proportion of patients receiving molecular testing increased over time from 68.8% in Group 1 to 86.9% in Group 2. The mean (standard deviation) number of mutations tested among those who underwent molecular testing also increased over time, from 6.1 (5.9) in Group 1 to 11.8 (7.4) in Group 2. Longer median (95% CI) OS was observed in patients who received molecular testing compared with those who did not: 14.0 months (11.0-17.0) versus 9.0 months (7.0-11.0) in Group 1; 16.0 months (13.0-19.0) versus 13.0 months (6.0-17.0) in Group 2. The proportion of patients receiving first-line treatment with intensive chemotherapy (IC) regimens was similar in the 2 time periods (Group 1, 51.0%; Group 2, 47.1%). Among patients not receiving IC, those in Group 2 increasingly received targeted therapies and venetoclax-based regimens and less-frequent low-intensity chemotherapy and supportive care. Conclusions In the AML cohort of Connect ® Myeloid, one of the longest-running US registries of myeloid diseases, we observed that patient characteristics at diagnosis were similar from 2013-2022. A statistically significant increase in median OS was observed over time. The increased rate of transplant, higher rates of molecular testing, and uptake of novel, targeted, treatments may have contributed to the improvement in survival. These results demonstrate the need for long-running, prospective observational studies to continue to understand rapidly changing treatment algorithms, combinations, and outcomes in AML.

Prognosis Following Surgery for Recurrent Ovarian Cancer and Diagnostic Criteria Predictive of Cytoreduction Success: A Systematic Review and Meta-Analysis.

For women achieving clinical remission after the completion of initial treatment for epithelial ovarian cancer, 80% with advanced-stage disease will develop recurrence. However, the standard treatment of women with recurrent platinum-sensitive diseases remains poorly defined. Secondary (SCS), tertiary (TCS) or quaternary (QCS) cytoreduction surgery for recurrence has been suggested to be associated with increased overall survival (OS). We searched five databases for studies reporting death rate, OS, cytoreduction rates, post-operative morbidity/mortality and diagnostic models predicting complete cytoreduction in a platinum-sensitive disease recurrence setting. Death rates calculated from raw data were pooled based on a random-effects model. Meta-regression/linear regression was performed to explore the role of complete or optimal cytoreduction as a moderator. Pooled death rates were 45%, 51%, 66% for SCS, TCS and QCS, respectively. Median OS for optimal cytoreduction ranged from 16-91, 24-99 and 39-135 months for SCS, TCS and QCS, respectively. Every 10% increase in complete cytoreduction rates at SCS corresponds to a 7% increase in median OS. Complete cytoreduction rates ranged from 9-100%, 35-90% and 33-100% for SCS, TCS and QCS, respectively. Major post-operative thirty-day morbidity was reported to range from 0-47%, 13-33% and 15-29% for SCS, TCS and QCS, respectively. Thirty-day post-operative mortality was 0-6%, 0-3% and 0-2% for SCS, TCS and QCS, respectively. There were two externally validated diagnostic models predicting complete cytoreduction at SCS, but none for TCS and QCS. In conclusion, our data confirm that maximal effort higher order cytoreductive surgery resulting in complete cytoreduction can improve survival.

Metformin shows anti-neoplastic properties by inhibition of oxidative phosphorylation and glycolysis in epidermolysis bullosa-associated aggressive cutaneous squamous cell carcinoma.

While most cutaneous squamous cell carcinomas (cSCCs) are treatable, certain high-risk cSCCs, such as those in recessive dystrophic epidermolysis bullosa (RDEB) patients, are particularly aggressive. Owing to repeated wounding, inflammation and unproductive healing, RDEB patients have a 68% cumulative risk of developing life-threatening cSCCs by the age of 35, and a 70% risk of death by the age of 45. Despite aggressive treatment, cSCC represents the leading cause of premature mortality in these patients, highlighting an unmet clinical need. Increasing evidence points to a role of altered metabolism in the initiation and maintenance of cSCC, making metabolism a potential therapeutic target. We sought to determine the feasibility of targeting tumour cell energetics as a strategy to selectively hinder the growth advantage of aggressive cSCC. We evaluated the cell energetics profiles of RDEB-SCC cells by analysing available gene expression data against multiple gene signatures and single-gene targets linked to metabolic reprogramming. Additionally, we employed real-time metabolic profiling to measure glycolysis and respiration in these cells. Furthermore, we investigated the anti-neoplastic properties of the metformin against human and murine high-risk cSCCs in vitro and in vivo. Gene expression analyses highlighted a divergence in cell energetics profiles between RDEB-SCC and non-malignant RDEB keratinocytes, with tumour cells demonstrating enhanced respiration and glycolysis scores. Real-time metabolic profiling supported these data and additionally highlighted a metabolic plasticity of RDEB-SCC cells. Against this background, metformin exerted an anti-neoplastic potential by hampering both respiration and glycolysis, and by inhibiting proliferation in vitro. Metformin treatment in an analogous model of fast-growing murine cSCC resulted in delayed tumour onset and slower tumour growth, translating to a 29% increase in median overall survival. Our data indicate that metformin exerts anti-neoplastic properties in aggressive cSCCs that exhibit high-risk features by interfering with respiration and glycolytic processes.

Long-Term Survival in Patients with Cancers: Surveillance, epidemiology and end results-based analysis.

This study aimed to explore real-world data on the long-term survival of cancer patients using historical records from the Surveillance, Epidemiology, and End Results (SEER) Programme. Long-term survival is an important endpoint in the management of different malignancies. It is rarely assessed due to the unfeasibility of follow-up for a long duration of time. Besides reporting the five-year relative survival, the 10- and 20-year survival rates for different types of cancers were analysed. Additionally, survival trends as a function of time, age and tumour type were reviewed and reported. The study used SEER*Stat (Version 8.3.6.1) for data acquisition from the SEER 9 Regs (November 2019) database. Data from patients diagnosed with cancer between 1975 and 2014 were retrieved and included in the analysis. For patients diagnosed with any malignant disease (N = 4,412,024), there was a significant increase in median overall survival over time (P <0.001). The 20-, 10-, and 5-year survival rates were higher in solid tumours compared to haematological malignancies (50.8% versus 38%; 57% versus 47.4%; and 62.2% versus 57.4%, respectively). The highest 20-year relative survival rates were observed in thyroid cancer (95.2%), germ cell and trophoblastic neoplasms (90.3%), melanoma (86.8%), Wilms' tumour (86.2%) and prostate cancer (83.5%). Long-term follow-up data were suggestive of high 20-year relative survival rates for most tumour types. Relative survival showed an improving trend over time, especially in solid tumours.

Phase II trial of XmAb20717 (vudalimab) in patients with advanced biliary tract cancers.

TPS4184 Background: For patients with advanced biliary tract cancers (BTCs), gemcitabine and cisplatin has been the standard-of-care first-line therapy, with a median overall survival (OS) of 11.7 months. More recently, TOPAZ-1 demonstrated a modest, but significant overall survival benefit (HR 0.80; 95% CI 0.66 – 0.97) to the addition of durvalumab to gemcitabine and cisplatin with a median OS of 12.8 months. However, for patients without targetable molecular variants, second-line and beyond options are limited, with FOLFOX demonstrating an overall response rate (ORR) of 5% and increase in median overall survival by 0.9 months compared to active symptom control. In patients with advanced BTCs, combination immunotherapy approaches with PD-1 or PD-L1 plus CTLA-4 inhibitors have been associated with improved ORRs of 10.8% - 23% compared to ORRs of 3 – 7% observed with single agent PD-1 or PD-L1 inhibitors. XmAb20717 (vudalimab) is a novel, bispecific antibody targeting PD-1 and CTLA-4 which demonstrated an ORR of 14.1% in a phase I dose expansion cohort of patients with advanced malignancies, including patients that had experienced disease progression on prior immune checkpoint inhibitors. Methods: We initiated a single-arm, phase II clinical trial with a Simon two-stage mini-max design to evaluate the efficacy of XmAb20717, in terms of ORR, in patients with advanced biliary tract cancers previously treated with gemcitabine-based chemotherapy. In the first stage, 13 patients evaluable for efficacy will be accrued. If no responses are observed in these 13 patients, the study will be stopped for futility. Otherwise, 14 additional patients evaluable for efficacy will be accrued to total 27 evaluable patients. If 4 or more responses are observed in these 27 patients, then the null hypothesis will be rejected. XmAb20717 (10 mg/kg) is administered intravenously on days 1 and 15 of a 28-day cycle. Important inclusion criteria include that patients with FGFR2 fusions, NTRK fusions, or IDH1 mutations must have received molecularly targeted therapy unless contraindicated or refused. Patients are not eligible if they have received prior immune checkpoint inhibitor therapy. Correlative studies will include longitudinal peripheral blood collection for circulating immune cell profiling. As of January, 2023, 8 patients have been enrolled with enrollment ongoing. Clinical trial information: NCT05297903 .

A phase III randomized trial of eribulin (E) with or without gemcitabine vs standard of care (SOC) for metastatic urothelial carcinoma (UC) refractory to or ineligible for PD/PDL1 antibody (Ab): SWOG S1937.

TPS4608 Background: UC is 2nd most common genitourinary cancer. Current SOC offers platinum-based (PB) first line chemotherapy (chemo) with ddMVAC or gemcitabine-cisplatin (GC) regimens. For cisplatin ineligible patients (pts), SOC includes gemcitabine-carboplatin (GCa), and in select pts pembrolizumab. Erdafitinib is approved for pts with FGFR alterations and Enfortumab vedotin (EV) is approved for previously treated pts. A phase I/II CTEP study of eribulin (E) for metastatic UC (mUC) established the activity of E in UC with objective response rate (ORR) of 37.5% and a median progression free survival (PFS) of 4.1 months (mo) and median overall survival (OS) of 9.5 mo (N=150). A phase II CTEP study of gemcitabine-eribulin (GE) in cisplatin ineligible mUC showed an ORR of 50%, median OS of 11.9 mo and median PFS of 5.3 mo (N=24). The most common Grade 3-4 toxicities included: neutropenia 63%, anemia and fatigue 29%. Pts with liver metastases benefited from therapy with 5 responders in 7 pts for GE vs 12 out 49 E. Methods: This is a phase III, randomized 3 arm study comparing E vs. GE vs. SOC (docetaxel, paclitaxel, or gemcitabine). E is given at 1.4mg/m2 on day (D) 1 and 8 of a 21 D cycle. In the GE arm, gemcitabine is added to E at 1000 mg/m2 dose to D1 and D8. SOC follows standard dosing of the agents. There is no limit to the number/sequence of prior regimens. A simplified summary of eligibility criteria is presented here. All pts must have: received frontline systemic treatment such as PB chemo or a non-platinum regimen; received PD1/PDL1 Ab or be deemed ineligible for PD1/PDL1 Ab; received EV. Assuming a median OS for the SOC arm of 7 mo the study seeks to find at least a 50% increase in median OS to 10.5 mo (Hazard Ratio (HR) = 0.667). One-sided 0.0125 type I error to account for testing of two primary hypotheses (Each arm vs. SOC). 87% power to detect a 3.5 mo improvement in OS. We require 140 eligible (155 total) pts in each arm for a total of 465. The study was activated in Feb 2021 and accrual is ongoing. Clinical trial information: NCT04579224 .

The Impact of Social Determinants of Health, Namely Financial Assistance, on Overall Survival in Advanced-Stage Non-Small Cell Lung Cancer Patients.

Non-small cell lung cancer (NSCLC) is the most prevalent form of lung cancer. Studies have evaluated the association of social determinants of health (SDH) with outcomes in early-stage NSCLC. These studies have shown statistically and clinically significant associations between overall survival (OS) and other SDH (e.g marital status, educational attainment).The aim of our study was to better understand the role of various SDH on OS in advanced-stage NSCLC patients in a community oncology practice in Florida. Methods: In this retrospective study, 125 patients with stage III and IV NSCLC were identified between January 1, 2014, and December 31, 2018. We performed Pearson's chi-square and Kruskal-Wallis test to evaluate the association between median OS and several independent variables, including; gender, race, marital status, insurance status, living status, receiving financial assistance (FA), alcohol use, and smoking histories. OS is defined as the date of diagnosis up to the date of death. Other confounders that were analyzed included histology, treatment modality, comorbidities, and performance status of the patients. Results: Our results demonstrated that patients receiving FA had nearly a two-fold increase in median OS compared to patients without FA (median OS = 1.01 years vs. 0.545 years, respectively; p = 0.012). Overall, this study highlighted the importance of reducing the financial burden of advanced-stage NSCLC on patients and how FA impacts patient outcomes. However, future prospective cohort studies with a larger sample size are warranted to identify other SDH, as well as the underlying mechanisms affecting median OS, in patients with advanced-stage NSCLC.

A phase III randomized trial of eribulin (E) with or without gemcitabine vs standard of care (SOC) for metastatic urothelial carcinoma (UC) refractory to or ineligible for PD/PDL1 antibody (Ab): SWOG S1937.

TPS581 Background: UC is 2nd most common genitourinary cancer. Current SOC offers platinum-based (PB) first line chemotherapy (chemo) with ddMVAC or gemcitabine-cisplatin (GC) regimens. For cisplatin ineligible patients (pts), SOC includes gemcitabine-carboplatin (GCa), and in select pts pembrolizumab. Erdafitinib is approved for pts with FGFR alterations and Enfortumab vedotin (EV) is approved for previously treated pts. A phase I/II CTEP study of eribulin (E) for metastatic UC (mUC) established the activity of E in UC with objective response rate (ORR) of 37.5% and a median progression free survival (PFS) of 4.1 months (mo) and median overall survival (OS) of 9.5 mo (N=150). A phase II CTEP study of gemcitabine-eribulin (GE) in cisplatin ineligible mUC showed an ORR of 50%, median OS of 11.9 mo and median PFS of 5.3 mo (N=24). The most common Grade 3-4 toxicities included: neutropenia 63%, anemia and fatigue 29%. Pts with liver metastases benefited from therapy with 5 responders in 7 pts for GE vs 12 out 49 E. Methods: This is a phase III, randomized 3 arm study comparing E vs. GE vs. SOC (docetaxel, paclitaxel, or gemcitabine). E is given at 1.4mg/m2 on day (D) 1 and 8 of a 21 D cycle. In the GE arm, gemcitabine is added to E at 1000 mg/m2 dose to D1 and D8. SOC follows standard dosing of the agents. There is no limit to the number/sequence of prior regimens. A simplified summary of eligibility criteria is presented here. All pts must have: received frontline systemic treatment such as PB chemo or a non-platinum regimen; received PD1/PDL1 Ab or be deemed ineligible for PD1/PDL1 Ab; received EV. Assuming a median OS for the SOC arm of 7 mo the study seeks to find at least a 50% increase in median OS to 10.5 mo (Hazard Ratio (HR) = 0.667). One-sided 0.0125 type I error to account for testing of two primary hypotheses (Each arm vs. SOC). 87% power to detect a 3.5 mo improvement in OS. We require 140 eligible (155 total) pts in each arm for a total of 465. The study was activated in Feb 2021 and accrual is ongoing. Funding: National Institutes of Health/National Cancer Institute grants U10CA180888, U10CA180819. Clinical trial information: NCT04579224 .

Real-World Treatment Outcomes and Toxicities of Outpatient R-CHOP/R-DHAP in Patients with Mantle Cell Lymphoma Eligible for Autologous Stem Cell Transplant

INTRODUCTION: Despite a significant increase in median overall survival (OS) over the past three decades, mantle cell lymphoma (MCL) remains incurable with no standard frontline therapy. The addition of R-DHAP to R-CHOP with autologous stem cell transplant (ASCT) in the European MCL Network - MCL younger trial showed significant improvement in median progression free survival (PFS), although some concerns remain regarding increased toxicity. On this basis, R-CHOP/R-DHAP was approved as first line therapy for MCL at CancerCare Manitoba (CCMB) in 2016. In contrast to the original study, R-DHAP is currently administered in an outpatient setting in Manitoba. OBJECTIVE: To assess the real-world, non-trial PFS, OS, and toxicities of patients with MCL eligible for autologous stem cell transplant receiving R-CHOP/R-DHAP, administered on an outpatient basis, as induction therapy in Manitoba. METHODS: All patients with MCL in Manitoba eligible for R-CHOP/R-DHAP induction between Jan 1, 2016 and Dec 31, 2021 were identified through the CCMB. Individual patient records were obtained and reviewed for baseline demographic data, laboratory data, treatment characteristics including response, and treatment toxicities. SPSS was then used for statistical analysis to calculate PFS and OS using the Kaplan-Meier method. RESULTS: 25 charts were identified. 5 were excluded based on duplicate data for a total of 20 patients (85% male). The mean age at diagnosis was 54.4 (range 42-67). 75% had stage IV disease and 35% had constitutional symptoms. 15% of patients had ECOG ≥2 at diagnosis. 50% had elevated LDH at diagnosis, and the mean β-2-microglobumin was 3.5mg/L (range 1.9-16.1). 10% of patient's largest nodal dimension was >=7.5cm, 20% had disease with Ki67>=40%, and 15% had high risk disease by MIPI. The median number of chemotherapy cycles completed was 6 (range 2-6), with 50% requiring modification to therapy (5% progression, 20% infection, 20% ototoxicity, 20% nephrotoxicity, 5% corneal toxicity, 5% patient preference). 70% received ASCT, with 100% complete response by PET post-ASCT. 75% of all patients received maintenance rituximab, with a median of 8 cycles completed (range 2-8). At the end of follow up, there were 3 progression events, 3 deaths, and 1 death attributed to MCL. At a median follow up of 56.8 months, median PFS and OS were not reached. CONCLUSION: Our real-world data show feasibility of administering R-CHOP/R-DHAP in the outpatient setting with comparable outcome and toxicities to original study where R-DHAP was administered as inpatient. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

NCMP-04. COMBINATION BRAF/MEK INHIBITION IMPROVES SURVIVAL WITH LEPTOMENINGEAL DISEASE FROM MELANOMA IN A SINGLE INSTITUTIONAL REVIEW AT MOFFITT CANCER CENTER

Abstract Melanoma is third most common cancer to metastasize to the leptomeningeal space and confers a dismal prognosis. We retrospectively identified 87 cases of melanoma related leptomeningeal disease (M-LMD) diagnosed between 2011-2020 at Moffitt Cancer Center. The average age at diagnosis was 54 years (range 28-93 years) with a male predominance (50 men vs 36 women). There was a significant increase in median overall survival (OS) for patients with BRAF V600E mutation, but only if they were treated with combined BRAF/MEK inhibitors after diagnosis of LMD (5.54 months vs 1.39 months; p &amp;lt; 0.01). Immune checkpoint inhibitors also associated with a small but significant increase in OS when given after diagnosis of M-LMD (2.73 months vs 1.38mths; p &amp;lt; 0.01). There was no association between OS and gender (p &amp;gt; 0.05). The current data supports use of BRAF/MEK inhibitors for treatment of BRAF V600E mutated M-LMD. More work is needed to improve OS for these patients and patients without a targetable mutation and M-LMD.

A ketogenic diet in combination with gemcitabine increases survival in pancreatic cancer KPC mice.

Pancreatic ductal adenocarcinoma (PDAC) continues to be a major health problem. A ketogenic diet (KD), characterized by a very low carbohydrate and high fat composition, has gained attention for its anti-tumor potential. We evaluated the effect and mechanisms of feeding a strict KD alone or in combination with gemcitabine in the autochthonous LSL-KrasG12D/+; LSL-Trp53 R172H/+; Pdx1-Cre (KPC) mouse model. For this purpose, both male and female pancreatic tumor-bearing KPC mice were allocated to a control diet (CD; %kcal: 70% carb, 14% protein, 16% fat), a KD (%kcal: 14% protein, 1% carb, 85% fat), a CD + gemcitabine (CG), or a KD + gemcitabine (KG) group. Mice fed a KD alone or in combination with gemcitabine showed significantly increased blood β-hydroxybutyrate levels compared to mice fed a CD or CG. KPC mice fed a KG had a significant increase in overall median survival compared to KPC mice fed a CD (increased overall median survival by 42%). Interestingly, when the data was disaggregated by sex, the effect of a KG was significant in female KPC mice (60% increase in median overall survival), but not in male KPC mice (28% increase in median overall survival). Mechanistically, the enhanced survival response to a KD combined with gemcitabine was multifactorial, including inhibition of ERK and AKT pathways, regulation of fatty acid metabolism and the modulation of the gut microbiota. In summary, a KD in combination with gemcitabine appears beneficial as a treatment strategy in PDAC in KPC mice, deserving further clinical evaluation.

A Pilot Study of Using Smartphone Application vs. Routine Follow-Up for Patient Care in Advanced Non-Small Cell Lung Cancer During the COVID-19 Pandemic Era.

IntroductionCancer care monitoring should be adapted regarding COVID-19 pandemic preparedness plans. Lung Cancer Care application was a mobile application program to monitor adverse events and report outcomes. This study is aimed to invent a new mobile application evaluating patient-reported outcome (PRO) for patients with non-small cell lung cancer (NSCLC) and to evaluate the validity of a mobile application, particularly during the COVID-19 pandemic era.MethodsThe validity of the application was tested, and Functional Assessment of Cancer Therapy-Lung (FACT-L) questionnaires were contained in the mobile application-based PRO. Patients were randomly assigned to use mobile application-based PRO vs. routine follow-up. The primary end point was to compare the quality of life (QoL) scores between two groups. A secondary end point was overall survival (OS) and the outcomes of progressive disease (PD) between the two groups.ResultsIn total, 33 patients with advanced NSCLC were enrolled. Patients in the mobile application group had higher FACT-L scores at 3 months than patients with a routine follow-up arm (106 ± 5.97 vs. 99.96 ± 5.74, p-value = 0.07). The median follow-up time was 5.43 months; patients with mobile application had an insignificant increase in median OS when compared with patients using routine follow-up (4.53 vs. 2.93 months, p-value = 0.85). The sensitivity, specificity, positive predictive value (PPV), and negative predictive (NPV) value of this application for predicting disease progression were 50, 83.3, 66.7, and 70%, respectively.ConclusionSelf-reported symptoms by Lung Cancer Care application improved QoL and were similar in monitoring outcomes to face-to-face follow-up. This tool is applicable for patients with cancer to make monitoring as safe as possible for physical distancing during the COVID-19 pandemic era.

A phase III randomized trial of eribulin (E) with or without gemcitabine versus standard of care (SOC) for metastatic urothelial carcinoma (UC) refractory to or ineligible for PD/PDL1 antibody (Ab): SWOG S1937.

TPS4608 Background: UC is 2nd most common genitourinary cancer. Current SOC offers platinum-based (PB) first line chemotherapy (chemo) with ddMVAC or gemcitabine-cisplatin (GC) regimens. For cisplatin ineligible patients (pts), SOC includes gemcitabine-carboplatin (GCa), and in select pts pembrolizumab. Erdafitinib is approved for pts with FGFR alterations and Enfortumab vedotin (EV) is approved for previously treated pts. A phase I/II CTEP study of eribulin (E) for metastatic UC (mUC) established the activity of E in UC with objective response rate (ORR) of 37.5% and a median progression free survival (PFS) of 4.1 months (mo) and median overall survival (OS) of 9.5 mo (N = 150). A phase II CTEP study of gemcitabine-eribulin (GE) in cisplatin ineligible mUC showed an ORR of 50%, median OS of 11.9 mo and median PFS of 5.3 mo (N = 24). The most common Grade 3-4 toxicities included: neutropenia 63%, anemia and fatigue 29%. Pts with liver metastases benefited from therapy with 5 responders in 7 pts for GE vs 12 out 49 E. Methods: This is a phase III, randomized 3 arm study comparing E vs. GE vs. SOC (docetaxel, paclitaxel, or gemcitabine). E is given at 1.4mg/m2 on day (D) 1 and 8 of a 21 D cycle. In the GE arm, gemcitabine is added to E at 1000 mg/m2 dose to D1 and D8. SOC follows standard dosing of the agents. There is no limit to the number/sequence of prior regimens. A simplified summary of eligibility criteria is presented here. All pts must have: received frontline systemic treatment such as PB chemo or a non-platinum regimen. received PD1/PDL1 Ab or be deemed ineligible for PD1/PDL1 Ab. received EV. Assuming a median OS for the SOC arm of 7 mo the study seeks to find at least a 50% increase in median OS to 10.5 mo (Hazard Ratio (HR) = 0.667). One-sided 0.0125 type I error to account for testing of two primary hypotheses (Each arm vs. SOC). 87% power to detect a 3.5 mo improvement in OS. We require 140 eligible (155 total) pts in each arm for a total of 465. The study was activated in Feb 2021 and accrual is ongoing. Clinical trial information: NCT04579224.

EA2183: A phase III study of consolidative radiotherapy in patients with oligometastatic HER2-negative esophageal and gastric adenocarcinoma.

TPS4162 Background: Advanced esophageal and gastric adenocarcinomas (EGA) have poor prognosis. Doublet chemotherapy with fluoropyrimidine and platinum agents in combination with nivolumab for PD-L1 positive tumors is now the standard first-line approach, but overall survival (OS) remains &lt; 1.5 years. A subset of EGA patients have limited burden of metastatic disease. There is accumulating evidence that patients with oligometastatic states across disease types may benefit from locoregional ablative therapies during the course of their treatment. EA2183 is the first prospective study to evaluate the potential benefits of consolidative radiotherapy (XRT) in oligometastatic EGA. Methods: This is a prospective, randomized phase 3 study evaluating the role of consolidative XRT in oligometastatic EGA. Patients with ≤3 metastases at the time of diagnosis of advanced disease are eligible for enrollment. After completion of 4 months of systemic therapy, patients whose disease has not progressed are randomized to consolidation with XRT to all sites of disease followed by continuation of systemic therapy or continuation of systemic therapy alone. Patients are able to enroll in the study at the time of diagnosis of advanced disease or after completion of induction therapy. Systemic therapy is left to the discretion of the treating physician and can include FOLFOX (5-fluorouracil, leucovorin, and oxaliplatin) or CAPOX (capecitabine, oxaliplatin) in combination with nivolumab. Unless there are contraindications to immunotherapy or a history of prior treatment with immune checkpoint inhibitors, nivolumab use is mandatory if tumor has PD-L1 combined positive score (CPS) ≥5. The goal of radiation is to consolidate gains made by chemotherapy by delivering the highest dose that maintains the greatest tumor control probability that is also safe to deliver given the anatomic and normal tissue constraints. Specific radiation dose and fractionation are recommended in the protocol but is left to the discretion of the treating radiation oncologist to choose the course that is most suitable. Radiation must be administered over a maximum of 15 treatment days to minimize systemic therapy treatment breaks. Primary endpoint is OS from the time of randomization. Secondary endpoints include progression free survival from the time of randomization and safety and tolerability of consolidative XRT. We hypothesize that consolidative XRT will prolong OS from 10 to 15.6 months (an increase in median OS of 55.6%). The study is planning to enroll 314 patients with the goal of randomizing 204 patients in a 2:1 fashion. Stratification factors include number of metastatic sites, choice of immunotherapy with relation to PD-L1 CPS, as well as time of registration to the protocol (before or after systemic therapy initiation). Enrollment to the study is ongoing. Clinical trial information: NCT04248452.

Downstaging of Pancreatic Adenocarcinoma With Either Neoadjuvant Chemotherapy or Chemoradiotherapy Improves Survival

Neoadjuvant chemotherapy (NAC) or chemoradiation (NAC+XRT) is incorporated into the treatment of localized pancreatic adenocarcinoma (PDAC), often with the goal of downstaging before resection. However, the effect of downstaging on overall survival, particularly the differential effects of NAC and NAC+XRT, remains undefined. This study examined the impact of downstaging from NAC and NAC+XRT on overall survival. The National Cancer Data Base (NCDB) was queried from 2006 to 2015 for patients with non-metastatic PDAC who received NAC or NAC+XRT. Rates of overall and nodal downstaging, and pathologic complete response (pCR) were assessed. Predictors of downstaging were evaluated using multivariable logistic regression. Overall survival (OS) was assessed with Kaplan-Meier and Cox proportional hazards modeling. The study enrolled 2475 patients (975 NAC and 1500 NAC+XRT patients). Compared with NAC, NAC+XRT was associated with higher rates of overall downstaging (38.3 % vs 23.6 %; p ≤ 0.001), nodal downstaging (16.0 % vs 7.8 %; p ≤ 0.001), and pCR (1.7 % vs 0.7 %; p = 0.041). Receipt of NAC+XRT was independently predictive of overall (odds ratio [OR] 2.28; p < 0.001) and nodal (OR 3.09; p < 0.001) downstaging. Downstaging by either method was associated with improved 5-year OS (30.5 vs 25.2 months; p ≤ 0.001). Downstaging with NAC was associated with an 8-month increase in median OS (33.7 vs 25.6 months; p = 0.005), and downstaging by NAC+XRT was associated with a 5-month increase in median OS (30.0 vs 25.0 months; p = 0.008). Cox regression showed an association of overall downstaging with an 18 % reduction in the risk of death (hazard ratio[HR] 0.82; 95 % confidence interval, 0.71-0.95; p = 0.01) CONCLUSION: Downstaging after neoadjuvant therapies improves survival. The addition of radiation therapy may increase the rate of downstaging without affecting overall oncologic outcomes.