Significant Improvement In Survival Research Articles

Efficacy of Chemoimmunotherapy versus Chemotherapy for Gastric Cancer: A Meta-Analysis of Survival Outcomes.

Gastric cancer has been traditionally treated with chemotherapy as the primary mode of treatment. However, recent studies have shown that chemoimmunotherapy is also effective and, in some cases, better than chemotherapy treatment. Current study aimed to find the efficacy of chemoimmunotherapy versus chemotherapy in the treatment of gastric cancer. Using electronic databases, including PubMed, Embase, and EBSCO, a thorough literature search was carried out for the years 2006 to 2023. The search strategy was designed to identify relevant studies based on chemoimmunotherapy and chemotherapy intervention, and the search was conducted using appropriate keywords and MeSH terms. The retrieved studies were screened for relevance based on their titles, abstracts, and full texts. The studies' inclusion criteria were predefined, and the selected studies were then subjected to a quality assessment using GradePro GDT. The data from selected studies were extracted and analyzed using Revman version 5.4. The study found that chemoimmunotherapy treatment resulted in a significant improvement in overall survival (OS) with a risk ratio (RR) of 1.54 and a 95% Confidence Interval (CI) of 1.25 to 1.89. The overall effect was also found to be significant, with a p-value of less than 0.001. Furthermore, we also observed an improvement in the 1-year, 3-year, and 5-year survival rates with risk ratio (RR) of 1.09 (95% CI: 1.01, 1.17), 1.43 (95% CI: 1.28, 1.60), and 1.59 (95% CI: 1.10, 2.30), respectively. In addition, it's also found that chemoimmunotherapy treatment also resulted in an improvement in DFS with an RR of 1.94 and a 95% CI of 1.44 to 2.59. Overall, these results suggest that chemoimmunotherapy treatment can be an effective approach in comparison to chemotherapy for improving overall survival and disease-free survival in the studied population. This study comparing chemoimmunotherapy versus chemotherapy for gastric cancer showed that both treatments were effective, but chemoimmunotherapy had more significant efficacy. To support these results, additional studies with a large sample size and a longer follow-up time are required.

Tislelizumab plus chemotherapy versus placebo plus chemotherapy as first line treatment for advanced gastric or gastro-oesophageal junction adenocarcinoma: RATIONALE-305 randomised, double blind, phase 3 trial

ObjectiveTo evaluate the efficacy and safety of tislelizumab added to chemotherapy as first line (primary) treatment for advanced gastric or gastro-oesophageal junction adenocarcinoma compared with placebo plus chemotherapy.DesignRandomised, double blind,...

Effect of PAWI-2 on pancreatic cancer stem cell tumors.

Worldwide, pancreatic cancer (PC) is a major health problem and almost 0.5million people were diagnosed with PC in 2020. In the United States, more than 64,000 adults will be diagnosed with PC in 2023. PC is highly resistant to currently available treatments and standard of care chemotherapies cause serious side effects. Most PC patients are resistant to clinical therapies. Combination therapy has showed superior efficacy over single-agent treatment. However, most therapy has failed to show a significant improvement in overall survival due to treatment-related toxicity. Developing efficacious clinically useful PC therapies remains a challenge. Herein, we show the efficacy of an innovative pathway modulator, p53-Activator Wnt Inhibitor-2 (PAWI-2) against tumors arising from human pancreatic cancer stem cells (i.e., hPCSCs, FGβ3 cells). PAWI-2 is a potent inhibitor of tumor growth. In the present study, we showed PAWI-2 potently inhibited growth of tumors from hPCSCs in orthopic xenograft models of both male and female mice. PAWI-2 worked in a non-toxic manner to inhibit tumors. Compared to vehicle-treated animals, PAWI-2 modulated molecular regulators of tumors. Anti-cancer results showed PAWI-2 in vivo efficacy could be correlated to in vitro potency to inhibit FGβ3 cells. PAWI-2 represents a safe, new approach to combat PC.

Abstract PR006: EG-70 (detalimogene voraplasmid), a novel, non-viral intravesical gene therapy for BCG-unresponsive non-muscle-invasive bladder cancer: Preclinical characterization and translation into the clinic

Abstract Background: EG-70 (detalimogene voraplasmid) is a novel, investigational, non-integrating, non-viral gene therapy specifically engineered to elicit local stimulation of anti-tumor immune response in the bladder and to drive durable efficacy in patients with BCG-unresponsive high-risk non-muscle-invasive bladder cancer (NMIBC), while mitigating the risk of systemic toxicities from immune stimulation. Previous preclinical data indicate that intravesical instillation (IVI) of EG-70 results in local expression of transgene products in murine and non-human primate models. Here we describe the latest preclinical data to support the mechanism of action of EG-70 and Phase 1 clinical study results for EG-70 in the treatment of BCG-unresponsive NMIBC. Methods: Preclinical: A murine surrogate formulation of EG-70 (mEG-70) was administered locally to the bladder by IVI in C57BL/6 mice. Efficacy was assessed in a luciferase-expressing MB49 model of orthotopic bladder cancer. Following confirmation of cancer cell implantation by in vivo imaging, mice received two weekly IVIs of mEG-70. Immune profiling was evaluated by assessing protein expression levels and cell compositions (via MSD, flow cytometry, and immunohistochemistry). Immune cell depletion studies were conducted using specific antibodies directed against CD4 or CD8 antigen to assess T-cell contribution to efficacy. Clinical: In a Phase 1/2 study in high-risk BCG-unresponsive NMIBC with carcinoma in situ (CIS) (LEGEND; NCT04752722), EG-70 was assessed in four separate dose groups. Results: Preclinical: In a mouse model of orthotopic bladder cancer, IVI of mEG-70 caused striking remodeling of the tumor microenvironment from an immunosuppressive phenotype to a pro-inflammatory milieu supportive of tumor clearance. This was demonstrated by a significant decrease in myeloid cells and IL-4 cytokine levels, an increase in NK-cells and T-cells, and an increase in pro-inflammatory cytokines in tumor tissue. Accordingly, administration of mEG-70 was associated with marked reduction in tumor burden and significant improvement of survival. The anti-tumor response was largely immune-mediated as demonstrated by the critical role of T-cells, durable clearance of tumors, and protection against subsequent tumorigenic re-challenge, both locally in the bladder as well as distally, after flank implantation. Clinical: Results from the Phase 1 portion of the LEGEND study show that IVI of EG-70 was well-tolerated in patients with high-risk BCG-unresponsive NMIBC with CIS across all dose levels, with an overall complete response rate of 73%. Conclusions: The latest preclinical findings demonstrate that EG-70 has the potential to deliver immunostimulatory payloads locally to the bladder. The mechanism of action described preclinically has been translated into the clinic, in the Phase 1 portion of the LEGEND study in patients with BCG-unresponsive NMIBC with CIS. Citation Format: Marie-Line Goulet, Shauna M Dauphinee, Daniel Veilleux, Kristine S Louis, David Lazure, Sarah Stevenson, Darius Bilimoria, Fazmina Zamzameer, Ximin Chen, Sébastien Sublemontier, Sahar Amirkhani, Carlos Fleet, Richard Bryce, Matthew Bui, Shreyas Joshi, Susan J. Kalota, Anthony Cheung, James Sullivan. EG-70 (detalimogene voraplasmid), a novel, non-viral intravesical gene therapy for BCG-unresponsive non-muscle-invasive bladder cancer: Preclinical characterization and translation into the clinic [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2024 May 17-20; Charlotte, NC. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(10_Suppl):Abstract nr PR006.

Abstract A008: Racial differences in characteristics and outcomes of adjuvant nivolumab for muscle-invasive urothelial carcinoma (MIUC) in the real-world setting

Abstract Objectives: Historically, African-American/Black patients with bladder cancer have worse clinical outcomes compared with White/Caucasian patients. In the CheckMate 274 trial, nivolumab demonstrated a significant improvement in disease-free survival compared with placebo among patients with MIUC at high risk of recurrence following radical surgery; however, African-American/Black patients were underrepresented (< 1%). The objective of this analysis was to describe the characteristics and outcomes of MIUC patients treated with adjuvant nivolumab across different racial subgroups in a real-world setting. Methods: This US retrospective medical chart review included African-American/Black and White/Caucasian patients with MIUC treated with adjuvant nivolumab following radical resection between 01-Sep-2021 and 10-Sep-2022. Patient characteristics and outcomes were abstracted from the medical charts by treating oncologists. Patient characteristics and landmark survival estimates based on Kaplan-Meier analyses were summarized descriptively. Results: The analysis included 223 patients (African-American/Black: 62; White/Caucasian: 161). A numerically higher proportion of African-American/Black vs White/Caucasian patients, respectively, was male (74.2% vs 66.5%), less than 60 years old (27.4% vs 20.5%), unemployed (16.1% vs 5.6%), and had Medicaid at therapy initiation (14.5% vs 6.2%). Similar proportions in both groups had ECOG performance status 0-1 (82.3% vs 82.6%), received neoadjuvant therapy (58.1% vs 56.5%), and completed adjuvant therapy (67.7% vs 66.5%). The median follow-up time (12.5 months vs 13.1 months) and median duration of adjuvant therapy (11.0 months vs 11.3 months) were comparable. Similar estimates were observed for 12-month overall survival (96.7% vs 91.4%), 12-month disease-free survival (88.3% vs 88.4%), and 12-month distant metastasis-free survival (88.3% vs 88.4%). Conclusions: Despite higher rates of socio-economic risk factors among African-American/Black patients, this real-world study suggests similar effectiveness of adjuvant nivolumab among MIUC patients across African-American/Black and White/Caucasian patient populations. Citation Format: Regina Barragan-Carrillo, Alexander Chehrazi-Raffle, Bruce Feinberg, William S. John, Taavy A. Miller, Sarah Lucht, Prathamesh Pathak, Emily Bland, Sarah Gordon, JaLyna Laney, Andrew J. Klink, Hedyeh Ebrahimi, Nisha Singh, Carmelo Alonso, Miraj Patel, Lisa Rosenblatt, Xin Yin. Racial differences in characteristics and outcomes of adjuvant nivolumab for muscle-invasive urothelial carcinoma (MIUC) in the real-world setting [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2024 May 17-20; Charlotte, NC. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(10_Suppl):Abstract nr A008.

EXERCISE PRESCRIPTION IN CARDIOVASCULAR PREVENTION: PRELIMINARY DATA OF A FIVE YEARS ACTIVITY OF SPORTS MEDICINE UNIT –ULSS 2 TREVISO

Abstract Physical exercise plays a pivotal role in primary and secondary prevention of non–communicable chronic diseases. Nonetheless, to date, exercise prescription to chronically ill subjects is not yet in line with guidelines indications. In Veneto region, the goal of reducing the gap between guidelines and their actual application has been pursued for several years thanks to a regional “model”of exercise prescription in chronic disease. However, regional data indicative of the real clinical impact of this "model" are lacking. We evaluated the impact of the regional model on a population of chronically ill people visited at our Clinic between 2014 and 2019. In this period, 366 subjects living in the province of Treviso (Veneto region, Italy) with a history of heart disease and/or diabetes have been admitted to our facility and have been provided with precise indications (in the form of prescription) about physical exercise to be practiced in secondary prevention. For each subject, adherence to the exercise prescription was assessed. The study population was therefore divided into 3 classes of activity in accordance with the physical activity practiced during the observation period: 0=not adherent at all at the exercise prescription (no exercise practice phase); 1= practice of unstructured physical activity/ not monitored physical exercise and/or not completely adhering to the exercise prescription in terms of intensity, duration and frequency; 2= practice of structured and monitored physical exercise, completely adherent to exercise prescription provided. By this way, any temporary suspension and subsequent resumption of the activity was considered and the period of cessation of the activity during the monitoring period was taken into account for each subject. Data on “health expenditure”, was collected for each subject at time zero as new hospitalizations and deaths were analyzed following our intervention (exercise prescription letter delivery). According to a preliminary analysis of our data, time spent in practicing exercise in class 1 and 2 lead to a significant improvement in survival and less hospitalizations for considered pathologies. Furthermore, time spent in class 2 exercise practice (structured and monitored physical exercise, at target for intensity, duration and frequency), seems to determine even greater protection compared to unstructured physical activity or structured but not monitored and/or non–targeted physical exercise (class 1).

Pancreatic body and tail adenocarcinoma: upfront resection versus neoadjuvant therapy, a contemporary analysis.

There is a paucity of data regarding the use of neoadjuvant therapy in pancreatic body or tail ductal adenocarcinomas. Given the differing tumour biology and aggressive nature of pancreatic body or tail adenocarcinomas, patients presenting with these tumours may benefit from upfront resection. A retrospective cohort study was performed analysing patients who underwent distal pancreatectomy for pancreatic ductal adenocarcinoma between January 2013 and June 2022. Patients who underwent upfront resection were compared to those who underwent neoadjuvant therapy. Forty-one patients underwent upfront distal pancreatectomy, while 40 patients underwent neoadjuvant therapy before curative intent resection. Neoadjuvant therapy did not improve overall survival (37 vs. 34 months, p = 0.962) or disease-free survival (13 vs. 15 months, p = 0.414), as compared with upfront resection. There was no significant difference in the rate or R0 resection or post-operative outcomes. No significant improvement in survival was demonstrated for patients undergoing neoadjuvant therapy for pancreatic ductal adenocarcinoma of the pancreatic body or tail when compared to upfront resection. Considering the potential for disease progression given the more aggressive tumour biology of pancreatic body and tail adenocarcinomas, appropriate surgical candidates should be offered upfront resection to provide the best chance of survival and cure.

Postoperative radiotherapy versus surgery alone in pN1 oral cavity cancer patients: A meta-analysis.

The aim of this meta-analysis is to evaluate the potential benefits of postoperative radiotherapy (PORT) in patients with pN1 oral cavity squamous cell carcinoma. A literature search through major databases was conducted until January 2023. The adjusted hazard ratio (aHR) or risk ratio (RR) with 95% confidence intervals (CIs) of different survival outcomes were extracted and pooled. Ten studies published between 2005 and 2022, with a pooled patient population of 2888, were included in this meta-analysis. Due to differences in study design and reported outcomes, the studies were categorized into distinct groups. In pN1 patients without extranodal extension (ENE), PORT was associated with a significant improvement in overall survival (OS) (aHR 0.76, 95% CI: 0.61-0.94). In pN1 patients without ENE and positive margins, PORT improved OS (aHR 0.71, 95% CI: 0.56-0.89) and was associated with a lower regional recurrence rate (RR 0.35, 95% CI: 0.15-0.83). However, in pN1 patients without ENE, positive margins, perineural invasion, and lymphovascular invasion, there were no significant differences observed between the PORT and observation groups in either 5-year OS (RR 0.48, 95% CI: 0.07-3.41) or 5-year disease-free survival (RR 0.37, 95% CI: 0.07-2.06). The current study demonstrated that PORT has the potential to improve OS in pN1 disease. However, the decision of whether to administer PORT still hinges on diverse clinical scenarios, and additional research is necessary to furnish a more conclusive resolution. 2.

Preferences of physicians for treatment-related toxicity vs. recurrence in melanoma (GERMELATOX-A): the doctors’ perspective

IntroductionAdjuvant treatment with immune checkpoint inhibitors, such as PD1-antibodies (ICI) ± CTLA4-antibodies (cICI) or targeted therapy with BRAF/MEK inhibitors (TT), has shown a significant improvement in disease-free survival (DFS) for high-risk melanoma patients. However, due to specific side effects, the choice of treatment is often influenced by the risk of toxicity. Therefore, the role of physicians in treatment decisions of patients is crucial. This study investigated for the first time in a multicenter setting the attitudes and preferences of dermatooncologists in Germany and Switzerland regarding adjuvant treatment with (c)ICI and TT.MethodsIn the GERMELATOX-A study, 108 physicians (median age: 32 yrs, 67.6% female) from 11 skin cancer centers were surveyed to rate typical side effect scenarios of (c)ICI and TT treatments and then compared to patients’ ratings evaluated in a previous analysis from the same centers. The scenarios described mild-to-moderate or severe toxicity and included melanoma relapse leading to death. The physicians were asked about the level of side effects they would tolerate in exchange for a reduction in melanoma relapse and an increase in survival at 5 years.ResultsThe preferences of physicians and patients revealed significant differences regarding adjuvant melanoma treatment with (c)ICI and TT (p < 0.05). Compared to patients, physicians tend to value a melanoma relapse less severe, according to a visual analog scale. They were also less threatened by all scenarios of side effects during adjuvant treatment with (c)ICI or TT, compared to patients. Physicians required lower risk reductions for disease-free survival (DFS) and overall survival (OS) for both ICI and TT and their drug-related side effects to accept these treatments. In case of severe side effects, physicians required similar 5-year DFS rates for ICI and TT (60–65%), while patients needed a 15% improvement of 5-year DFS for ICI compared to TT (80%/65%). For survival, physicians expected an OS improvement of + 10% for all three treatment modalities, whereas patients required a higher increase: + 18–22% for ICI and + 15% for TT.ConclusionOur study highlights the importance of understanding the patient’s perspective and a potential difference to the doctor’s view when making decisions about adjuvant melanoma treatment with (c)ICI and TT, especially as these treatments are increasingly being implemented in earlier stages.

Postoperative radiotherapy does not improve survival in patients with Masaoka-Koga stage IIB thymomas: A propensity score matching study based on the SEER database.

This study, based on a population, explored the prognostic value of postoperative radiotherapy (PORT) for Masaoka-Koga IIB stage thymomas. Patients diagnosed with thymoma from 2004 to 2017 in the Surveillance, Epidemiology, and End Results (SEER) database were included in the retrospective study. Through propensity score matching, the baseline characteristics of the patients were successfully matched to mitigate the selection bias of PORT. Survival rates and survival curves were compared between the PORT and non-PORT groups, with potential confounding factors addressed using a multivariate Cox regression model. In this study, 785 cases of IIB stage thymoma were included from the SEER database, and 303 patients were successfully matched between PORT and non-PORT groups through propensity score matching, with no significant differences in baseline characteristics. In the PORT and non-PORT groups, 10-year overall survival rates were 65.2% versus 59.6%, and cancer-specific survival rates were 87.0% vs. 84.4%, PORT did not yield statistically significant improvements in overall survival (P = .275) or cancer-specific survival (P = .336) for stage IIB thymomas. Based on the SEER database, the results of our study indicated that PORT does not confer a significant survival benefit for IIB stage thymomas.

Trends in patterns of treatment and survival of colorectal cancer patients using cancer registry data in Japan: 1995-2015.

Recent advances in treating colorectal cancer (CRC) have increased the importance of multidisciplinary treatment. This study aimed to clarify trends in the treatment and survival of CRC using population-based cancer registry data in Japan. We analyzed the survival of CRC cases diagnosed from 1995 through 2015 from a population-based cancer registry of six prefectures. The year of diagnosis was classified into five periods, and the trends in the detailed categorization of treatments and survival were identified. We calculated net survival and excess hazard of death from cancer using data on 256,590 CRC patients. The use of laparoscopic surgery has been increasing since 2005 and accounts for the largest proportion of treatment types in the most recent period. Net survival of CRC patients diagnosed after 2005 remained high for laparoscopic surgery and endoscopic surgery (endoscopic mucosal resection or endoscopic submucosal dissection). There was an upward trend in treatment with chemotherapy in addition to open and laparoscopic surgery. Using the excess hazard ratio at the regional stage since 2005, there has been a significant improvement in survival in the younger age group and the rectum cancer group. By type of treatment, there was a tendency toward significant improvement in the open surgery + chemotherapy group. We clarified the trends in treating CRC and the associated trends in survival. Continuous survey based on population-based data helps monitor the impact of developments in treatment.

Abstract PO3-16-10: Real-world outcomes with first-line ribociclib + endocrine therapy in patients with metastatic HR+, HER2– breast cancer: Fourth interim analysis of REACH AUT trial

Abstract Background: Ribociclib (RIB), a cyclin-dependent kinase 4 and 6 inhibitor (CDK4/6i) in combination with endocrine therapy (ET) yielded significant improvement in progression-free survival (PFS) and overall survival (OS) across three phase III MONALEESA trials including patients (pts) with hormone receptor–positive (HR+), human epidermal growth factor receptor 2–negative (HER2–) metastatic breast cancer (MBC) in first-line (1L) and second-line (2L) setting. In the previous interim analyses of REACH AUT trial, 1L RIB + ET showed tolerable safety and favorable PFS results in a real-world setting. Results from the preplanned fourth interim analysis are reported here. Methods: REACH AUT is a noninterventional study conducted in Austria reporting data on the real-world clinical experience of RIB + ET (aromatase inhibitor [AI] or fulvestrant [FUL]) in premenopausal, perimenopausal, or postmenopausal pts with HR+, HER2– MBC. Pts with no prior ET for advanced disease and maximum up to 1 prior line of chemotherapy (CT) in the advanced setting were included. Results: At data cutoff (March 27, 2023) with a median duration of follow-up of 23.8 months, out of 281 analyzed pts (12.5% of premenopausal/perimenopausal and 85.1% of postmenopausal, 2.5% of unknown status) 31.7% of pts were receiving ongoing treatment. The most common reasons for treatment discontinuations (68.3%) were disease progression (39.1%) and adverse events (AEs, 22.1%). The median age was 63 years (&amp;lt; 65 years, n=156, 55.5%; ≥65 years, n=125, 44.5%) and ECOG PS ≥2: 1.8%. In 106 pts (37.7%), de novo metastatic disease was reported. Visceral metastases (lung, liver) were present in 116 pts (41.3%) and bone-only metastases in 80 pts (28.5%). Prior adjuvant therapy was received by 139 pts (49.5%): AI ± GnRH: n=80 (26.7% without and 1.8% with GnRH); tamoxifen ± GnRH: n=74 (21.7% without and 4.6% with GnRH); CT: n=56 (19.9%); antibody therapy n=3 (1.1%). In the metastatic setting, 1L RIB was prescribed in combination with an AI in 223 pts (79.4%; letrozole: n=139 [49.5%]; anastrozole: n=48 [17.1%]; exemestane: n=47 [16.7%]) and with FUL in 52 pts (18.5%). Prior CT for MBC was received by 5 pts (1.8%). The median PFS was 29.7 months in the overall population; 28.3 months in pts with bone only and 26.9 months in pts with visceral metastatic disease. In pts evaluable for response, the objective response rate and clinical benefit rate were 31.3% and 60.9%, respectively. The OS rates were 91.9%, 81.7%, and 63.7% at 12 months, 24 months, and 36 months, respectively. The trial is ongoing with ~40% of subjects end of documentation and ~27% of deaths. In total, 69.4% of pts had RIB dose interruptions and 48.8% of pts had a RIB dose reduction. The majority of all reported AEs were grade 1 (50.1%) or grade 2 (31.2%); the median time to first AE was 0.5 months. The most common AE was neutropenia (all grades: n=143, 50.9%; grade 1: n=39, 13.9%; grade 2: n=68, 24.2%; grade 3: n=98, 34.9%; grade 4: n=5, 1.8%). QTc prolongation of any grade was observed in 32 pts (11.4%; grade 1: n=24, 8.5%; grade 2: n=11, 3.9%; grade 3: n=1, 0.4%). Hepatobiliary toxicity of any grade was observed in 42 pts (14.9%; grade 1: n=12, 4.3%; grade 2: n=18, 6.4%; grade 3: n=22, 7.8%; grade 4: n=3, 1.1%). Overall, currently 101 pts (35.9%) received a follow-up therapy after progression on RIB + ET. The most common first subsequent therapies were targeted therapies + ET (40.0%), followed by cytotoxic chemotherapy (22.0%) and endocrine monotherapy (19.0%). Conclusion: 1L RIB + ET continues to show favorable efficacy and a tolerable safety profile in the routine clinical practice. The results are consistent with the data from MONALEESA trials. The OS is showing a positive trend but is still immature during this study follow-up. Efficacy Outcomes With RIB + ET in Patients With HR+, HER2– MBC (Overall Population, Nf281) XX XX Citation Format: Christian F. Singer, Daniel Egle, Richard Greil, Edgar Petru, Leopold Oehler, Marija Balic, Laurenz Schöffmann, Georg Pfeiler, Maximilian Marhold, Christine Brunner, Karin Haider, Arik Galid, Ursula Pluschnig, Ferdinand Haslbauer, Michael Hubalek, Andreas Redl, Julia Flatschacher, Shanow Uthman, Bernhard Mraz, Rupert Bartsch. Real-world outcomes with first-line ribociclib + endocrine therapy in patients with metastatic HR+, HER2– breast cancer: Fourth interim analysis of REACH AUT trial [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-16-10.

Abstract PO3-06-14: Phase I/II study of pembrolizumab in combination with oral binimetinib in patients with unresectable locally advanced or metastatic triple-negative breast cancer

Abstract Background: Activation of the RAS/MAPK pathway is associated with reduced tumor-infiltrating lymphocytes and poor outcomes in triple-negative breast cancer (TNBC). This trial evaluated the efficacy of pembrolizumab in combination with binimetinib, a MEK inhibitor. Methods: Patients with unresectable locally advanced or metastatic TNBC with ≤ 3 prior lines of therapy were enrolled. Treatment includes a 2-week run-in with binimetinib followed by pembrolizumab. There were 2 dose levels (DL) with binimetinib at 45 mg at DL 0 and 30 mg at DL -1. A standard 3+3 design was used in Phase I, and Simon’s two-stage Optimal design was used in Phase II. PD-L1 22C3 was performed in archival samples with CPS ≥ 10 considered as positive (PD-L1+). Tumor-infiltrating lymphocytes (TILs) were quantified into 0, 1, 2, and 3+. Circulating tumor cells (CTC) and circulating cancer-associated macrophage-like cells (CAML) were isolated using CellSieve microfilters and immunofluorescently labeled with PD-L1 and p-ERK. Wilcoxon rank sum test, Chi-square test, Cox regression model, and Spearman correlation were used for analysis. Results: 22 patients were enrolled with a median age of 58 years old. Dose-limiting toxicity (DLT) was observed in 2 out of 4 patients in DL 0, with grade 3 ALT abnormality, flank pain, and nausea. In the next 6 patients in DL -1, there was 1 DLT with grade 3 AST/ALT abnormality. There were 17 patients treated with DL -1 and were evaluable for response. The objective response rate (ORR) was 29.41% (95% CI: 10.31-55.9) with 1 complete response (CR) and 4 partial responses (PR). The clinical benefit rate (CBR ≥ 24 weeks) was 35.29% (95% CI: 14.21-61.67). ORR in patients without liver metastases was 55.56% (95% CI: 21.20 - 86.30) and CBR was 66.67% (95% CI: 29.93-92.51). No response was observed in all 5 patients with liver metastases. There were 40.9% of patients with PD-L1 CPS ≥ 10. ORR in patients with PD-L1+ was 80%. However, 11.1% of patients with PD-L1 negative tumors also had an objective response and 44.4% of patients had clinical benefit ≥ 24 weeks. PD-L1 expression in archival tissue was associated with ORR (p 0.032) but not CBR (p 0.198), progression-free survival (PFS, p 0.373), and overall survival (p 0.348). TILs in archival tissue were also not associated with CBR (p 0.155) and PFS (p 0.157). One patient with TILs 0 had a stable disease ≥ 24 weeks and 2 patients TILs 1+ also had an objective response. We further evaluated blood-based biomarkers with CTC and CAML. Baseline PD-L1 in CAML (p 0.04) and decline in CAML size (p 0.02) after 1 cycle was significantly associated with CBR. However, baseline CTC count, CAML count (p 0.64), CAML size (p 0.46), p-ERK in CAML (p 0.23), and changes in CTC count, CAML count (p 0.83), p-ERK (p 0.07), and PD-L1 (p 0.08) in CAML were not significantly associated with responses. Using Cox regression analysis, a reduction in CAML count (p 0.02), CAML size (p 0.01), and PD-L1 in CAML (p 0.03) were associated with significant improvement in overall survival but not the reduction in p-ERK (p 0.6). However, PD-L1 expression in CAML is not associated with PD-L1 expression in archival tissue (Spearman correlation 0.13). Conclusions: Pembrolizumab and binimetinib at 30 mg are safe with manageable toxicities. Consistent with the preclinical data that MEKi can restore T cell function, promising activity was observed even in patients with low TILs and PD-L1 negative, particularly in patients without liver metastases. PD-L1 expression in peripheral blood CAML rather than archival tumor tissue may serve as a better biomarker to predict the clinical benefit of this combination. Early reductions in CAML count and size, were also significantly associated with responses. Future larger clinical trials are warranted to further evaluate the efficacy of this chemotherapy-free combination. Citation Format: Saranya Chumsri, Joseph Larson, Daniel Adams, Kathleen Tenner, Cha-Mei Tang, Morgan Weidner, Amanda Arnold, Dana Haley, Pooja Advani, Kostandinos Sideras, Alvaro Moreno-Aspitia, Edith Perez, Keith Knutson. Phase I/II study of pembrolizumab in combination with oral binimetinib in patients with unresectable locally advanced or metastatic triple-negative breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-06-14.

Abstract PS16-02: Efficacy and safety of first-line atezolizumab + bevacizumab + paclitaxel in patients with advanced triple-negative breast cancer: the ATRACTIB phase 2 trial

Abstract BACKGROUND Triple-negative breast cancer (TNBC) is an aggressive tumor characterized by poor outcomes and new treatment strategies are urgently required. The programmed cell death-ligand 1 (PD-L1) antibody (Ab) atezolizumab (ATZ) combined with first-line (1L) nab-paclitaxel (nab-PTX) is approved in multiple countries for the treatment of PD-L1-positive patients (pts) with advanced TNBC (aTNBC) based on a significant improvement in progression-free survival (PFS) and a numerically higher and clinically meaningful median overall survival (OS). A synergism between antiangiogenic therapy and immunotherapy (IO)-based strategies has been observed preclinically and in different tumor types, but data in aTNBC is lacking. METHODS ATRACTIB (NCT04408118) is an international, open-label, single-arm, phase 2 trial evaluating the efficacy and safety of 1L ATZ + BVZ + PTX for pts with aTNBC, regardless of their tumors’ PD-L1 status. Adult pts with untreated, unresectable locally advanced/metastatic TNBC were included. Pts who had received (neo)adjuvant taxane-based chemotherapy (CT) and/or IO and/or an antiangiogenic agent had to have had a relapse with a disease-free interval beyond 12 months (mo). Pts received intravenous ATZ 840 mg + BVZ 10 mg/kg on days (D)1 and D15 + PTX 90 mg/m2 on D1, 8, and 15 of every 28-day cycle until disease progression, intolerable toxicity, death, or patient withdrawal. Tumor assessments were performed every 8 weeks for the first 12 mo and every 12 weeks thereafter. Baseline PD-L1 expression was centrally assessed using 22C3 (combined positive score [CPS]) and SP142 (expression on tumor-infiltrating immune cells [ICs]) Abs. The primary endpoint was investigator-assessed PFS by RECIST v.1.1. Key secondary endpoints included OS, objective response rate (ORR), clinical benefit rate (CBR), duration of response (DoR), and safety. Median PFS was analyzed with exponential maximum likelihood estimation (H0: ≤7.0 mo; HA: ≥9.5 mo). We estimated that enrolling 100 pts would provide 80% power at one-sided α nominal level of 5%, assuming a 10% drop-out rate. RESULTS Between October 2020 and May 2022, 100 female pts from 28 centers across 5 European countries were included. Median age was 55.0 years (32.0 - 84.0), 57.0% of pts had visceral disease, 46.0% had ≥3 metastatic sites, and 70.0% had received prior treatment for early BC (taxane-based CT in 87.1% of them). A total of 82 and 85 tumor samples out of 100 pts were available for PD-L1 assessment using 22C3 and SP142 assays, respectively. Most pts had PD-L1-negative tumors (87.8% with 22C3 [CPS &amp;lt; 10] and 97.6% with SP142 [expression on &amp;lt; 1% positive of ICs]). At data cutoff (15th September 2023), 23 pts were still on therapy. With a median follow-up of 16.7 mo (1.1 - 34.1), median PFS was 11.0 mo (95% CI, 9.0 - 13.2). OS data were immature at data cutoff, with 30 events. Estimated 18-month OS was 69.4% (95% CI, 58.4% - 78.1%). ORR was 63.0% (95% CI, 52.8% - 72.4%), CBR was 79.0% (95% CI, 69.7% - 86.5%), and median DoR was 10.0 mo (95% CI, 7.2 - 13.8). Regarding safety, the most common treatment-emergent adverse events (TEAEs) were peripheral neuropathy (68.0%) and fatigue (62.0%). Grade (G) 3/4 treatment-related TEAEs occurred in 47.0% of pts, mainly peripheral neuropathy (13.0%) and neutropenia (12.0%). Any-grade immune-related TEAEs, thrombosis or embolism, and bleeding occurred in 13.0% (5.0%; G≥3), 4.0% (1.0%; G≥3), and 10.0% (0.0%; G≥3) of pts, respectively. There were no drug-related deaths. CONCLUSIONS 1L ATZ + BVZ + PTX demonstrated encouraging anti-tumor activity in aTNBC pts, most of them presenting with PD-L1-negative tumors. Median PFS seems to be much higher compared with that previously reported with other IO-based regimens in a similar patient population. The safety profile was consistent with the known safety data of ATZ and BVZ combined with CT, without significant added toxicity. These results merit further research of this combination for PD-L1-negative aTNBC. Citation Format: Maria Gion, Patricia Cortez-Castedo, Isabel Blancas, Alfonso Cortés, Frederik Marmé, Salvador Blanch, Serafin Morales Murillo, Nieves Díaz, Isabel Calvo-Plaza, Sabela Recalde, Alejandro Martínez-Bueno, Manuel Ruiz-Borrego, Elisenda Llabres, María Teresa Taberner, Michelino de Laurentiis, José Ángel García-Sáenz, Jana Repkova, Antonio Antón, Joseph Gligorov, Susana de la Cruz, Oliver Hoffmann, Jacques Medioni, Melissa Phillips, Miguel Sampayo-Cordero, Daniel Alcalá-López, José Manuel Pérez-García, Antonio Llombart-Cussac, Javier Cortés. Efficacy and safety of first-line atezolizumab + bevacizumab + paclitaxel in patients with advanced triple-negative breast cancer: the ATRACTIB phase 2 trial [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS16-02.

Extracorporeal Support Strategies in Liver Failure - Focus on Albumin Dialysis and Therapeutic Plasma Exchange

Combining albumin dialysis for the removal of hydrophobic substances with classical haemodialysis in the treatment of acute liver failure (ALF) and acute-on-chronic liver failure (ACLF) has a strong theoretical rational and clinical data showed a positive effect on laboratory and partly clinical characteristics of ALF and ACLF. However, neither the MARS nor the Prometheus System has so far been able to demonstrate a mortality benefit in ALF or ACLF patients. To date, only the use of therapeutic plasma exchange (TPE) has demonstrated significant removal of pathogen-associated (PAMPs), damage-associated molecular patterns (DAMPs) and pro-inflammatory cytokines. In addition, TPE also acts simultaneously by replacing protective but depleted mediators, thus improving multiple key pathophysiological principles of both ALF and ACLF. In ALF, both high-volume and standard-volume TPE showed a significant improvement in survival. The data on the use of TPE in ACLF is still sparse, with only two Chinese monocentric studies in patients with exclusively hepatitis B-associated ACLF suggesting potentially improved survival with TPE. The currently recruiting APACHE study will include patients with the modern EASL-CLIF definition of ACLF.

Durvalumab plus gemcitabine and cisplatin in advanced biliary tract cancer (TOPAZ-1): patient-reported outcomes from a randomised, double-blind, placebo-controlled, phase 3 trial

In the ongoing, randomised, double-blind phase 3 TOPAZ-1 study, durvalumab, a PD-L1 inhibitor, plus gemcitabine and cisplatin was associated with significant improvements in overall survival compared with placebo, gemcitabine, and cisplatin in people with advanced biliary tract cancer at the pre-planned intermin analysis. In this paper, we present patient-reported outcomes from TOPAZ-1. In TOPAZ-1 (NCT03875235), participants aged 18 years or older with previously untreated, unresectable, locally advanced, or metastatic biliary tract cancer with an Eastern Cooperative Oncology Group performance status of 0 or 1 and one or more measurable lesions per Response Evaluation Criteria in Solid Tumors (RECIST; version 1.1) were randomly assigned (1:1) to the durvalumab group or the placebo group using a computer-generated randomisation scheme. Participants received 1500 mg durvalumab or matched placebo intravenously every 3 weeks (on day 1 of the cycle) for up to eight cycles in combination with 1000 mg/m2 gemcitabine and 25 mg/m2 cisplatin intravenously on days 1 and 8 every 3 weeks for up to eight cycles. Thereafter, participants received either durvalumab (1500 mg) or placebo monotherapy intravenously every 4 weeks until disease progression or other discontinuation criteria were met. Randomisation was stratified by disease status (initially unresectable vs recurrent) and primary tumour location (intrahepatic cholangiocarcinoma vs extrahepatic cholangiocarcinoma vs gallbladder cancer). Patient-reported outcomes were assessed as a secondary outcome in all participants who completed the European Organisation for Research and Treatment of Cancer's 30-item Quality of Life of Cancer Patients questionnaire (QLQ-C30) and the 21-item Cholangiocarcinoma and Gallbladder Cancer Quality of Life Module (QLQ-BIL21). We calculated time to deterioration-ie, time from randomisation to an absolute decrease of at least 10 points in a patient-reported outcome that was confirmed at a subsequent visit or the date of death (by any cause) in the absence of deterioration-and adjusted mean change from baseline in patient-reported outcomes. Between April 16, 2019, and Dec 11, 2020, 685 participants were enrolled and randomly assigned, 341 to the durvalumab group and 344 to the placebo group. Overall, 345 (50%) of participants were male and 340 (50%) were female. Data for the QLQ-C30 were available for 318 participants in the durvalumab group and 328 in the placebo group (median follow-up 9·9 months [IQR 6·7 to 14·1]). Data for the QLQ-BIL21 were available for 305 participants in the durvalumab group and 322 in the placebo group (median follow-up 10·2 months [IQR 6·7 to 14·3]). The proportions of participants in both groups who completed questionnaires were high and baseline scores were mostly similar across treatment groups. For global health status or quality of life, functioning, and symptoms, we noted no difference in time to deterioration or adjusted mean changes from baseline were observed between groups. Median time to deterioration of global health status or quality of life was 7·4 months (95% CI 5·6 to 8·9) in the durvalumab group and 6·7 months (5·6 to 7·9) in the placebo group (hazard ratio 0·87 [95% CI 0·69 to 1·12]). The adjusted mean change from baseline was 1·23 (95% CI -0·71 to 3·16) in the durvalumab group and 0·35 (-1·63 to 2·32) in the placebo group. The addition of durvalumab to gemcitabine and cisplatin did not have a detrimental effect on patient-reported outcomes. These results suggest that durvalumab, gemcitabine, and cisplatin is a tolerable treatment regimen in patients with advanced biliary tract cancer. AstraZeneca.

Pegylated liposomal doxorubicin combined with trabectedin as a treatment option in uterine sarcomas: a single-institution retrospective analysis

ObjectiveThe use of conventional doxorubicin in combination with trabectedin leads to a considerable prolongation of progression-free survival in the treatment of uterine sarcomas but is associated with dose-limiting toxicities. Significant...

Pancreas after kidney transplantation, is it the time to overcome the stigma?

Pancreas transplantation is the most effective treatment to improve quality of life and overcome complications in patients with end-stage renal disease and diabetes mellitus. One of the main approaches for concurrent renal disease and diabetes mellitus which has been underutilized during the past decade is a pancreas transplant after kidney transplantation. Our study aimed to quantify outcomes following pancreas after kidney transplants (PAKs) in the United States from 2001 to 2020 with an emphasis on graft and patient survival. A retrospective registry analysis was performed by accessing the OPTN/UNOS database for PAKs that were performed in the United States from January 2001 to April 2020. The study population was divided into two subgroups: patients receiving a pancreas transplant between 2001 and 2010 and those receiving a pancreas transplant between 2011 and 2020. The study examined a total number of 3706 PAK recipients; patients who received a PAK from January 2001 through December 2010 (n=2892) and those who received a PAK from January 2011 to April 2020 (n=814). The selection process of transplant recipients did not drastically change throughout the 2001-2010 and 2011-2020 periods. Length of stay at the hospital after the transplantation improved significantly in the 2011-2020 group relative to the 2001-2010 group (8.48 vs. 10.08days, mean, p<0.01). Additionally, more transplantation with 4-6 human leukocyte antigen mismatch occurred in the 2011-2020 group than in the 2001-2010 group (80.6% vs. 71.4%, p<0.01). The pancreas preservation time of 13.35h in the 2001-2010 group decreased significantly to 11.17h in the 2011-2020 group (p<0.001). The mean donor's amylase and lipase also decreased significantly in the 2011-2020 cohort. Significant graft survival improvement was observed in the 2011-2020 group compared to the 2001-2010 group after a long-term follow-up (p<0.001). The mean Calculated Pancreas Donor Risk Index was 1.08 for the 2001-2010 group and 0.99 for the 2011-2020 group with a significant difference (p<0.001). The beneficial results and improved outcomes observed in PAK patients demonstrate the effectiveness of the operation for individuals in need of a pancreas transplant. PAKs can prove to be a meaningful solution to overcome long waiting times, decrease the donor-recipient imbalance, expand the donor pool, and overcome the current underutilization in order to improve the short- and long-term quality of life in the groups of interest.

Safety of early antiplatelet therapy for non-cardioembolic mild stroke patients with thrombocytopenia.

To investigate the safety of early antiplatelet therapy for non-cardioembolic mild stroke patients with thrombocytopenia. Data of acute ischemic stroke patients with baseline National Institutes of Health Stroke Scale (NIHSS) score ≤3 and a platelet count <100×109/L were obtained from a multicenter register. Those who required anticoagulation or had other contraindications to antiplatelet therapy were excluded. Short-term safety outcomes were in-hospital bleeding events, while the long-term safety outcome was a 1-year all-cause death. The short-term neurological outcomes were evaluated by modified Rankin scale (mRS) score at discharge. A total of 1868 non-cardioembolic mild stroke patients with thrombocytopenia were enrolled. Multivariate regression analyses showed that mono-antiplatelet therapy significantly increased the proportion of mRS score of 0-1 at discharge (OR=1.657, 95%CI: 1.253-2.192, P<0.01) and did not increase the risk of intracranial hemorrhage (OR=2.359, 95%CI: 0.301-18.503, P>0.05), compared with those without antiplatelet therapy. However, dual-antiplatelet therapy did not bring more neurological benefits (OR=0.923, 95%CI: 0.690-1.234, P>0.05), but increased the risk of gastrointestinal bleeding (OR=2.837, 95%CI: 1.311-6.136, P<0.01) compared with those with mono-antiplatelet therapy. For patients with platelet counts ≤75×109/L and >90×109/L, antiplatelet therapy significantly improved neurological functional outcomes (both P<0.05). For those with platelet counts (>75-90)×109/L, antiplatelet therapy resulted in a significant improvement of 1-year survival (P<0.05). For patients even with concurrent coagulation abnormalities, mono-antiplatelet therapy did not increase the risk of various types of bleeding (all P>0.05) but improved neurological functional outcomes (all P<0.01). There was no significant difference in the occurrence of bleeding events, 1-year all-cause mortality risk, and neurological functional outcomes between aspirin and clopidogrel (all P>0.05). For non-cardioembolic mild stroke patients with thrombocytopenia, antiplatelet therapy remains a reasonable choice. Mono-antiplatelet therapy has the same efficiency as dual-antiplatelet therapy in neurological outcome improvement with lower risk of gastrointestinal bleeding.

A multicentric randomized controlled phase III trial of adaptive and 18F-FDG-PET-guided dose-redistribution in locally advanced head and neck squamous cell carcinoma (ARTFORCE)

Background and purposeThis multicenter randomized phase III trial evaluated whether locoregional control of patients with LAHNSCC could be improved by fluorodeoxyglucose-positron emission tomography (FDG-PET)-guided dose-escalation while minimizing the risk of increasing toxicity using a dose-redistribution and scheduled adaptation strategy. Materials and methodsPatients with T3-4-N0-3-M0 LAHNSCC were randomly assigned (1:1) to either receive a dose distribution ranging from 64-84 Gy/35 fractions with adaptation at the 10thfraction (rRT) or conventional 70 Gy/35 fractions (cRT). Both arms received concurrent three-cycle 100 mg/m2cisplatin. Primary endpoints were 2-year locoregional control (LRC) and toxicity. Primary analysis was based on the intention-to-treat principle. ResultsDue to slow accrual, the study was prematurely closed (at 84 %) after randomizing 221 eligible patients between 2012 and 2019 to receive rRT (N = 109) or cRT (N = 112). The 2-year LRC estimate difference of 81 % (95 %CI 74–89 %) vs. 74 % (66–83 %) in the rRT and cRT arm, respectively, was not found statistically significant (HR 0.75, 95 %CI 0.43–1.31,P=.31). Toxicity prevalence and incidence rates were similar between trial arms, with exception for a significant increased grade ≥ 3 pharyngolaryngeal stenoses incidence rate in the rRT arm (0 versus 4 %,P=.05). In post-hoc subgroup analyses, rRT improved LRC for patients with N0-1 disease (HR 0.21, 95 %CI 0.05–0.93) and oropharyngeal cancer (0.31, 0.10–0.95), regardless of HPV. ConclusionAdaptive and dose redistributed radiotherapy enabled dose-escalation with similar toxicity rates compared to conventional radiotherapy. While FDG-PET-guided dose-escalation did overall not lead to significant tumor control or survival improvements, post-hoc results showed improved locoregional control for patients with N0-1 disease or oropharyngeal cancer treated with rRT.