Pegylated Liposomal Doxorubicin Research Articles

Pegylated liposomal doxorubicin in partially platinum-sensitive, platinum-resistant, or platinum-refractory ovarian cancer: a prospective study.

This study aimed to evaluate the efficacy and safety of pegylated liposomal doxorubicin (PLD) for patients with partially platinum-sensitive, platinum-resistant, or platinum-refractory ovarian cancer. Patients with partially platinum-sensitive, platinum-resistant, or platinum-refractory ovarian cancer were recruited in this prospective, open-label, single-arm, multicenter study. Eligible patients were given 4-6 cycles of PLD (40mg/m2 on day 1, every 4 weeks). The primary endpoint was progression-free survival (PFS). Secondary endpoints were overall survival (OS), objective response rate (ORR), disease control rate (DCR), quality of life, and safety. Exploratory endpoints included the change trend of CA125 and platinum-free interval. Between June 2017 and November 2020, 167 eligible patients were included in the full analysis set. The median PFS and OS were 6.8 months (95% CI, 4.4-9.3 months) and 19.1 months (95% CI, 15.0-23.3 months), respectively. The ORR and DCR were 32.3% and 60.5%, respectively. The ORR (62.3 vs 22.5%) and DCR (84.9 vs 60.7%) of patients with a CA125 decrease after the first cycle were significantly higher than those without a CA125 decrease (all P < .05). Grade ≥ 3 and serious adverse events were reported in 9.9% and 3.9% of patients, respectively. No treatment-related death was observed. PLD showed promising efficacy and manageable tolerability in patients with partially platinum-sensitive, platinum-resistant, or platinum-refractory ovarian cancer.ClinicalTrials.gov Identifier: Chinese Clinical Trial Registry, ChiCTR1900022962.

Nanoparticle-Binding Immunoglobulins Predict Variable Complement Responses in Healthy and Diseased Cohorts.

Systemic administration of nanomedicines results in the activation of the complement cascade, promoting phagocytic uptake and triggering proinflammatory responses. Identifying the biomarkers that can predict the "risk" of abnormally high complement responders can improve the safety and efficacy of nanomedicines. Polyethylene glycol (PEG) and dextran are two types of clinically approved polymer coatings that trigger complement activation. We performed a multifaceted analysis of the factors affecting the complement activation by PEGylated liposomal doxorubicin (PLD) and dextran-coated superparamagnetic iron oxide nanoworms (SPIO NWs) in plasma from patients with different inflammatory disease conditions and healthy donors. The complement activation (measured as deposition of the complement protein C3) varied greatly, with 29-fold and 26-fold differences for PLD and SPIO NWs, respectively. Chronic inflammation, acute infection, use of steroids, and sex had minor effects on the variable complement activation, whereas age inversely correlated with the complement activation. C-reactive protein level was not predictive of high (top 20th percentile) complement responses. Plasma concentrations of the main complement factors, as well as total IgG and IgM, showed no correlation with the activation by either nanoparticle. On the other hand, plasma concentrations of anti-PEG IgG and IgM showed a strong positive correlation with the activation by PLD. Particularly, titers of anti-PEG IgM showed the best predictive value for the "risk" of high complement activation by PLD. Titers of antidextran IgG and IgM showed a lower correlation with the activation by SPIO NWs and poor predictive value of the top 20% complement responses. Nanoparticle-bound immunoglobulins showed the best correlation with complement activation and a strong predictive value, supporting the critical role of immunoglobulins in inciting complement. The opsonization of PLD with C3 in plasma with high anti-PEG antibodies was predominantly via the alternative pathway. Characterizing the nature of nanoparticle-binding antibodies has important implications in mitigating and stratifying nanomedicine safety.

Enhancing the potency of anti-P32-active targeted PEGylated liposomal doxorubicin using various spacers: In silico, in vitro and in vivo studies

Even though nanoliposomal drug delivery systems are superior to conventional drug delivery methods, studies indicate that they may deliver small quantities of drugs through passive targeting. Specific peptides are used to decorate the surface of the liposomes for active targeting of tumors. Among these, CGKRK is the tumor homing peptide to target p32 protein on the surface of endothelial and tumor cells. In the present study, serine-glycine (SG) and glycine-glycine-glycine (GGG) spacer were added to CGKRK, an anti-P32 peptide and in silico molecular docking studies were conducted. PEGylated liposomal doxorubicin (PLD) was then surface modified with these peptides. All liposomal formulations had the sizes between 96 and 110 nm, negative zeta potentials and there were spherical in shape. The release of the doxorubicin (Dox) followed the same pattern for all formulations during 24 h. The cytotoxic effects of the formulations during 1, 3 and 6 h of the incubation, indicated the time-dependent cytotoxicity of formulations, while the PLD-CGGGKRK was the most potent. Apoptosis and antiangiogenic assays were also demonstrated the ability of PLD-CGGGKRK in inducing apoptosis and decreasing vessels densities. The in vivo anti-tumor study demonstrated the efficacy of CGGGKRK surface-modified PLDs in delaying tumor growth and increasing the median survival. Our findings indicated that the GGG spacer could improve the efficacy of anti-P32 peptide, CGKRK, in targeting breast cancer tumor models in mice and merit further investigation.

Impact of formulation parameters and circulation time on PEGylated liposomal doxorubicin related hand-foot syndrome

PEGylated liposomal doxorubicin (PLD) has effectively reduced the cardiac toxicity of free doxorubicin (DOX) due to its unique nanoscale properties. However, an unexpected accumulation of PLD in the skin has led to hand-foot syndrome (HFS), negatively impacting quality of life and psychological well-being. In this study, self-limiting HFS rat models were created to mimic human symptoms through varying dosing schedules and intensities of PLD. The effects of PLD formulation parameters on HFS were also investigated. The results demonstrated that replacing ammonium sulfate with citric buffer, increasing liposome size, or reducing DSPE-mPEG2000 modification density alleviated HFS. Additionally, liposomes without DSPE-mPEG2000 modification completely avoided HFS, suggesting that PEGylated phospholipid was the key formulation parameter contributing to PLD-induced HFS. Furthermore, the correlation between liposome pharmacokinetics and HFS indicated that PEGylation, rather than the extended circulation time of liposomes, may mediated PLD-related HFS. Better understanding of the formulation parameters that trigger HFS can guide reformulation strategies to mitigate or prevent this syndrome.

Liposomes with Low Levels of Grafted Poly(ethylene glycol) Remain Susceptible to Destabilization by Anti-Poly(ethylene glycol) Antibodies.

Binding of anti-PEG antibodies to poly(ethylene glycol) (PEG) on the surface of PEGylated liposomal doxorubicin (PLD) in vitro and in rats can activate complement and cause the rapid release of doxorubicin from the liposome interior. Here, we find that irinotecan liposomes (IL) and L-PLD, which have 16-fold lower levels of 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE)-PEG2000 in their liposome membrane as compared to PLD, generate less complement activation but remain sensitive to destabilization and drug release by anti-PEG antibodies. Complement activation and liposome destabilization correlated with the theoretically estimated number of antibody molecules bound per liposome. Drug release from liposomes proceeded through the alternative complement pathway but was accelerated by the classical complement pathway. In contrast to PLD destabilization by anti-PEG immunoglobulin G (IgG), which proceeded by the insertion of membrane attack complexes in the lipid bilayer of otherwise intact PLD, anti-PEG IgG promoted the fusion of L-PLD, and IL to form unilamellar and oligo-vesicular liposomes. Anti-PEG immunoglobulin M (IgM) induced drug release from all liposomes (PLD, L-PLD, and IL) via the formation of unilamellar and oligo-vesicular liposomes. Anti-PEG IgG destabilized both PLD and L-PLD in rats, indicating that the reduction of PEG levels on liposomes is not an effective approach to prevent liposome destabilization by anti-PEG antibodies.

Comparison of the Efficacy, Safety, and Quality of Life of Pegylated Liposomal Doxorubicin-Cyclophosphamide versus Epirubicin-Cyclophosphamide in Patients with Early-Stage HER2-Negative Breast Cancer: A Prospective, Randomized, Multicenter, Phase II Study

Plain Language SummaryThis study compared two chemotherapy treatments for human epidermal growth factor receptor 2 (HER2)-negative early-stage breast cancer: one using a drug called pegylated liposomal doxorubicin (PLD) and the other using epirubicin. A total of 256 women with stage I or II breast cancer from multiple medical centers in Taiwan were included in this study. They were randomly assigned to receive either PLD or epirubicin along with another drug called cyclophosphamide. Traditional treatments like anthracyclines (including doxorubicin and epirubicin) have been widely used but can have serious side effects. PLD is a newer drug that seems to work as well as traditional anthracyclines but with fewer harmful effects. The study found that both treatments were equally effective in 5-year disease-free survival and overall survival. However, the PLD treatment caused fewer severe side effects, such as hair loss and blood-related problems. Also, patients who received PLD reported feeling better during and after treatment compared to those who received epirubicin. This study is one of the first to directly compare PLD and epirubicin in a randomized trial for HER2-negative early-stage breast cancer patients. The results suggest that PLD could be a treatment option for these patients, offering similar effectiveness with fewer side effects to epirubicin treatments.

Retrospective multicenter study of elderly patients with platinum-sensitive relapsed ovarian cancer treated with trabectedin and pegylated liposomal doxorubicin (pld) in a real-world setting: a geico study

BackgroundTrabectedin in combination with pegylated liposomal doxorubicin (PLD) is approved for the treatment of patients with platinum-sensitive relapsed ovarian cancer. Nevertheless, there is currently limited information regarding this treatment in elderly patients with ovarian cancer in a real-world setting.MethodsThis observational and multicentric study retrospectively evaluated trabectedin plus PLD in a real-world setting treatment of elderly patients diagnosed with platinum-sensitive relapsed ovarian cancer, treated according to the Summary of Product Characteristics (SmPC) from 15 GEICO-associated hospitals. Patients ≥ 70 years old at the time of treatment initiation and platinum-free intervals ≥ 6 months were considered eligible.ResultsForty-three patients with a median age of 74.0 years were treated between January 1st, 2015, and December 31st, 2019 in 15 Spanish centers. Four patients achieved complete response (9.3%), 14 (32.6%) partial response, and 13 (30.2%) stable disease as the best radiological response. In the analysis of biological overall response according to CA125 serum levels (i.e., Rustin criteria), 14 responded to the treatment (32.6%), 11 responded and normalized (25.6%), three patients stabilized (7.0%) and three progressed (7.0%). Median progression-free survival (PFS) and overall survival (OS) in the study population were 7.7 and 19.5 months, respectively. The most common grade 3/4 adverse events were neutropenia (n = 8, 18.7%) and asthenia (n = 5, 11.6%).ConclusionsThis analysis demonstrated that trabectedin combined with PLD is a feasible and effective treatment in elderly patients with platinum-sensitive relapsed ovarian cancer, showing an acceptable safety profile, which is crucial in the palliative treatment of these patients.

Ultrasound -Induced Thermal Effect Enhances the Efficacy of Chemotherapy and Immunotherapy in Tumor Treatment.

The inadequate perfusion, frequently resulting from abnormal vascular configuration, gives rise to tumor hypoxia. The presence of this condition hinders the effective delivery of therapeutic drugs and the infiltration of immune cells into the tumor, thereby compromising the efficacy of treatments against tumors. The objective of this study is to exploit the thermal effect of ultrasound (US) in order to induce localized temperature elevation within the tumor, thereby facilitating vasodilation, augmenting drug delivery, and enhancing immune cell infiltration. The selection of US parameters was based on intratumor temperature elevation and their impact on cell viability. Vasodilation and hypoxia improvement were investigated using enzyme-linked immunosorbent assay (ELISA) and immunofluorescence examination. The distribution and accumulation of commercial pegylated liposomal doxorubicin (PLD) and PD-L1 antibody (anti-PD-L1) in the tumor were analyzed through frozen section analysis, ELISA, and in vivo fluorescence imaging. The evaluation of tumor immune microenvironment was conducted using flow cytometry (FCM). The efficacy of US-enhanced chemotherapy in combination with immunotherapy was investigated by monitoring tumor growth and survival rate after various treatments. The US irradiation condition of 0.8 W/cm2 for 10 min effectively elevated the tumor temperature to approximately 40 °C without causing any cellular or tissue damage, and sufficiently induced vasodilation, thereby enhancing the distribution and delivery of PLD and anti-PD-L1 in US-treated tumors. Moreover, it effectively mitigated tumor hypoxia while significantly increasing M1-phenotype tumor-associated macrophages (TAMs) and CD8+ T cells, as well as decreasing M2-phenotype TAMs. By incorporating US irradiation, the therapeutic efficacy of PLD and anti-PD-L1 was substantially boosted, leading to effective suppression of tumor growth and prolonged survival in mice. The application of US (0.8 W/cm2 for 10 min) can effectively induce vasodilation and enhance the delivery of PLD and anti-PD-L1 into tumors, thereby reshaping the immunosuppressive tumor microenvironment and optimizing therapeutic outcomes.

Tumor Microenvironment Reprogramming Improves Nanomedicine-Based Chemo-Immunotherapy in Sarcomas.

Sarcomas are a heterogeneous group of rare cancers that originate in soft tissues or bones. Their complexity and tendency for metastases make treatment challenging, highlighting the need for new therapeutic approaches to improve patient survival. The difficulties in treating these cancers primarily stem from abnormalities within the tumor microenvironment (TME), which leads to reduced blood flow and oxygen levels in tumors. Consequently, this hampers the effective delivery of drugs to tumors and diminishes treatment efficacy despite higher toxic doses of chemotherapy. In this study, we tested the mechanotherapeutic ketotifen combined with either pegylated liposomal doxorubicin (PLD) or pegylated liposomal coencapsulated alendronate-doxorubicin (PLAD) plus anti-programmed cell death protein 1 antibody in mouse models of fibrosarcoma and osteosarcoma. We found that ketotifen successfully reprogrammed the TME by reducing tumor stiffness and increasing perfusion, proven by changes measured by shear-wave elastography and contrast-enhanced ultrasound, respectively, and enhanced the therapeutic efficacy of our nanomedicine-based chemo-immunotherapy protocols. Furthermore, we observed a trend toward improved antitumor responses when nano-chemotherapy is given alongside anti-programmed cell death protein 1 and when the immunomodulator alendronate was present in the treatment. We next investigated the mechanisms of action of this combination. Ketotifen combined with nanomedicine-based chemo-immunotherapy increased T-cell infiltration, specifically cytotoxic CD8+ T cells and CD4+ T helper cells, and decreased the number of regulatory T cells. In addition, the combination also altered the polarization of tumor-associated macrophages, favoring the M1 immune-supportive phenotype over the M2 immunosuppressive phenotype. Collectively, our findings provide evidence that ketotifen-induced TME reprogramming can improve the efficacy of nanomedicine-based chemo-immunotherapy in sarcomas.

Pegylated liposomal doxorubicin combined with cyclophosphamide and vincristine in pediatric patients with relapsed/refractory solid tumor: a single-arm, open-label, phase I study

The combined vincristine, pegylated liposomal doxorubicin (PLD), and cyclophosphamide (VPC) regimen has never been studied in pediatric patients. This open-label, single-center, single-arm phase I study utilizing a "3+3" design enrolled children with relapsed/refractory (R/R) solid tumors. Three dose levels of PLD (Duomeisu®) were studied (30, 40, or 50mg/m2) in combination with cyclophosphamide (1500mg/m2), mesna (1500mg/m2), and vincristine (1.5mg/m2, maximum 2mg) once every 3 weeks. The primary endpoints included safety, the maximum tolerated dose (MTD) of PLD (Duomeisu®), and the recommended phase 2 dose (RP2D) of PLD (Duomeisu®) for further phase 2 investigation. The secondary endpoints were objective response rate (ORR) and disease control rate (DCR). This study is registered with ClinicalTrials.gov, NCT04213612. Between January 7, 2020, and November 18, 2021, 34 patients were eligible and evaluable for toxicity, while 26 patients were evaluable for response. The MTD of PLD (Duomeisu®) was 30mg/m2. The most common adverse event (AE) was grade 3 or 4 neutropenia (61.8%). The most common grade 1 or 2 non-hematologic AE and cardiotoxicity effects were vomiting (35.3%) and abnormal electrocardiogram T waves (20.6%), respectively. ORR and DCR to VPC regimen after two cycles were 50.0% and 92.3%, respectively. Targeted gene panel sequencing revealed the activation of TP53 mutation may be an adverse prognostic factor. The VPC regimen showed a promising safety profile and had preliminary efficacy in children with R/R solid tumors. The RP2D for PLD (Duomeisu®) combined with cyclophosphamide and vincristine is 30mg/m2 once every 3 weeks. CSPC Ouyi Pharmaceutical Co., Ltd., Shijiazhuang, the National Key Research and Development Program of China [No. 2022YFC2705005], the National Natural Science Foundation of China [No. 82203303], and the Basic and Applied Basic Research Foundation of Guangdong Province [No. 2021A1515110234].

Population pharmacokinetics of TLD-1, a novel liposomal doxorubicin, in a phase I trial.

TLD-1 is a novel pegylated liposomal doxorubicin (PLD) formulation aiming to optimise the PLD efficacy-toxicity ratio. We aimed to characterise TLD-1's population pharmacokinetics using non-compartmental analysis and nonlinear mixed-effects modelling. The PK of TLD-1 was analysed by performing a non-compartmental analysis of longitudinal doxorubicin plasma concentration measurements obtained from a clinical trial in 30 patients with advanced solid tumours across a 4.5-fold dose range. Furthermore, a joint parent-metabolite PK model of doxorubicinentrapped, doxorubicinfree, and metabolite doxorubicinol was developed. Interindividual and interoccasion variability around the typical PK parameters and potential covariates to explain parts of this variability were explored. Medians standard deviations of dose-normalised doxorubicinentrapped+free Cmax and AUC0-∞ were 0.342 0.134mg/L and 40.1 18.9mg·h/L, respectively. The median half-life (95h) was 23.5h longer than the half-life of currently marketed PLD. The novel joint parent-metabolite model comprised a one-compartment model with linear release (doxorubicinentrapped), a two-compartment model with linear elimination (doxorubicinfree), and a one-compartment model with linear elimination for doxorubicinol. Body surface area on the volumes of distribution for free doxorubicin was the only significant covariate. The population PK of TLD-1, including its release and main metabolite, were successfully characterised using non-compartmental and compartmental analyses. Based on its long half-life, TLD-1 presents a promising candidate for further clinical development. The PK characteristics form the basis to investigate TLD-1 exposure-response (i.e., clinical efficacy) and exposure-toxicity relationships in the future. Once such relationships have been established, the developed population PK model can be further used in model-informed precision dosing strategies. ClinicalTrials.gov-NCT03387917-January 2, 2018.

Atezolizumab versus placebo in combination with bevacizumab and non-platinum-based chemotherapy in recurrent ovarian cancer: Final overall and progression-free survival results from the AGO-OVAR 2.29/ENGOT-ov34 study.

LBA5501 Background: Paclitaxel or pegylated liposomal doxorubicin (PLD) in combination with bevacizumab (bev) are standard treatment options in patients with relapsed ovarian cancer not candidates for platinum, but responses are usually short-lived. Recently, two trials have reported a numerical but non-significant advantage from the addition of atezolizumab (atezo) to chemo plus bev in the recurrent setting (ATALANTE, Kurtz JE et al., J Clin Oncol &amp; NRG GY009, O'Cearbhaill et al, IGCS 2023). AGO-OVAR 2.29 investigated the efficacy of atezo in combination with bev and non-platinum-based chemo. Methods: AGO-OVAR 2.29 is a randomized, double blind, phase III trial evaluating the efficacy and safety of atezo plus bev and chemo in patients (pts) with recurrent ovarian cancer. Eligible patients had a 1st/2nd relapse within 6 months after completing platinum-based chemo or a 3rd relapse regardless of treatment-free interval. A fresh biopsy for central PD-L1 testing (VENTANA SP142 assay) prior to randomization was mandatory. All pts received weekly paclitaxel or PLD and bev until disease progression or intolerable toxicity and were randomized 1:1 to either atezolizumab 840 mg q14 days or placebo until progression or for a maximum duration of 24 months. Number of prior lines, planned chemo, prior bev and PD-L1 status served as stratification factors. Overall survival (OS) and progression-free survival (PFS) in the intention to treat (ITT) population were primary endpoints, both to be analyzed after observation of 391 deaths. Data cut-off (DCO) occurred on 26/01/2024. OS and PFS analysis is based on a multiple Cox regression with treatment arm and stratification factors as covariates. Safety is reported for pts who received at least one dose of study treatment. Results: 574 pts were randomly assigned to atezo (285) or placebo (289). 45.1% received PLD and 53.7% paclitaxel. 7 pts did not start study treatment. 36.1% of pts had received 3 prior lines and 72.5% prior bev. 25.8% were PD-L1 positive. At DCO 418 OS and 505 PFS events have occurred. Median OS was 14.3 months (mos) in the atezo and 13.0 mos in the placebo arm (HR 0.83, 95% CI 0.68-1.01; p=0.06) and PFS 6.3 mos for atezo vs 6.6 mos for placebo arm (HR 0.88, 95% CI 0.73-1.05; p=0.15). Similar HR were observed in PD-L1 positive and negative pts. In total, 580 SAE and 141 AESI were reported. AEs of ≥ grade 3 were reported in 71.5% in the atezo and 68.9% in the placebo arm. 63.7% of pts in the atezo and 51.4% in the placebo arm experienced serious AEs. Conclusions: The addition of atezo to chemo plus bev did not significantly improve OS or PFS in pts. with recurrent ovarian cancer who are no candidates for platinum. Safety was within the expected range. Translational research is ongoing. Clinical trial information: NCT03353831 .

A phase I/II study of maplirpacept in combination with pegylated liposomal doxorubicin (PLD) in patients with platinum-resistant ovarian cancer (OC): Phase 1 results.

e17546 Background: CD47, an overexpressed factor correlated with poor clinical characteristics and prognosis in OC, is an innate immune checkpoint that binds signal regulatory protein alpha (SIRPα) and delivers a signal to suppress macrophage phagocytosis. Maplirpacept (PF-07901801) is a fusion protein consisting of the CD47-binding domain of human SIRPα linked to the Fc region of human IgG4, enhancing phagocytosis by blocking CD47. Blockade of CD47, both alone and combined with doxorubicin, has shown anti-tumor activity in vitro and in vivo in xenograft animal models. PLD 40mg/m2 conveyed poor efficacy (PFS 4 months; ORR 8%), as did bevacizumab + PLD (PFS 5 months; ORR 14%) (AURELIA), highlighting the need for new treatments for platinum-resistant OC. C4971002 [NCT05261490] is an open label, multicenter dose-escalation and expansion study evaluating the safety, preliminary anti-tumor activity, pharmacokinetics and -dynamics of maplirpacept in combination with PLD in patients with platinum-resistant recurrent OC. Methods: The study included adults with platinum-resistant recurrent epithelial OC (PD ≤6 months after platinum-based therapy or unable/unwilling to receive platinum-based therapy). PLD while platinum-resistant or directly prior to study was not permitted. Patients received maplirpacept (12mg/kg Dose Level [DL] 1; 24mg/kg DL2; 48mg/kg DL3) weekly in Cycle 1 and every 2 weeks in Cycle 2+, and PLD (40mg/m2) on Day 1 of each 4-week cycle. Assessments of adverse events (AEs) were based on CTCAE v5.0. Response assessments (RECIST v1.1) were performed every 8 weeks. Results of the Phase I portion, aiming to evaluate the DLTs, the MTD and the RP2D, are presented as of 18 December 2023, after all patients completed the 28-day DLT assessment period. Results: 10 patients were treated (DL1 n=3; DL2 n=3; DL3 n=4) with a median (min, max) age of 69 (53, 77) years, 80% ECOG 1, 60% serous adenocarcinoma. Median (min, max) treatment duration was 14 (8, 32) weeks. Most common adverse events are shown in the table. No DLTs occurred in the assessment period. 1 serious AE (gait disturbance &amp; muscle weakness) related to maplirpacept was reported (DL3). 2 deaths occurred &gt;120 days after 1st dose, both due to disease. 5 (50%) patients had a best response of stable disease, 2 of which were treated into at least Cycle 6. Conclusions: Despite immature anti-tumor activity, maplirpacept + PLD was tolerable at all dose levels, not reaching the MTD. The encouragingly tolerable dose of 48mg/kg thus represents the RP2D which could support further development for this population. Clinical trial information: NCT05261490 . [Table: see text]

Neoadjuvant pegylated liposomal doxorubicin-containing chemotherapy in combination with trastuzumab and pertuzumab in patients with HER2-positive early breast cancer: A randomized phase II study (METIS).

596 Background: In the neoadjuvant phase, anti-HER2 therapy is usually delayed when combined with anthracycline-containing chemotherapy regimens, since conventional anthracycline and anti-HER2 agents cannot be given simultaneously. Pegylated liposomal doxorubicin (PLD) is a modified form of doxorubicin that can lower the risk of heart damage while preserving its anticancer activity. In this study, we aimed to explore whether PLD could replace conventional anthracycline and be used earlier with anti-HER2 agents to enhance neoadjuvant efficacy without increasing cardiotoxicity. Methods: The METIS study was an investigator-initiated, multicenter, open-label, randomized, phase II study conducted at 11 centers in China. Patients aged 18 to 70 years old with previously untreated stage II–III histologically documented HER2-positive breast cancer were randomly assigned (1:1) to receive PLD-containing or epirubicin-containing neoadjuvant chemotherapy. The PLD-containing regimen consisted of 4 cycles of PLD (35 mg/m2) and cyclophosphamide (600 mg/m2) every 3 weeks, followed by 4 cycles of a taxane of the investigator's choice (docetaxel, paclitaxel, or nab-paclitaxel). The epirubicin-containing regimen consisted of 4 cycles of epirubicin (90 mg/m2) and cyclophosphamide (600 mg/m2) every 3 weeks, followed by 4 cycles of a taxane of the investigator's choice. Both regimens included trastuzumab (8 mg/kg loading dose, then 6 mg/kg maintenance dose) and pertuzumab (840 mg loading dose, then 420 mg maintenance dose) every 3 weeks. Trastuzumab and pertuzumab were given with all chemotherapy cycles in the PLD-containing group, and with the taxane cycles only in the epirubicin-containing group. The primary end point was investigator-assessed total pathological complete response (tpCR) rate in the intention-to-treat population. Results: From August 2019 to March 2023, 156 were enrolled and randomly assigned to receive PLD-containing (n=80) or epirubicin-containing (n=76) treatment. At date of data analysis, the median follow-up duration was 16.3 months. The PLD-containing treatment group had a higher rate of pathological complete response (67.5%, 95% CI 56.1-77.6) than the epirubicin-containing group (48.7%, 95% CI 37.0-60.4), with a rate difference of 18.8% (p=0.033). Only one patient in the epirubicin-containing group experienced a grade 3 decrease in left ventricular ejection fraction, while none did in the PLD-containing group. Other adverse events were similar in both groups. Conclusions: A combination of PLD and cyclophosphamide with trastuzumab and pertuzumab, followed by a taxane, trastuzumab, and pertuzumab, significantly increased the rate of tpCR without more cardiotoxicity in neoadjuvant treatment for early-stage HER2-positive breast cancer patients. Clinical trial information: NCT04172259 .

Consolidation therapy with autologous stem cell transplantation after remission of induction chemotherapy prolongs the survival of patients with peripheral T-cell lymphoma.

There was little evidence of autologous stem cell transplantation (ASCT) as consolidation therapy after remission of induction for patients with Peripheral T-cell lymphoma (PTCL). In this study, we conducted a comparative analysis of real-world survival outcomes between consolidation therapy and observation in patients with PTCL. A total of 92 patients with peripheral T-cell lymphoma (PTCL) who were admitted to the Department of Hematology, Huadong Hospital Affiliated with Fudan University from January 2013 to April 2019 were divided into two groups based on whether they were treated with high-dose therapy (HDT) followed by autologous hematopoietic stem cell transplantation (ASCT): ASCT as consolidation therapy (n=30) and observation (n=62). Clinical characteristics, treatment patterns, and survival outcomes were analyzed between the two groups. Univariate and Cox multivariate regression analyses were also performed to detect prognostic factors of survival. With a median follow-up time of 41 months, the median overall survival (OS) of peripheral T-cell lymphoma patients treated with ASCT was not reached; the median progression-free survival (PFS) was 77.0 months, which was much higher than that of patients without ASCT (p<0.003 for OS, p=0.015 for PFS). Subgroup analysis found that patients with high risks benefited more from ASCT. Combination with hemophagocytic lymphohistiocytosis (HLH) (p<0.001), clinical stage more than III (p=0.014), IPI score above 3 (p=0.049), and bone marrow involvement (p=0.010) were the independent prognostic factors significantly associated with worse OS and PFS. Additionally, pegylated liposomal doxorubicin (PLD)-containing chemotherapy regimen could bring a higher overall response rate (ORR) and prolong the survival of patients with PTCL who underwent ASCT. ASCT may improve the long-term survival of patients with PTCL as consolidation therapy after achieving complete or partial remission of induction treatment, particularly for those with high risks. The chemotherapy regimen containing pegylated liposomal doxorubicin may induce deeper remission than traditional doxorubicin in PTCL. It is crucial to identify the specific groups most likely to benefit from upfront ASCT.

Peposertib, a DNA-PK Inhibitor, Enhances the Anti-Tumor Efficacy of Topoisomerase II Inhibitors in Triple-Negative Breast Cancer Models.

Triple-negative breast cancer (TNBC) remains the most lethal subtype of breast cancer, characterized by poor response rates to current chemotherapies and a lack of additional effective treatment options. While approximately 30% of patients respond well to anthracycline- and taxane-based standard-of-care chemotherapy regimens, the majority of patients experience limited improvements in clinical outcomes, highlighting the critical need for strategies to enhance the effectiveness of anthracycline/taxane-based chemotherapy in TNBC. In this study, we report on the potential of a DNA-PK inhibitor, peposertib, to improve the effectiveness of topoisomerase II (TOPO II) inhibitors, particularly anthracyclines, in TNBC. Our in vitro studies demonstrate the synergistic antiproliferative activity of peposertib in combination with doxorubicin, epirubicin and etoposide in multiple TNBC cell lines. Downstream analysis revealed the induction of ATM-dependent compensatory signaling and p53 pathway activation under combination treatment. These in vitro findings were substantiated by pronounced anti-tumor effects observed in mice bearing subcutaneously implanted tumors. We established a well-tolerated preclinical treatment regimen combining peposertib with pegylated liposomal doxorubicin (PLD) and demonstrated strong anti-tumor efficacy in cell-line-derived and patient-derived TNBC xenograft models in vivo. Taken together, our findings provide evidence that co-treatment with peposertib has the potential to enhance the efficacy of anthracycline/TOPO II-based chemotherapies, and it provides a promising strategy to improve treatment outcomes for TNBC patients.

Abstract PO1-09-09: The journey of HR positive, HER2 negative metastatic breast cancer’s patients: heterogeneities and barriers in Brazilian public health system- a national survey

Abstract Background: Breast cancer is the most common neoplasm in Brazilian women, with high percent of patients diagnosed in advanced stages. Metastatic breast cancer (mBC) is a challenge in the country, where 75% of the population is covered by public health system (Sistema Único de Saúde, SUS). We conducted an on-line survey to describe the journey of human epidermal growth factor receptor 2-negative (HER2-), hormone receptor positive (RH+) mBC patients across public scenario in Brazil. Methods: An on-line survey comprised of 39 to 48 (depending on the kind of some questions, which could open another question in case of affirmative answer) objective questions were sent by e-mail to180 oncologists working in public and private health care system. Questions were focused on assessing wait time for first treatment after admission in the hospital in both systems, availability of oncological drugs within SUS according to essential medicines list by World Health Organization, and presence of palliative and multidisciplinary teams in both systems. Continuous variables were measured by median and mean. The level of statistical significance adopted was 5% with Teste p two-sided. Analyses were performed using SAS statistical software (version 25.0). Results: We had 150 respondents working in SUS and private health system, which fulfilled the inclusion criteria to participate in this survey. The other 30 respondents were excluded from the study because they worked exclusively in SUS or exclusively in the private system, and their answers were not analyzed. Median wait time for surgery was 60 days in the SUS (N=150) and 30 days in the private health system (N=150) e (p &amp;lt; 0,0001). Regardless of chemotherapy provided, median waiting time was 30 and 15 days in the SUS (N=150) and the private health system (N=150), respectively (p &amp;lt; 0,0001). Most oncologists in the SUS (N=125, 83.3%) pointed to endocrine therapy as their first-choice treatment in mBC. Concerning endocrine therapy in the SUS, Gonadotropin-Releasing Hormone Agonist (GnRHa) was available, and it was prescribed by 54 (36.0%) and Fulvestrant for 72 (48.0%) of respondents. Considering chemotherapy, weekly paclitaxel alone or combined with platin were available and they were prescribed by 124 (82.6%) and 109 (72.6%) of oncologists respectively. Vinorelbine was available and it was prescribed according to oncologists’ report by 109 (72.6%) and Pegylated liposomal doxorubicin (PLD) by 38 (25.3%) of oncologists. Oncologists answered agree or strongly agree that they had a multidisciplinary care team in SUS 77,3% (N =116) versus 87,3% (N=131) in the private system (p=0.022). Concerning palliative care 66,09% (N= 99) in the SUS versus 82,0% (N=123) in the private system answered that they agreed or strongly agreed that this service was available (p=0.001). Conclusions: The Brazilian government has continuously improved delivery of services and medicines via the public system (SUS), but there are still significant differences within this system and versus the private sector. Unavailability of endocrine therapy agents as GnRHa and Fulvestrant, and some chemotherapy agents as PLD and Vinorelbine for high percentage of patients, raises the existence of disparities within SUS. Also, longer waiting times for treatment in the SUS, lower availability of support teams such multidisciplinary and palliative care, they point out disparities between SUS and private health systems. The lack of a National Cancer Control Program and low health investment by Brazilian government might explain the difference in cancer patients’ access. Citation Format: Heloísa Resende, Igor Soares, Angélica Renó, Ana Cunha, Vinícius Aguiar, Letícia Tureta, Viviane Pereira. The journey of HR positive, HER2 negative metastatic breast cancer’s patients: heterogeneities and barriers in Brazilian public health system- a national survey [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 PO1-09-09.

Abstract PO1-01-02: Final analysis of neoadjuvant chemotherapy with pegylated liposomal doxorubicin/cyclophosphamide followed by taxanes with full-course trastuzumab/pertuzumab for HER2-positive breast cancer: a single-arm, phase II study

Abstract Background: The optimal neoadjuvant treatment regimen for HER2-positive breast cancer remains unclear, especially regarding the use of anthracycline. We conducted a prospective phase II study to evaluate sequential neoadjuvant chemotherapy with pegylated liposomal doxorubicin (PLD)/cyclophosphamide followed by taxanes in the presence of full-course trastuzumab/pertuzumab in HER2-positive early breast cancer patients. Methods: In this single-arm, open-label, multicenter, phase II study, eligible patients with confirmed HER2-positive early breast cancer were recruited from four independent hospitals. Patients received four cycles of PLD (35 mg/m2) and cyclophosphamide (600 mg/m2), followed by four cycles of taxanes (docetaxel, 100 mg/m2 or nab-paclitaxel, 260 mg/m2), concomitant with eight cycles of trastuzumab (8 mg/kg loading dose, then 6 mg/kg) and pertuzumab (840 mg loading dose, then 420 mg) every 3 weeks. The primary endpoint was total pathological complete response (ypT0/is ypN0, tpCR). Secondary endpoints included breast pCR (bpCR), objective response rate (ORR), disease control rate, the proportion of patients requiring breast-conserving surgery, and safety. For biomarkers analysis, tumor tissues were collected at baseline and evaluated for Topoisomerase 2 Alpha (TOP2A) expression assessed prospectively with immunohistochemistry (IHC) assay by independent pathologists. Results: Between May 27, 2020 and May 11, 2022, 78 eligible patients were treated and underwent surgery, of whom 42 (53.8%) patients underwent breast-conserving surgery. After neoadjuvant therapy, 47 (60.3%, 95% CI, 48.5%-71.2%) patients achieved a tpCR in the breast and axilla. The bpCR was observed in 49 (62.8%) patients. ORRs were 76.9% (95% CI, 66.0%-85.7%) and 93.6% (95% CI, 85.7%-97.9%) after 4-cycle and 8-cycle neoadjuvant therapy, respectively. All (100%) patients achieved disease control since the end of the first cycle. No correlations between clinicopathological variables and pathological response were observed. Grade 3 or worse AEs occurred in 35 (44.9%) patients. Nine (11.5%) patients experienced asymptomatic LVEF reduction (≥10% from baseline), but all with a minimum value of &amp;gt;55%. No treatment-related surgical delay or death occurred. For biomarkers analysis, the status of TOP2A was not found to be associated with pCR or 4th-cycle ORR. Conclusions: This dual HER2-blockade plus polychemotherapy as sequential neoadjuvant regimen demonstrates promising anti-tumor activity and acceptable tolerability for patients with HER2-positive breast cancer. Citation Format: Yaping Yang, Liang Jin, Yudong li, Fengxia Gan, Nanyan Rao, Jun Zhang, Ruifa Feng, Zhenzhen Liu, Qiang Liu. Final analysis of neoadjuvant chemotherapy with pegylated liposomal doxorubicin/cyclophosphamide followed by taxanes with full-course trastuzumab/pertuzumab for HER2-positive breast cancer: a single-arm, phase II study [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 PO1-01-02.

Abstract 5314: Improved breast cancer tumor control with addition of CD40 agonist and Flt3 ligand to pegylated liposomal doxorubicin is only partially mediated by CD8 T cells

Abstract Background: There is a need for improved immunotherapy strategies beyond current FDA approved treatments for triple negative breast cancer. Defective antigen presentation has been shown to play a contributory role in deficient anti-tumor immunity in breast cancers. Flt3 ligand (Flt3L) is a growth factor that increases differentiation into DC1 dendritic cells. CD40 agonist (CD40a) activates all 3 classes of antigen presenting cells - DCs, B cells, and macrophages. Synergy with chemotherapy and CD40a has been seen in other cancers but not explored in breast cancers. Methods: C57BL/6 mice (aged 6-8 weeks) were injected with 150,000 E0771 breast cancer cells within the mammary fat pad. Tumors were allowed to grow to a volume of ~50 mm3 before randomization into treatment groups. Mice were treated with triplet therapy of pegylated liposomal doxorubicin (PLD) via tail vein followed by Flt3L intraperitoneal (IP) daily for 5 days and CD40a IP 1 week later as well as monotherapy and doublet therapy controls. Tumor growth and survival were monitored throughout the experiment. Tumors were harvested for single cell RNA sequencing (scRNAseq) and immunohistochemistry. To further study subset specific effects on efficacy of the immunotherapy, CD8 and CD4 T-cells were systemically depleted with anti-CD8 and anti-CD4 antibodies administered IP every 4 days starting 2 days before PLD treatment. Results: Triplet therapy led to improved tumor control compared to no treatment, monotherapy, and doublet controls (p&amp;lt;0.0001). Increased tumor infiltration with CD8 T cells was observed with triplet therapy via immunohistochemistry. scRNAseq showed increased cDC1 subset with Flt3L treatment. Contrastingly, CD40a decreased DC subsets likely due to activation and emigration out of the tumor, remodeled macrophage populations, and decreased T regulatory cells. CD8 depletion led to faster tumor growth whereas CD4 depletion reduced tumor growth. Triplet therapy maintained efficacy over PLD with both CD8 and CD4 depletion but showed reduced magnitude of benefit with CD8 T cell depletion suggesting a partial CD8 mediated process. CD4 T cell depletion did not hinder triplet therapy efficacy compared to PLD but depletion further enhanced tumor control in combination with triplet therapy, with 20% (2/10) of animals achieving complete regression. Conclusion: Triplet therapy with PLD, Flt3L, and CD40a improved tumor control and survival in syngeneic E0771 breast cancer mouse model. Added benefit of immunotherapy to PLD is partially CD8 T cell mediated. CD4 depletion further enhances tumor control in combination with triplet therapy. Experiments to explore the interactive effect of triplet therapy with other pertinent immune subsets are ongoing. A clinical trial with this combination in metastatic triple negative breast cancer patients is open and recruiting (NCT05029999). Citation Format: Preteesh L. Mylabathula, Shruthi Nooka, Anas Alkhani, James Zhu, Ashley Vu, Riyasat Ali, Varshini Ramasamy Balasubramanian, Isaac Chan, Sangeetha M. Reddy. Improved breast cancer tumor control with addition of CD40 agonist and Flt3 ligand to pegylated liposomal doxorubicin is only partially mediated by CD8 T cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5314.

The Survival Benefit of Pegylated Liposomal Doxorubicin-Based Neoadjuvant Chemotherapy in the Management of Breast Cancer.

Purpose: This study aims to evaluate the short-term outcomes and prognosis and the cardiac safety of pegylated liposomal doxorubicin (PLD)-based neoadjuvant chemotherapy (NAC) compared with epirubicin-based therapy in breast cancer treatment. Methods: In total, 304 patients diagnosed with stages II and III breast cancer were enrolled that included 97 cases treated with PLD and 207 controls treated with epirubicin in NAC. The effectiveness of the antibreast cancer treatment was evaluated using overall survival (OS) and disease-free survival (DFS) metrics, whereas cardiac toxicity was measured through the left ventricular ejection fraction (LVEF) and electrocardiogram (ECG) assessments. Results: The 5-year DFS and OS rates in the PLD group were 84.5% and 88.7% (with 15 recurrences and 11 deaths), respectively, whereas in the control group, these rates were 72.9% and 79.2% (with 56 recurrences and 43 deaths). Regarding cardiac toxicity, there was no significant difference in ECG abnormalities or LVEF decline between the two groups. Conclusions: The study suggests that PLD-based NAC may provide substantial benefits in terms of DFS and OS, along with a safe cardiac toxicity profile, in patients with stage II-III breast cancer.