Standard Chemotherapy Research Articles

Study Protocol of a Randomized, Two-Arm, Phase I/II Trial Investigating the Feasibility, Safety, and Efficacy of Local Treatment with US-Guided High-Intensity Focused Ultrasound in Combination with Palliative Chemotherapy in Inoperable Pancreatic Cancer.

Pancreatic adenocarcinoma (PaC) still has a dismal prognosis, and despite medical advances, a bleak 5-year survival rate of only 8%, largely due to late diagnosis and limited curative surgical options for most patients. Frontline palliative treatment shows some survival advantages. However, the high disease mortality is accompanied by high morbidity including cancer-related pain and additional symptoms, which strongly impair patients' quality of life (QOL). At present, there is no established strategy for local therapy for PaC primarily aiming to manage local tumor growth and alleviate associated symptoms, particularly pain. In recent years, non-invasive high-intensity focused ultrasound (HIFU) has shown promising results in reducing cancer pain and tumor mass, improving patients' QOL with few side effects. This is the first randomized controlled trial worldwide including 40 patients with inoperable pancreatic adenocarcinoma randomized into two groups: group A undergoing standard chemotherapy; and group B undergoing standard chemotherapy plus local HIFU treatment. This study aims to establish a robust evidence base by examining the feasibility, safety, and efficacy of US-guided HIFU in combination with standard palliative systemic therapy for unresectable PaC. Primary endpoint assessments will focus on parameters including safety issues (phase I), and local response rates (phase II).

Discovery, identification and mechanism of chemosensitivity-relate biomarker inter-α-trypsin inhibitor heavy chain 4 in metastatic colorectal cancer

Predictive biomarkers of response to chemotherapy in patients with metastatic colorectal cancer (mCRC) are needed to better characterize tumors and enable more tailored therapies. Here we used serum proteomics to screen for chemotherapy predictive markers. We found that higher baseline serum inter-α-trypsin inhibitor Heavy Chain 4 (ITIH4) expression in newly diagnosed mCRC patients was associated with poorer response to standard first-line chemotherapy. In addition, the higher expression of ITIH4 in CRC tissue also suggested poorer prognosis mCRC patients. Moreover, the overexpression of ITIH4 could promote the proliferation of CRC cells and reduce the sensitivity of CRC cells to 5-fluorouracil (5-FU) by inhibiting apoptosis in vivo and vitro. Through RNA-seq combined with bioinformatics analysis, we speculated that ITIH4 may activate phosphatidyl 3-kinase-protein kinase B (PI3K-AKT) pathway to inhibit apoptosis, thereby reducing the sensitivity of CRC cells to 5-FU. In conclusion, our findings unveil that ITIH4 is associated with CRC resistance to 5-FU, and may serve as a potential predictive biomarker for the sensitivity of advanced CRC patients to standard first-line chemotherapy regimens, and also provide a potential therapeutic target to render 5-FU resistance in CRC patients.

A combination of 5-azacytidine and nivolumab is a potentially effective rescue therapy in relapsed/refractory AITL.

Angioimmunoblastic T-cell lymphoma (AITL) is a peripheral T-cell lymphoma characterized by a T follicular helper cell phenotype expressing PD-1 (programmed cell death-1). AITL exhibits a poor response to conventional chemotherapy, with a median 5-year overall survival of 44% and a progression-free survival of 32%. Relapse is common, resulting in a median overall survival of 6 months. Recurrent mutations are detected in genes regulating DNA methylation, including TET2, DNMT3A, and IDH2 variants, along with the prevalent RHOA G17V mutation. In this context, patients treated with the hypomethylating agent 5-azacytidine achieved overall response and complete response rates of 75% and 41%, respectively. We hypothesized that targeted therapies combining anti-PD-1 checkpoint blockers with hypomethylating agents could be efficient in AITL patients and less toxic than standard chemotherapy. Here, we report the efficacy of a regimen combining 5-azacytidine and nivolumab in nine relapsed or refractory AITL patients. This regimen was well-tolerated, especially in elderly patients. The overall response rate was 78%, including four partial responses (44%) and three complete responses (33%). Allogeneic hematopoietic stem cell transplantation was performed in two patients who reached complete response. These preliminary favorable results may serve as a basis for further investigation in prospective studies.

Antibody-drug conjugates as a novel therapeutic modality to treat recurrent refractory germ cell tumors.

This review provides a rationale for using the Food and Drug Administration (FDA)-approved antibody-drug conjugates (ADCs) for implementing as therapy in recurrent refractory germ cell tumors similar to their position in the treatment of other types of chemoresistant solid tumors. Germ cell tumors (GCTs) originate from germ cells; they most frequently develop in ovaries or in the testes, while being the most common type of malignancy in young men. GCTs are very sensitive to cisplatin-based chemotherapy, but therapeutic resistance occurs in a considerable number of cases, which is associated with disease recurrence and poor patient prognosis. ADCs are a novel type of targeted antitumor agents that combine tumor antigen-specific monoclonal antibodies with chemically linked chemotherapeutic drugs (payload) exerting a cytotoxic effect. Several FDA-approved ADCs use as targeting moieties the antigens that are also detected in the GCTs, offering a benefit of this type of targeted therapy even for patients with relapsed/refractory testicular GCTs (rrTGCT) unresponsive to standard chemotherapy.

Women patients with small-cell lung cancer using immunotherapy in a real-world cohort achieved long-term survival.

Usage of immune checkpoint inhibitors (ICIs) has prolonged the overall survival (OS) of patients with extensive-stage small-cell lung cancer (ES-SCLC). In clinical trials, males accounted for a large proportion, leading to the uncertainty of its efficacy in female patients. We therefore conducted this study to explore the efficacy and safety of using ICIs in female patients with ES-SCLC. We retrospectively enrolled female SCLC patients and subdivided them into two groups. Group A (n = 40) was defined as ES-SCLC patients who received first-line standard chemotherapy with or without ICIs. Group B (n = 47) included relapsed SCLC patients who were administered with second-line therapies. Kaplan-Meier methodology was used to calculate survival analysis. Chi-squared tests were used to analyze the incidence of adverse events (AEs). Median progression-free survival (PFS) and median OS favored the ICI-contained cohorts (Group A PFS: 8.3 vs. 6.1 months; OS: not reached vs. 11.3 months; Group B PFS: 15.1 vs. 3.3 months; OS: 35.3 vs. 8.3 months), especially in those patients who received second-line immunotherapies. Patients who received immunotherapy had a slightly higher incidence rate of grade ≥3 AEs (Group A: 71.4% vs. 46.2%; Group B: 44.5% vs. 13.2%). Those who developed grade ≥3 AEs in first-line ICIs cohort had a more favorable survival (PFS: 8.3 vs. 3.2 months; OS: not reached vs. 5.1 months). Our study suggested that female ES-SCLC patients treated with immunotherapy tended to achieve a relatively longer survival. The incidence of AEs (grade ≥3) was higher in women patients receiving ICIs, which requires monitoring more closely.

Efficacy and Safety of BRCA-targeted Therapy (Polyadenosine Diphosphate-ribose Polymerase Inhibitors) in Treatment of BRCA-mutated Breast Cancer: A Systematic Review and Meta-analysis.

Breast cancer is the second leading cause of women's cancer deaths after lung cancer. Risk factors such as environment, lifestyle, and genetics contribute to its development, including mutation in the breast cancer (BRCA) gene. Polyadenosine diphosphate-ribose polymerase inhibitors (PARPi) target these mutations, benefiting patients with advanced cancers. This review summarizes PARPi' safety and efficacy in the treatment of BRCA-mutated breast cancer. PubMed, The Cochrane Library for Clinical Trials, and Science Direct, were searched for articles from inception to April 2024. Eligible articles were analyzed, and data were extracted for meta-analysis using RevMan 5.4 software with a random-effect model. Out of 430 articles identified from online databases, only 6 randomized control trials including 3610 patients were included in the analysis. PARPi therapy improved progression-free survival (hazard ratio: 0.64; 95% CI: 0.56, 0.73; P< 0.00001) and overall survival (hazard ratio: 0.84; 95% CI: 0.73, 0.98 P = 0.02), according to the analysis. In our safety analysis, the risk of adverse events was not statistically different between PARPi versus chemotherapy (relative risk [RR]: 1.08; 95% CI: 0.44, 2.68; P = 0.86), and combined PARPi and standard chemotherapy (RR: 1.00; 95% CI: 0.93, 1.07; P = 0.80). The only statistically significant difference was observed in anemia, where PARPi increased the risk of developing anemia compared with standard chemotherapy (RR: 6.17; 95% CI: 2.44, 15.58; P = 0.0001). In BRCA-mutated breast cancer, PARPi treatment shows better overall survival and progression-free survival compared with standard chemotherapy or placebo. Furthermore, PARPi, either alone or in combination therapy, does not increase the risk of adverse events in these patients, as per the meta-analysis.

PH/glutathione-responsive theranostic nanoprobes for chemoimmunotherapy and magnetic resonance imaging of ovarian cancer cells

The integration of immunotherapy and standard chemotherapy holds great promise for enhanced anticancer effects. In this study, we prepared a pH- and glutathione (GSH)-sensitive manganese-doped mesoporous silicon (MMSNs) based drug delivery system by integrating paclitaxel (PTX) and anti-programmed cell death-ligand 1 antibody (aPD-L1), and encapsulating with polydopamine (PDA) for chemoimmunosynergic treatment of ovarian cancer cells. The nanosystem was degraded in response to the tumor weakly acidic and reductive microenvironment. The Mn2+ produced by degradation can be used as a contrast agent for magnetic resonance (MR) imaging to provide visual exposure to tumor tissue. The released PTX can not only kill tumor cells directly, but also induce immunogenic death (ICD) of tumor cells, which can play a synergistic therapeutic effect with aPD-L1. Therefore, our study is expected to provide a promising strategy for improving the efficacy of cancer immunotherapy and the detection rate of cancer.

TRLS-09. CONNECT1903: A PILOT AND SURGICAL STUDY OF LAROTRECTINIB FOR TREATMENT OF CHILDREN WITH NEWLY DIAGNOSED HGG WITH NTRK FUSION (NCT04655404)

Abstract BACKGROUND Recurrent fusions in neurotrophic tropomyosin-receptor kinase genes NTRK 1-3 are found in variety of cancers, including pediatric HGG: DIPG (~4%) and non-brainstem HGG (~10%). For non-brainstem HGG seen in children &amp;lt;3 years of age, approximately 40% harbor NTRK alterations. NTRK fusions provide a promising target for gliomas and to that end, Larotrectinib, a globally approved, highly potent, small molecule inhibitor of TRKA/B/C, has previously been investigated and has shown tolerability and efficacy in children with recurrent solid tumors. Compassionate use in a case of infantile GBM showed proof-of-concept with blood-brain penetrance and efficacy. Further evidence of efficacy in two earlier clinical trials has also been previously demonstrated in children with recurrent TRK-fusion primary intracranial tumors (NCT02637687, NCT02576431). METHODS This international trial conducted through the CONNECT consortium, supported in part by Bayer, investigates larotrectinib monotherapy; its feasibility and tolerability in combination with standard systemic chemotherapy (Baby POG or HIT-SKK) or radiation therapy whereby treatment plan determination is response-based. Objectives include: to assess disease control rate (CR, CCR, PR and SD) after two cycles of larotrectinib monotherapy (28-day cycles); to assess feasibility and to describe toxicities of larotrectinib in combination with standard chemotherapy; to assess objective response rate (CR and PR); to assess OS and PFS as compared to historical data from Baby POG, HIT-SKK and radiotherapy. A phase 0 surgical cohort will be explored whereby patients who are planned to undergo a definitive resection will receive pre-surgery larotrectinib, and target inhibition, intratumoral and plasma pharmacokinetics will be investigated. Radiographic responses will also be quantitated. This trial is currently open to accrual at ten CONNECT sites across North America and Australia and has enrolled five patients to date. Sites in UK, Germany and Netherlands are pending activation. A total of 15 patients are anticipated to be enrolled and evaluable.

Improved Survival With Adjuvant Cyclooxygenase 2 Inhibition in PIK3CA-Activated Stage III Colon Cancer: CALGB/SWOG 80702 (Alliance).

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.Observational studies have associated aspirin or cyclooxygenase 2 (COX-2) inhibitor usage either before or after colorectal cancer diagnosis with lower risk of recurrence and suggest that PIK3CA mutational status is predictive of better response to COX-2 inhibition. To prospectively test whether adding the COX-2 inhibitor celecoxib to standard adjuvant chemotherapy reduces the risk of recurrence and improves survival, the National Cancer Institute sponsored the CALGB/SWOG 80702 trial (ClinicalTrials.gov identifier: NCT01150045) for patients with stage III resected colon cancer. Although the primary hypothesis for all patients did not show a statistically significant improvement in disease-free survival (DFS) with celecoxib, subgroup analysis by PIK3CA mutational status was a preplanned study. PIK3CA gain-of-function mutations were detected in 259 of 1,197 tumors with available whole-exome sequencing data. When stratified by PIK3CA status, patients with PIK3CA gain-of-function mutations treated with celecoxib exhibited improved DFS (adjusted hazard ratio [HR], 0.56 [95% CI, 0.33 to 0.96]) compared with PIK3CA wildtype patients (adjusted HR, 0.89 [95% CI, 0.70 to 1.14]), although the interaction test was nonsignificant (Pinteraction = .13). Overall survival was similarly improved for patients with PIK3CA gain-of-function mutations (adjusted HR, 0.44 [95% CI, 0.22 to 0.85]) compared with PIK3CA wildtype patients (adjusted HR, 0.94 [95% CI, 0.68 to 1.30]; Pinteraction = .04). Although the test for heterogeneity in DFS did not reach statistical significance, the results suggest potential utility of PIK3CA to consider selective usage of COX-2 inhibitors in addition to standard treatment for stage III colon cancer.

MDB-43. SHARED DECISION-MAKING (SDM) REGARDING RADIATION-AVOIDING (RA) THERAPY IN YOUNG CHILDREN WITH MEDULLOBLASTOMA (MB)

Abstract BACKGROUND Standard treatment for MB in patients age ≥ 3 years includes craniospinal radiation with tumor bed boost and chemotherapy. Radiation carries substantial risk of long-term issues, particularly in the youngest patients: second malignancy, neurocognitive issues, vasculopathy and endocrinopathies. Numerous trials have attempted to decrease or avoid the use of radiation by intensifying chemotherapy, some using high dose chemotherapy with autologous hematopoietic stem cell rescue (HDC). One of the most successful RA protocols, Children’s Oncology Group ACNS0334 enrolled children age &amp;lt; 36 months and treated with 3 cycles of induction (+/- high dose methotrexate) and 3 cycles HDC without planned radiation. Since 2012, we offer SDM with caregivers regarding treatment of their children ages 3-7 years with MB. Caregivers may choose standard radiation and chemotherapy (SRC) or the RA treatment above. OBJECTIVE Describe patient and disease characteristics and outcomes in patients aged 3-7 years treated for MB with SDM regarding the use of radiation. METHODS Retrospective analysis of diagnosis, treatment and clinical outcomes in all children &amp;lt;8 y.o. who completed treatment for MB between 2012 and 2023. RESULTS There were 16 patients offered SDM (all gross total resection without metastases) 7 chose RA and 9 SRC. The SRC group was enriched with molecularly high-risk patients (4 MYC or MYCN amplification, 1 SHH with P53 mutation). In the RA group, relapse occurred in 14% (n=1 of 7). In the SRC group, 44% relapsed (n=4 of 9). One patient developed high-grade glioma in the radiation boost field 10 years later. There was 1 death in the RA group due to disease progression and 5 deaths in the SRC group, 1 due to second malignancy. CONCLUSIONS We report excellent survival with RA therapy for appropriately selected young children (age 3-7 years) when SDM is used with families to determine the best treatment for their child.

MDB-100. RETROSPECTIVE ANALYSIS OF CUMULATIVE DOSING OF CHEMOTHERAPY AGENTS AND THE EFFECT ON SURVIVAL IN PATIENTS WITH AVERAGE RISK MEDULLOBLASTOMA TREATED ON CHILDRENS ONCOLOGY GROUP STUDY ACNS0331

Abstract BACKGROUND Although survival outcomes for average risk (AR) medulloblastoma remain good, patients may experience significant acute and long-term toxicities from therapy. To evaluate the effect of dose modifications among children with AR medulloblastoma, we examined the effect of cumulative chemotherapy dose on overall and event-free survival. METHODS We retrospectively examined the association between the proportion of scheduled chemotherapy dose received on survival outcomes (OS and EFS) using Cox regression models and log-rank tests for patients treated on ACNS0331. We evaluated all chemotherapy agents for the group as a whole and within the four major subgroups. Dose intensity was analyzed continuously and categorically (&amp;gt;75% or &amp;lt;75% of planned dose) for each agent. RESULTS 274 evaluable children (medulloblastoma by methylation, received standard dose craniospinal radiation and chemotherapy) were followed for a median of 9.3 years (range, 7.0-10.4 years). Vincristine and cisplatin showed the most variable dose intensity (25.2% and 31.8% of patients received &amp;lt;75% of expected dosing, respectively). Cyclophosphamide and lomustine were not examined due to low dose variability (17.2% and 11.7%, respectively). The effect of dose intensity was evaluated in 235 patients who completed planned therapy. Molecular subgroup remained a significant predictor of outcome in AR medulloblastoma (EFS (p=0.012) and OS (p=0.008)). Although survival curves were lower for less dose intense treatments, no significant difference in EFS or OS was found due to reduced dose intensity for vincristine (p=0.36 EFS, p=0.35 OS) or cisplatin (p=0.49 EFS, p=0.52 OS). The hazard ratio [95% confidence interval] for chemotherapy proportion and EFS was 0.998[0.977-1.019] (vincristine) and 0.989[0.966-1.012] (cisplatin). There was no difference in the effect of dose reductions by molecular subgroup. CONCLUSIONS Moderate reductions in vincristine and cisplatin dose intensity do not significantly affect survival in AR medulloblastoma. It is unknown whether this reduction would reduce chemotherapy-related toxicity.

MDB-39. HOW DO TUMOUR DERIVED EXTRACELLULAR VESICLES INTERACT WITH THE DEVELOPING NERVOUS SYSTEM AND LEAD TO ALTERED PAIN PROCESSING IN CANCER SURVIVORS?

Abstract BACKGROUND Childhood cancer-related pain and its treatment lack sufficient clinical attention due to limited understanding of the underlying mechanisms. While chemotherapy-induced peripheral neuropathic pain (CIPN) mechanisms in adults have been extensively studied, those in early life remain unexplored. In the CIPN literature there is a growing body of evidence for tumour derived factors altering pain processing. Our study aims to understand how tumour derived extracellular vesicles (EVs) interact with the developing nervous system and impact pain processing in childhood brain tumour survivors. METHODS We determined dose-response curves and IC50 values for several medulloblastoma (MB) cell lines using standard-of-care chemotherapy drugs: vincristine, etoposide, cisplatin, and lomustine. EVs were isolated via size exclusion chromatography and characterised through western blotting, flow cytometry and electron microscopy. We quantified the effects of chemotherapy on EV release using ZetaView analysis. We then tested whether EVs from relevant MB cell lines could influence axon development in primary mouse embryonic day 16.5 dorsal root ganglion (DRG) neurons in vitro after pre-treatment with chemotherapy-treated EVs. RESULTS EVs from chemotherapy-treated and untreated cells exhibited similar size and shape. However, a combination of vincristine, etoposide, and cisplatin at low concentrations significantly increased EV secretion by MB cell lines. Moreover, 24-hours following treatment with chemotherapeutic exposed EVs there was complete cell death of embryonic DRG neurons compared to the PBS or control EV treated neurons. CONCLUSION Standard chemotherapy drugs substantially enhanced EV release from MB cells, and co-culture of embryonic DRG neurons with chemotherapy exposed EVs resulted in neuronal death. Our next step is to investigate whether administering these selected EVs in healthy animals alters pain responses and pain maturation. We also aim to study the biodistribution of these EVs within the nervous system and body, after infusion into the cerebrospinal fluid as well as how EV cargo is altered by chemotherapeutics.

NURS-17. SHOULD EVERY CENTRE HAVE A TARGETED THERAPY CLINIC?

Abstract There is increased use of targeted therapies for children with Central Nervous System (CNS) tumours both at presentation and at relapse. Eighteen months ago, a dedicated CNS targeted therapy clinic was set up at The Great North Children’s Hospital in Newcastle upon Tyne. Referrals are accepted from all major centres in the north of the UK. Within our monthly clinic, five targeted therapies have been used so far including Selumetinib and Tovorafenib with an average of eight children per clinic. General practitioners are asked to carry out all blood investigations forty-eight hours prior to clinic. This has been audited and initial analyses show we have successfully reduced the time children spend in hospital from four hours to one hour. Having blood results prior to clinic means treatment can be prescribed and dispensed promptly. Furthermore, obtaining bloods in the community has reduced the workload for our oncology day unit. The side effect profile of targeted therapies differ from those of standard chemotherapy and requires specific expertise from members of the multidisciplinary team. We are able to predict trends in symptoms and manage them successfully and efficiently. We have direct access to the ophthalmology and Neurofibromatosis team at each clinic. We offer skin care management prior to beginning treatment and will refer to the dermatology team for a same day review where needed. Finally, this clinic has enabled us to offer informal peer support for children and their families, which enhances their overall hospital experience. In summary, our Targeted Therapy Clinic, with the invaluable input of many members of the MDT, has improved the quality of care for children being treated on targeted agents. Given these benefits, we are keen to support other Primary Treatment Centres to develop similar clinics, especially with the increased use of targeted treatments across CNS tumours.

LGG-38. UNRESECTABLE PEDIATRIC LOW-GRADE GLIOMAS OF THE BRAIN: TARGETED THERAPY COMPARED WITH STANDARD CHEMOTHERAPY AS FIRST-LINE TREATMENT

Abstract BACKGROUND Pediatric low-grade gliomas (pLGG) frequently harbor MAPK-pathway mutations that determine poor response to standard chemotherapy (sCt). Targeted agents against BRAF-V600E mutation (MAPK-i) are emerging as molecularly driven treatments. Few studies have compared sCt with MAPK-i. We aimed to compare response and progression-free survival (PFS) of unresectable brain pLGG treated with sCt or MAPK-i. MAPK-i were used in first line or at relapse. METHODS We conducted a single-center observational retrospective study of all brain pLGG consecutively diagnosed and treated at Gaslini Children’s Hospital between January 2008 and December 2021. Treatment was assessed using RAPNO criteria at 6, 12-18 months, and at last follow-up. MRI studies were reviewed by two experienced neuroradiologists. RESULTS Seventy-one patients were enrolled: 66 received sCt and 10 MAPK-i (5 in first line, 5 after sCt failure). All patients who received MAPK-i were BRAF-V600E mutated. Groups were homogeneous for tumor location and dissemination. sCt group was enriched for pilocytic astrocytoma, MAPK-I group for ganglioglioma. sCt patients were younger. SCt lasted 12-18 months, MAPK-i were continuously given. Tumor size reduction was 19.5% at 6 months and 40.5% at 12-18 months for sCt group; 48% at 6 months and 43.5% at 12-18 months for MAPK-i group. SCt determined at least stable disease in 74.2% of patients; 60% of responders reached the best response at 6 months, 40% at 12-18 months. 5y-PFS was 40.3% (median time for progression: 2.5 years). MAPK-i determined at least stable disease in all patients at first evaluation with long-lasting response (median time of follow-up: 5.1 years). CONCLUSIONS In our study sCt was effective in inducing response but prolonged disease control is not always achieved. BRAF-V600E mutated patients upon MAPK-i start gained a rapid disease control with long-lasting response, also if they have been pretreated. Acknowledgement: this study was supported by ARTUCEBA ONLUS.

Large-scale, prospective observational study of regorafenib in Japanese patients with advanced gastrointestinal stromal tumors in a real-world clinical setting.

Regorafenib improves overall survival (OS) of patients with advanced progressive gastrointestinal stromal tumors (GISTs) after standard chemotherapy in phase III trials in the 3rd-line setting. This large-scale, prospective observational study evaluated the safety and effectiveness of regorafenib in Japanese patients with GIST in a real-world clinical setting. Patients with GIST received oral regorafenib at a maximum daily dose of 160 mg for weeks 1-3 of each 4-week cycle (dose could be modified at investigator's discretion). The primary objective was to assess safety, particularly significant adverse drug reactions (ADRs), as well as the frequency of occurrence of ADRs, hand and foot syndrome (HFS), discontinuation of treatment due to disease progression and adverse events. A Cox proportional hazards model was used to evaluate associations between OS or time to treatment failure (TTF) and baseline characteristics or HFS. Between August 2013 and March 2021, 143 evaluable patients were enrolled. ADRs occurred in 90.2% of patients and led to treatment discontinuation in 28.3%. The most frequent ADRs were HFS, hypertension, and liver injury. The overall response rate was 11.3% and disease control rate 56.5% (RECIST) based on investigators' assessments. Median OS was 17.4 months (95% CI 14.24-23.68). Median TTF was 5.3 (95% CI 4.0-6.5) months. Improved OS and TTF responses occurred in patients with an Eastern Cooperative Oncology Group performance status (ECOG-PS) of 0 or 1. The outcomes in this real-world study were consistent with those seen in clinical trials. No new safety concerns were identified. https://clinicaltrials.gov, identifier NCT01933958.

Safety and efficacy analysis of neoadjuvant pertuzumab, trastuzumab and standard chemotherapy for HER2–positive early breast cancer: real–world data from NeoPowER study

BackgroundThe addition of pertuzumab (P) to trastuzumab (H) and standard chemotherapy (CT) as neoadjuvant treatment (NaT) for patients with HER2 + breast cancer (BC), has shown to increase the pathological complete response (pCR) rate, without main safety concerns. The aim of NeoPowER trial is to evaluate safety and efficacy of P + H + CT in a real–world population.MethodsWe retrospectively reviewed the medical records of stage II–III, HER2 + BC patients treated with NaT: who received P + H + CT (neopower group) in 5 Emilia Romagna institutions were compared with an historical group who received H + CT (control group). The primary endpoint was the safety, secondary endpoints were pCR rate, DRFS and OS and their correlation to NaT and other potential variables.Results260 patients were included, 48% received P + H + CT, of whom 44% was given anthraciclynes as part of CT, compared to 83% in the control group. The toxicity profile was similar, excluding diarrhea more frequent in the neopower group (20% vs. 9%). Three patients experienced significant reductions in left ventricular ejection fraction (LVEF), all receiving anthracyclines. The pCR rate was 46% (P + H + CT) and 40% (H + CT) (p = 0.39). The addition of P had statistically correlation with pCR only in the patients receiving anthra-free regimens (OR = 3.05,p = 0.047). Preoperative use of anthracyclines (OR = 1.81,p = 0.03) and duration of NaT (OR = 1.18,p = 0.02) were statistically related to pCR. 12/21 distant-relapse events and 14/17 deaths occurred in the control group. Patients who achieve pCR had a significant increase in DRFS (HR = 0.23,p = 0.009).ConclusionsAdding neoadjuvant P to H and CT is safe. With the exception of diarrhea, rate of adverse events of grade > 2 did not differ between the two groups. P did not increase the cardiotoxicity when added to H + CT, nevertheless in our population all cardiac events occurred in patients who received anthracycline-containing regimens. Not statistically significant, higher pCR rate is achievable in patients receiving neoadjuvant P + H + CT. The study did not show a statistically significant correlation between the addition of P and long-term outcomes.

Blinatumomab in pediatric acute lymphoblastic leukemia: one center experience

Background. Despite the successes achieved in the treatment of B-cell acute lymphoblastic leukemia (B-ALL), overcoming the toxicity of standard chemotherapy regimens and the treatment of relapsed/refractory (r/r) forms of the disease remains relevant. The most promising option is to use immunotherapy (IT), including a monoclonal antibody blinatumomab (BM). The purpose of the study. To analyze indications of using, as well as efficacy and tolerability of BM in children with V-ALL. Materials and methods. From April 2016 to January 2024 a retrospective assessment of using of BM in children with B-ALL in the chemotherapy department of oncohematological diseases and TCM for children in Almazov National Medical Research Centre was performed. Results. The study included 53 patients, including 28 (53 %) girls and 25 (47 %) boys with median age of 7,7 (2,08–19,8) years. Indications for using of BM were as follows: (1) consolidation of remission (CR) with primary ALL (n = 17, 32 %); (2) persistence of minimal residual disease (MRD) (n = 23, 43 %) after completion of chemotherapy (CT) induction or before the stage of allogeneic haematopoietic stem cell transplantation (alloHSCT); (3) replacement of the standard CR due to the previous toxicity of СT or other contraindications to its implementation (n = 12, 23 %); (4) salvage therapy for r/r ALL (n = 1, 1,9 %). The status of MRD-negative remission after the 1st course of IT was achieved in 89 % of cases. Therapy using BM in a patient with the r/r ALL and total blast infiltration of the bone marrow was effective and facilitated reducing the tumor population to 7,2% by day 15 of therapy, however, there was a fatal outcome due to development and progression of preexisted severe infection. The most common variants of grade III–IV toxicity were leuko-/neutropenia (28 %) and neurotoxicity (3,7 %). BM dose reduction for the purpose of relieving toxicity was required in 19 % of patients, while the median days of therapy with dose reduction was 4. Corticosteroids were used for this purpose in 11 % of cases, antibacterial therapy — in 13 %. At the time of results evalution, there were no relapses of the disease in the study group. The article analyzes the international experience of using BM in patients with B-ALL.Conclusion. Our experience and the presented literature data demonstrate a reasonable expansion of indications for using of BM in children with B-ALL with high efficacy and satisfactory toxicity profile.

BEAT-meso: A randomized phase III study of bevacizumab (B) and standard chemotherapy (C) with or without atezolizumab (A), as first-line treatment (TX) for advanced pleural mesothelioma (PM)—Results from the ETOP 13-18 trial.

LBA8002 Background: The currently approved frontline TXs for PM are the combination of ipilimumab/nivolumab or platinum plus pemetrexed. The addition of B to C has been shown to improve overall survival in a randomized clinical trial. While combined immunotherapy or single agent immunotherapy with C is superior to C alone, there is potential for a synergistic triple combination of C, B, and immunotherapy. Methods: BEAT-meso (NCT03762018) is an international open-label, 1:1 randomized phase III trial, stratified by histology and stage. The objective is to determine the efficacy and safety of adding A (1200 mg, Q3W until progression) to B (15mg/kg, Q3W until progression) and standard C (4-6 cycles of carboplatin AUC5 with pemetrexed 500 mg/m2, Q3W), as first-line TX for advanced PM. The trial is designed to detect an increase in the median overall survival (OS, primary endpoint) with the addition of A, aiming for a hazard ratio (HR) of 0.708, at 2.5% 1-sided alpha and 82% power (284 deaths, sample size 400 patients (pts)). In the pre-specified interim efficacy analysis (80% of the events, 01/2023), boundary was not crossed, and the trial continued to completion. Secondary endpoints include progression-free survival (PFS), objective response rate (ORR), disease control rate, duration of response (DoR), adverse events (AEs) assessed by CTCAE v5.0 and symptom-specific and global quality of life (QoL). Results: Between 04/2019 and 03/2022, a total of 400 pts was randomized, 200 per arm. The median age was 70 years, 79% were male, 50% were former smokers, 65% had ECOG performance status 1 and 78% had epithelioid histology. At a median follow-up of 35 months (m) (as of 1/09/2023), median OS was 20.5m [95% CI: 17.5-23.3] in the ABC and 18.1m [15.7-20.9] in the BC arm (deaths: 145 &amp; 150; HRABC vs BC=0.84; [0.66 - 1.06], 2-sided stratified p=0.14, ITT final analysis). PFS was significantly longer in ABC with median 9.2m [8.1-10.9] vs 7.6m [6.9-8.3] in BC (HR=0.72; [0.59 - 0.89], 2-sided stratified p=0.0021). Histology shows a significant TX interaction for both PFS and OS. The OS HR is 0.51 [0.32-0.80] for non-epithelioid and 1.01 [0.77-1.32] for epithelioid (interaction p=0.012). In an exploratory analysis, post-progression OS was significantly different between the two arms, adjusted for post-progression TX (HR=0.76; [0.58 - 0.99]). The ORR was 55% in ABC and 49% in BC (p=0.27), while median DoR was 8.2m [6.8-9.7] in ABC and 5.6m [4.8-7.0] in BC (p=0.0041). Global QoL change was not significantly different between the two arms. Grade≥3 TX-related AEs occurred in 55% of pts in ABC and 47% of pts in BC (grade 5: 7 and 1 pt, respectively). Conclusions: The significant increase in median PFS with the addition of A did not translate into a significant increase in median OS. ABC demonstrated superiority over BC in non-epithelioid cases. Clinical trial information: NCT03762018 .

Final results of BrUOG 354: A randomized phase II trial of nivolumab alone or in combination with ipilimumab for people with ovarian and other extra-renal clear cell carcinomas.

LBA5500 Background: Extra-renal clear cell cancer (CCC) are rare tumors that can arise from any organ. Gynecologic CCC can originate from the ovaries, endometrium, or cervix. Compared to serous carcinomas, ovarian CCC is associated with poorer outcomes to standard chemotherapy, warranting a focused evaluation for innovative therapies. We completed a two-stage two-arm phase 2 trial evaluating immunotherapy for extra-renal CCC and present the final results of treatment using nivolumab (N) monotherapy and in combination with ipilimumab (I) in this population. Methods: This is a randomized two-stage phase II study evaluating single-agent N (240mg IV every two weeks) or in combination with I (1mg/kg every six weeks) (N/I) in people with relapsed extra-renal CCC after at least one prior therapy (no prior immunotherapy). Measurable disease was required. In the first stage, volunteers were randomly assigned to N or N/I with stratification by tumor site (ovarian vs extra-ovarian). Treatment was continued until disease progression or unacceptable toxicity. Each arm was evaluated for overall response rate (ORR) separately at stage 1 using RECIST and iRECIST criteria. In January 2022, the N arm was closed, and subsequent volunteers were treated with N/I. The study completed enrollment in April 2023. Results: Between July 2018 and April 2023, 46 volunteers provided consent for the study and 44 were treated (14 N, 30 N/I). The median age was 57 (range, 18-75) years. Across the study, 75% were White, 9.1% Black, 4.5% were Asian, and 11.4% were Hispanic. All volunteers had a gynecologic primary, 36 (82%) with ovarian CCC. The median number of prior lines was 1 (range, 1-7). The Overall Response Rate (ORR) is 14.3% (2 Partial Responses) with N and 33% (4 Complete and 6 Partial Responses) with N/I. Four people continue on treatment with N/I as of December 2023. With a median follow up of 11.3 (range, 1.6-46.4) months, the median Progression-Free Survival is 2.2 (95% CI 1.2-3.4) months with N and 5.6 (95% CI 1.6-29.1) months with N/I. The median Overall Survival is 17 (95% CI 2.1-NR) and 24.6 (95% CI 5.9-NR) months, respectively. Serious treatment-related adverse events were recorded in 3 (21%) treated with N (all grade 3) and 14 (47%) treated with N/I (two of whom had grade 4 pancreatic enzyme elevations). No new safety signals were noted, and no treatment-related deaths were observed in either arm. Conclusions: Immunotherapy demonstrated important, meaningful, and durable activity in people with previously treated gynecologic CCC including four (12%) volunteers who achieved a complete response with N/I. N/I warrant further evaluation against standard treatment for people with ovarian CCC, given the historically chemotherapy-resistant nature of the disease. Clinical trial information: NCT03355976 .

Targeting PAX8 sensitizes ovarian cancer cells to ferroptosis by inhibiting glutathione synthesis.

Ovarian cancer is a malignant tumor originating from the ovary, characterized by its high mortality rate and propensity for recurrence. In some patients, especially those with recurrent cancer, conventional treatments such as surgical resection or standard chemotherapy yield suboptimal results. Consequently, there is an urgent need for novel anti-cancer therapeutic strategies. Ferroptosis is a distinct form of cell death separate from apoptosis. Ferroptosis inducers have demonstrated promising potential in the treatment of ovarian cancer, with evidence indicating their ability to enhance ovarian cancer cell sensitivity to cisplatin. However, resistance of cancer cells to ferroptosis still remains an inevitable challenge. Here, we analyzed genome-scale CRISPR-Cas9 loss-of function screens and identified PAX8 as a ferroptosis resistance protein in ovarian cancer. We identified PAX8 as a susceptibility gene in GPX4-dependent ovarian cancer. Depletion of PAX8 rendered GPX4-dependent ovarian cancer cells significantly more sensitive to GPX4 inhibitors. Additionally, we found that PAX8 inhibited ferroptosis in ovarian cancer cells. Combined treatment with a PAX8 inhibitor and RSL3 suppressed ovarian cancer cell growth, induced ferroptosis, and was validated in a xenograft mouse model. Further exploration of the molecular mechanisms underlying PAX8 inhibition of ferroptosis mutations revealed upregulation of glutamate-cysteine ligase catalytic subunit (GCLC) expression. GCLC mediated the ferroptosis resistance induced by PAX8 in ovarian cancer. In conclusion, our study underscores the pivotal role of PAX8 as a therapeutic target in GPX4-dependent ovarian cancer. The combination of PAX8 inhibitors such as losartan and captopril with ferroptosis inducers represents a promising new approach for ovarian cancer therapy.