Increase In Progression-free Survival Research Articles

Abstract PO4-19-08: Randomized phase II study of talazoparib vs talazoparib plus atezolizumab for patients with premenopausal HR+/HER2- metastatic breast cancer harboring homologous recombination deficiency scar (Young-PALETTA, KCSG BR21-09)

Abstract Background Cyclin D kinase-4/6(CDK4/6) inhibitor combined with endocrine treatment have significantly increased progression free survival(PFS) and overall survival(OS) of patients with hormone receptor(HR)-positive/HER2-negative metastatic breast cancer, and currently is a standard 1st line endocrine treatment option. Homologous recombination deficiency(HRD) including germline(g) BRCA1/2 pathogenic mutation is known to be prevalent among young premenopausal patients. Recently several retrospective data suggested that patients with germline BRCA1/2 pathogenic mutation or HRD have poorer outcome with CDK4/6 inhibitor treatment, however there is no prospective evidence. Poly ADP-ribose polymerase(PARP) inhibitors have shown significant benefit over standard chemotherapy in patients with HER2-neg metastatic breast cancer and gBRCA1/2 pathogenic mutation in two Phase 3 trials. Since preclinical data suggested that PARP inhibitors play a role in anti-tumor immune modulation, immunotherapy combined with PARP inhibitors were explored and showed promising antitumor efficacy in several single arm trials. In this trial, we investigate talazoparib and atezolizumab combination compared with talazoparib monotherapy in premenopausal women with HR+/HER2- metastatic breast cancer with HRD-scar after failure with 1st line palbociclib and endocrine treatment combination. Methods This study is a multicenter, randomized, open-label phase II trial comparing talazoparib versus talazoparib with atezolizumab in premenopausal women with HR+/HER2- metastatic breast cancer harboring HRD scar whose disease have progressed with endocrine and palbociclib combination as the 1st-line endocrine treatment. Prior one line of cytotoxic chemotherapy other than platinum for metastatic setting is allowed, but prior palliative endocrine treatment is not allowed. Eligible patients will be pre-screened with tumor tissue biopsy and peripheral blood sampling before endocrine and palbociclib treatment commencement. HRD status is determined through targeted sequencing(SOLIDaccuTestTM by NGeneBio) of tumor tissue and germline HRD genes including BRCA1/2 variant test. Whole genome sequencing and RNA sequencing are performed for biomarker analyses. Patients harboring HRD scar will receive first line endocrine treatment with palbociclib plus aromatase inhibitor with ovarian suppression. After progression with 1L endocrine treatment, patients will be randomized to either talazoparib alone or talazoparib plus atezolizumab combination. Germline BRCA1/2 pathogenic mutation is a stratification factor. Primary endpoint is a progression free survival after randomization(PFS2). Secondary objectives are a composite of PFS1 and PFS2, PFS1, overall survival, patient reported outcome, and biomarkers for treatment response. A total of 178 subjects are required to detect hazard ratio of 0.62 (median PFS2 of at least 10.5 months with talazoparib and atezolizumab combination vs 6.5 months with talazoparib alone), to achieve 80% power at a two-sided a significance level at 10%, considering drop-out rate of 5%. The study period is expected to be 72 months overall(36 months for accrual and randomization and 24 months of follow-up for primary endpoint PFS2). Citation Format: Hee Kyung Ahn, Jieun Lee, Jee Hung Kim, Kyung-Hun Lee, Jee Hyun Kim, Min Hwan Kim, Minsuk Kwon, Han Jo Kim, Kyung Hae Jung, Yeon Hee Park. Randomized phase II study of talazoparib vs talazoparib plus atezolizumab for patients with premenopausal HR+/HER2- metastatic breast cancer harboring homologous recombination deficiency scar (Young-PALETTA, KCSG BR21-09) [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 PO4-19-08.

Efficacité et tolérance du dichlorure de radium 223 chez les patients traités pour cancer de la prostate résistant à la castration avec métastases osseuses

IntroductionThe aim of our study was to evaluate the efficacy and tolerance of 223RaCl2 in patients with mCRPC with bone metastases, then analyse the impact of any change in treatment protocol on the efficacy of 223RaCl2 in mCRPC patients with bone metastases, by determining overall survival, progression-free survival and events occurring during therapeutic monitoring. Materiel and methodsOur retrospective, analytical and descriptive study, carried out in Luxembourg, included patients eligible for le 223RaCl2 treatment who were assessed during and at the end of treatment, and 3 to 4months after the end of treatment. ResultsOur sample included 41 cases. The mean age of patients was 74years (min=52, max=87), with 32 (78.1%) deaths recorded. Median overall survival was 18.0months (95% CI: 12.1–23.9): 11months for those who experienced progression during treatment versus 47 months for those who experienced a partial response. Median progression-free survival was 15.0 months (95% CI: 0.0–36.4). Overall survival was positively correlated with progression-free survival (Rho Spearman=0.713, P-value<0.001); however, a one-month increase in progression-free survival decreased the risk of death by 6% and thus increased overall survival (HR=0.937, 95% CI : 0.903–0.973, P<0.001). ConclusionAdministration of the complete 223RaCl2 protocol improved overall survival and progression-free survival in patients treated for mCRPC with bone metastases, with good hematological tolerability despite the occurrence of complications such as epiduritis and fractures.

Feasibility of functional precision medicine for guiding treatment of relapsed or refractory pediatric cancers

Children with rare, relapsed or refractory cancers often face limited treatment options, and few predictive biomarkers are available that can enable personalized treatment recommendations. The implementation of functional precision medicine (FPM), which combines genomic profiling with drug sensitivity testing (DST) of patient-derived tumor cells, has potential to identify treatment options when standard-of-care is exhausted. The goal of this prospective observational study was to generate FPM data for pediatric patients with relapsed or refractory cancer. The primary objective was to determine the feasibility of returning FPM-based treatment recommendations in real time to the FPM tumor board (FPMTB) within a clinically actionable timeframe (<4 weeks). The secondary objective was to assess clinical outcomes from patients enrolled in the study. Twenty-five patients with relapsed or refractory solid and hematological cancers were enrolled; 21 patients underwent DST and 20 also completed genomic profiling. Median turnaround times for DST and genomics were within 10 days and 27 days, respectively. Treatment recommendations were made for 19 patients (76%), of whom 14 received therapeutic interventions. Six patients received subsequent FPM-guided treatments. Among these patients, five (83%) experienced a greater than 1.3-fold improvement in progression-free survival associated with their FPM-guided therapy relative to their previous therapy, and demonstrated a significant increase in progression-free survival and objective response rate compared to those of eight non-guided patients. The findings from our proof-of-principle study illustrate the potential for FPM to positively impact clinical care for pediatric and adolescent patients with relapsed or refractory cancers and warrant further validation in large prospective studies. ClinicalTrials.gov registration: NCT03860376.

A comprehensive analysis of CD47 expression in various histological subtypes of soft tissue sarcoma: exploring novel opportunities for macrophage-directed treatments

PurposeThe CD47 molecule, often referred to as the “do not eat me” signal, is frequently overexpressed in tumor cells. This signaling pathway limits phagocytosis by macrophages. Our objective was to determine CD47 abundance in various soft tissue sarcomas (STS) to investigate whether it could serve as a potential evasion mechanism for tumor cells. Additionally, we aimed to assess the prognostic value of CD47 expression by examining its association with different clinicopathological factors. This study aimed to elucidate the significance of CD47 in the context of emerging anti-tumor targeting approaches.MethodsIn this retrospective study, formalin-fixed paraffine-embedded (FFPE) tumor tissues of 55 treatment-naïve patients were evaluated by immunohistochemistry for the abundance of CD47 molecule on tumor cells. The categorization of CD47 positivity was as follows: 0 (no staining of tumor cells), 1 + (less than 1/3 of tumor area positive), 2 + (between 1/3 and 2/3 of tumor area positive), and 3 + (more than 2/3 of tumor area positive for CD47). Next, we compared CD47 abundance between different tumor grades (G1–3). We used Kaplan–Meier survival curves with log-rank test to analyze the differences in survival between patients with different CD47 expression. Moreover, we performed Cox proportional hazards regression model to evaluate the clinical significance of CD47.ResultsCD47 is widely prevalent across distinct STS subtypes. More than 80% of high grade undifferentiated pleiomorphic sarcoma (UPS), 70% of myxofibrosarcoma (MFS) and more than 60% of liposarcoma (LPS) samples displayed a pattern of moderate-to-diffuse positivity. This phenomenon remains consistent regardless of the tumor grade. However, there was a tendency for higher CD47 expression levels in the G3 group compared to the combined G1 + G2 groups when all LPS, MFS, and UPS were analyzed together. No significant associations were observed between CD47 abundance, death, and metastatic status. Additionally, high CD47 expression was associated with a statistically significant increase in progression-free survival in the studied cohort of patients.ConclusionThis study highlights the potential of the CD47 molecule as a promising immunotherapeutic target in STS, particularly given its elevated expression levels in diverse sarcoma types. Our data showed a notable trend linking CD47 expression to tumor grade, while also suggesting an interesting correlation between enhanced abundance of CD47 expression and a reduced hazard risk of disease progression. Although these findings shed light on different roles of CD47 in STS, further research is crucial to assess its potential in clinical settings.

Cutaneous metastasis in a case of carcinoma floor of mouth- A rare case report

The incidence of cutaneous metastasis in head and neck cancers is less than 1%. Carcinoma of the oral cavity is one of the most common cancers of the head neck region with frequent metastasis to internal organs, especially the lungs, liver, and bone.We present a case of Carcinoma of floor of mouth with cutaneous metastasis.A 55 year old lady presented to our department with complaints of non-healing ulcer in the oral cavity and ulcerated nodules over neck and chest. On examination, mouth opening tongue mobility was restricted with grade 2 trismus. An ulcer in left gb sulcus, bilateral lymphadenopathy and multiple ulcerated skin nodules on neck and chest wall were noted. CECT Face and Neck showed heterogenously ehancing mass at the floor of mouth involving left buccal mucosa and erosion of mandible, lymph node mets and skin nodules. ECOGPS was 1.She was treated with palliative systemic chemotherapy and thereafter Palliative radiation. Now she is having stable disease and is on metronomic chemotherapy with regular follow up.Our case has highlighted that cutaneous metastasis can be seen in the cancers of floor of mouth. Palliative chemotherapy and radiotherapy can significantly increase Progression free survival and hence the Quality of life of patients with such presentation.

Cabozantinib Increases Progression–free Survival in Radioiodine–Refractory Differentiated Thyroid Cancer across Tumor Histologies and after Previous Anti–VEGF Therapy

Cabozantinib Increases Progression–free Survival in Radioiodine–Refractory Differentiated Thyroid Cancer across Tumor Histologies and after Previous Anti–VEGF Therapy

Standard-of-care systemic therapy with or without stereotactic body radiotherapy in patients with oligoprogressive breast cancer or non-small-cell lung cancer (Consolidative Use of Radiotherapy to Block [CURB] oligoprogression): an open-label, randomised, controlled, phase 2 study

Most patients with metastatic cancer eventually develop resistance to systemic therapy, with some having limited disease progression (ie, oligoprogression). We aimed to assess whether stereotactic body radiotherapy (SBRT) targeting oligoprogressive sites could improve patient outcomes. We did a phase 2, open-label, randomised controlled trial of SBRT in patients with oligoprogressive metastatic breast cancer or non-small-cell lung cancer (NSCLC) after having received at least first-line systemic therapy, with oligoprogression defined as five or less progressive lesions on PET-CT or CT. Patients aged 18 years or older were enrolled from a tertiary cancer centre in New York, NY, USA, and six affiliated regional centres in the states of New York and New Jersey, with a 1:1 randomisation between standard of care (standard-of-care group) and SBRT plus standard of care (SBRT group). Randomisation was done with a computer-based algorithm with stratification by number of progressive sites of metastasis, receptor or driver genetic alteration status, primary site, and type of systemic therapy previously received. Patients and investigators were not masked to treatment allocation. The primary endpoint was progression-free survival, measured up to 12 months. We did a prespecified subgroup analysis of the primary endpoint by disease site. All analyses were done in the intention-to-treat population. The study is registered with ClinicalTrials.gov, NCT03808662, and is complete. From Jan 1, 2019, to July 31, 2021, 106 patients were randomly assigned to standard of care (n=51; 23 patients with breast cancer and 28 patients with NSCLC) or SBRT plus standard of care (n=55; 24 patients with breast cancer and 31 patients with NSCLC). 16 (34%) of 47 patients with breast cancer had triple-negative disease, and 51 (86%) of 59 patients with NSCLC had no actionable driver mutation. The study was closed to accrual before reaching the targeted sample size, after the primary efficacy endpoint was met during a preplanned interim analysis. The median follow-up was 11·6 months for patients in the standard-of-care group and 12·1 months for patients in the SBRT group. The median progression-free survival was 3·2 months (95% CI 2·0-4·5) for patients in the standard-of-care group versus 7·2 months (4·5-10·0) for patients in the SBRT group (hazard ratio [HR] 0·53, 95% CI 0·35-0·81; p=0·0035). The median progression-free survival was higher for patients with NSCLC in the SBRT group than for those with NSCLC in the standard-of-care group (10·0 months [7·2-not reached] vs 2·2 months [95% CI 2·0-4·5]; HR 0·41, 95% CI 0·22-0·75; p=0·0039), but no difference was found for patients with breast cancer (4·4 months [2·5-8·7] vs 4·2 months [1·8-5·5]; 0·78, 0·43-1·43; p=0·43). Grade 2 or worse adverse events occurred in 21 (41%) patients in the standard-of-care group and 34 (62%) patients in the SBRT group. Nine (16%) patients in the SBRT group had grade 2 or worse toxicities related to SBRT, including gastrointestinal reflux disease, pain exacerbation, radiation pneumonitis, brachial plexopathy, and low blood counts. The trial showed that progression-free survival was increased in the SBRT plus standard-of-care group compared with standard of care only. Oligoprogression in patients with metastatic NSCLC could be effectively treated with SBRT plus standard of care, leading to more than a four-times increase in progression-free survival compared with standard of care only. By contrast, no benefit was observed in patients with oligoprogressive breast cancer. Further studies to validate these findings and understand the differential benefits are warranted. National Cancer Institute.

Combining Dual Checkpoint Immunotherapy with Ablative Radiation to All Sites of Oligometastatic Non-Small Cell Lung Cancer: Toxicity and Efficacy Results of a Phase 1b Trial

BackgroundAblative local treatment of all radiographically detected metastatic sites in patients with oligometastatic NSCLC increases progression free survival (PFS) and overall survival (OS). Prior studies demonstrated safety of combining stereotactic body radiation therapy (SBRT) with single agent immunotherapy. We investigated the safety of combining SBRT to all metastatic tumor sites with dual checkpoint, anti-CTLA-4 and anti-PD-L1 immunotherapy for patients with oligometastatic NSCLC. MethodsWe conducted a phase Ib clinical trial in patients with oligometastatic NSCLC with up to 6 sites of extracranial metastatic disease. All sites of disease were treated with stereotactic body radiation therapy (SBRT) to a dose of 30 – 50 Gy in 5 fractions. Dual checkpoint immunotherapy was started 7 days following completion of radiation utilizing anti-CTLA-4 (tremelimumab) and anti-PD-L1 (durvalumab) immunotherapy for a total of four cycles followed by durvalumab alone until progression or toxicity. ResultsSeventeen patients were enrolled on study, with 15 patients receiving at least one dose of combination immunotherapy per protocol. The study was closed early (17 of planned 21 patients) due to slow accrual during COVID 19 pandemic. Grade 3+ treatment related adverse events were seen in 6 patients (40%). Of these, only one was felt possibly related to the addition of SBRT to immunotherapy. Median PFS was 42 months while median OS has not yet been reached. ConclusionsDelivering ablative SBRT to all sites of metastatic disease in combination with dual checkpoint immunotherapy did not result in excessive rates of toxicity compared to historical studies of dual checkpoint immunotherapy alone. While not powered for treatment efficacy results, durable PFS and OS results suggest potential therapeutic benefit compared to immunotherapy or radiation alone in this patient population.

BIOM-28. PROGNOSTIC BIOMARKERS IN GLIOBLASTOMA PATIENTS TREATED WITH TEMOZOLOMIDE

Abstract OBJECTIVE Identifying blood biomarkers that predict favorable outcomes for patients with glioblastoma treated with temozolomide (TMZ). BACKGROUND Glioblastoma is the most aggressive primary brain tumor. The standard of care is maximum safe resection, then radiation plus oral TMZ, followed by six months of cyclic oral TMZ. Previous studies have revealed that TMZ-induced myelosuppression is associated with improved overall survival. METHODS Adults with glioblastoma who completed radiation therapy and received temozolomide for at least 6-months at Beth Israel Deaconess Medical Center between 2018-2021 were identified. Baseline and nadir white blood cell count, absolute neutrophil count, absolute lymphocyte count, red blood cells, and platelets were collected retrospectively. Additionally, IDH1 R132H, MGMT promoter methylation, progression free survival (PFS), and overall survival (OS) were also collected retrospectively. Data was combined with that of Vaios et al. and Ho et al. Kaplan-Meier analysis and multivariate testing were performed. RESULTS Leukopenia is associated with increased overall survival (p = 0.008) and progression free status (p = 0.02). Grade 3 thrombocytopenia is associated with decreased PFS (p = 0.0005) and OS (p = 0.0006). Grade 1 &amp; 2 lymphopenia is associated with increased progression free survival (p = 0.01 and p = 0.03). Lower baseline absolute lymphocyte count is associated with improved OS (p = 0.007). Higher baseline absolute neutrophil count is associated with worse OS (p = 0.002). CONCLUSION Cytopenia may serve as a prognostic biomarker for OS and PFS. Leukopenia may reflect adequate temozolomide dosing, anti-tumor activity, or changes in the tumor micro-environment. Peripheral biomarker monitoring may improve prognostic stratification and lead to personalized treatment with improved outcomes.

GLIOMA-04 BRIDGING THE GAP ON ADULT GLIOMA IMAGING, DIAGNOSIS AND FOLLOW UP IN SUB-SAHARAN AFRICA

Abstract Cerebral Gliomas are the most common and devastating primary brain tumors. Prior to 2016 WHO CNS tumor classification update, the grading of gliomas, mainly relied on histological features, including cellularity, nuclear atypia, mitotic activity, vascularity, and necrosis, observed on light microscopy with the aid of immunohistochemistry. A number of studies confirmed that diffuse gliomas demonstrates different growth pattern, clinical behavior, and prognostication based on their genomic alterations, these findings necessitated incorporation of molecular subtypes in glioma classification, and leads to 2016 WHO CNS tumors Classification update. Introduction of molecular criteria into the classification of gliomas has given rise to interesting, wide-ranging implications regarding glioma management. In the current classification, all diffuse gliomas have been grouped based on their growth pattern, clinical behavior, and specifically sharing of the mutational state of the gene that codes for isocitrate dehydrogenase (IDH) in its isoforms (IDH1 and IDH2). Regardless of grade, the first phase in glioma molecular characterization is IDH testing. Mutations in IDH1 and IDH2 are associated with significant increase in progression free survival and overall survival. Immunohistochemistry, Molecular subtyping, Both FISH and genetic sequencing have significant implications in gliomas management and clinical outcome, yet they are not available in our low resource settings. Advanced MRI techniques (DTI, MR Perfussion, MR Spectroscopy, and Functional MRI) have a significant impact in presurgical planning and follow up of glioma patients after surgery and chemo radiation treatment. Radiographic findings can bridge the gap on accurate glioma diagnosis in sub-Saharan Africa through predicting Glioma Molecular subtypes based on clinical presentation and utilizing conventional MRI as a radio genomic tool. Also to emphasis in the utilization of available advanced MRI techniques (DTI, MR Perfussion, and MR spectroscopy) for presurgical planning and follow up of patients after Glioma treatment.

EP12.01-74 Increased Progression Free Survival of Patients with EGFR positive mutation NSCLC Treated with Afatinib in Regard to Toxicity

EP12.01-74 Increased Progression Free Survival of Patients with EGFR positive mutation NSCLC Treated with Afatinib in Regard to Toxicity

Treatment Efficacy Outcomes Combining Dual Checkpoint Immunotherapy with Ablative Radiation to All Sites of Oligometastatic Non-Small Cell Lung Cancer: Survival Analysis of a Phase IB trial

Aggressivelocal treatment to a limited number of metastatic sites in patients with oligometastatic NSCLC increases progression free survival (PFS) and overall survival (OS). Prior studies have shown the safety of combining high dose stereotactic body radiation therapy (SBRT) with single agent anti-PD1/PD-L1 therapy. Here, we report secondary survival endpoint outcomes from a phase Ib clinical trial investigating the safety of combining ablative, high dose radiation with dual checkpoint, anti-CTLA-4 and anti-PD-L1 immunotherapy for patients with oligometastatic NSCLC. Patients with up to 6 sites of extracranial metastatic disease were eligible for trial enrollment. All sites of disease were treated with stereotactic body radiation therapy to a dose of 30 - 50 Gy in 5 fractions. Dual checkpoint immunotherapy was started 7 days following completion of radiation utilizing anti-CTLA-4 (Tremelimumab) and anti-PD-L1 (Durvalumab) immunotherapy for a total of four cycles followed by durvalumab alone until dose limiting toxicity or progression was observed. Primary toxicity outcomes were previously reported. Progression free and overall survival was analyzed using Kaplan Meier statistical methods. Fifteen patients were treated with SBRT and received at least one dose of dual agent immunotherapy per protocol. The median follow up was 43 months. The median number of extracranial metastatic sites was 2. Seven patients had 3 or more sites of extracranial disease. The most commonly treated sites were separate metastatic pulmonary lesions or osseous metastatic lesions. Median progression free survival (PFS) was 42 months and median overall survival (OS) was 48 months. Seven patients remain alive without evidence of progressive disease. Prior history of brain metastases was associated with significantly worse PFS (Median PFS 4 months vs 42 months, HR 6.1 (95% CI 1.6 - 37.0) p = 0.0248), but no difference in OS (Median OS 24 vs 42 months, HR 1.9 (95% CI 0.3 - 10.4). Ablative SBRT radiation to up to 6 sites of disease followed by dual checkpoint immunotherapy in oligometastatic NSCLC resulted in a favorable progression free survival (42 months) and overall survival (48 months) compared to historical controls. These findings suggest potential benefit to patient outcomes compared to immunotherapy or radiation alone in this patient population and warrant further investigation.

Secondary cytoreduction in platinum sensitive relapsed ovarian cancer: an individual patient level meta-analysis

ObjectiveTo synthesize the role of secondary cytoreduction in recurrent ovarian cancer from the results of randomized studies.MethodsWe conducted a meta-analysis of randomized controlled trials which compared secondary cytoreductive surgery versus...

Safety and toxicity of cabozantinib monotherapy in patients with advanced renal cell carcinoma: a Russian multicenter observational study

Aim. To assess the safety and to analyze an influence of cabozantinib monotherapy toxicity on treatment efficacy in unselected Russian patients with metastatic renal cell carcinoma (mRCC).&#x0D; Materials and methods. Medical data of 92 patients with verified mRCC were included in the study. The median age of the patients was 56 (1979) years, most of them - 60 (65.2%) were of male gender. Twenty five (27.2%) persons had Eastern Cooperative Oncology Group performance status (ECOG PS). At the time of cabozantinib monotherapy start 5 (5.4%) patients had favorable, 54 (58.7%) intermediate, and 33 (35.9%) unfavorable prognosis by International Metastatic Renal Cancer Database Consortium (IMDC) model. Eighty-three (90.2%) patients were pretreated, including 76 (82.6%) patients who previously received anti-angiogenic agents. All patients were administered with cabozantinib monotherapy (60 mg/day); dose adjustment was performed according to the instruction.&#x0D; Results. Adverse events (AEs) were reported in 81 (88.0%) of 92 patients; 30 (32.6%) AEs were grade 34. Toxicity-related dose reduction of cabozantinib was required in 28 (30.4%), treatment interruption in 15 (16.3%), and discontinuation in 2 (2.2%) patients. The most common AEs were hypertension (69 patients, 75.0%), asthenia (47 patients, 51.1%), diarrhea (43 patients, 46.7%), and palmar-plantar erythrodysesthesia (43 patients, 46.7%). The most common severe AEs were: arterial hypertension (17 patients, 18.5%), diarrhea (6 patients, 6.5%), and palmar-plantar erythrodysesthesia (2 patients, 2.2%). The most frequent laboratory abnormalities during therapy were elevated serum transaminases (33 patients, 35.9%), anemia (13 patients, 14.1%), and thrombocytopenia (10 patients, 10.9%). No previously unreported AEs or laboratory abnormalities were observed. There was a significant increase in progression-free survival (hazard ratio 2.5; 95% confidence interval 1.05.9; p=0.046) and overall survival (hazard ratio 3.0; 95% confidence interval 1.28.3; p0.025) in patients with treatment-related arterial hypertension.&#x0D; Conclusion. The observational study confirmed the acceptable safety profile of cabozantinib in the first and subsequent lines of treatment in mRCC patients. No new safety signals were identified. Treatment-related arterial hypertension may be a favorable predictor of survival.

SYST-25 MICROGLIA-SECRETED LIPID SPECIES DRIVE GLIOMA INVASION

Abstract The capacity of gliomas, including GBMs, to invade and infiltrate normal brain tissues makes their complete surgical removal impossible. The most crucial survival predictor is still the extent of surgical resection, urging the need to identify treatments that block the invasive growth of glioma to improve surgical resection and overall survival. Using a combination of single-cell transcriptomics, lipidomics, and high-resolution spatial metabolomics in genetically engineered GBM mouse models, reminiscent of human disease, and validation in human GBM samples, we found that 1) tumor cells infiltrating the normal brain parenchyma associate with and activate specific pathways in microglial cells (MGs), the residential brain macrophages. In turn, MGs undergo metabolic rewiring and secrete lipid species that promote glioma invasion of the different GBM subtypes by activating distinct signaling cues. Thus, blocking the MG-tumor cell axis or metabolic MG rewiring targets several GBM types and, in combination with standard therapy, results in small circumscribed tumors that should be easier excised and lead to a substantial increase in progression-free survival in glioma patients.

Assessment of the safety and efficacy of combination chemotherapy and PD-1/PD-L1 inhibitor treatment of breast cancer: A meta-analysis.

As the efficacy of programmed cell death-1/programmed death-ligand 1 (PD-1/PD-L1) inhibitors combined with chemotherapy in curing breast cancer is still controversial, this meta-analysis compares the efficacy and safety of PD-1/PD-L1 inhibitors combined with chemotherapy and chemotherapy alone in the treatment of breast cancer, which provides guidance for the clinical treatment. Relevant studies published as of April 2022 in the various databases including EMBASE, PubMed, and Cochrane Library were selected. Randomized controlled trials (RCTs) in which control patients underwent chemotherapy alone and experimental group patients underwent combination chemotherapy and PD-1/PD-L1 inhibitor treatment were included in this investigation. Investigations without complete information, researches from which information could not be extracted, duplicate articles, animal studies, review articles, and systematic reviews were excluded. STATA 15.1 was employed for all statistical analyses. In total, eight eligible studies were identified, revealing that combination chemotherapy and PD-1/PD-L1 inhibitor treatment was linked to significant increases in progression-free survival (PFS) relative to chemotherapy alone (hazard ratio [HR] = 0.83, 95% confidence interval [CI]: 0.70-0.99, P = 0.032) but not overall survival (HR = 0.92, 95% CI: 0.80-1.06, P = 0.273). Pooled adverse event rates were also increased within the group of combination treatment relative to the chemotherapy group (risk ratio [RR] = 1.08, 95% CI: 1.03-1.14, P = 0.002). Specifically, nausea rates were lesser within the group of combination treatment relative to the group of chemotherapy (RR = 0.48, 95% CI: 0.25-0.92, P = 0.026). Subgroup analyses indicated that the PFS of patients who underwent combination atezolizumab or pembrolizumab and chemotherapy treatment were substantially longer than those of patients who underwent chemotherapy alone (HR = 0.79, 95% CI: 0.69-0.89, P ≤0.001; HR = 0.79, 95% CI: 0.67-0.92, P = 0.002). The pooled results suggest that combination chemotherapy and PD-1/PD-L1 inhibitor treatment approaches help prolong PFS in breast cancer patients, but have no statistically significant effect on overall survival (OS). Additionally, combination therapy can significantly improve complete response rate (CRR) compared with chemotherapy alone. However, combination therapy was associated with greater rates of adverse events.

A phase 3 trial of fianlimab (anti–LAG-3) plus cemiplimab (anti–PD-1) versus pembrolizumab in patients with previously untreated unresectable locally advanced or metastatic melanoma.

TPS9602 Background: Fianlimab (anti-lymphocyte activation gene 3 [LAG-3]) and cemiplimab (anti- programmed cell death-1 [PD-1]) are both high-affinity, fully human, IgG4 monoclonal antibodies (Abs). Concurrent blockade of anti-LAG-3 and anti-PD-1 has shown enhanced efficacy (increase in progression free survival [PFS]) in advanced melanoma (Mel). We previously presented data from a phase 1 study showing a 63.8% objective response rate (ORR) across two separate cohorts of advanced PD-(L)1 naïve metastatic Mel patients (pts) treated with fianlimab plus cemiplimab with an acceptable risk-benefit profile. Methods: This is a randomized, double-blind, phase 3 study to evaluate fianlimab plus cemiplimab compared to pembrolizumab in pts with previously untreated unresectable locally advanced or metastatic Mel (NCT05352672). This study will be conducted globally, at approximately 200 sites. Key inclusion criteria are: (1) ≥12 years of age; (2) histologically confirmed unresectable Stage III and Stage IV (metastatic) Mel (3) no prior systemic therapy for advanced unresectable disease, prior (neo)adjuvant therapies are allowed with treatment/disease-free interval of 6 months; (4) measurable disease per Response Evaluation Criteria in Solid Tumors version 1.1; (5) valid LAG-3 results; (6) Eastern Cooperative Oncology Group performance status (PS) of 0 or 1 (for adult pts), Karnofsky PS ≥70 (pts ≥16 years) or Lansky PS ≥70 (pts &lt; 16 years); and (7) anticipated life expectancy of at least 3 months. There are 4 arms to the study: (1) Arm A: fianlimab (1600 mg) + cemiplimab (350 mg) every 3 weeks (Q3W), intravenously (IV); (2) Arm A1: fianlimab (400 mg) + cemiplimab (350 mg) Q3W, IV; (3) Arm B: pembrolizumab (200 mg Q3W, IV) + saline/dextrose placebo (placebo); (4) Arm C: cemiplimab (350 mg Q3W, IV) + placebo. The trial is expected to enroll approximately 1590 pts. The primary endpoint is progression-free survival. The key secondary endpoints are overall survival and objective response rate. The additional secondary endpoints include disease control rate, duration of response, safety, pharmacokinetics of cemiplimab and fianlimab, and immunogenicity (incidence and titer of anti-drug Abs and neutralizing Abs). The study is currently open for enrollment. Clinical trial information: NCT05352672 .

Response to subsequent platinum-based chemotherapy post PARP inhibitor in recurrent epithelial ovarian cancer.

5578 Background: Maintenance therapy with PARP inhibitors (PARPi) can increase progression free survival (PFS) for recurrent or metastatic platinum-sensitive epithelial ovarian cancer (EOC). Little is known about disease trajectory following treatment with these agents, though some evidence suggests a decreased response to subsequent platinum-based chemotherapy. This retrospective cohort study assessed real-world response rates to platinum-based chemotherapy for recurrent high grade EOC following treatment with a PARPi. Methods: All patients prescribed a PARPi as maintenance therapy for recurrent or metastatic EOC at the Ottawa Regional Cancer Center (ORCC) from September 2017 to May 2022 were included. PFS following penultimate therapy (line of therapy preceding PARPi initiation) as well as the PFS following subsequent platinum-based chemotherapy in patients with disease progression more than 6 months after penultimate therapy were calculated. Incidence of platinum resistance in patients with disease progression following PARPi therapy was determined. Results: 91 patients were included in the analysis including 54 patients on niraparib and 36 patients on olaparib. Follow-up after initiation of PARPi ranged from 4.6 months to 62.0 months with a median of 16.3 months. 54 (59.3%) of patients experienced disease progression after initiation of PARPi therapy, including 10 (11.0%) who progressed within 6 months of their penultimate therapy. Of the 44 patients who experienced disease progression more than 6 months following penultimate therapy, 32 (72.7%) were rechallenged with platinum-based chemotherapy. Of these, 16 (50.0%) experienced further disease progression with 14 (43.8%) progressing within 6 months of their platinum rechallenge. Median PFS following platinum rechallenge was 4.4 months (from 0.8 months to 34.9 months), significantly lower than previous reports. Conclusions: Patients who experienced disease progression following PARPi therapy showed a poor response to subsequent platinum-based chemotherapy, even when progression occurred more than 6 months after completion of their penultimate platinum-based chemotherapy. This supports the theory that PARPi resistance may be a surrogate for platinum resistance and raises concern for possible contribution of PARPi in the induction of platinum resistance in recurrent EOC.

Overall Survival Outcome In Patients With New Treatment Approaches For Glioblastoma Multiforme In Randomized Controlled Trials (P3-13.004)

<h3>Objective:</h3> ○ Analyze and compare <b>the current standard treatment</b> for <b>glioblastoma multiforme</b> with <b>new treatment approaches</b> with an emphasis on overall survival in <b>randomized controlled trials</b>. <h3>Background:</h3> ○ <b>Glioblastoma multiforme</b> is the most common malignant brain tumor in adults, accounting for approximately 16% of all CNS neoplasms. The <b>current standard treatment</b> for glioblastoma consists of maximal surgical resection, radiotherapy and concomitant or adjuvant chemotherapy with temozolomide. While overall mortality remains high, the understanding of gene mutations and molecular mechanisms combined with clinical trials are opening new ways to approach this disease. <h3>Design/Methods:</h3> The search in <b>PUBMED/MEDLINE</b> included the keywords: “<b>Glioblastoma</b>”, “ <b>Temozolomide</b>”, resulting in 2,618 articles, the filter of the last 5 years was applied as well as randomized clinical trials, this yielded 37 results. A reading of the abstract and title was made. Referenced articles were also used. Finally, 12 articles were used. Subsequent analysis was performed with <b>PRISMA</b>. <h3>Results:</h3> Among the new treatment approaches, the use of Tumor – treating fields <b>(TTFields)</b> plus <b>temozolomide</b> increases progression free survival and overall survival compared to standard of care, while therapies such as <b>ipilimumab</b> plus <b>temozolomide</b> and <b>velipaprib</b> did not show significant differences in overall survival, progression free survival rate did not improve compared to the use of <b>radiotherapy</b> and <b>concomitant or adjuvant chemotherapia</b> with <b>temozolomide</b>. <h3>Conclusions:</h3> To summarize up due to the high mortality associated with glioblastoma, a search for efficacy of alternative treatments is necessary. The effect of different treatment strategies on survival and other health outcomes remains largely unknown, although in treating fields (TTFields) there was a statistically significant increase in survival, it is an efficient and safe treatment that will increase the overall survival in this disease where recurrence and lethality are high and where the quality and lengthening of life become the central axis. <b>Disclosure:</b> Ms. Castillo Vaca has nothing to disclose. Dr. Arreola Flores has nothing to disclose. Dr. Bermudez-Faz has received publishing royalties from a publication relating to health care. Dr. Chavez has nothing to disclose. Dr. Chavez has nothing to disclose. Mr. Carrillo Rodríguez has nothing to disclose. Ms. Estrada Posadas has nothing to disclose. Miss Estrada Ortega has nothing to disclose. Miss Rojas Martínez has nothing to disclose. Mr. Zamorano has nothing to disclose.

Abstract 2849: The oral SERD Elacestrant in combination with the PI3K inhibitor MEN1611 inhibits tumor growth in ER+/HER2- breast cancer in vitro and in PDX models

Abstract In estrogen receptor (ER)+/HER2-breast cancer(BC), the addition of CDK4/6 inhibitors (CDK4/6i) to endocrine therapies (ET) leads to a significant increase in progression-free survival. Nevertheless, clinical resistance emerges. The upregulation of the PI3K/AKT/mTOR signaling pathway is one of the multiple acquired mechanisms of resistance to the CDK4/6i and ET combination. Thus, the extensive crosstalk between the PI3K/AKT/mTOR and ER pathways underlines the importance of targeting both pathways to overcome drug resistance in ER+/HER2- BC. Here we have evaluated the antitumor activity of Elacestrant, the oral selective estrogen receptor degrader (SERD) and antagonist, in combination with the σ-sparing PI3K inhibitor MEN1611, in vitro and in vivo in different clinically relevant BC Patient-Derived Xenograft (PDX) models, resistant to CDK4/6i and to ET, harboring mutations in PIK3CA and/or ESR1 genes. In cell-based proliferation assays, the combination of Elacestrant and MEN1611 showed a synergistic effect in inhibiting the growth of ER+ BC cell lines. In vivo data in MCF7- and patient-derived xenograft models showed compelling antitumor activity using the combination at tolerable and clinically relevant doses, compared to the single agents. In the PDX HBxC-3, wild-type for PIK3CA and ESR1 genes, the Tumor Volume-Inhibition (TVI) was 56.2%, 48.7% and 71.7% for MEN1611, Elacestrant and the combination group, respectively. In this model, the combination showed improved anti-tumor activity in comparison to the single agent treatments. In the PDX models HBxC-19 and CTG-2308, wild-type for ESR1 gene, but harboring a PIK3CA mutation, the TVI of the combination was 94.6% and 61.4%, respectively. In the latter model the combination was significantly superior to the single agents. In the PDX model CTG-1260, with PIK3CA and ESR1 mutations, MEN1611 and Elacestrant single agent treatment showed tumor growth inhibition with TVIs of 63.2% and 52.3%, while the combination showed a significant TVI of 86.9%. Overall, in all the tested in vivo models the combination of Elacestrant and MEN1611 was superior in comparison to the single agents by overcoming resistance to ER inhibition potentially driven by PI3K pathway activation in PIK3CA mutated tumors. The current data support the use of Elacestrant, the first oral SERD with positive phase III results in the EMERALD trial (Bidard et al.; JCO 2022), in combination with the PI3K inhibitor MEN1611, in ER+/HER2- mBC patients harboring PIK3CA mutations and who progressed to CDK4/6i plus ET. Citation Format: Giuseppe Merlino, Alessio Fiascarelli, Simone Talucci, Patrizia Tunici, Mario Bigioni, Alessandro Bressan, Monica Binaschi. The oral SERD Elacestrant in combination with the PI3K inhibitor MEN1611 inhibits tumor growth in ER+/HER2- breast cancer in vitro and in PDX models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2849.