Experienced Disease Progression Research Articles

Cost-effectiveness analysis of tislelizumab vs. camrelizumab for the treatment of second-line locally advanced or metastatic esophageal squamous cell carcinoma

BackgroundEsophageal carcinoma is a type of cancer that occurs in the esophagus. For patients with locally advanced or metastatic esophageal squamous cell carcinoma who have either experienced disease progression following first-line standard chemotherapy or are intolerant to it, the prognosis is typically poor. Additionally, these patients often bear a substantial economic burden during the course of their treatment. Tislelizumab is a selective PD-1 inhibitor with efficacy proven in locally advanced or metastatic esophageal squamous cell carcinoma. The study aims to evaluate the cost-effectiveness of tislelizumab versus camrelizumab as the second-line treatment in locally advanced or metastatic esophageal squamous cell carcinoma (ESCC) patients in China.MethodsFrom the perspective of China’s healthcare system, the partitioned survival model with three health states was established in a 3-week cycle and a lifetime horizon. Anchored matching adjusted indirect comparison was used for survival analyses based on individual patient data from RATIONALE 302 trial and the published ESCORT study due to the lack of head-to-head clinical trials. Only direct medical costs were included. Costs and utility values were derived from local charges, the published literature, and related databases. Sensitivity analyses and a scenario analysis were also performed to verify the robustness of the model results.ResultsCompared with camrelizumab monotherapy, tislelizumab monotherapy incurred a lower lifetime cost ($8,346 vs. $8,851) and yielded higher quality-adjusted life-years (QALYs) (0.87 vs. 0.63), which resulted in an incremental cost-effectiveness ratio (ICER) of -$2,051/QALY. Tislelizumab monotherapy is a dominant option over camrelizumab monotherapy in China. The three primary parameters upon which this result was most sensitive were the unit cost of camrelizumab, the unit cost of tislelizumab, and the duration of reactive cutaneous capillary endothelial proliferation (RCCEP). According to the probabilistic sensitivity analysis (PSA), tislelizumab monotherapy was 100% cost-effective when the WTP was 1–3 times GDP per capita in China($11,207/QALY∼$33,621/QALY). Scenario analysis showed that the result was consistent.ConclusionTislelizumab monotherapy is a dominant option compared with camrelizumab monotherapy as the second-line treatment for locally advanced or metastatic ESCC in China.

A nutrition-based radiomics–clinical model to predict the prognosis of patients with acute-on-chronic liver failure

BackgroundAcute-on-chronic liver failure (ACLF) lead to high short-term mortality. Effective identification of patients with poor prognoses and early intervention are crucial. Meanwhile, the nutritional status of patients is vital in the prognosis of chronic liver diseases. Hence, the study applies artificial intelligence to extract nutrition-based radiomics features in ACLF patients and construct a radiomics-clinical model to predict the 90-day prognosis. Patients and methods163 ACLF patients were recruited from our hospital. The patients were randomly assigned to the training cohort (n = 99) and the test cohort (n = 64). The skeletal muscle, subcutaneous fat and visceral fat radiomics features were extracted. The blood markers were collected. The LASSO regression model was applied to select radiomics features and form the best feature subset. Finally, the linear discriminant classifier was used for endpoint prediction. ResultsIn both the training and test cohorts, 30.3 % and 29.7 % of patients, respectively, experienced disease progression. In the training cohort, this progression included 23.2 % experiencing death and 7.1 % undergoing liver transplantation. Similarly, in the test cohort, 20.3 % experienced death, while 9.4 % underwent liver transplantation. LASSO regression screened 15 features for constructing a radiomics-clinical model, 6 of 15 features were texture features of skeletal muscles. The area under the curve (AUC) of this model in the test cohort was 0.873 (95 % CI 0.773–0.972). To use Delong test compared the AUC of the radiomics-clinical model with sub-models (radiomics model and clinical model) and traditional classical models (MELD and MELD-Na). The results showed that the radiomics-clinical model was superior to any of the above models (p < 0.05). ConclusionThe nutrition-based radiomics-clinical machine learning model can effectively predict the 90-day adverse prognosis of ACLF patients.

Antibody-Drug Conjugates as Novel Therapeutic Agents for Non-Small Cell Lung Carcinoma with or without Alterations in Oncogenic Drivers.

Antibody-drug conjugates (ADCs) are an emerging class of therapeutics for lung cancer, and several are currently in development for this malignancy. The structure of these molecules is based on an antibody that targets a protein on the lung cancer cell surface and a cytotoxic payload attached by a linker. Many protein targets, including TROP2, c-MET, CEACAM5, HER2, and HER3 have been identified. In metastatic non-small cell lung carcinoma (NSCLC) without alterations in oncogenic drivers, platinum-based chemotherapy and immune checkpoint inhibitors (ICIs) targeting the programmed death-1/programmed death-ligand 1 (PD1/PDL1) interaction are the standard first-line treatments. In patients with EGFR-mutated or ALK-rearranged NSCLC, tyrosine kinase inhibitors (TKIs) are recommended. However, although the prognosis of patients with metastatic NSCLC differs between such with and without alterations in oncogenic drivers, most patients eventually experience disease progression. A novel therapeutic class is needed in routine practice to overcome the mechanisms of resistance to ICIs and EGFR/ALK TKIs. Several ADCs have already been approved for other cancers, such as breast cancer and urothelial carcinoma. This review summarizes the knowledge about the efficacy and tolerance profiles of ADCs targeting TROP2, HER2, HER3, CEACAM5 and c-MET in metastatic NSCLC with and without alterations in oncogenic drivers.

The prognostic role of 18F-FDG PET/CT-based response evaluation in children with stage 4 neuroblastoma.

To evaluate the association between metabolic response on 18F-FDG PET/CT and long-term survival in children with neuroblastoma (NB). A total of 39 consecutive children with newly diagnosed stage 4 NB undergoing both 18F-FDG PET/CT imaging at baseline and after chemotherapy were retrospectively analyzed. The associations between metabolic parameters, including SUVmax of the lesion with the most intense 18F-FDG uptake at baseline (SUVb), after chemotherapy (SUVe), and the percentage change between SUVb and SUVe, and long-term survival were evaluated. With a median follow-up of 56 months, 22 patients who had achieved complete resolution on PET (no residual 18F-FDG uptake higher than the surrounding backgrounds) after chemotherapy had superior 5-year overall survival (OS) (73.6% vs. 39.0%, p = 0.044). SUVb > 6.9 indicated significantly poorer 5-year event-free survival (EFS) (12.5% vs. 59.3%, p = 0.005), as did SUVe > 1.2 (18.8% vs. 41.7%, p = 0.041). Children with SUVe > 1.2 had shorter 5-year OS (33.9% vs. 75.0%, p = 0.018). Multivariate analysis identified SUVe > 1.2 as an independent predictor for both EFS [hazard ratio (HR), 3.479, 95% CI, 1.381-8.761, p = 0.008] and OS (HR, 6.948, 95% CI, 1.663-29.025, p = 0.008), while SUVb > 6.9 was a predictor for EFS (HR, 2.889, 95% CI, 1.064-7.842, p = 0.037). Among 11 children with both SUVb > 6.9 and SUVe > 1.2, all experienced disease progression or relapse within 2 years since diagnosis. 18F-FDG PET/CT could be of useful to evaluate treatment response in children with stage 4 NB. 18F-FDG PET/CT after chemotherapy exhibits prognostic significance in neuroblastoma and holds potential as an alternative imaging modality for response evaluation, especially in cases with metaiodobenzylguanidine-nonavid or persistent avid disease. The prognostic value of chemotherapy response on 18F-FDG PET/CT in advanced neuroblastoma is unknown. Higher 18F-FDG uptake after chemotherapy was associated with worse long-term event-free survival and overall survival. 18F-FDG PET/CT after chemotherapy holds prognostic significance in children with stage 4 neuroblastoma.

Long-term survival outcomes and immune checkpoint inhibitor retreatment in patients with advanced cervical cancer treated with camrelizumab plus apatinib in the phase II CLAP study.

Camrelizumab plus apatinib have demonstrated robust antitumor activity and safety in patients with advanced cervical cancer (CLAP study; NCT03816553). We herein present the updated long-term results of the CLAP study and explore potential biomarkers for survival. The outcomes of patients who underwent immune checkpoint inhibitor (ICI) retreatment were also reported. In this phase II trial, eligible patients received camrelizumab 200 mg intravenously every two weeks and apatinib 250 mg orally once daily in 4-week cycles for up to two years. Treatment was continued until disease progression, unacceptable toxicity, or withdrawal of consent. Between January 21 and August 1, 2019, a total of 45 patients were enrolled. Data were analyzed as of July 31, 2023, representing > 48 months since treatment initiation for all patients. Nine (20.0%) patients completed the 2-year study. The median duration of response (DOR) was 16.6 months, and 45.0% of patients achieved a DOR of ≥ 24 months. The 12-month progression-free survival (PFS) rate was 40.7% (95% confidence interval [CI], 25.2-55.6), with an 18-month PFS rate of 37.8% (95% CI, 22.7-52.8). The median overall survival (OS) was 20.3 months (95% CI, 9.3-36.9), and the 24-month OS rate was 47.8% (95% CI, 31.7-62.3). Age > 50 years, programmed death-ligand 1 (PD-L1) combined positive score (CPS) ≥ 1 (versus [vs.] < 1), CPS ≥ 10 (vs. < 1), high tumor mutational burden, and PIK3CA mutations were associated with improved PFS (hazard ratio [HR] < 1) and longer OS (HR < 1). Eight patients who initially responded in the CLAP trial but later experienced disease progression were retreated with ICIs. Among them, 2 (25.0%) achieved a partial response, while 5 (62.5%) had stable disease. Notably, four patients who received retreatment with ICIs survived for more than 45 months. No new safety signals were identified in the present study. Long-term survival follow-up data demonstrated that camrelizumab plus apatinib has robust, sustained, and durable efficacy in patients with advanced cervical cancer who progress after first-line platinum-based chemotherapy. No new safety signals were noted with long-term treatment.

Clinical and Demographic Characteristics of Pyruvate Kinase Deficiency Patients: A Comprehensive Case Series Analysis.

Introduction Pyruvate kinase deficiency (PKD) is a rare autosomal recessive disorder characterized by mutations in the PKLR gene, causing impaired glycolysis in red blood cells and leading to diverse clinical manifestations. The prevalence of PKD in Saudi Arabia remains understudied, particularly in the context of consanguinity and non-specialized medical facilities. Methods We conducted a retrospective analysis of seven PKD patients of Arab ethnicity, focusing on demographics, medical history, clinical features, laboratory results, treatments, and outcomes. Results Our patient cohort comprised five males and two females, aged 10 to 38 years, of Arab ethnicity. Consanguinity was prevalent, and hereditary connections were identified in five patients. PKD exhibited varying clinical presentations, with early-onset symptoms including neonatal jaundice and symptomatic anemia. One patient experienced severe hepatic disease progression leading to multiorgan failure. Blood transfusions were universally required, indicating the severity of the disorder. Anemia severity varied among patients, with diverse hematological irregularities. Splenectomy was performed for most patients, improving hemoglobin levels and transfusion needs in some cases. Iron chelation was administered, although iron overload persisted. Thrombocytosis and venous thromboembolism were observed post splenectomy. Jaundice and gallstones were common, leading to cholecystectomy. Laboratory findings remained consistent, with heightened reticulocyte counts and altered enzyme levels. Discussion PKD is a rare disorder characterized by diverse clinical manifestations. Prevalence estimation is complex due to various factors, and its diagnosis is challenged by clinical similarities with other disorders. Our cohort exhibited a spectrum of complications, highlighting the necessity for tailored interventions. Iron overload remained a concern, necessitating continuous monitoring. Although endocrine disorders and osteoporosis were absent in our cohort, vigilance is essential due to the disease's progressive nature. Genetic factors were prominent, supporting the genetic basis of PKD. Splenectomy improved anemia but had a limited impact on gallstones. Iron overload management and bone health remain crucial considerations. Conclusion This study offers comprehensive insights into the clinical and demographic characteristics of PKD patients, illustrating the complex nature of the disorder. The findings underscore the need for personalized management strategies and vigilant monitoring to address the diverse clinical manifestations and challenges associated with PKD.

Association between bronchiectasis exacerbations and longitudinal changes in FEV1 in patients from the US bronchiectasis and NTM research registry

BackgroundThis study aimed to evaluate the association between the number of non-cystic fibrosis bronchiectasis (bronchiectasis) exacerbations during baseline and follow-up (objective 1) and to identify longitudinal changes in FEV1 associated with exacerbation frequency (objective 2). MethodsThis was a retrospective cohort study of adult patients enrolled in the US Bronchiectasis and Nontuberculous Mycobacteria Research Registry September 2008 to March 2020. Objective 1 outcome was association between exacerbations during baseline (24 months) and 0-to-24 month and 24-to-48 month follow-up windows. Objective 2 outcomes were change in FEV1 and FEV1 % predicted over 24 months stratified by baseline exacerbation frequency. ResultsObjective 1 cohort (N = 520) baseline frequency of any exacerbations was 59.2%. Overall, 71.4% and 75.0% of patients with ≥1 baseline exacerbations had ≥1 exacerbations during the 0-to-24 and 24-to-48 month follow-ups. Having ≥1 exacerbation during baseline was significantly associated with ≥1 exacerbation during the 0-to-24 month (P = 0.0085) and 24-to-48 month follow-ups (P=<0.0001). Objective 2 cohort (N = 431) baseline FEV1 was significantly lower in patients who had more exacerbations; however, decline in FEV1 from baseline was not significantly different between patients with 0, 1, and ≥2 exacerbations. In patients with more baseline exacerbations, FEV1 % predicted was significantly lower at baseline (P < 0.0001) and at 12 (P = 0.0002) and 24 month follow-ups (P < 0.0001). ConclusionsPatients with frequent bronchiectasis exacerbations may be more likely than those with less frequent exacerbations to experience disease progression based on future exacerbation frequency and lower FEV1 at baseline, although FEV1 decline may not differ by baseline exacerbation frequency.

Clinical actionability of BRCA2 alterations in uterine leiomyosarcoma: a molecular tumor board case report and a cBioPortal comprehensive analysis.

Uterine leiomyosarcoma (uLMS) represents one of the most common sarcoma histotypes, demonstrating an overall dismal prognosis. Previous studies reported uLMS to carry recurrent somatic BRCA2 homozygous deletions, related to significant clinical benefits from the use of PARP inhibitors. To investigate the prevalence in uLMS of genomic alterations (alt) in BRCA2 and other homologous recombination (HR) and DNA damage response (DDR) genes, cBioPortal was accessed and data were retrieved from studies including pan-sarcoma histologies. HR-/DDR-genes included BRCA1, BRCA2, ATM, BARD1, BRIP1, CHEK1, CHEK2, FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCL, FANCM, NBN, PALB2, RAD51C, RAD51D, RAD50, and ATR. Only oncogenic/likely oncogenic alterations were included according to OncoKB. We reported a clinical case of a patient affected by a highly pretreated uLMS discussed at the European Institute of Oncology Molecular Tumor Board. A targeted next-generation sequencing panel demonstrated a somatic BRCA2 homozygous deletion (homDel). Upon access to Niraparib, a remarkable response of 15 months was observed before experiencing disease progression. In the genomic query, among 2393 cases, uLMS (n = 193) displayed 9 of all 31 BRCA2alt observed, representing the only sarcoma histotype showing an enrichment in BRCA2alt (4.66%; q < 0.001). All of 9 BRCA2alt were represented by homDel, which related to a high fraction of genome altered. uLMS displays a significant frequency of somatic BRCA2alt homDel. Considering their dismal prognosis, further investigation is warranted to test the use of PARPi in uLMS, and particularly in the setting of BRCA1/2 alterations.

HER2 mutation as an emerging target in advanced breast cancer.

HER2 activating mutations have emerged as oncogenic drivers and therapeutic targets in a variety of human tumors. In breast cancer, these deregulations occur at low frequency, and are mostly detected in HER2-nonamplified, metastatic disease. Preclinical evidence has clarified the role of hotspot mutations in HER2 constitutive activation, defining them as an alternative mechanism to HER2 gene amplification. Furthermore, recent clinical studies have indicated the emergence of newly acquired HER2 deregulations in significant proportions of breast cancer patients who experience disease progression following both endocrine and HER2-targeted therapies. As the involvement of HER2 mutation in therapy resistance may profoundly impact patient outcomes on successive therapies, several clinical trials are currently investigating the efficacy of various HER2-targeted drugs in HER2-mutant breast cancer. In this review, we firstly summarize the structural organization of the HER2 oncogene and its historical impact on breast cancer prognosis and therapeutic advancement. Then, we provide an overview of the frequencies and functional relevance of clinically recurrent HER2 mutations in breast cancer with a special focus on their role in therapeutic resistance. Finally, we provide a collection of the clinical trials that are currently exploring novel therapeutic approaches for this patient subset and discuss the related perspectives and challenges.

Chordoma Genetic Aberrations and Targeted Therapies Panorama: A Systematic Literature Review.

Background: Chordomas pose a challenge in treatment due to their local invasiveness, high recurrence, and potential lethality. Despite being slow-growing and rarely metastasizing, these tumors often resist conventional chemotherapies (CTs) and radiotherapies (RTs), making surgical resection a crucial intervention. However, achieving radical resection for chordomas is seldom possible, presenting therapeutic challenges. The accurate diagnosis of these tumors is vital for their distinct prognoses, yet differentiation is hindered by overlapping radiological and histopathological features. Fortunately, recent molecular and genetic studies, including extracranial location analysis, offer valuable insights for precise diagnosis. This literature review delves into the genetic aberrations and molecular biology of chordomas, aiming to provide an overview of more successful therapeutic strategies. Methods: A systematic search was conducted across major medical databases (PubMed, Embase, and Cochrane Library) up to 28 January 2023. The search strategy utilized relevant Medical Subject Heading (MeSH) terms and keywords related to "chordomas", "molecular biology", "gene aberrations", and "target therapies". The studies included in this review consist of preclinical cell studies, case reports, case series, randomized controlled trials, non-randomized controlled trials, and cohort studies reporting on genetic and biological aberrations in chordomas. Results: Of the initial 297 articles identified, 40 articles were included in the article. Two tables highlighted clinical studies and ongoing clinical trials, encompassing 18 and 22 studies, respectively. The clinical studies involved 185 patients diagnosed with chordomas. The tumor sites were predominantly sacral (n = 8, 44.4%), followed by clivus (n = 7, 38.9%) and lumbar spine (n = 3, 16.7%). Primary treatments preceding targeted therapies included surgery (n = 10, 55.6%), RT (n = 9, 50.0%), and systemic treatments (n = 7, 38.9%). Various agents targeting specific molecular pathways were analyzed in the studies, such as imatinib (a tyrosine kinase inhibitor), erlotinib, and bevacizumab, which target EGFR/VEGFR. Common adverse events included fatigue (47.1%), skin reactions (32.4%), hypertension (23.5%), diarrhea (17.6%), and thyroid abnormalities (5.9%). Clinical outcomes were systematically assessed based on progression-free survival (PFS), overall survival (OS), and tumor response evaluated using RECIST or CHOI criteria. Notably, stable disease (SD) occurred in 58.1% of cases, and partial responses (PRs) were observed in 28.2% of patients, while 13.7% experienced disease progression (PD) despite targeted therapy. Among the 22 clinical trials included in the analysis, Phase II trials were the most prevalent (40.9%), followed by I-II trials (31.8%) and Phase I trials (27.3%). PD-1 inhibitors were the most frequently utilized, appearing in 50% of the trials, followed by PD-L1 inhibitors (36.4%), CTLA-4 inhibitors (22.7%), and mTOR inhibitors (13.6%). Conclusions: This systematic review provides an extensive overview of the state of targeted therapy for chordomas, highlighting their potential to stabilize the illness and enhance clinical outcomes.

Abstract ED04-02: Combination endocrine therapy following progression on first-line therapy

Abstract Assessing genomic status is critical to make treatment decisions in patients who have experienced disease progression following a CDK 4/6 inhibition with endocrine therapy. Three trials have evaluated CDK 4/6 inhibition with endocrine therapy through progression and show that switching CDK 4/6 inhibitor results in modest efficacy while continuing the same CDK 4/6 inhibitor is not effective. The optimal therapy for patients whose tumors have a PI3-kinase mutation is alpelisib and fulvestrant. Other PIK3-ca inhibitors have not shown efficacy to date. Everolimus with endocrine therapy is an effective second line approach. Emerging data demonstrate efficacy of AKT inhibition with endocrine therapy. Several other agents are in clinical development. Citation Format: R. O'Regan. Combination endocrine therapy following progression on first-line therapy [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 ED04-02.

Abstract PO4-15-06: Genomic landscape characterization after exposure to cyclin dependent kinase 4/6 inhibitors: a retrospective multi-institutional consortium analysis

Abstract Background: Limited data are available to determine the best therapeutic strategy for hormone-receptor positive (HR+) HER2 negative (HER2-) advanced breast cancer (ABC) after progression on cyclin dependent kinase 4/6 inhibitors (CDK4/6i). The aim of this study was to characterize the genomic and prognostic profile of patients (pts) that experienced disease progression after first-line therapy with a CDK4/6i. Methods: The study retrospectively analyzed a multi-institutional cohort of 75 patients (pts) with HR+/HER2- ABC after experiencing progression on first-line endocrine therapy (ET) with CDK4/6i and characterized by circulating tumor DNA (ctDNA) next-generation sequencing (Guardant 360). Oncogenic pathways (i.e., RTK, RAS, RAF, MEK, NRF2, ER, WNT, MYC, p53, cell cycle, notch, and PI3K) were defined based on previous research (Sanchez-Vega et al. Cell, 2018). Associations across single nucleotide variations (SNVs), copy number variations (CNVs), and pathway classification were tested by uni- and multivariable logistic regression with respect to a CDK4/6i naïve group comprising 247 patients with HR+/HER2- ABC (control). Prognosis was analyzed through Cox regression for overall survival (OS). Result: Our study cohort included 75 ABC pts who experienced progression after first line CDK4/6i plus ET: 43 pts (57.3%) were treated with ET while 31 (41.3%) with a non-ET- second line therapy. The most common histology was invasive ductal carcinoma (70.6%), 37.3% of pts were negative for progesterone expression and 26.7% had de novo metastatic disease. The PI3K (33.3%), p53 (28%) and ER (25.3%) pathways were the most mutated in the CDK4/6i-treated cohort. Comparing our population with a CDK4/6i naïve cohort (N=247), the multivariate analysis showed a higher prevalence in the study cohort of SNVs mutations in: i) ESR1 gene [Odds ratio (OR) 2.93; p=0.005]; ii) cell-cycle pathway (OR 4.24; p=0.033); iii) ER pathway (OR 2.04; p= 0.034). Moreover, in the study cohort a numerical but not significant increase of RB1 SNVs was also observed. Multivariable analyses of the 43 pts that received ET second line therapy showed a negative prognostic impact with TP53 SNVs in both progression-free survival (PFS) [Hazard ratio (HR) = 3.34; 95% CI: 1.15-9.66, p=0.026] and OS (HR = 3.85; 95% CI: 1.52-9.77, p=0.005). The prognostic role of p53 pathway mutations was also confirmed for both PFS (HR = 4.71, 95% CI: 1.64-13.50; p=0.004) and OS (HR = 3.25; 95% CI: 1.27-8.3; p=0.014). The potential interaction between the prognostic oncogenic pathways and the outcome was investigated according to the treatment strategy (ET vs non-ET). A consistent impact was observed across the above prognostic pathways both for PFS and OS. A numerical difference was observed in terms of PFS in pts with p53 pathway mutations that underwent non-ET second line. Conclusions: The genomic landscape of progressive disease after CDK4/6i exposure is significantly different from the genomic alterations detectable in treatment-naïve pts, which could potential impact future treatment strategies for patients with disease progression after adjuvant CDK4/6i exposure. Our data suggest that the choice of second-line treatment could potentially be guided by the identification of actionable mutation by ctDNA, although further prospective studies are needed to validate the clinical utility of this approach. Citation Format: Letizia Pontolillo, Carolina Reduzzi, Andrew Davis, Lorenzo Gerratana, Arielle Medford, Katherine Clifton, Whitney L. Hensing, Marko Velimirovic, Ami N. Shah, Jeannine Donahue, Laura Munoz Arcos, Charles S. Dai, Jennifer Keenan, Amir Behdad, William Gradishar, Emilio Bria, Cynthia Ma, Aditya Bardia, Massimo Cristofanilli. Genomic landscape characterization after exposure to cyclin dependent kinase 4/6 inhibitors: a retrospective multi-institutional consortium analysis [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 PO4-15-06.

Abstract PO3-02-12: Dalpiciclib combination with letrozole as neoadjuvant therapy for HR-positive HER2-negative breast cancer: a single-arm, prospective exploratory clinical study

Abstract Background: CDK4/6 inhibitors effectively block tumor cells from progressing from the G1 phase to the S phase, thereby interrupting the cell cycle progression and inhibiting tumor cell proliferation. Dalpiciclib is a novel CDK4/6 inhibitor developed independently in China, which has been approved for use in combination with fulvestrant for the treatment of HR-positive/HER2-negative recurrent or metastatic breast cancer in patients who have experienced disease progression after prior endocrine therapy, or in combination with aromatase inhibitors as initial treatment for HR-positive/HER2-negative locally advanced or metastatic breast cancer patients. This study aims to explore the efficacy and safety of dalpiciclib in combination with letrozole as neoadjuvant therapy for HR-positive, HER2-negative breast cancer. Methods: This is a single-arm, open-label study that enrolled female breast cancer patients with early or locally advanced HR-positive, HER2-negative tumors and an ECOG performance status of 0 to 1. After enrollment, patients first received 4 cycles of dalpiciclib (150mg po qd, d1-21, q4w) in combination with letrozole as neoadjuvant therapy. Breast MRI was performed every 2 cycles, and treatment response was evaluated according to the RECIST 1.1 criteria. If patients achieved a confirmed complete response (CR) or partial response (PR) after 4 cycles, they would continue to receive an additional 4 cycles of dalpiciclib in combination with letrozole treatment. If the treatment response was stable disease (SD) or disease progression (PD), the investigator might modify other treatment regimens based on the individual circumstances of the subjects. The primary endpoint was residual cancer burden (RCB 0/I), and the secondary study endpoints were objective response rate (ORR), complete cell cycle arrest (CCCA, C1D15 Ki67≤2.7%) rate and safety. This study is registered at the Chinese Clinical Trial Registry Centre (registration No. ChiCTR2200057104). Results: From April 2022 to June 2023, a total of 38 patients were screened and enrolled in the study. All patients had ER ≥ 50%, and 84% (32/38) had Ki67 ≥ 88%. Among the 21 patients who completed the assessment after 4 cycles, the overall response rate (ORR) was 81% (17/21). Additionally, among the 22 patients who underwent C1D15 biopsy and Ki67 analysis, 55% (12/22) had C1D15 Ki67 ≤ 2.7%. After completing 8 cycles of neoadjuvant treatment with the combination of dalpiciclib and letrozole,12 patients underwent surgery. The postoperative RCB scores were as follows: 1 patient had RCB (0-I), and 11 patients had RCB (II-III). The most common adverse event was decreased neutrophil count (25/38 [66%]). Among the 38 patients, 16 (42%) experienced grade 3 or worse treatment-related adverse events. There were no occurrences of grade 4 or worse adverse events. Conclusions: The combination of dalpiciclib and letrozole has shown efficacy in downstaging and shrinking tumors in patients with early or locally advanced HR-positive/HER2-negative breast cancer. Patients who exhibit a positive response in the assessment after 4 cycles may consider it as a viable option for chemo-free neoadjuvant treatment. Citation Format: Jingruo Li, Yuanting Gu, Chuang Du, Jianhua Zhang, Yingying Zhang, Linfeng Zhang, Nan Wang, Lin Li, Fang Wang, Pengwei Lv, Hong Zong, Xinhong Pei, Bingjian Xue, Yan Wang, Dongcheng Gao. Dalpiciclib combination with letrozole as neoadjuvant therapy for HR-positive HER2-negative breast cancer: a single-arm, prospective exploratory clinical 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 PO3-02-12.

Abstract PO2-05-08: ISM5043, a novel, selective KAT6 inhibitor for the treatment of advanced and refractory ER+ breast cancer

Abstract Breast cancer is the most commonly diagnosed cancer and the second leading cause of cancer death among women in the US. Approximately 70% of human breast tumors are estrogen receptor positive (ER+), and endocrine therapy (ET), which inhibits the estrogen signaling pathway, remains the backbone of therapy for ER+ breast cancer. However, ET resistance often develops, and patients eventually experience disease progression. This is a significant clinical challenge and highlights the urgent need for novel therapies that may help overcome the resistance. KAT6A is a histone (lysine) acetyltransferase (HAT) belonging to the MYST family. KAT6A and its paralog KAT6B play important roles in cell cycle progression, neuron stem cell maintenance and hematopoietic development via acetylation of H3K23. Molecular dysregulation of KAT6A, including amplification and fusion, has been reported in many cancers. In breast cancer, KAT6A is amplified as part of the 8p11 amplicon in about 10-15% of the ER+ breast cancer population, where it functions as an epigenetic modulator of ER expression, and is associated with a worse clinical outcome. Therefore, inhibition of KAT6A may be a promising therapy for ER+ breast cancer. Here, we evaluated ISM5043, a novel, small molecule KAT6 inhibitor for anti-tumor effects in ER+/HER2- breast cancer cell lines and animal models. ISM5043 demonstrated potent inhibitory activity against KAT6A (IC50, 8 nM) and KAT6B (IC50, 16 nM) with selectivity over KAT7 (IC50, 344 nM) and other HATs (IC50 &amp;gt;2000 nM). The compound showed robust, dose-dependent, anti-proliferation activity (IC50 &amp;lt; 10 nM) in multiple ER+/HER2- breast cancer cell lines with KAT6A amplification, in accordance with its suppression of H3K23 acetylation. Investigation of the mechanism of action revealed that treatment with ISM5043 resulted in the downregulation of the expression of ERα in these breast cancer cells. In the ZR-75-1 (ER+, HER2-) xenograft model, ISM5043 demonstrated robust and dose-dependent anti-tumor activity, as monotherapy, with Tumor Growth Inhibition (TGI) between 80~110% at doses ranging from 0.3 to 10 mg/kg, QD. ISM5043 (0.3 mg/kg, QD), in combination with tamoxifen (20 mg/kg, QD) exhibited synergistic effect against tumor growth, with a Q value of 1.25 based on Jin’s equation. Notably, ISM5043 displayed a strong anti-tumor effect (TGI of 67.7% and 83.6% at 3 and 10 mg/kg QD, respectively) as monotherapy, in a patient-derived ER+/HER2- breast cancer xenograft model representing disease progression following multiple prior lines of treatment (including palbociclib in combination with letrozole). ISM5043 also showed favorable ADME properties as well as good pharmacokinetic and safety profiles. Taken together, these data support the clinical evaluation of ISM5043 as a targeted therapy in patients with advanced and refractory ER+ breast cancer. Citation Format: Xin Cai, Xin Cheng, Luoheng Qin, Man Zhang, Junwen Qiao, Supriya Bavadekar, Sujata Rao, Feng Ren. ISM5043, a novel, selective KAT6 inhibitor for the treatment of advanced and refractory ER+ breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-05-08.

Abstract PO2-20-02: A Phase 3 study of gedatolisib plus fulvestrant with and without palbociclib in patients with HR+/HER2- advanced breast cancer previously treated with a CDK4/6 inhibitor plus a non-steroidal aromatase inhibitor (VIKTORIA-1)

Abstract Patients who receive frontline CDK4/6 inhibitor (CDK4/6i) therapy eventually experience disease progression. Resistance to CDK4/6i is likely a transient adaptive mechanism that may be reversed by inhibition of the PI3K/mTOR pathway. Thus, combination of CDK4/6i and PI3K/mTORi after disease progression on CDK4/6i could restore sensitivity to CDK4/6i and prevent activation of the PI3K/mTOR pathway. This hypothesis was evaluated in a Phase 1b study (Layman SABCS 2021) of gedatolisib (geda), a potent inhibitor of PI3K and mTOR. Subjects with HR+/HER2- ABC treated with prior CDK4/6i received geda (180 mg IV weekly for 3 weeks, then one week off) with palbociclib (P) and fulvestrant (F). Median PFS was 12.9 months with 63% overall response rate. Efficacy was observed regardless of PIK3CA mutation status (Wesolowski SABCS 2022). Geda was well tolerated, with few discontinuations due to treatment-related adverse events (4%). The most common AE was stomatitis; hyperglycemia of any grade occurred in 26% of patients. This preliminary data, dosing schedule, and study population characteristics form the basis for the Phase 3 trial, VIKTORIA-1. This Phase 3 multinational clinical trial will evaluate geda and F with or without P in patients with HR+/HER2- ABC previously treated with any CDK4/6i in combination with a non-steroidal aromatase inhibitor (AI) therapy. Those without tumor PIK3CA mutations will be assigned to Study 1 (n=351) and randomized to Arm A (geda, P, and F), Arm B (geda and F), or Arm C (F). Those with PIK3CA mutations will be assigned to Study 2 (n=350) and randomized to Arm D (geda, P, and F), Arm E (alpelisib and F), or Arm F (geda and F). Key eligibility criteria include adults with confirmed metastatic or locally advanced breast cancer, any menopausal status, radiologically evaluable disease, and prior CDK4/6i treatment in combination with a non-steroidal AI. Prior hormonal therapy, including SERDs, is allowed. Key exclusion criteria include prior treatment with a PI3K, Akt, or mTOR inhibitor, prior treatment with chemotherapy for advanced disease, more than two lines of prior endocrine therapy, bone only disease with no soft tissue components, active CNS metastases, and type 1 diabetes or uncontrolled type 2 diabetes. The primary endpoint is PFS assessed by blinded independent central review per RECIST v1.1. Secondary endpoints included overall survival (OS), safety and tolerability, ORR, duration of response, time to response, CBR, quality of life, and pharmacokinetics. Enrollment is ongoing. This trial abstract was previously presented at the 2022 San Antonio Breast Cancer Symposium, December 6-10, 2022. Citation Format: Sara Hurvitz, Fabrice André, Massimo Cristofanilli, Giuseppe Curigliano, Antonio Giordano, Hyo Han, Miguel Martín, Barbara Pistilli, Hope Rugo, Robert Wesolowski, Igor Gorbatchevsky, Sibylle Loibl. A Phase 3 study of gedatolisib plus fulvestrant with and without palbociclib in patients with HR+/HER2- advanced breast cancer previously treated with a CDK4/6 inhibitor plus a non-steroidal aromatase inhibitor (VIKTORIA-1) [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 PO2-20-02.

Risk Score Model for Predicting COVID-19 Progression in Iranian Patients: Development and Validation Study

Background: The recent novel coronavirus disease 2019 (COVID-19) pandemic has underlined the importance of risk score models in public health emergencies. This study aimed to develop a risk prediction score to identify high-risk hospitalized patients for disease progression on admission. Methods: This prospective cohort study included 171 COVID-19 patients, identified through the reverse transcription polymerase chain reaction test, admitted to Bohlool Hospital in Gonabad City, Iran, between April 4 and June 5, 2021. The patients’ demographic, clinical, and laboratory data were collected upon admission, and clinical outcomes were monitored until the end of the study. The discovery dataset (80% of the data) was used to develop the risk score model based on clinical and laboratory features and patient characteristics to predict COVID-19 progression. An additive risk score model was developed based on the regression coefficients of the significant variables in a multiple logistic regression model. The performance of the risk score model was evaluated on the validation dataset (20% of the data) using the receiver operating characteristic (ROC) curve. Statistical analyses were performed with SPSS software, version 21. Results: The Mean±SD for age of participants was 59.54±20.52 years, and 48.6% were male. Most patients (82.5%) fully recovered or showed improvement, while 5.2% experienced disease progression and 12.3% died. Three variables, interleukin-6, neutrophil-to-lymphocyte ratio, and lung involvement, were found to be significant in predicting risk, with a good discriminatory ability, having an area under the ROC curve of 0.970 (95% CI, 0.935%, 1.00%) in the discovery set and 0.973 (95% CI, 0.923%, 1.00%) in the validation set. Conclusion: The developed risk score model in this study can be used as a clinical diagnostic tool to identify COVID-19 patients at higher risk of disease progression and aid in informed decision-making and resource utilization in similar situations, such as respiratory disease outbreaks in the post-corona era.

Cost of disease progression among US patients with human epidermal growth factor receptor 2-positive metastatic breast cancer.

Aim: The objectives were to investigate the differences in per patient per month (PPPM) healthcare resource utilization (HCRU) and costs among commercially insured and Medicare Advantage patients with human epidermal growth factor receptor 2 positive (HER2+) metastatic breast cancer (mBC) who experience disease progression in 12months compared with those who don't investigate the impact of progression timing on cumulative healthcare costs. Patients & methods: This claims-based study included patients diagnosed with mBC between 1January 2013 and 30April 2020 and received HER2-targeted therapy. Patients were categorized as progressed or nonprogressed. For objective one, monthly HCRU and costs were assessed for up to two lines of therapy (LOTs). Data were summarized descriptively and compared using a generalized linear model (GLM). For objective two, patients with at least 6 months of follow-up were assessed and cumulative healthcare costs were estimated in the 3 years following the start of LOT1 or LOT2 using a GLM and Kaplan-Meier weighting. Results: Among the 4113 patients in the study sample, 3406 had at least 12 months of follow-up (or less if due to death). Compared with nonprogressed patients, progressed patients had higher mean PPPM healthcare costs (LOT1: $22,014 vs $18,372, p<0.001; LOT2: $19,643 vs $16,863, p=0.001), and HCRU, including number of emergency room visits and inpatient stays (both p<0.001) in the 12 months following LOT start. Progressed patients had higher 3-year mean cumulative healthcare costs than nonprogressed patients following LOT1 and LOT2 and this difference was greater for patients who progressed earlier. Conclusion: Disease progression was associated with significant increases in HCRU and costs. Delays in progression were associated with lower cumulative healthcare costs. Earlier use of more clinically effective treatments to delay progression may reduce the economic burden among these patients.

Treatment outcomes in patients with large B-cell lymphoma after progression to chimeric antigen receptor T-cell therapy.

Over 60% of relapsed/refractory (R/R) large B-cell lymphoma (LBCL) patients who receive chimeric antigen receptor (CAR) T cells will experience disease progression. There is no standard next line of therapy and information in this setting is scarce and heterogeneous. We analyzed 387 R/R LBCL patients who progressed after CAR T cells from July 2018 until March 2022 in Spain and the United Kingdom. Median overall survival (OS) was 5.3 months, with significant differences according to the interval between infusion and progression (<2 months [1.9 months], 2-6 months [5.2 months], and >6 months [not reached]). After progression, 237 (61%) patients received treatment. Focusing on the first subsequent therapy, overall (complete) response rates were 67% (38%) for polatuzumab-bendamustine-rituximab (POLA), 51% (36%) for bispecific antibodies (BsAb), 45% (35%) for radiotherapy (RT), 33% (26%) for immune checkpoint inhibitors (ICIs), 25% (0%) for lenalidomide (LENA), and 25% (14%) for chemotherapy (CT). In terms of survival, 12-month progression-free survival and OS was 36.2% and 51.0% for POLA, 32.0% and 50.1% for BsAb, 30.8% and 37.5% for RT, 29.9% and 27.8% for ICI, 7.3% and 20.8% for LENA, and 6.1% and 18.3% for CT. Thirty-two (14%) patients received an allogeneic hematopoietic cell transplant with median OS not reached after a median follow-up of 15.1 months. In conclusion, patients with R/R LBCL who progress within the first 2 months after CAR T-cell therapy have dismal outcomes. Novel targeted agents, such as polatuzumab and BsAbs, can achieve prolonged survival after CAR T-cell therapy failure.

Special issue PRO] A demonstration of estimands and sensitivity analyses for time-to-deterioration of patient reported outcomes

ABSTRACT In oncology trials, health-related quality of life (HRQoL), specifically patient-reported symptom burden and functional status, can support the interpretation of survival endpoints, such as progression-free survival. However, applying time-to-event endpoints to patient-reported outcomes (PRO) data is challenging. For example, in time-to-deterioration analyses clinical events such as disease progression are common in many settings and are often handled through censoring the patient at the time of occurrence; however, disease progression and HRQoL are often related leading to informative censoring. Special consideration to the definition of events and intercurrent events (ICEs) is necessary. In this work, we demonstrate time-to-deterioration of PRO estimands and sensitivity analyses to answer research questions using composite, hypothetical, and treatment policy strategies applied to a single endpoint of disease-related symptoms. Multiple imputation methods under both the missing-at-random and missing-not-at-random assumptions are used as sensitivity analyses of primary estimands. Hazard ratios ranged from 0.52 to 0.66 over all the estimands and sensitivity analyses modeling a robust treatment effect favoring the treatment in time to disease symptom deterioration or death. Differences in the estimands include how people who experience disease progression or discontinue the randomized treatment due to AEs are accounted for in the analysis. We use the estimand framework to define interpretable and principled approaches for different time-to-deterioration research questions and provide practical recommendations. Reporting the proportions of patient events and patient censoring by reason helps understand the mechanisms that drive the results, allowing for optimal interpretation.

The Impact of Radiation Therapy in Patients with Systemic Sclerosis and Head and Neck Cancer

ObjectiveSystemic sclerosis (SSc) is considered a relative, or in some cases, absolute contraindication for radiation therapy for various cancers; however, radiation is standard of care and the best option for tumor control for locally advanced head and neck (H&N) cancer. We present a case series to document the post-radiation outcomes in patients with SSc and H&N cancer. MethodsPatients with SSc and H&N cancer treated with radiation were identified from two large Scleroderma Center research registries. Through chart review, we identified whether patients developed pre-determined acute and late side effects or changes in SSc activity from radiation. We further describe therapies used to prevent and treat radiation-induced fibrosis. ResultsThirteen patients with SSc who received radiation therapy for H&N cancer were included. Five-year survival was 54%. Nine patients (69%) developed local radiation-induced skin thickening and seven (54%) developed reduced neck range of motion. Two patients required long-term percutaneous endoscopic gastrostomy use due to radiation therapy complications. No patients required respiratory support related to radiation therapy. Regarding SSc disease activity among the patients with established SSc prior to radiation therapy, none experienced interstitial lung disease progression in the post-radiation period. Following radiation, one patient had worsening skin disease outside the radiation field, however, this patient was within the first year of SSc when progressive skin disease is expected. Treatment strategies to prevent radiation fibrosis included pentoxifylline, amifostine and vitamin E, while intravenous immunoglobulin (IVIG) was used to treat it. ConclusionWhile some patients with SSc who received radiation for H&N cancer developed localized skin thickening and reduced neck range of motion, systemic flares of SSc were uncommon. This observational study provides evidence to support the use of radiation therapy for H&N cancer in patients with SSc when radiation is the best treatment option.