Citations

PURPOSE To report the results of OPAL (ClinicalTrials.gov identifier: NCT03574779 ) cohort A, a single-arm substudy of niraparib plus dostarlimab and bevacizumab for the treatment of advanced, platinum-resistant ovarian cancer (PROC). METHODS Participants with PROC who received 1-2 previous lines of therapy were treated with niraparib (200 or 300 mg once daily), dostarlimab (500 mg once every 3 weeks for four 21-day cycles, followed by 1,000 mg once every 6 weeks), and bevacizumab (15 mg/kg once every 3 weeks). The primary end point was investigator-assessed objective response rate (ORR) per RECIST v1.1. Safety was also assessed. Exploratory biomarker end points included evaluation of changes in the tumor molecular profile and microenvironment using baseline and on-treatment tumor samples. RESULTS Of 41 enrolled participants (median age, 66.0 years [range, 37-83 years]), 9.8% had tumors that were BRCA-mutated, 19.5% were homologous recombination (HR)–deficient, and 17.1% were HR repair (HRR)–mutated. As of the cutoff date, all participants discontinued treatment. The ORR was 17.1% (80% CI, 9.8 to 27.0), including one complete response (2.4%); the disease control rate was 73.2% (80% CI, 62.3 to 82.2). Two participants withdrew before first postbaseline scan because of adverse events (AEs). Grade ≥3 treatment-emergent AEs were reported in 92.7% of participants, with the most common being hypertension (26.8%). Response was not correlated with BRCA, HRR, HR deficiency (HRD), or PD-L1 status. Changes suggesting immune activation were observed in on-treatment samples after triplet therapy. CONCLUSION Results demonstrated modest activity of niraparib, dostarlimab, and bevacizumab in participants with PROC, many of whom had prognostic factors for poor treatment response. Most participants with response were bevacizumab-naïve. No association was found with HRD, BRCA, or PD-L1 status. AEs were consistent with previous monotherapy reports, except that hypertension was reported more frequently.

Abstract Background: Latin Americans are more likely to be diagnosed with aggressive early-stage breast cancer compared to Non-Hispanic White. Multiple factors may contribute to this, including metabolic factors and ancestry. In a previous study, we identified upregulated immune pathway genes in Luminal B tumors from obese Black patients compared to matched White patients. In this study, we report clinical and transcriptomic profiles of breast tumors from Latin and White patients to enhance understanding of factors contributing to aggressive tumor biology in Latin patients. Methods: We matched 311 Latin and 311 White breast cancer patients enrolled in FLEX by age, T stage, N stage and clinical subtype (ER/PR and HER2 status). FLEX (NCT03053193) is a prospective, observational trial that includes stage I-III breast cancer patients who receive MammaPrint (with or without BluePrint) as standard of care and consent to whole transcriptome and clinical data collection. MammaPrint is a 70-gene risk of distant recurrence signature that classifies patients as Low Risk or High Risk. BluePrint is an 80-gene molecular subtyping signature, categorizes tumors as Luminal-, HER2- or Basal-Type. MammaPrint further groups Luminal into A (Low Risk) and B (High Risk). ImPrint is a 53-gene signature that has been shown to predict the likelihood of achieving pCR with PD1-PDL1 immune checkpoint inhibitors. Statistical analyses on groups were conducted using arsenal R package and p-value < 0.05 was considered significant. Whole transcriptome comparisons were made, using limma R package, between Latin and White patients stratified by BluePrint subtype Luminal and weight categories normal (body-mass-index (BMI) 18.5 to < 25) and obese (BMI ≥30). Significant differentially expressed genes had an adjusted p-value < 0.05. Gene set enrichment analysis (GSEA) was conducted using fgsea R package. Results: Latin patients had significantly higher percentage of type 2 diabetes (23.3% vs 8.5%), BMI obese (49.0% vs 39.4%), BluePrint Basal (14.8% vs 9.3%) and ImPrint Immune Sensitive (12.0% vs 5.1%) compared to matched White patients. When comparing whole transcriptome of tumors from Latin and White patients, only tumors stratified by Luminal B and obesity resulted in differentially expressed genes: Latin patients had higher expression (>2-fold change) of 42 immunoglobulin genes compared to White, with only IGKV6-21 being statistically significant. Additional immune related genes such as IKZF1 and AGER, as well as UTS2 (gene encoding a vasoconstrictor agent and contributor of angiogenesis) were significantly upregulated in Latin patients. Upregulation of immune related pathways such as inflammatory response, interferon alpha/gamma response and downregulation of adipogenesis, oxidative phosphorylation and MYC targets were identified in Latin patients compared to White using GSEA Hallmarks gene sets. Conclusion: There were additional clinical and genomic differences between tumors from Latin and White patients, even when controlling for age, T stage, N stage and clinical subtype. Particularly, there were more type 2 diabetes, BMI obese, BluePrint Basal, and ImPrint Immune Sensitive among Latin patients. In addition, transcriptomic differences between obese Latin and matched White patients were found in Luminal B subgroup that may contribute to the aggressive tumor biology; immunoglobulin genes and immune related pathways were associated with higher expression in Latin patients. This study suggests that biological differences in breast tumors, particularly from obese patients, may result from shared background and reflects the need for inclusion of diverse patient groups in clinical trials. Citation Format: Marcela Mazo-Canola, Virginia Kaklamani, Pooja Advani, Sailaja Kamaraju, Alfredo A. Santillan-Gomez, Robert Maganini, Julie Barone, Sahra Uygun, Lavanya Samraj, William Audeh, Joyce O'Shaughnessy, FLEX Investigators' Group. Racial disparities in breast cancer and effect of obesity: MammaPrint, BluePrint and whole transcriptome analyses of tumors in Latin American patients in FLEX trial [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS18-04.

Abstract Background: Abemaciclib is approved both for high-risk early breast cancer as well as advanced breast cancer (ABC) in the first- and second-line setting. In MONARCH 2, the addition of abemaciclib to fulvestrant significantly improved both progression-free survival (PFS) and overall survival (OS) in patients with HR+, HER2- ABC with disease progression on prior endocrine therapy (ET). In MONARCH 3, the addition of abemaciclib to a nonsteroidal aromatase inhibitor (NSAI) significantly improved PFS (HR, 0.540; 95% CI, 0.418-0.698; p=0.000002) as initial therapy in HR+, HER2- ABC. At the last interim OS analysis (~252 events, at 5.8 years follow-up [FU]), a numerically favorable median OS difference (12.6 months) was observed (HR, 0.754; 95% CI, 0.584-0.974; p=0.0301, non-significant [NS]). Here, we present the final OS analysis of MONARCH 3 (NCT02246621). Methods: MONARCH 3 is a randomized, double-blind, Phase 3 study of abemaciclib + NSAI (anastrozole or letrozole) vs placebo + NSAI in postmenopausal women with HR+, HER2- ABC without prior systemic therapy in the advanced setting. OS was a gated secondary endpoint and chemotherapy-free survival (CFS) an exploratory endpoint. Final OS analysis was planned after approximately 315 OS events had occurred in the intent-to-treat (ITT) population with a split alpha between the ITT population and the subgroup with visceral disease (sVD) according to a prespecified graphical testing scheme. Kaplan-Meier method and stratified Cox proportional hazards models were used for time-to-event analyses. All reported p-values are two-sided. Results A total of 493 women were randomized 2:1 to receive abemaciclib + NSAI (n=328) or placebo + NSAI (n=165). After a median FU of 8.1 years, 7% of patients were still receiving treatment in the abemaciclib arm vs 3% in the placebo arm. In the ITT population, 314 OS events were observed (198 deaths among 328 patients [60%] in the abemaciclib arm and 116 among 165 [70%] in the placebo arm; HR, 0.804; 95% CI, 0.637-1.015; p=0.0664, NS). Median OS was 66.8 months in the abemaciclib arm and 53.7 months in the placebo arm, a numerical difference of 13.1 months in the ITT population. In the sVD, 178 events were observed (113 deaths among 173 patients [65%] in the abemaciclib arm and 65 among 90 [72%] in the placebo arm; HR, 0.758; 95% CI, 0.558-1.030; p=0.0757, NS). Median OS was 63.7 months in the abemaciclib arm and 48.8 months in the placebo arm, a numerical difference of 14.9 months in the sVD. Consistent OS differences were observed across prespecified subgroups. PFS benefit was sustained (median 29.0 vs 14.8 months; HR, 0.535; 95% CI, 0.429-0.668; nominal p<0.0001) with substantial difference in 6-year PFS rates (23.3% vs 4.3% for abemaciclib vs placebo). CFS was also improved with abemaciclib vs placebo (median 46.7 vs 30.6 months; HR, 0.693; 95% CI, 0.557-0.863; nominal p=0.0010). No new safety signals were observed with longer term use. Conclusion In patients with HR+, HER2- ABC, abemaciclib in combination with a NSAI resulted in numerically longer OS compared to NSAI alone; however, statistical significance was not reached after a median FU of 8.1 years. The clinically meaningful improvement in median OS (>13 months) combined with the sustained significant improvement in median PFS (>14 months) and substantial extension in median CFS (>16 months) continue to support the use of abemaciclib in combination with NSAI as first-line therapy in ABC. Citation Format: Matthew Goetz, Masakazu Toi, Jens Huober, Joo Hyuk Sohn, Olivier Trédan, Inhae Park, Mario Campone, Shin-Cheh Chen, Luis Manual Manso, Shani Paluch-Shimon, Orit C. Freedman, Valerie Andre, Abhijoy Saha, Gertjan van Hal, Ashwin Shahir, Hiroji Iwata, Stephen RD Johnston, Joyce O'Shaughnessy, Xavier Pivot, Sara Tolaney, Sara Hurvitz, Antonio Llombart. MONARCH 3: Final overall survival results of abemaciclib plus a nonsteroidal aromatase inhibitor as first-line therapy for HR+, HER2- advanced 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 GS01-12.

Importance Effects of antiamyloid agents, targeting either fibrillar or soluble monomeric amyloid peptides, on downstream biomarkers in cerebrospinal fluid (CSF) and plasma are largely unknown in dominantly inherited Alzheimer disease (DIAD). Objective To investigate longitudinal biomarker changes of synaptic dysfunction, neuroinflammation, and neurodegeneration in individuals with DIAD who are receiving antiamyloid treatment. Design, Setting, and Participants From 2012 to 2019, the Dominantly Inherited Alzheimer Network Trial Unit (DIAN-TU-001) study, a double-blind, placebo-controlled, randomized clinical trial, investigated gantenerumab and solanezumab in DIAD. Carriers of gene variants were assigned 3:1 to either drug or placebo. The present analysis was conducted from April to June 2023. DIAN-TU-001 spans 25 study sites in 7 countries. Biofluids and neuroimaging from carriers of DIAD gene variants in the gantenerumab, solanezumab, and placebo groups were analyzed. Interventions In 2016, initial dosing of gantenerumab, 225 mg (subcutaneously every 4 weeks) was increased every 8 weeks up to 1200 mg. In 2017, initial dosing of solanezumab, 400 mg (intravenously every 4 weeks) was increased up to 1600 mg every 4 weeks. Main Outcomes and Measures Longitudinal changes in CSF levels of neurogranin, soluble triggering receptor expressed on myeloid cells 2 (sTREM2), chitinase 3–like 1 protein (YKL-40), glial fibrillary acidic protein (GFAP), neurofilament light protein (NfL), and plasma levels of GFAP and NfL. Results Of 236 eligible participants screened, 43 were excluded. A total of 142 participants (mean [SD] age, 44 [10] years; 72 female [51%]) were included in the study (gantenerumab, 52 [37%]; solanezumab, 50 [35%]; placebo, 40 [28%]). Relative to placebo, gantenerumab significantly reduced CSF neurogranin level at year 4 (mean [SD] β = −242.43 [48.04] pg/mL; P < .001); reduced plasma GFAP level at year 1 (mean [SD] β = −0.02 [0.01] ng/mL; P = .02), year 2 (mean [SD] β = −0.03 [0.01] ng/mL; P = .002), and year 4 (mean [SD] β = −0.06 [0.02] ng/mL; P < .001); and increased CSF sTREM2 level at year 2 (mean [SD] β = 1.12 [0.43] ng/mL; P = .01) and year 4 (mean [SD] β = 1.06 [0.52] ng/mL; P = .04). Solanezumab significantly increased CSF NfL (log) at year 4 (mean [SD] β = 0.14 [0.06]; P = .02). Correlation analysis for rates of change found stronger correlations between CSF markers and fluid markers with Pittsburgh compound B positron emission tomography for solanezumab and placebo. Conclusions and Relevance This randomized clinical trial supports the importance of fibrillar amyloid reduction in multiple AD-related processes of neuroinflammation and neurodegeneration in CSF and plasma in DIAD. Additional studies of antiaggregated amyloid therapies in sporadic AD and DIAD are needed to determine the utility of nonamyloid biomarkers in determining disease modification. Trial Registration ClinicalTrials.gov Identifier: NCT04623242

Objectives: CABG and PCI are used for revascularization of multivessel coronary artery disease (MVCAD). However, limited information is available comparing the rates of in-hospital and 30-day major adverse cardiac and cerebrovascular event (early MACCE), including early death, stroke, myocardial infarction (MI), and repeat revascularization, among patients with multiple arterial CABG (MultArt) vs PCI. Methods: We reviewed 12,615 MVCAD patients with isolated primary CABG or PCI from 1993 through 2009. CABG patients (n=6,667) were grouped by number of arterial grafts into left internal mammary artery/saphenous vein (LIMA/SV) (n=5,712) or MultArt (n=955); PCI patients (n=5,948) into balloon angioplasty (BA) (n=1,020), bare metal stent (BMS) (n=3,242), and drug-eluting stent (DES) (n=1,686). Results: Early MACCE rate was significantly greater for PCI than CABG (8.5% vs 4.1% [P<.001]) and lower for MultArt than LIMA/SV or PCI (1.5% vs 4.5% and 8.5%, respectively [P<.001]). Stroke and early death rates were higher in CABG vs PCI (2.2% vs 0.4% [P<.001], and 1.5% vs 1.0% [P=0.01], respectively), whereas MI and repeat revascularization were lower (0.5% vs 6.0% and 0.3% vs 2.2%, respectively [P<.001]). Stroke and early death were similar in MultArt and PCI and lower vs LIMA/SV (0.6% and 0.4% vs 2.6%, and 0.5% and 1.0% vs 1.7%, respectively [P<.001]); MI and repeat revascularization rates were similar in MultArt and LIMA/SV and lower vs PCI (0.4% and 0.6% vs 6.0%, and 0.3% and 0.3% vs 2.3%, respectively [P<.001]). In propensity score-matched analysis, CABG had significantly improved early MACCE rate compared with BA (4.7% vs 13.2% [P<.001]), BMS (4.3% vs 8.3% [P<.001]), and DES (2.9% vs 5.5% [P=.008]), and MultArt compared with PCI (1.8% vs 7.8% [P<.001]) fig. Conclusions: In MVCAD patients undergoing isolated primary revascularization, CABG conferred lower early MACCE rate vs PCI. Early MACCE rate was markedly decreased after MultArt compared with LIMA/SV, BA, BMS, and DES.

Introduction: We compared outcome of repeat CABG (RCABG) and PCI in patients with previous CABG. Hypothesis: RCABG may improve survival versus PCI. Methods: From 1993 through 2009, 3,058 patients underwent revascularization after previous CABG. RCABG patients (n=530) were grouped by the use of arterial grafts (n=396), or saphenous vein grafts (SVG; n=134). At previous CABG, 37% of RCABG patients received IMA graft. PCI patients (n=2,528) were grouped into balloon angioplasty (BA; n=491), bare metal stent (BMS; n=1,267), and drug-eluting stent (DES; n=769). PCI patients were further stratified by the treated target into native coronary artery (n=1,637), bypass grafts (n=674), or both (n=216). Propensity score analysis matched 287 patients. Results: RCABG had increased 30-day mortality compared with PCI (HR=3.92; 95% CI, 2.25-6.84; P <.001) in multivariable analysis, while in propensity matched analysis it did not ( P =.09). Overall survival, however, was greater for RCABG compared with PCI in multivariable analysis (HR=0.70; 95% CI, 0.59-0.83; P <.001), as well as in propensity matched analysis (10-year survival rates were 52% vs 37%, respectively [ P =.005]). Compared with RCABG, PCI involving bypass grafts had increased mortality (HR, 1.39; 95% CI, 1.09-1.78; P =.008), whereas PCI targeting only the native coronaries did not (HR, 1.12; 95% CI, 0.85-1.47; P =.43); BMS patients had increased mortality (HR, 1.34; 95% CI, 1.06-1.68; P =.013), but DES did not (HR, 1.28; 95% CI, 0.77-2.12; P =.35). At RCABG, 318 patients (60%) received an IMA graft and late survival was similar to those receiving SVG; The use of IMA in previous CABG was associated with improved survival (HR=0.82; 95% CI, 0.72-0.92; P <.001]. Conclusions: Long-term survival after previous CABG is improved with RCABG compared to PCI, especially when PCI involves bypass grafts. There is no difference in long-term survival between RCABG using arterial grafts vs SVG only if IMA is used in either previous or RCABG.

Introduction: While left ventricular assist devise (LVAD) support improves the prognosis of end-stage heart failure (HF) patients, the long-term outcomes remains suboptimal. Improved outcomes may occur with organ protection including reverse myocardial remodeling. Cenderitide (CDNP) is a Mayo engineered designer natriuretic peptide (NP) that co-activates particulate guanylyl cyclase A and B receptors and functions via the second messenger cGMP. We reported a NP deficient state in the heart with LVAD support which lays the rationale for NP replacement therapy with Cenderitide which has cardiorenal protective actions in experimental HF. We sought to determine if Cenderitide co-therapy would be safe and activate cGMP in patients with LVAD support. Hypothesis: Acute single dose of subcutaneous (SQ) Cenderitide will be safe and activate cGMP in patients with LVAD support. Methods: Stable HF patients with LVAD support (Heartmate II, all males) were enrolled in a cross-over design comparing SQ placebo and low (Low-C, 5 ug/kg, n=8) or high dose (High-C, 10 ug/kg, n=8) Cenderitide (Capricor Therapeutics) administration. Vital signs, plasma C(D)NP, cGMP, Aldosterone (Aldo), and NT-proBNP levels were measured before or after drug administration over 24 hours. All parameters in Cenderitide group were adjusted by those in placebo. Results: Both Low-C and High-C group demonstrated significantly increased plasma C(D)NP and cGMP levels for 2 hours after drug injection and those in High-C group showed more prolonged and higher increases than Low-C group. Mean arterial pressure (MAP) in Low-C did not show any changes but in High-C group tended to be lower for 18 hours but this was not significant. Plasma Aldo and NT-proBNP levels in Low-C group did not show any change but those in High-C group tended to be lower after drug injection s similar to the change in MAP. No adverse events were observed in the study. Conclusions: SQ Cenderitide was successfully absorbed, activated cGMP and well tolerated in patients with LVAD support. High dose Cenderitide may have cardiac unloading effects suggested by decreases in NT-proBNP. Further clinical trial for efficacy is warranted to clarify cardiorenal protective effects of Cenderitide in the LVAD population to improve outcomes.