Nebraska Hematology-Oncology

Abstract Background: In early-stage triple-negative breast cancer (TNBC), there is accumulating evidence of a correlation between tumor-infiltrating lymphocytes in tumor tissue and favorable clinical outcomes, with a high CD8+/regulatory T-cell (Treg) ratio after neoadjuvant chemotherapy being predictive of overall survival and associated with pathologic complete response (Ladoire S, et al. Br J Cancer. 2011; Park YH, et al. Nat Commun. 2020). Trilaciclib is a transient inhibitor of cyclin-dependent kinase 4/6 that is administered intravenously prior to chemotherapy. In preclinical studies, trilaciclib has been shown to have immune-enhancing effects by differentially arresting CD8+ T-cell and Treg subsets, which is followed by the faster recovery of CD8+ T cells than Tregs in the tumor microenvironment. Methods: This phase 2, single-arm, open-label study aims to evaluate neoadjuvant, single-dose trilaciclib followed by trilaciclib plus dose-dense anthracycline/cyclophosphamide and taxane in patients with early-stage TNBC (NCT05112536). Patients with previously untreated, non-metastatic, confirmed TNBC and a primary tumor ≥ 1.5 cm of any nodal status receive a single dose of trilaciclib 240 mg/m2 during the lead-in phase, followed by 4 cycles of doxorubicin 60 mg/m2 plus cyclophosphamide 600 mg/m2, and 12 weekly cycles of paclitaxel 80 mg/m2. Trilaciclib 240 mg/m2 is administered prior to the first chemotherapy dose of each cycle. Pembrolizumab 400 mg every 6 weeks starting on day 1, cycle 1, and/or carboplatin AUC 1.5 every week starting on day 1, cycle 5, is allowed per investigator discretion. Tumor biopsies and peripheral blood samples are collected prior to any treatment, 7 days ± 1 day post administration of trilaciclib, and during surgery, with an additional blood sample collection on day 1, cycle 2. The primary objective is to evaluate the immune-based mechanism of action of trilaciclib after a single dose of trilaciclib, as measured by changes in the CD8+/Treg ratio in tumor tissue. Pathologic complete response, safety and tolerability, and additional exploratory immune biomarker endpoints will also be assessed. Results: As of June 3, 2022, 9 patients with early-stage TNBC had been enrolled and 8 patients had received the trilaciclib lead-in dose and initiated doxorubicin/cyclophosphamide. Patients had a median age of 53.0 years, and all had stage II tumors at diagnosis, with 7 having ductal carcinoma. The median number of chemotherapy cycles received was 3 (range 1–6), and all 8 patients received pembrolizumab. Seven patients continue study treatment; 1 patient discontinued due to disease progression. Five patients had an adverse event (AE) related to any study treatment, including 4 patients with ≥ 1 trilaciclib-related AE. There were no grade ≥ 3 treatment-related AEs or serious AEs. On-treatment, post-trilaciclib monotherapy biopsies were available for 4 patients. Following neoadjuvant trilaciclib treatment, the median density of stromal CD8+ T cells increased from 103.1/mm2 at baseline to 229.8/mm2 at day 7. The median CD8+/Treg ratio increased in 2 patients from 1.85 at baseline to 1.90 at day 7. Conclusions: Preliminary analysis of on-treatment tumor biopsies from 4 patients suggests that a single dose of trilaciclib may modulate the immune cell composition in the tumor microenvironment to support antitumor immune responses. The increase in CD8+ T cells following 7-day neoadjuvant treatment with trilaciclib supports previous data suggesting a role in T-cell infiltration. The complete dataset from all patients (estimated enrollment: N ≈ 24) and additional biomarker analyses will be presented. Citation Format: Michael Danso, Joyce O’Shaughnessy, Lisa S. Wang, Kailash Mosalpuria, Sara Hurvitz, Shom Goel, Sarah Ahn, Subing Cao, John S. Yi, Taofik Oyekunle, Amanda Jacobson, Andrew Beelen, Jeremy Force. Trilaciclib induces immune changes within the tumor microenvironment in early-stage triple-negative breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-06-03.

BackgroundHuman epidermal growth factor receptor 2 (HER2)-positive metastatic gastric and gastroesophageal adenocarcinoma (GEA) is globally treated with chemotherapy plus trastuzumab. Novel therapeutic strategies strive to not only optimize efficacy, but also limit toxicities. In MAHOGANY cohort A, margetuximab, an Fc-engineered, anti-HER2 monoclonal antibody (mAb) was combined with retifanlimab, an anti-programmed cell death protein 1 mAb, in the first-line HER2-positive/programmed death-ligand 1 (PD-L1)-positive GEA.Patients and methodsMAHOGANY cohort A part 1 is a single-arm trial to evaluate margetuximab plus retifanlimab in patients with HER2 immunohistochemistry 3+, PD-L1-positive (combined positive score ≥1%), and non-microsatellite instability-high tumors. Primary objectives for cohort A were safety/tolerability and the confirmed objective response rate (ORR).ResultsAs of 3 August 2021, 43 patients were enrolled and received margetuximab/retifanlimab. Nine grade 3 treatment-related adverse events (TRAEs) were reported in eight (18.6%) patients and eight serious TRAEs in seven (16.3%) patients. There were no grade 4/5 TRAEs. Three patients discontinued margetuximab/retifanlimab because of immune-related adverse events. The ORR by independent assessment was 53% [21/40 (95% confidence interval (CI) 36.1-68.5)], with a median duration of response of 10.3 months (95% CI 4.6-not evaluable); disease control rate was 73% [29/40 (95% CI 56.1-85.4)]. The study sponsor discontinued the study in advance of the planned enrollment when it became apparent that the study design would no longer meet the requirements for drug approval because of recent advances in the treatment of GEA.ConclusionsThe chemotherapy-free regimen of combined margetuximab/retifanlimab as first-line treatment in double biomarker-selected patients demonstrated a favorable toxicity profile compared with historical outcomes using chemotherapy plus trastuzumab. The ORR observed in this study compares favorably versus ORR observed with other chemotherapy-free approaches.

8015 Background: Acala is a next-generation, highly selective, covalent Bruton tyrosine kinase inhibitor approved for patients (pts) with CLL including those with R/R CLL. The efficacy and safety of acala alone vs IdR or BR were shown in R/R CLL pts in a preplanned interim analysis of ASCEND; final results are reported herein. Methods: In this randomized, multicenter, phase 3, open-label study (NCT02970318), R/R CLL pts were randomized 1:1 to receive oral (PO) acala 100 mg BID or investigator’s (INV) choice of IdR (Id: 150 mg PO BID until progression or toxicity; R: 375 x1 then 500 mg/m2 intravenously [IV] for 8 total infusions) or BR (B: 70 mg/m2 IV and R: 375 x1 then 500 mg/m2 IV for 6 total cycles) until progression or toxicity. Progression-free survival (PFS), overall survival (OS), overall response rate (ORR), and safety were assessed. Results: 310 pts (acala, n=155; IdR, n=119; BR, n=36) were enrolled (median age: 67 y; del(17p) 16%, del(11q) 27%, Rai stage 3/4 42%). At a median follow-up of 22.0 m, acala significantly prolonged INV-assessed PFS vs IdR/BR (median: not reached vs 16.8 m; hazard ratio: 0.27, P<0.0001); 18-m PFS rates were 82% for acala and 48% for IdR/BR. 18-m OS rate was 88% for both treatment regimens. ORR was 80% with acala vs 84% with IdR/BR (ORR + partial response with lymphocytosis: 92% vs 88%, respectively). Common adverse events (AEs) are listed in the Table. AEs led to drug discontinuation in 16% of acala, 56% of IdR, and 17% of BR pts. AEs of interest included atrial fibrillation (acala 6%, IdR/BR 3%), major hemorrhage (all grade; acala 3%, IdR/BR 3%), grade ≥3 infections (acala 20%, IdR/BR 25%), and second primary malignancies excluding non-melanoma skin cancer (acala 5%, IdR/BR 2%). Conclusions: Final ASCEND results with additional follow-up confirm earlier findings and support the favorable efficacy and safety of acala compared with standard-of-care regimens in R/R CLL pts. Clinical trial information: NCT02970318 . [Table: see text]

The MitraClip (Abbott) is a commercially available device to perform percutaneous transcatheter mitral valve repair (TMVR) for patients with symptomatic mitral regurgitation (MR). Recent data support its role in appropriately selected patients with functional MR, and its use is poised to increase. However, limited safety data in "real-world" practice are available after market introduction. We queried all available adverse event reports from the publicly available Manufacturer and User Facility Device Experience (MAUDE) database including "injuries" and "deaths" from October 2013 (date of Food and Drug Administration [FDA] premarket approval) to September 2017 using the following search limits: brand name ("MitraClip") and product code ("NKM," a unique FDA designation linked to MitraClip). During the first 4 years after FDA approval, MAUDE received 200 death reports and 1666 injury reports containing 2974 unique adverse events. Of all death reports, 21% described deaths occurring >1 year post MitraClip and 30% included limited details. The top three known causes of death included complications requiring rescue high-risk surgery, clip detachment or unsuccessful clip placement, and damage to the valvular apparatus. Similar non-fatal events were reported. Additional procedures or surgical intervention were required in 227 injury events (8%). While injuries reported to the FDA have steadily increased with more widespread use of TMVR, device- or procedure-related death reports have accrued more slowly, corroborating a potential institutional or operator learning curve with this device. However, in light of incomplete and poor data quality, higher-fidelity systems of postmarketing safety surveillance are needed in the evaluation of emerging devices.

[This corrects the article DOI: 10.1371/journal.pone.0221519.].

Abstract Background:POLARIS is a prospective, real-world (RW) study of palbociclib (PAL) in patients (pts) with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2–) advanced breast cancer (ABC) in the US and Canada. Analyses include evaluating the association between circulating tumor DNA (ctDNA) and clinical response to PAL. Methods: All pts provided informed consent. Blood samples are collected on day 1 of each 4-wk cycle for 6 cycles, at day 1 of every 2-3 cycles, and end of treatment. ctDNA is sequenced using the Guardant360 platform for somatic single-nucleotide variants in complete or critical exons of 73 genes. Analyses include association between clinical outcomes and ctDNA mutation frequencies at baseline and change from baseline to cycle 2, day 1 (C2D1), stratified by line of prior therapy. Results: As of July 2018, 127 pts had ≥1 evaluable ctDNA measurement. Of these, 104 had baseline and C2D1 results; 96 had tumor response assessed. The most common mutations at baseline were PIK3CA (41%), TP53 (33%), and ESR1 (20%). PAL was associated with a decline in mutation frequency of PIK3CA, TP53, and ESR1alleles but not all genes, highlighting differential response based on genomic profile and clonal heterogeneity (Table). Overall, fast progressors (progression <6 mo, n=19) tended to have higher baseline ctDNA values and displayed smaller decreases in ctDNA at C2D1 than slow progressors (progression ≥6 mo, n=4). Conclusions: This study is among the first to provide RW data on blood-based genotyping. Interim data indicate that genomic architecture and longitudinal changes may be predictive and prognostic in pts with HR+/HER2– ABC receiving PAL. Updated data from 239 pts will be presented, including association between individual ctDNA mutation dynamics, clonal heterogeneity, and clinical outcomes (therapeutic response and progression-free survival). Pfizer; NCT03280303 Change from baseline in ctDNA mutation frequencyMutationOverall (n=104)*First Line (n=70)Second Line and Later (n=34)Baseline, n (%)†C2D1, n (%)†Baseline, n (%)†C2D1, n (%)†Baseline, n (%)†C2D1, n (%)†PIK3CA43 (41)26 (25)27 (39)14 (20)16 (47)12 (35)TP5334 (33)27 (26)23 (33)17 (24)11(32)10 (29)ESR121 (20)11 (11)9 (13)3 (4)12 (35)8 (24)ARID1A19 (18)14 (13)13 (19)7 (10)6 (18)7 (21)NF111 (11)11 (11)7 (10)6 (9)4 (12)5 (15)BRCA210 (10)10 (10)8 (11)7 (10)2 (6)3 (9)GATA310 (10)5 (5)8 (11)5 (7)2 (6)O (O)None detected13 (13)24 (23)7 (10)20 (29)6 (18)4 (12)ctDNA=circulating tumor DNA; C2D1=cycle 2, day 1. *Patients with both baseline and C2D1 ctDNA data available. †Percentages are relative to the corresponding number of patients (n). Citation Format: Aditya Bardia, Joanne L. Blum, Steven L. McCune, Kamal Patel, Richard C. Frank, Kailash Mosalpuria, Meghan S. Karuturi, Lloyd A. Shabazz, Gabrielle B. Rocque, Yuan Liu, Zhe Zhang, Jian Wang, Yao Wang, Debu Tripathy. Blood-based genotyping and clinical outcomes in patients with advanced breast cancer receiving the CDK4/6 inhibitor palbociclib in real-world settings: Results from POLARIS [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 443.

Background: Acalabrutinib is a highly selective, potent, covalent Bruton tyrosine kinase inhibitor that has shown clinical benefit in patients (pts) with RR CLL. In this randomized, global, multicenter, open-label Phase 3 study, the efficacy and safety of acalabrutinib monotherapy were evaluated vs the investigator's choice of IdR or BR in RR CLL (NCT02970318). Methods: Eligible pts with RR CLL were randomized 1:1 to 100 mg oral acalabrutinib BID until progression vs IdR (150 mg oral Id BID combined with ≤8 IV infusions of R [375 or 500 mg/m2]), or BR (70 mg/m2 IV B on Day 1 and 2 of each cycle combined with R [375 or 500 mg/m2 IV] on Day 1 of each 28-d cycle for ≤6 cycles). Stratification was by del(17p) status (y vs n), ECOG status (0-1 vs 2), and prior therapy lines (1-3 vs ≥4). The primary endpoint was progression-free survival (PFS) assessed by independent review committee (IRC). Secondary endpoints included overall survival (OS), overall response rate (ORR; by IRC), and safety. Pts with confirmed progression on IdR/BR could cross over to receive acalabrutinib monotherapy. Results: 310 pts were randomized to acalabrutinib (n=155) or IdR/BR (n=155 [IdR, n=119; BR, n=36]); median age was 67 y (range, 32-90); 16% had del(17p); 27% had del(11q); 42% had Rai stage III/IV CLL. Median (range) no. of prior therapies was 1 (1-8) for acalabrutinib and 2 (1-10) for IdR/BR. Discontinuation due to AEs occurred in 11% of pts on acalabrutinib vs 49% Id, 12% R in IdR, 11% B and 17% R in BR. At a median follow-up of 16.1 mo, acalabrutinib significantly prolonged IRC-assessed PFS vs IdR/BR (median NR vs 16.5 mo; HR 0.31, 95% CI 0.20-0.49, P<.0001; Figure). PFS rates at 12 mo were 88% with acalabrutinib and 68% with IdR/BR; improvement was seen across subgroups, including del(17p), TP53 mutation and Rai stage. ORR by IRC was similar with acalabrutinib vs IdR/BR (81% vs 75%; p<.22). 12-mo OS rates were 94% and 91% (with 15 and 18 deaths) for acalabrutinib and IdR/BR, respectively. 23% of IdR/BR pts crossed over to acalabrutinib monotherapy. All-grade AEs (≥15%) with acalabrutinib were headache (22%), neutropenia (19%), diarrhea (18%), anemia and cough (15% each); with IdR, diarrhea (47%), neutropenia (45%), pyrexia (18%) and cough (15%); with BR, neutropenia (34%), infusion-related reaction and fatigue (23% each), nausea (20%) and pyrexia (17%). Grade ≥3 AEs (≥5%) with acalabrutinib were neutropenia (16%), anemia (12%) and pneumonia (5%); with IdR (≥15%), neutropenia (40%) and diarrhea (24%); with BR (≥5%), neutropenia (31%), anemia (9%) and constipation (6%). AEs of interest were atrial fibrillation (5.2% of pts on acalabrutinib vs 3.3% on IdR/BR), bleeding AEs (26% vs 7.2%; including major hemorrhage [1.9% vs 2.6%]), Grade ≥3 infections (15% vs 24%) and 2nd primary malignancies (excluding NMSC; 6.5% vs 2.6%).