Trilaciclib prior to chemotherapy reduces the usage of supportive care interventions for chemotherapy-induced myelosuppression in patients with small cell lung cancer: Pooled analysis of three randomized phase 2 trials.

BACKGROUND: Supportive care interventions used to manage chemotherapy-induced myelosuppression (CIM), including granulocyte colony-stimulating factors (G-CSFs), erythropoiesis-stimulating agents (ESAs), and red blood cell (RBC) transfusions, are burdensome to patients and associated with greater costs to health care systems. We evaluated the utilization of supportive care interventions and their relationship with the myeloprotective agent, trilaciclib. METHODS: Data were pooled from three independent randomized phase 2 clinical trials of trilaciclib or placebo administered prior to chemotherapy in patients with extensive-stage small cell lung cancer (ES-SCLC). The impact of supportive care on the duration of severe neutropenia (DSN), occurrence of severe neutropenia (SN), and occurrence of RBC transfusions on/after week 5 was analyzed across cycles 1-4. Concordance and association between grade 3/4 anemia, RBC transfusions on/after week 5, and ESA administration was also evaluated. RESULTS: The use of G-CSFs, ESAs, or RBC transfusions on/after week 5 was significantly lower among patients receiving trilaciclib versus placebo (28.5% vs. 56.3%, p < 0.0001; 3.3% vs. 11.8%, p = 0.0254; and 14.6% vs. 26.1%, p = 0.0252, respectively). Compared with placebo, trilaciclib significantly reduced DSN and SN, irrespective of G-CSF administration. RBC transfusions and ESAs were most often administered in patients with grade 3/4 anemia; however, patients typically received RBC transfusions over ESA administration. CONCLUSIONS: By improving CIM and reducing the need for associated supportive care, trilaciclib has the potential to reduce the burden of myelosuppression on patients receiving myelosuppressive chemotherapy for the treatment of ES-SCLC. TRIAL REGISTRATION: ClinicalTrials.gov (NCT02499770; NCT03041311; NCT02514447).

Exploratory composite endpoint demonstrates benefit of trilaciclib across multiple clinically meaningful components of myeloprotection in patients with small cell lung cancer.

Chemotherapy-induced myelosuppression is an acute, dose-limiting toxicity of chemotherapy regimens used in the treatment of extensive-stage small cell lung cancer (ES-SCLC). Trilaciclib protects haematopoietic stem and progenitor cells from chemotherapy-induced damage (myeloprotection). To assess the totality of the myeloprotective benefits of trilaciclib, including analysis of several clinically relevant but low-frequency events, an exploratory composite endpoint comprising five major adverse haematological events (MAHE) was prospectively defined: all-cause hospitalisations, all-cause chemotherapy dose reductions, febrile neutropenia (FN), prolonged severe neutropenia (SN) and red blood cell (RBC) transfusions on/after Week 5. MAHE and its individual components were assessed in three randomised, double-blind, placebo-controlled Phase 2 trials in patients receiving a platinum/etoposide or topotecan-containing chemotherapy regimen for ES-SCLC and in data pooled from the three trials. A total of 242 patients were randomised across the three trials (trilaciclib, n = 123; placebo, n = 119). In the individual trials and the pooled analysis, administering trilaciclib prior to chemotherapy resulted in a statistically significant reduction in the cumulative incidence of MAHE compared to placebo. In the pooled analysis, the cumulative incidences of all-cause chemotherapy dose reductions, FN, prolonged SN and RBC transfusions on/after Week 5 were significantly reduced with trilaciclib vs placebo; however, no significant difference was observed in rates of all-cause hospitalisations. Additionally, compared to placebo, trilaciclib significantly extended the amount of time patients remained free of MAHE. These data support the myeloprotective benefits of trilaciclib and its ability to improve the overall safety profile of myelosuppressive chemotherapy regimens used to treat patients with ES-SCLC.

Trilaciclib dose selection: an integrated pharmacokinetic and pharmacodynamic analysis of preclinical data and Phase Ib/IIa studies in patients with extensive-stage small cell lung cancer.

PURPOSE: Trilaciclib is a first-in-class CDK4/6 inhibitor that transiently arrests hematopoietic stem and progenitor cells (HSPCs) in the G1 phase of the cell cycle to preserve them from chemotherapy-induced damage (myelopreservation). We report integrated analyses of preclinical and clinical data that informed selection of the recommended Phase II dose (RP2D) used in trilaciclib trials in extensive-stage small cell lung cancer (ES-SCLC). METHODS: A semi-mechanistic pharmacokinetic/pharmacodynamic (PK/PD) model developed from preclinical data guided selection of an optimal dose for G1 bone marrow arrest in a first-in-human Phase I study (G1T28-1-01). PK, PD, safety, and efficacy data from G1T28-1-01 and two Phase Ib/IIa studies (G1T28-02/-03) in ES-SCLC were analyzed to support RP2D selection. RESULTS: Model simulation of bone marrow arrest based on preclinical data predicted that a ≥ 192 mg/m2 dose would induce a 40-50% decrease in total bone marrow proliferation in humans and almost 100% cell cycle arrest of cycling HSPCs. Consistent with this model, analysis of bone marrow aspirates in healthy volunteers after trilaciclib 192 mg/m2 administration demonstrated almost 100% G1 arrest in HSPCs and 40% decrease in total bone marrow proliferation, with minimal toxicity. G1T28-02/-03 reported similar PK parameters with trilaciclib 200 mg/m2 but slightly lower exposures than expected compared with healthy volunteers; consequently, 240 and 280 mg/m2 doses were also tested to match healthy volunteer exposures. Based on PK and relevant safety data, 240 mg/m2 was selected as the RP2D, which was also favored by myelopreservation endpoints in G1T28-02/-03. CONCLUSION: Integrated PK/PD, safety, and efficacy data support 240 mg/m2 as the RP2D for trilaciclib. CLINICALTRIALS. GOV IDENTIFIERS: NCT02243150; NCT02499770; NCT02514447.

CDK4/6 inhibition enhances antitumor efficacy of chemotherapy and immune checkpoint inhibitor combinations in preclinical models and enhances T-cell activation in patients with SCLC receiving chemotherapy.

BACKGROUND: Combination treatment with chemotherapy and immune checkpoint inhibitors (ICIs) has demonstrated meaningful clinical benefit to patients. However, chemotherapy-induced damage to the immune system can potentially diminish the efficacy of chemotherapy/ICI combinations. Trilaciclib, a highly potent, selective and reversible cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor in development to preserve hematopoietic stem and progenitor cells and immune system function during chemotherapy, has demonstrated proof of concept in recent clinical trials. Furthermore, CDK4/6 inhibition has been shown to augment T-cell activation and antitumor immunity in preclinical settings. Therefore, addition of trilaciclib has the potential to further enhance the efficacy of chemotherapy and ICI combinations. METHODS: In murine syngeneic tumor models, a schedule of 3 weekly doses of trilaciclib was combined with chemotherapy/ICI regimens to assess the effect of transient CDK4/6 inhibition on antitumor response and intratumor T-cell proliferation and function. Peripheral T-cell status was also analyzed in patients with small cell lung cancer (SCLC) treated with chemotherapy with or without trilaciclib to gain insights into the effect of transient exposure of trilaciclib on T-cell activation. RESULTS: Preclinically, the addition of trilaciclib to chemotherapy/ICI regimens enhanced antitumor response and overall survival compared with chemotherapy and ICI combinations alone. This effect is associated with the modulation of the proliferation and composition of T-cell subsets in the tumor microenvironment and increased effector function. Transient exposure of trilaciclib in patients with SCLC during chemotherapy treatment both preserved and increased peripheral lymphocyte counts and enhanced T-cell activation, suggesting that trilaciclib not only preserved but also enhanced immune system function. CONCLUSIONS: Transient CDK4/6 inhibition by trilaciclib was sufficient to enhance and prolong the duration of the antitumor response by chemotherapy/ICI combinations, suggesting a role for the transient cell cycle arrest of tumor immune infiltrates in remodeling the tumor microenvironment. These results provide a rationale for combining trilaciclib with chemotherapy/ICI regimens to improve antitumor efficacy in patients with cancer.

Screening for abdominal aortic aneurysms.

Ultrasonography remains the screening modality of choice for abdominal aortic aneurysms despite many advances in imaging modalities. Several randomized trials were performed that demonstrated the effectiveness of ultrasound-based screening to reduce aneurysm-related mortality. Ultrasound is both cost effective and low risk. Controversies do persist in selecting the appropriate populations for screening, and several national societies have set recommendations.

The impact of sex on angioplasty and primary stenting for femoropopliteal occlusive disease: results of the DURABILITY II trial.

BACKGROUND: This study investigates the impact of sex on angioplasty and primary stenting for the treatment of claudicants with femoropopliteal occlusive disease (FPOD). METHODS: Two hundred eighty-seven patients enrolled in the Safety and Effectiveness Study of EverFlex Stent to Treat Symptomatic Femoral-popliteal Atherosclerosis (DURABILITY II) trial (a prospective, nonrandomized, core laboratory audited, and independently adjudicated investigational device exemption trial) were stratified by sex (190 men and 97 women) and reviewed. RESULTS: Women presented with FPOD at an older age than men (71.3 ± 11.2 vs. 65.9 ± 9.9 years; P < 0.001). Men were more likely to be hyperlipidemic (89.5% vs. 79.4%; P = 0.030). No other statistically significant differences were observed with regard to periprocedural comorbidities and demographics. Clinically, women presented more often with severe claudication (64.9% vs. 51.1%; P = 0.033) as compared with men that had more moderate claudication (44.2% vs. 29.9%; P = 0.022). The incidence of rest pain and tissue loss was low and did not vary between sexes. Angiographically, women had smaller reference vessels (4.4 ± 0.8 mm vs. 5.0 ± 0.9 mm; P < 0.001). Longer lesions (91.6 ± 46.8 mm vs. 87.8 ± 43.9 mm) and higher primary (79.0% vs. 76.5%), primary-assisted (90.6% vs. 85.1%), and secondary patency (90.6% vs. 85.7%) rates in women did not achieve statistical significance (P = NS). Mean percent stenosis and occlusion rates were similar between groups, but men were more likely to have severe calcification (47.9% vs. 34.0%; P = 0.020). Inter-Society Consensus for the Management of Peripheral Arterial Disease II classifications were similar between groups. The target lesion revascularization, major adverse event, and mortality rates were similar between groups. At baseline, the absolute claudication distance was 0.29 miles for men, while women only reached 0.14 miles (P < 0.0001). Walking improvement questionnaire scores were also compared; women had significantly lower scores at baseline and at 1 year. CONCLUSIONS: Despite presenting with FPOD at a later age, with more severe claudication, a shorter absolute claudication distance, and smaller vessels than men, women achieved equal patency rates using angioplasty and primary stenting with similar target lesion revascularization, major adverse event, and mortality rates. Despite these findings, women subjectively have worse symptoms at baseline and at 1 year.

The effect of statin use on embolic potential during carotid angioplasty and stenting.

BACKGROUND: Statin use results in atherosclerotic plaque stabilization. We sought to determine the effects of statins on the size and number of embolic particles generated during carotid artery stenting (CAS). METHODS: Embolic debris from carotid filters following CAS was analyzed using photomicroscopy and imaging software. Patient comorbidities, pre-operative cerebrovascular symptoms, statin use, and outcomes (peri-operative major adverse events, MAE) were reviewed. RESULTS: Carotid filters from 62 consecutive CAS procedures were examined. The mean age is 68.7 ± 9.8 years, 64% were men, 41 (66%) were on statins at the time of CAS, and 27 (43.5%) had neurological symptoms pre-procedurally. The mean intra-procedural stenosis was similar between groups (statin: 89.4 ± 7.4% vs. no statin: 88.4 ± 5.9%, P = NS). There was no significant difference in overall pre-operative symptoms between the two groups. Statin users were more likely to have coronary artery disease (CAD, P = 0.02), hyperlipidemia (HL, P = 0.047), or have undergone coronary artery bypass (CABG, P = 0.01). Statin use was associated with significantly less embolic particles (statin: 16.4 ± 2.1 vs. no statin: 42.4 ± 9.5, P = 0.001) during CAS. Further, multivariate analysis controlling for CAD, HL, and CABG confirmed that statin use was independently associated with less captured debris (P = 0.005). There was no significant difference in the mean particle size (statin: 326.2 µm ± 31.1 vs. no statin 310.5 µm ± 41.8), peri-procedural stroke, and MAE between the two groups (P = NS). CONCLUSIONS: Statin use is associated with less embolic debris during CAS. Further investigation utilizing a larger study group is necessary to assess the impact of statin use on peri-procedural outcomes.

Current endovascular treatment of infrarenal abdominal aortic aneurysms and future directions.

The paradigm in elective surgical management of infrarenal abdominal aortic aneurysms (AAAs) has quickly shifted from major open surgical repairs to less invasive, endovascular procedures. In the last few years, there have been numerous advancements to commercially available devices making the endovascular approach more attractive and efficacious. This review serves to detail the similarities, differences, advantages, and disadvantages of currently available endovascular stent-grafts as well as preview future and emerging technologies in endovascular aortic therapies.

A novel approach to the management of an inflammatory abdominal aortic aneurysm associated with crossed-fused renal ectopia.

BACKGROUND: Crossed-fused renal ectopia is a rare anomaly that poses a therapeutic challenge in the management of abdominal aortic aneurysms (AAAs). Such challenges include preservation of renal blood flow in the setting of multiple aberrant renal arteries and ureteral anomalies. Several surgical approaches to this dilemma, including the use of traditional surgical techniques, have been described in the literature. We describe a novel approach to the management of a 7-cm inflammatory AAA associated with crossed renal ectopia with fusion. METHODS: During routine surveillance computed tomography angiography (CTA) in a 63-year-old man, a rapidly enlarging AAA with new inflammatory changes was detected. The aneurysm had increased in size from 4.8 to 7 cm over a period of 6 months. At the time of presentation, he was found to be hemodynamically stable. Findings from the laboratory tests conducted at the time of admission were normal, with a baseline glomerular filtration rate of 91.2 mL/min and creatinine of 1. The CTA revealed significant thickening of the aortic wall, suggestive of aortic inflammation, the presence of crossed renal ectopia with fusion, and numerous anomalous renal arteries. We identified two right renal arteries arising from the proximal aneurysm sac and three left renal arteries arising from the common iliac arteries. Given the aortic inflammation, an open repair approach was considered high risk compared with an endovascular aneurysm repair (EVAR). However, given the uncharacteristic arterial anatomy, a staged surgical and endovascular management option was selected. We performed an aortic debranching and renal artery revascularization, followed by an EVAR. RESULTS: We preserved renal function and excluded the aneurysm. The patient was discharged on the postoperative day 6 without periprocedural complications. A CTA was performed at 1- and 6-month follow-up period. This revealed a type 2 endoleak, which was confirmed by MR angiography. However, the aneurysm diameter had decreased in size from 7 to 6.3 cm in 1 month, and from 6.3 to 5.5 cm in 6 months. No further intervention was performed. CONCLUSION: Inflammatory AAAs associated with crossed-fused renal ectopia can be successfully managed with aortic debranching and renal artery revascularization followed by an EVAR. This epitomizes the growing role for advanced endovascular therapies in conjunction with open surgical techniques.

Predicting embolic potential during carotid angioplasty and stenting: analysis of captured particulate debris, ultrasound characteristics, and prior carotid endarterectomy.

INTRODUCTION: Extracranial carotid stenoses exhibit significant variance in embolic potential, with restenotic lesions having a particularly low propensity for embolization. This study sought to identify characteristics associated with increased generation of embolic debris during carotid angioplasty and stenting (CAS). METHODS: Captured particulate was available for analysis in 56 consecutive patients. Demographics were mean age, 74 years (range, 60-94 years); mean stenosis, 88% (range, 70%-99%); symptomatic, 27%; prior carotid endarterectomy (CEA), 27%; prior radiotherapy, 7%. Plaque echogenicity, heterogenicity, ulceration, and irregularity were assessed with B-mode duplex ultrasound analysis. Gray scale median (GSM) was calculated from normalized B-mode VHS video recordings. Calcification and degree of stenosis were determined angiographically. Captured particulate debris was evaluated for total number; number >200 microm, >500 microm, >1000 microm; mean and median size. Hematoxylin and eosin, trichrome, and von Kossa stains were used for histologic analysis of captured material. RESULTS: Restenotic carotid stenoses after prior CEA generated minimal embolic debris compared with primary stenoses. Four of 15 patients (27%) with restenotic lesions demonstrated embolic particles; all debris was <500 microm. All 41 patients with primary stenoses had some embolic debris; particulate size was >200 microm in 91%, >500 microm in 72%, and >1000 microm in 43%. In primary lesions, the number and size of captured particulate correlated with GSM and with the combined ultrasound findings of echogenicity, heterogenicity, and luminal irregularity/ulceration (P < .02, 95% confidence interval, 4.5-27.6). None of these ultrasound factors correlated independently with embolic particulate (P = NS). Patients aged >70 years exhibited more total particles (8.1 vs 2.3, P = .008) and increased mean particle size (370 vs 157 mum, P = .02). No significant correlation was observed between the number and size of captured embolic particulate and any other variable (stenosis percentage, prior radiotherapy, preprocedural symptoms, periprocedural symptoms, and calcification). Histologically, the embolic debris consisted of extensive amorphous, acellular proteinaceous material. Calcium debris in the embolic particulate was associated with heavily and moderately calcified lesions. CONCLUSIONS: Considerable variation exists in the number and size of embolic particles generated during CAS. Embolic potential is positively correlated with lesion GSM and the combination of lesion echogenicity, heterogenicity, and irregularity. Restenosis after prior CEA is associated with minimal embolic particulate generation, suggesting that embolic protection may not be necessary for CAS of restenotic lesions.

Tips and techniques in carotid artery stenting.

Significant technical advances have made carotid artery stenting an option for high-risk patients. These advances bring forth new challenges that must be overcome. Preprocedural planning is essential for optimal outcome for every patient given the high risk for significant neurologic complications. In this article we describe a standard approach for performing carotid artery stenting and techniques used to circumvent challenges that may be encountered. In addition, implementation of modifications and advanced techniques in challenging cases may allow successful treatment of carotid stenosis. Maintenance of proficiency in carotid artery stenting requires significant and ongoing experience.