Safety of extended pirtobrutinib exposure in relapsed and/or refractory B-cell malignancies.

INTRODUCTION: Pirtobrutinib, a highly selective, non-covalent (reversible) Bruton tyrosine kinase inhibitor, has demonstrated promising efficacy in B-cell malignancies and is associated with low rates of discontinuation and dose reduction. Pirtobrutinib is administered until disease progression or toxicity, necessitating an understanding of the safety profile in patients with extended treatment. METHODS: Here we report the safety of pirtobrutinib in patients with relapsed/refractory B-cell malignancies with extended (≥12-months) drug exposure from the BRUIN trial. Assessments included median-time-to-first-occurrence of adverse events (AEs), dose reductions, and discontinuations due to treatment-emergent AEs (TEAEs) and select AEs of interest (AESIs). RESULTS: Of 773 patients enrolled, 326 (42%) received treatment for ≥12 months. In the extended exposure cohort, the median-time-on-treatment was 19 months. The most common all-cause TEAEs were fatigue (32%) and diarrhea (31%). TEAEs leading to dose reduction occurred in 23 (7%) and discontinuations in 11 (3%) extended exposure patients. One patient had a fatal treatment-related AE (COVID-19 pneumonia). Infections (73.0%) was the most common AESI with a median-time-to-first-occurrence of 7.4 months. Majority of TEAEs and AESIs occurred during the first-year of therapy. CONCLUSIONS: Pirtobrutinib therapy continues to demonstrate an excellent safety profile amenable to long-term administration without evidence of new or worsening toxicity signals.

Pirtobrutinib versus venetoclax in covalent Bruton tyrosine kinase inhibitor-pretreated chronic lymphocytic leukemia: a matching-adjusted indirect comparison.

Venetoclax is a standard treatment for patients with CLL following covalent BTK inhibitor (cBTKi) therapy, despite relatively limited prospective data in this setting. Pirtobrutinib is a highly selective, non-covalent (reversible) BTKi that was designed to overcome the pharmacologic limitations of cBTKi and re-establish BTK inhibition. An unanchored matching-adjusted indirect comparison (MAIC) was conducted to estimate the treatment effect of pirtobrutinib versus venetoclax monotherapy in patients with cBTKi pre-treated CLL. Data from patients with CLL who were venetoclax-naïve and pre-treated with cBTKi received pirtobrutinib (n=146) in the phase 1/2 BRUIN study were compared with the only identified trial of patients with CLL receiving venetoclax after a cBTKi (n=91), as administered as monotherapy until progression. Outcomes included progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and treatment-emergent adverse events (TEAEs). Both unweighted and weighted analyses were conducted. PFS and OS of pirtobrutinib and venetoclax were comparable in both unweighted and weighted analyses (weighted hazard ratios for PFS: 1.01, 95% CI: 0.58-1.73, p=0.98 and OS: 0.64, 95% CI: 0.25-1.67, p=0.34). ORR was significantly higher for pirtobrutinib (80.2% vs 64.8%, p=0.01). Grade ≥3 TEAEs were lower in weighted analyses for pirtobrutinib vs venetoclax (all p.

MAJIC: a phase III trial of acalabrutinib + venetoclax versus venetoclax + obinutuzumab in previously untreated chronic lymphocytic leukemia or small lymphocytic lymphoma.

Here we describe the rationale and design of MAJIC, a phase III, prospective, multicenter, randomized trial comparing the combination of the BTK inhibitor acalabrutinib plus the BCL2 inhibitor venetoclax versus the combination of venetoclax plus obinutuzumab as frontline treatment for chronic lymphocytic leukemia or small lymphocytic lymphoma. In both treatment arms, disease response (assessed by International Workshop on Chronic Lymphocytic Leukemia criteria) and minimal residual disease will be used to guide therapy duration, with all patients ultimately discontinuing treatment after a maximum of 2 years. The primary end point is progression-free survival. Key secondary end points include rates of undetectable minimal residual disease, overall response and overall survival. This study will address key unanswered questions in frontline chronic lymphocytic leukemia/small lymphocytic lymphoma therapy by investigating the optimal duration of finite treatment and identifying the optimal venetoclax doublet regimen.

This article describes the design of the MAJIC clinical trial, which investigates two different treatment combinations for patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) who have not received treatment for their disease previously. Patients will be randomized (put into a group by chance) to receive either acalabrutinib + venetoclax (AV) or venetoclax + obinutuzumab (VO). VO is already an approved initial treatment option for CLL/SLL. Acalabrutinib is also an approved initial treatment option when given by itself, but the AV combination is not yet approved. We are doing this study to better understand and directly compare how well AV and VO work when used for the treatment of CLL/SLL. A test done on the blood and bone marrow called 'minimal residual disease' will be used to help guide the length of time that patients receive treatment. Clinical Trial Registration: NCT05057494 (ClinicalTrials.gov).

Matching-adjusted indirect comparisons of safety and efficacy of acalabrutinib versus other targeted therapies in patients with treatment-naïve chronic lymphocytic leukemia.

Acalabrutinib is a highly selective, potent, next-generation, covalent Bruton tyrosine kinase inhibitor with minimal off-target activity. Matching-adjusted indirect comparisons (MAICs) were performed to estimate the safety and efficacy of acalabrutinib compared to other targeted therapies for treatment-naïve patients with chronic lymphocytic leukemia (CLL). Individual patient data for acalabrutinib (ELEVATE-TN trial) were matched to aggregate baseline characteristics for comparators. After matching, acalabrutinib (with or without obinutuzumab) showed improved safety outcomes, except for increased risk of neutropenia (p < 0.001) for acalabrutinib plus obinutuzumab versus ibrutinib and increased risk of leukopenia (p < 0.05) for acalabrutinib (with or without obinutuzumab) versus venetoclax plus obinutuzumab. There was no statistically significant difference in progression-free survival between acalabrutinib (with or without obinutuzumab) and any of the comparators. This MAIC demonstrated a favorable safety profile for acalabrutinib-based therapy compared with other targeted therapies in treatment-naïve patients with CLL, without compromising efficacy.

Comparative Efficacy of Acalabrutinib in Frontline Treatment of Chronic Lymphocytic Leukemia: A Systematic Review and Network Meta-analysis.

PURPOSE: The goal of this study was to estimate the relative efficacy of acalabrutinib (monotherapy and in combination with obinutuzumab) compared with standard frontline treatments for chronic lymphocytic leukemia (CLL) in fludarabine-ineligible patients, through a network meta-analysis (NMA). METHODS: The efficacy of acalabrutinib from ELEVATE-TN (study of Obinutuzumab + Chlorambucil, Acalabrutinib [ACP-196] + Obinutuzumab, and Acalabrutinib in Subjects With Previously Untreated CLL) was compared to bendamustine + rituximab, chlorambucil-based therapy, alemtuzumab, ibrutinib mono/combination therapy and venetoclax + obinutuzumab using data from eight randomized controlled trials (RCTs). Relevant RCTs were identified using a systematic literature review. Two evidence networks were constructed: Network A, composed solely of RCTs that met the inclusion criteria; and Network B, composed of 7 RCTs and a published cross-trial comparison of ibrutinib from RESONATE-2 and chlorambucil + obinutuzumab from iLLUMINATE. Bayesian NMAs were conducted on progression-free survival (PFS) and overall survival (OS) endpoints; results were reported by using hazard ratios (HRs) and 95% credible intervals (CrIs). HRs were considered significant if their CrIs did not cross 1. Treatments were ranked by using the surface under the cumulative ranking area (SUCRA) values. Expert opinion from 2 hematologists was sought to validate results. FINDINGS: Both networks showed a significant improvement in PFS for acalabrutinib + obinutuzumab over all comparators. Both networks also showed a significant improvement in PFS for acalabrutinib monotherapy versus most comparators, with a significant difference to ibrutinib monotherapy found in Network A but not Network B. Conversely, a significant difference in PFS was observed for acalabrutinib monotherapy versus venetoclax + obinutuzumab in Network B but not Network A. Although OS HRs all favored acalabrutinib, most were not significant and were characterized by wide CrIs, indicating a high level of uncertainty. Acalabrutinib + obinutuzumab ranked highest in terms of PFS improvement (SUCRA values, 98% and 100%) and OS improvement (SUCRA values, 92% and 94%), followed by acalabrutinib monotherapy (SUCRA values for PFS, 88% and 90%; OS, 83% and 87%) in Networks A and B, respectively. IMPLICATIONS: Acalabrutinib was associated with favorable PFS and OS compared with frontline CLL therapies and ranked highest in treatment efficacy over the other comparators. The NMA was limited by heterogeneity in patient baseline characteristics across trials, variable treatment regimens, and short study follow-up times. Despite these limitations, the NMA provides insights into the relative efficacy of acalabrutinib compared with frontline CLL therapies in the absence of head-to-head clinical trials.

Matching-adjusted Indirect Comparisons of the Efficacy and Safety of Acalabrutinib Versus Other Targeted Therapies in Relapsed/Refractory Mantle Cell Lymphoma.

PURPOSE: Mantle cell lymphoma (MCL) is a rare subtype of B-cell non-Hodgkin lymphoma that can be either aggressive or indolent. Although MCL usually responds well to initial treatment with chemotherapy-based regimens, the disease often relapses or becomes refractory within a few years. Acalabrutinib is a highly selective, potent, covalent Bruton tyrosine kinase inhibitor with minimal off-target activity. WIthout head-to-head clinical trial data, estimation of the comparative efficacy and safety of new therapeutic entities provides valuable information for patients, clinicians, and health care payers. The objective of this analysis was to compare the efficacy and safety of acalabrutinib versus other targeted therapies employed for the treatment of relapsed/refractory MCL by using matching-adjusted indirect comparisons. METHODS: Individual data from 124 patients treated with acalabrutinib in the Phase II ACE-LY-004 trial were adjusted to match average baseline characteristics of populations from studies using alternative targeted treatment regimens for relapsed/refractory MCL (for monotherapy: ibrutinib, bortezomib, lenalidomide, and temsirolimus; for combination therapies: ibrutinib + rituximab, bendamustine + rituximab, and lenalidomide + rituximab). Patient populations were matched on age, sex, race, Eastern Cooperative Oncology Group performance status, Simplified MCL International Prognostic Index score, tumor bulk, lactate dehydrogenase concentration, extranodal disease, bone marrow involvement, and number of previous treatment regimens. Outcomes assessed included overall response rate (ORR), complete response (CR) rate, overall survival (OS), progression-free survival (PFS), and adverse events. FINDINGS: After matching, acalabrutinib was associated with significant increases in ORR and CR rate (estimated treatment difference [95% CI]) versus ibrutinib (ORR, 9.3% [0.3-18.3]; CR, 14.9% [5.4-24.3]), bortezomib (ORR, 50.6% [40.2-61.0]; CR, 18.8% [9.1-28.5]), lenalidomide (ORR, 38.1% [27.1-49.1]; CR, 43.5% [34.8-52.3]), and temsirolimus (ORR, 40.7% [31.0-50.4]; CR, 27.1% [19.2-35.0]). PFS (hazard ratio [95% CI]) with acalabrutinib was significantly increased versus bortezomib (0.36 [0.26-0.51]), lenalidomide (0.65 [0.48-0.89]), lenalidomide + rituximab (0.57 [0.35-0.93]), and temsirolimus (0.33 [0.24-0.45]). Acalabrutinib was associated with significantly increased OS (hazard ratio) versus bortezomib (0.36 [0.22-0.61]) and temsirolimus (0.32 [0.23-0.44]). The overall safety profile of acalabrutinib was similar or better compared with the monotherapies; however, infection risk increased versus bendamustine + rituximab, and anemia increased risk versus lenalidomide + rituximab and ibrutinib + rituximab. IMPLICATIONS: This comparison of targeted therapies used in the treatment of relapsed/refractory MCL showed that acalabrutinib has the potential to provide increased response rates, with trends for increased PFS and OS, and an improved safety profile.

Post hoc analyses of East Asian patients from the randomized placebo-controlled PREVAIL trial of enzalutamide in patients with chemotherapy-naïve, metastatic castration-resistant prostate cancer.

BACKGROUND: Enzalutamide is an androgen receptor (AR) inhibitor that acts on different steps in the AR signaling pathway. In PREVAIL, an international, phase III, double-blind, placebo-controlled trial, enzalutamide significantly reduced the risk of radiographic progression by 81% (hazard ratio [HR], 0.19; P < .0001) and reduced the risk of death by 29% (HR, 0.71; P < .0001) compared with placebo in chemotherapy-naïve men with metastatic castration-resistant prostate cancer. METHODS: To evaluate treatment effects, safety, and pharmacokinetics of enzalutamide in East Asian patients from the PREVAIL trial, we performed a post hoc analysis of the Japanese, Korean, and Singaporean patients. PREVAIL enrolled patients with asymptomatic or mildly symptomatic chemotherapy-naïve metastatic castration-resistant prostate cancer who had progressed on androgen deprivation therapy. During the study, patients received enzalutamide (160 mg/d) or placebo (1:1) until death or discontinuation because of radiographic progression or skeletal-related event and initiation of subsequent therapy. Centrally assessed radiographic progression-free survival (rPFS) and overall survival (OS) were coprimary endpoints. The secondary endpoints of the PREVAIL trial were investigator-assessed rPFS, time to initiation of chemotherapy, time to prostate-specific antigen (PSA) progression, and PSA response (≥50% decline). RESULTS: Of 1717 patients, 148 patients were enrolled at sites in East Asia (enzalutamide 73, placebo 75). Treatment effect of enzalutamide versus placebo was consistent with that for the overall population as indicated by the HRs (95% confidence interval) of 0.38 (0.10-1.44) for centrally assessed rPFS, 0.59 (0.29-1.23) for OS, 0.33 (0.19-0.60) for time to chemotherapy, and 0.32 (0.20-0.50) for time to PSA progression. In East Asian patients, PSA responses were observed in 68.5% and 14.7% of enzalutamide- and placebo-treated patients, respectively. The enzalutamide plasma concentration ratio (East Asian:non-Asian patients) was 1.12 (90% confidence interval, 1.05-1.20) at 13 weeks. Treatment-related adverse events grade ≥ 3 occurred in 1.4% and 2.7% of enzalutamide- and placebo-treated East Asian patients, respectively. CONCLUSIONS: Treatment effects and safety of enzalutamide in East Asian patients were generally consistent with those observed in the overall study population from PREVAIL. CLINICALTRIALS. GOV NUMBER: NCT01212991.

BRAFV600 mutations in solid tumors, other than metastatic melanoma and papillary thyroid cancer, or multiple myeloma: a screening study.

BACKGROUND: Mutations in the BRAF gene have been implicated in several human cancers. The objective of this screening study was to identify patients with solid tumors (other than metastatic melanoma or papillary thyroid cancer) or multiple myeloma harboring activating BRAFV600 mutations for enrollment in a vemurafenib clinical study. METHODS: Formalin-fixed, paraffin-embedded tumor samples were collected and sent to a central laboratory to identify activating BRAFV600 mutations by bidirectional direct Sanger sequencing. RESULTS: Overall incidence of BRAFV600E mutation in evaluable patients (n=548) was 3% (95% confidence interval [CI], 1.7-4.7): 11% in colorectal tumors (n=75), 6% in biliary tract tumors (n=16), 3% in non-small cell lung cancers (n=71), 2% in other types of solid tumors (n=180), and 3% in multiple myeloma (n=31). There were no BRAFV600 mutations in this cohort of patients with ovarian tumors (n=68), breast cancer (n=86), or prostate cancer (n=21). CONCLUSION: This multicenter, national screening study confirms previously reported incidences of BRAFV600 mutations from single-center studies. Patients identified with BRAFV600 mutations were potentially eligible for enrollment in the VE-BASKET study.

Treatment patterns and outcomes in BRAF V600E-mutant melanoma patients with brain metastases receiving vemurafenib in the real-world setting.

Brain metastases are a common and serious complication among patients with metastatic melanoma. The selective BRAF inhibitor vemurafenib has demonstrated clinical efficacy in patients with BRAF V600E-mutant melanoma brain metastases (MBM). We examined the real-world application and clinical outcomes of vemurafenib in this patient population. Demographic, treatment patterns, response, and survival data were collected from medical charts. Clinical data on 283 patients with active BRAF V600E-mutant MBM treated with vemurafenib were provided by 70 US oncologists. Mean age was 57.2 years, 60.8% were male, 67.5% had ECOG performance status of 0-1, and 43.1% used corticosteroids at vemurafenib initiation. Median follow-up was 5.7 months. Following vemurafenib initiation, 48.1% of patients experienced intracranial response and 45.6% experienced extracranial response. The Kaplan-Meier estimate for overall survival was 59% at 12 months. Multivariate analyses showed associations between intracranial response and both corticosteroid use and vemurafenib as initial therapy after MBM diagnosis. Larger size (5-10 mm vs. < 5 mm) and number of brain metastases (≥ 5 vs. < 2) and progressive extracranial disease at treatment initiation were associated with decreased intracranial response and increased risk of disease progression. Multiple extracranial sites (2 vs. < 2) and the absence of local treatments were also associated with increased risk of progression. Increased risk of death was associated with ≥ 2 extracranial disease sites, progressive extracranial disease, and ≥ 5 brain metastases. Subgroups of MBM patients may derive more benefit with vemurafenib, warranting prospective investigation.

Comparative healthcare costs in patients with metastatic melanoma in the USA.

Recent advances have increased treatment options for, and improved clinical outcomes in, metastatic melanoma (mM). Using a large claims database, this retrospective study compared healthcare and adverse event (AE) costs in a US managed care population of mM patients initiating vemurafenib (VEM), ipilimumab (IPI), dacarbazine (DTIC), paclitaxel (PAC), or temozolomide (TMZ) from July 2009 to September 2012. Treatment episodes were identified from the start of study drugs (index date) to a switch to a different study drug, or a gap greater than 45 days (>112 days for IPI). Grade 3/4 adverse events occurring ≥5% from study drug package inserts were selected for this analysis. All-cause costs for treatment episodes and AEs were normalized as monthly costs. Generalized estimating equation models with log link and gamma distribution provided adjusted monthly treatment episode and AE costs. A total of 809 treatment episodes were identified in 541 mM patients, with a mean (SD) age of 57.5 (11.5) years. The total mean (SD) all-cause cost per treatment episode for VEM was $77 687 ($60 329), for IPI was $153 062 ($134 048), for DTIC was $35 243 ($33 641), for TMZ was $42 870 ($41 384), and for PAC was $58 991 ($81 306). The adjusted mean monthly treatment episode cost for VEM was significantly lower than that for IPI and comparable to that for other drugs. VEM had a significantly lower monthly AE cost than IPI, DTIC, and PAC. In combination with safety and efficacy findings, these results may assist clinicians, patients, policy makers, and payers in the treatment of mM.

Neuropeptide Y acts at Y1 receptors in the rostral ventral medulla to inhibit neuropathic pain.

Brain microinjection studies in the rat using local anesthetics suggest that the rostral ventral medulla (RVM) contributes to the facilitation of neuropathic pain. However, these studies were restricted to a single model of neuropathic pain (the spinal nerve ligation model) and to just two stimulus modalities (non-noxious tactile stimulus and heat). Also, few neurotransmitter systems have been shown to modulate descending facilitation. After either partial sciatic nerve ligation (PSNL) or spared nerve injury (SNI), we found that unilateral or bilateral microinjection of lidocaine into the RVM reduced not only mechanical allodynia (decreased threshold to von Frey hairs and/or an automated device) and mechanical hyperalgesia (increased paw lifting in response to a noxious pin), but also cold hypersensitivity (increased lifting in response to the hindpaw application of a drop of acetone). Application of a drop of water did not elicit paw withdrawal, indicating that the acetone test is indeed a measure of cold hypersensitivity. We found significant neuropeptide Y Y1-like immunoreactivity within, and lateral to, the midline RVM. Intra-RVM injection of neuropeptide Y (NPY) dose-dependently inhibited the mechanical and cold hypersensitivity associated with PSNL or SNI, an effect that could be blocked by the Y1 receptor antagonist BIBO 3304. We conclude that medullary facilitation spans multiple behavioral signs of allodynia and hyperalgesia in multiple models of neuropathic pain. Furthermore, NPY inhibits behavioral signs of neuropathic pain, possibly by acting at Y1 receptors in the RVM.

Right atrial dimension-pressure relation during volume expansion is unaltered by pregnancy in the rat.

Blood volume expands significantly during pregnancy, but afferent signals from cardiac receptors are reduced. In addition, during exogenous volume expansion, right atrial pressure (RAP) increases more for equivalent volumes in pregnant animals, implying reduced atrial compliance. To examine possible gestational alterations in atrial dimension during volume expansion, we compared the effects of volume expansion on RAP and right atrial dimension (RAD) in pregnant vs. virgin rats. Anesthetized animals were ventilated and catheterized for measurement of arterial pressure and RAP and for drug infusion. Through a parasternal incision, ultrasonic crystals were glued to the medial and lateral surfaces of the right atrium for measurement of RAD. Plasma volume and hematocrit were determined before experimentation. RAP, RAD, and arterial pressure were recorded at baseline and during progressive volume expansion (6% dextran, 60% of initial blood volume). Baseline RAP was similar in the two groups: 2.82 +/- 0.40 and 2.72 +/- 0.47 mmHg in pregnant and virgin rats, respectively. Basal RAD was significantly larger in pregnant than in virgin rats: 4.36 +/- 0.66 vs. 3.36 +/- 0.48 mm. Despite increased basal RAD in pregnant rats, the slope of the RAD-RAP relation during volume expansion was similar in the two groups. Results indicate that resting RAD is increased in pregnant rats and that the change in dimension during volume loads is similar to that in virgin rats. Thus, during pregnancy, the right atrium appears to accommodate the increased blood volume, and reduced afferent signaling most likely is due to mechanisms other than mechanical alterations of the atrium by expanded volume.