Tyrosine Kinase Inhibitors Research Articles

Clinical Characteristics and Survival Analysis of Single Center Adult Chronic Myeloid Leukemia in Chronic Phase

To investigate the clinical characteristics and prognosis of single center adult chronic myeloid leukemia in chronic phase (CML-CP). Clinical data of 41 adult CML-CP patients in Department of Hematology, Shanghai Fengxian District Central Hospital from January 2015 to May 2021 were retrospectively analyzed. The clinical characteristics and prognosis of patients between <60 years group and ≥60 years group were compared. The 41 patients included 27 (65.9%) males and 14 (34.1%) females. The median age of the patients was 56(19-84) years, with 22 cases (53.7%) <60 years and 19 cases (46.3%) ≥60 years. Univariate analysis indicated that the proportions of patients with comorbidities, intermediate/high-risk Sokal score, myelofibrosis, and lactate dehydrogenase ≥1 000 U/L were significantly increased in ≥60 years group compared with <60 years group at initial diagnosis (all P <0.05). There were no statistical differences in the distribution of sex, ELST score, white blood cell count, platelet count, peripheral blood basophil percentage, peripheral blood eosinophil percentage and bone marrow primitive cell percentage between the two groups (P >0.05). The proportion of patients taking reduced-dose imatinib in ≥60 years group significantly increased (P <0.001). Patients <60 years had a higher proportion of molecular biological remission after treatment of tyrosine kinase inhibitors (TKIs) than patients ≥60 years (P <0.001). The incidence of non-hematologic adverse reactions to TKI therapy significantly increased in patients ≥60 years (P <0.001). Multivariate analysis showed that no adverse factors affecting the efficacy and prognosis of TKI. Compared with adult CML-CP patients <60 years, patients ≥60 years gain fewer benefits from TKI treatment and increased adverse reactions.

PSMD2 overexpression as a biomarker for resistance and prognosis in renal cell carcinoma treated with immune checkpoint and tyrosine kinase inhibitors.

Integrated immune checkpoint inhibitors (ICIs) plus tyrosine kinase inhibitors (TKIs) are now the recommended first-line therapy to manage renal cell carcinoma (mRCC). Proteasome 26S subunit non-ATPase 2 (PSMD2) overexpression in tumors has been correlated with tumor progression. Currently, mRCC lacks an established biomarker for the combination of ICI+TKI. This study involved RNA sequencing of RCC patients from two cohorts treated with ICI+TKI (ZS-MRCC and JAVELIN-Renal-101). We utilized immunohistochemistry alongside flow cytometry, aiming at assessing immune cell infiltration and functionality in high-risk localized RCC samples. Response and progression-free survival (PFS) were evaluated relying upon RECIST criteria. PSMD2 was significantly overexpressed in advanced RCC and among non-responders to ICI+TKI therapy. Overexpressed PSMD2 was correlated with poor PFS in the ZS-MRCC and JAVELIN-101 cohorts. Multivariate Cox analysis validated PSMD2 as an independent PFS predictor. PSMD2 overexpression was related to a reduction in CD8+ T cells, especially GZMB+ CD8+ T cells, besides an increase in PD1+ CD4+ T cells. Additionally, tumors with high PSMD2 levels showed enhanced T cell exhaustion levels and a higher regulatory T cell presence. A Machine Learning (ML) model based on PSMD2 expression and other screened factors was subsequently developed to predict the effectiveness of ICI+TKI. Elevated PSMD2 expression is linked to resistance and decreased PFS in mRCC patients undergoing ICI+TKI therapy. High PSMD2 levels are also associated with impaired function and increased exhaustion of tumor-infiltrating lymphocytes. An ML model incorporating PSMD2 expression could potentially identify patients who may have a higher likelihood of benefiting from ICI+TKI.

First-Line Tyrosine Kinase Inhibitors in Soft-Tissue Sarcomas: A Role for Anlotinib?

The optimal medical treatment of chemotherapy-ineligible patients affected by advanced soft-tissue sarcomas is unclear. In this population, tyrosine kinase inhibitors represent an appealing alternative treatment strategy. First-line use of the tyrosine kinase inhibitor anlotinib in chemotherapy-ineligible patients with soft-tissue sarcoma showed promising activity across multiple histologies. See related article by Li et al., p. 4310.

Being Present-CML: A mindfulness-based intervention for patients with chronic myeloid leukemia taking tyrosine kinase inhibitors.

353 Background: Tyrosine kinase inhibitors (TKIs) prolong the lives of patients with chronic phase chronic myeloid leukemia (CP-CML) but can cause side effects that negatively impact quality of life. Mindfulness-based interventions (MBIs) have improved symptoms in patients with solid tumors but have not been studied in patients with CP-CML. We sought to determine if a MBI is feasible and acceptable to patients with CP-CML and explored its preliminary efficacy. Methods: Being Present-CML is a prospective, single-arm clinical trial of an 8-week, online MBI developed for patients with GI cancers (Atreya, et al. PLoS One, 2018) and adapted to include qigong. Participants were recruited from a single academic institution. Eligibility included adult patients with CP-CML taking TKIs. Participants played audio-guided meditations at least 5 times per week on a secure website and participated in weekly, instructor-led meditation and qigong sessions on Zoom. Feasibility was assessed through measurement of recruitment and attrition. Adherence was determined by web capture. Acceptability was determined from surveys and qualitative interviews. Preliminary efficacy was evaluated by patient-reported outcome measures (PROMs) at baseline (week 0) and post-intervention (week 8). Descriptive statistics and two-tailed paired t-tests (p&lt;0.05) were used to summarize the data. Interim results were presented previously; here we report the final results. Results: Between October 2020-September 2021, 121 eligible participants were approached to participate, and 46 patients (38%) consented. The median age was 49.5 years (range 23-75), 54.3% (n=25/46) were male, and 82.6% (n=38/46) were non-Hispanic White. At time of study start, 82.6% (n=38/36) were taking dasatinib, 84.7% (n=39/46) had a BCR-ABL1 PCR transcript ≤1%, and a median time since diagnosis of 70.5 months (range 1-234). Of 46 participants, 35 (76.1%) completed end of study procedures. The median number of audio meditations listened to per participant was 28.7 with an average of 4.1 per week. The median number of 8 weekly classes attended and/or recordings viewed per participant was 7 (range 0-8). At baseline, participants had an average NCCN Distress Thermometer score of 4.86 (range 0-8), which improved to 3.5 by week 8 (p=0.02). Nearly all participants would recommend the to others (median score of 9 on a 1-10 scale; 10=extremely likely). Conclusions: Patients with CP-CML taking TKIs found the MBI to be feasible and acceptable. PROM results suggest potential for distress reduction in this patient population. Clinical trial information: NCT04605211 .

What do we know about the role of neoadjuvant targeted therapy in early-stage EGFR-mutant and ALK-fused non-small cell lung cancer?-a narrative review of the current literature.

The standard first-line treatment for patients with advanced non-small cell lung cancer (NSCLC) harbouring epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) fusions is targeted therapy using tyrosine kinase inhibitors (TKIs). However, data are still lacking on the use of TKIs as a neoadjuvant or induction approach. Therefore, this narrative review aims to summarize the current knowledge on resectable EGFR-mutant and ALK-fused NSCLC regarding available perioperative treatment regimens and off-label neoadjuvant use of targeted therapy. The relevant literature was identified by using PubMed and ClinicalTrials.gov (last search phase June 2024) and was restricted to English language. Peer-reviewed manuscripts but also conference abstracts that did not undergo peer-review were included. Patients with EGFR-mutations and ALK-fusions have typically been excluded from available phase III perioperative immunotherapy trials due to lower efficacy and higher toxicity of immunotherapy in those patients. In the adjuvant setting, recent evidence from the phase III ALINA and ADAURA trials demonstrated efficacy and safety of targeted therapy in resected ALK-fused and EGFR-mutant NSCLC. However, to date there is no approval for the use of TKIs as neoadjuvant or induction therapy in those patients. We have therefore identified a number of case series and phase II trials using targeted therapy in resectable EGFR-mutant and ALK-fused NSCLC. Current evidence suggests that targeted therapies might be effective in patients with resectable EGFR-mutant and ALK-positive NSCLC, but ongoing trials will need to provide further evidence on the safety and efficacy of perioperative TKI therapy.

New ABL1 Kinase Domain Mutations in BCR::ABL1-Positive Acute Lymphoblastic Leukemia.

Since the development of the first-generation Tyrosine Kinase Inhibitor (TKI), it has played a crucial role in the treatment of BCR::ABL1-positive acute lymphoblastic leukemia (ALL) and chronic myeloid leukemia (CML). However, ABL1 kinase domain (ABL1 KD) mutations confer resistance to several TKIs. These mutations have been extensively studied in chronic myeloid leukemia (CML) but less so in BCR::ABL1-positive acute lymphoblastic leukemia (ALL). Our study aimed to analyze the the ABL1 KD mutations in 97 consecutive newly-diagnosed adults with BCR::ABL1-positive ALL before therapy, in cytogenetic complete remission and at relapse with next generation sequencing (NGS). The relationship between ABL1 KD mutations and TKI selection was also analyzed. Previously unreported ABL1 KD mutations R239G, F401V/L, R516L and K262T were the most prevalent in pre-therapy and cytogenetic remission samples, whereas T315I/P and P-loop mutations were most prevalent in relapse samples. R239G, F401V/L, R516L and K262T are related to the BCR::ABL1 structure, whereas T315I/P and P-loop mutations directly alter kinase activity. BaF3 cells transfected with ABL1 KD F401V, K262T, R239G, or R516L mutations were resistant to imatinib but strongly inhibited by olverembatinib with IC50 values of 0.73 to 1.52nM. Meanwhile, olverembatinib had advantages in increasing complete molecular response (CMR) and good prognosis. Overall, our findings indicate the prevalence and impact of new ABL1 KD mutations in BCR::ABL1-positive ALL patients, highlighting the necessity for effective therapies targetingthese mutations.

The role of cytoreductive nephrectomy in the era of immune checkpoint inhibitors: A review of current evidence and ongoing trials.

Renal cell carcinoma (RCC) was diagnosed in over 400 000 individuals globally in 2020, making it a significant global health concern. The incidence of RCC varies by region and overall mortality rates have been declining. This decline is attributed in part to advancements in early cancer detection through imaging and the development of more effective systemic therapies. Cytoreductive nephrectomy (CN) was adopted as a standard treatment for metastatic RCC (mRCC) based on clinical experience and early clinical trials. However, the treatment landscape has shifted with the introduction of tyrosine kinase inhibitors (TKI) in 2007 and, more recently, immune checkpoint inhibitors (ICIs). Dual ICI therapy and combinations of ICIs with TKIs are collectively referred to as immuno-combination therapies and have become standard first-line treatments. This review examines the evolving role of CN in the era of immuno-combination therapies, with a focus on patient selection and the timing of surgery. The immunogenic nature of RCC, characterized by spontaneous tumor regression and immune cell infiltration, suggests a potential benefit from combining CN with ICI therapy to enhance treatment outcomes. This is supported by several clinical studies that reported improved outcomes; however, these were limited by their retrospective nature. Ongoing clinical trials, such as NORDIC-SUN, PROBE, and SEVURO-CN, are expected to provide critical insights into the role of CN in the ICI era. Their findings will ultimately guide future clinical decision-making and further refine treatment strategies for mRCC.

Repotrectinib: Redefining the therapeutic landscape for patients with ROS1 fusion-driven non-small cell lung cancer.

The ROS1 proto-oncogene encodes a receptor tyrosine kinase with structural homology to other oncogenic drivers, including ALK and TRKA-B-C. The FDA-approved tyrosine kinase inhibitors (TKIs) crizotinib and entrectinib have demonstrated efficacy in treating ROS1 fusion-positive NSCLC. However, limitations such as poor blood-brain barrier penetration and acquired resistance, particularly the ROS1 G2032R solvent-front mutation, hinder treatment durability. Repotrectinib, a next-generation macrocyclic TKI, was rationally designed to overcome on-target resistance mutations and improve brain distribution through its low molecular weight. In the TRIDENT-1 clinical trial, repotrectinib demonstrated significant efficacy in both TKI-naïve and TKI-pretreated patients with ROS1-rearranged NSCLC, including those with CNS metastases and G2032R resistance mutations. In the TKI-naïve cohort (n = 71), 79% of patients achieved an objective response, with a median progression-free survival (PFS) of 35.7 months, surpassing all previously approved ROS1 TKIs. In patients who had received one prior ROS1 TKI but were chemotherapy-naïve (n = 56), objective responses were observed in 38%, and median PFS was 9.0 months. The safety profile of repotrectinib was consistent with earlier-generation ROS1 TKIs and common adverse events included anemia, neurotoxicity, increased creatine kinase levels, and weight gain. These findings underscore the potential of repotrectinib to address unmet needs in ROS1-rearranged NSCLC, offering durable responses and improved intracranial activity. Future research should prioritize developing next-generation, selective ROS1 inhibitors to reduce Trk-mediated toxicities and improve treatment tolerance.

Phase 2 trial of regorafenib in recurrent or metastatic adenoid cystic carcinoma.

There is a significant need for effective therapies to treat recurrent/metastatic (R/M) adenoid cystic carcinoma (ACC). This study evaluated the multi-targeted, vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI) regorafenib in patients with R/M ACC. Patients with progressive R/M ACC were treated with regorafenib until disease progression, consent withdrawal, or excessive toxicity. The primary endpoints were best overall response (BOR) and 6-month progression-free survival (PFS). Genomic and transcriptomic biomarker analyses were performed in tumors from trial participants. Thirty-eight patients were enrolled, including 7 (18%) patients with prior VEGFR-TKIs. No objective responses were observed. Six-month PFS was 45%, and median PFS was 7.2 months (95%CI 5.2-11.9 months). Presence of either activating NOTCH1 (22%) or KDM6A alterations (24%) was associated with decreased PFS (HR 2.6, 95%CI 1.1-6.1, p=0.03). Bulk RNA sequencing of pre-treatment tumors revealed that regorafenib clinical benefit (CB; PFS≥6 months; n=11) was associated with native enrichment of immune-related signatures. Immune deconvolution revealed a greater degree of macrophage and T-cell infiltration in CB tumors. Tumors from patients with no clinical benefit (NCB; PFS<6 months; n=9) had greater expression of signatures related to cell cycle progression (E2F targets, G2/M checkpoint). The trial failed to meet the pre-specified 6-month PFS and BOR targets. We hypothesize that TKI efficacy may be reliant upon an interplay between kinase inhibition and the ACC immune microenvironment, while programs promoting cell cycle progression may contribute to TKI resistance. These observations suggest that trials evaluating CDK4/6 inhibition plus a VEGFR-TKI should be considered.

Le cancer thyroïdien différencié réfractaire à l’iode : quelle prise en charge en 2024 ?

TREATING RADIO-IODINE REFRACTORY DIFFERENTIATED THYROID CANCER IN 2024: About 5 to 10% of patients with differentiated thyroid cancer (DTC) have advanced tumors at presentation or recurrence, with invasive cervical disease and/or distant metastases that cannot be effectively treated by conventional treatment, i.e. thyroid surgery and radioactive iodine. These DTC cases are defined as refractory to radioiodine (RAIR) and require expert multidisciplinary management. In France, patients are referred to centers of the ENDOCAN-TUTHYREF Network. This review summarizes current management of RAIR DTC patients and therapeutic options available in 2024. We discuss following topics : epidemiological data, modalities of local ablative treatment for selected metastatic lesions, molecular tests to be performed, optimum timing for initiating systemic therapy, choice of first-line treatment among validated tyrosine kinase inhibitors (TKIs), alternative targeted treatments (including selective TKIs adapted to the molecular profile, some of which can redifferentiate and restore radioactive iodine uptake), proactive management of TKI side effects, and finally give an overview of systemic strategies. Management of RAIR DTC is still challenging but substantial progress has been made over the last decade that has significantly improved outcome for these more aggressive thyroid cancer.

Exploration of protein and genetic targets causing atrioventricular block: mendelian-randomization analyses based on eQTL data and pQTL data

BackgroundAtrioventricular block (AVB) is a heterogeneous group of arrhythmias. AVB can lead to sudden arrest of the heart and subsequent syncope or sudden cardiac death. Few scholars have investigated the underlying molecular mechanisms of AVB. Finding molecular markers can facilitate understanding of AVB and exploration of therapeutic targets.MethodsTwo-sample Mendelian randomization (MR) analysis was undertaken with inverse variance weighted (IVW) model and Wald ratio as the primary approach. Reverse MR analysis was undertaken to identify the associated protein targets and gene targets. Expression quantitative trait loci (eQTL) data from the eQTLGen database and protein quantitative trait loci (pQTL) data from three previous large-scale proteomic studies on plasma were retrieved as exposure data. Genome-wide association study (GWAS) summary data (586 cases and 379,215 controls) for AVB were retrieved from the UK Biobank database. Colocalization analyses were undertaken to identify the effect of filtered markers on outcome data. Databases (DrugBank, Therapeutic Target, PubChem) were used to identify drugs that interacted with targets.ResultsWe discovered that 692 genes and 42 proteins showed a significant correlation with the AVB phenotype. Proteins (cadherin-5, sTie-1, Notch 1) and genes (DNAJC30, ABO) were putative molecules to AVB. Drug–interaction analyses revealed anticancer drugs such as tyrosine-kinase inhibitors and TIMD3 inhibitors could cause AVB. Other substances (e.g. toxins, neurological drugs) could also cause AVB.ConclusionsWe identified the proteins (cadherin-5, sTie-1, Notch 1) and gene (DNAJC30, ABO) targets associated with AVB pathogenesis. Anticancer drugs (tyrosine-kinase inhibitors, TIMD3 inhibitors), toxins, or neurological drugs could also cause AVB.

Pembrolizumab in combination with lenvatinib in participants with hepatocellular carcinoma (HCC) before liver transplant as neoadjuvant therapY-PLENTY pilot study.

The high recurrent rate after liver transplantation (LT) remains a clinical challenge, especially for those exceeding the Milan criteria (MC) and with high RETREAT scores. Therefore, the authors aim to investigate whether neoadjuvant systemic therapy allows safely administered and effectively reduces post-LT recurrence for those patients. In this prospective, randomized, open-label, pilot study, patients with HCC exceeding the MC were randomly assigned to PLENTY or control group before LT. The primary endpoint of the study was the recurrence-free survival after LT. Twenty-two patients were enrolled and randomly assigned: 11 to the PLENYT group and 11 to the control group. The 30-month tumor-specific RFS was 37.5% in the PLENTY group and 12.5% in the control group. The 12-month tumor-specific RFS after LT was significantly improved in the PLENTY group (87.5%) compared to the control group (37.5%) (P=0·0022). The objective response rate in the PLENTY group was 30 and 60% when determined by RECIST 1.1 and mRECIST, respectively. Six patients (60%) had significant tumor necrosis, including three (30%) who had complete tumor necrosis at histopathology. No acute allograft rejection after LT occurred in the PLENTY and Control group. Neoadjuvant pembrolizumab plus lenvatinib before LT appears to be safe and feasible, associated with significantly better RFS for patients exceeding the MC. Despite the limitations of small sample size, this is the first RCT to evaluate neoadjuvant PD-1 blockade combined with tyrosine kinase inhibitors in LT recipients, the results of this study will inform future research.

Hepatitis B and/or C virus reactivation in patients receiving chemotherapy: An observational study

Background: Viral hepatitis reactivation occurs during various chemotherapy treatments. Patients with high serum titer levels of Hepatitis B virus (HBV) DNA before chemotherapy and those receiving intensive chemotherapy for hematological malignancies are particularly at risk. Aims and Objectives: This study aimed to determine the incidence, predictors, and clinical significance of HBV and hepatitis C virus reactivations during chemotherapy. Materials and Methods: This prospective observational study was conducted at a tertiary care center. Hepatitis B and C virus status was identified before the initiation of cancer treatment. Liver function was monitored in all patients before each cycle of chemotherapy. Patients with deranged liver function were subjected to repeated viral antigen tests and DNA/RNA titer levels. Results: A total of 110 patients were identified as having hepatitis virus reactivation out of 1190 patients. The sites of malignancy were breast, 39.1% (43 patients); colorectal, 11.8% (13 patients); upper gastrointestinal, 10% (11 patients); ovary, 9.1% (10 patients); hematological malignancies, 8.2% (9 patients); lung, 5.6% (6 patients); genitourinary, 4.5% (5 patients); head-and-neck, 4.5% (5 patients); biliary tract, 3.6% (4 patients); brain tumor, 1.8% (2 patients); and others, 1.8% (2 patients). Most of the patients with reactivation received 5-FU/Capecitabine-based chemotherapy 37.3%, (41 patients), taxane plus platinum (10.9%, 12 patients), taxane only (10%, 11 patients), trastuzumab (8.2%, 9 patients), platinum-based (6.4%, 7 patients), tyrosine kinase inhibitors (6.4%, 7 patients), monoclonal antibodies (MABs) (3.6%, 4 patients), anthracyclines (2.7%, 3 patients), immunomodulators (2.7%, 3 patients), and other agents (11.8%, 13 patients). Conclusion: We recommend that Hepatitis B and C virus Screening must me performed before chemotherapy and that non-reactive patients should be vaccinated.

Cromolyn sodium and masitinib combination inhibits fibroblast-myofibroblast transition and exerts additive cell-protective and antioxidant effects on a bleomycin-induced invitro fibrosis model.

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal fibrotic lung disease. While recent studies have suggested the potential efficacy of tyrosine kinase inhibitors in managing IPF, masitinib, a clinically used tyrosine kinase inhibitor, has not yet been investigated for its efficacy in fibrotic lung diseases. In a previous study on an invitro neurodegenerative model, we demonstrated the synergistic antitoxic and antioxidant effects of masitinib combined with cromolyn sodium, an FDA-approved mast cell stabilizer. This study aims to investigate the anti-fibrotic and antioxidant effects of the masitinib-cromolyn sodium combination in an invitro model of pulmonary fibrosis. Fibroblast cell cultures treated with bleomycin and/or hydrogen peroxide (H2O2) were subjected to masitinib and/or cromolyn sodium, followed by assessments of cell viability, morphological and apoptotic nuclear changes, triple-immunofluorescence labeling, and total oxidant/antioxidant capacities, besides ratio of Bax and Bcl-2 mRNA expressions as an indication of apoptosis. The combined treatment of masitinib and cromolyn sodium effectively prevented the fibroblast myofibroblast transition, a hallmark of fibrosis, and significantly reduced bleomycin / H2O2-induced apoptosis and oxidative stress. This study is the first to demonstrate the additive anti-fibrotic, cell-protective, and antioxidant effects of the masitinib-cromolyn sodium combination in an invitro fibrosis model, suggesting its potential as an innovative therapeutic approach for pulmonary fibrosis. Combination therapy may be more advantageous in that both drugs could be administered in lower doses, exerting less side effects, and at the same time providing diverse mechanisms of action simultaneously.

Carfilzomib, lenalidomide, dexamethasone (KRD) in BTKi relapsed or refractory mantle cell lymphoma: A phase II study fromFondazione Italiana Linfomi.

Mantle cell lymphoma (MCL) is a rare lymphoproliferative neoplasm considered incurable, with a median survival of 3-5 years. In recent years, Bruton's tyrosine kinase inhibitors (BTKi) have been introduced, demonstrating high therapeutic activity. However, the prognosis for MCL patients failing ibrutinib therapy is particularly poor, with a survival expectation of a few months. In this phase II trial, we assessed the efficacy and safety of the carfilzomib-lenalidomide-dexamethasone (KRD) combination in MCL patients who were relapsed/refractory (R/R) or intolerant to BTKi and in need of treatment. The primary objective of the study was to evaluate the antitumor efficacy of the KRD combination in terms of 12-month overall survival (12-month OS). From September 2019 to December 2020, 16 patients were enrolled from 11 Italian centers. After a median follow-up of 2.37 months (95% CI 0.92-6.47), the 12-month OS was 13%. The rate of grade 3-4 adverse events (AEs) was 35%, and the overall response rate (ORR) was 19%. These results led to the premature termination of enrollment, as defined in the protocol stopping rules. The efficacy of the KRD combination in advanced-stage MCL patients who are R/R to BTKi is unsatisfactory and too toxic.

EP.12A.34 Chemotherapy and/or Immunotherapy after Progression on Tyrosine Kinase Inhibitors in EGFR Mutant Non-Small Cell Lung Cancer Patients.

EP.12A.34 Chemotherapy and/or Immunotherapy after Progression on Tyrosine Kinase Inhibitors in EGFR Mutant Non-Small Cell Lung Cancer Patients.

Hypercalcemia in a Patient with Cancer on an Immune Checkpoint Inhibitor, a Tyrosine Kinase Inhibitor, and Amiloride: Which Is the Culprit?

Hypercalcemia in a Patient with Cancer on an Immune Checkpoint Inhibitor, a Tyrosine Kinase Inhibitor, and Amiloride: Which Is the Culprit?

The impact of oral oncology drugs in the era of value-based care.

15 Background: Oncology drug expenditures are a significant contributor to increasing total cost of care (TCOC). Oral oncolytics (OO), such as small molecule inhibitors (CDK 4/6 inhibitors, tyrosine kinase inhibitors, etc.), and immunomodulators, have revolutionized the treatment landscape for many cancers. We evaluated the patterns of OO use and spend for Medicare patients over time at a large community oncology practice participating in the Center for Medicare and Medicaid Innovation (CMMI)’s Value-based care (VBC) Program, the Oncology Care Model (OCM), with a focus on the seven cancers that are part of a successor model, the Enhancing Oncology Model. Methods: Using CMMI claims for attributed 6-month OCM episodes, we evaluated drug use and expenditures by performance period (PP) from July 2016 – June 2022 (11 PPs), with an emphasis on OO drugs. We used Part D expenditures as a proxy for OO. Results: From 2016-22, average TCOC per PP increased by 15.5% in the 7 EOM diagnoses (breast, lung, colon, prostate cancer, myeloma, lymphoma, and chronic leukemia). Average drug expenditures per PP grew 33% percent and represented 71% of total cost by PP11, up from 61% in PP1. Average expenditures per episode increased by 11.7% for Part B and 82.6% for Part D drugs (p&lt;0.01). Increase in Part D drug expenditures was partly due to an increase in the number of unique oral drugs which grew by 32% over the evaluation period. The greatest increases in Part D drug expenditures occurred in breast cancer (87%) and lymphoma (153.7%). Table reports average OO expenditures per PP, percent change from PP1 to PP11, and the change in the % Part D drugs contributed to TCOC. Conclusions: Increases in drug expenditures represent the greatest impact on TCOC for cancer patients. OO medicines have an increasing role in the treatment landscape and represent a growing focus in VBC models. Utilization and cost of OO medication have a significant bearing on VBC performance. Diagnosis Avg. OO Expenditures PP1 Avg. OO Expenditures PP11 Avg. OO Expenditures Change Contribution of OO to TCOC Change from PP1 - 11 Breast $4,208 $7,869 87.0% 9.9% Leukemia $25,334 $41,128 62.3% 19.9% CRC $1,206 $2,158 78.9% 3.1% Lung $3,650 $3,625 -0.7% -2.5% Lymphoma $4,193 $10,637 153.7% 13.0% Myeloma $25,109 $39,298 56.5% 6.7% Prostate $18,815 $20,114 6.9% 3.2% Total $8,291 $15,140 82.6% 10.8%

Aspirin reduces Ponatinib-induced cardiovascular toxic phenotypes and death in zebrafish

BackgroundPonatinib (Iclusig) is an oral tyrosine kinase BCR-ABL inhibitor for treating patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) and chronic myeloid leukemia (CML) who are resistant to the therapies with other tyrosine kinase inhibitors. However, adverse cardiovascular events caused by Ponatinib are a serious issue that affects patients' survival rates. Thus, it is necessary to search for candidate drugs to reduce the cardiovascular toxicity of Ponatinib. PurposeTo investigate the effects of Aspirin on Ponatinib-induced cardiovascular toxicity in zebrafish. MethodsAB strain of wild type zebrafish (Danio rerio), Tg (cmlc2: GFP) transgenic zebrafish, and Tg (gata1: dsRed) transgenic zebrafish were used as in vivo models to assess survival, blood flow, cardiac morphology, and function. Thrombus formation was detected using O-dianisidine staining. The transcriptome of zebrafish larvae treated with Ponatinib was assessed using RNA sequencing. ResultsPonatinib not only reduced survival rate but also caused cardiovascular toxic events such as pericardial edema, abnormal heart structure, low heart rate, and thrombosis. In addition, whole-body transcriptome analysis showed that Ponatinib up-regulated the expression of cyclooxygenase-1 (COX-1). Compared with other antithrombotic drugs, a COX-1 inhibitor Aspirin more effectively reduced ponatinib-induced cardiovascular toxicity events and improved the survival rate of zebrafish larvae. ConclusionOur findings suggest that Aspirin exhibits the potential to reduce Ponatinib-induced cardiovascular toxicity.

MO4-5 Efficacy of selpercatinib as tyrosine kinase inhibitor in RET-mutant medullary thyroid cancer: a systematic review

MO4-5 Efficacy of selpercatinib as tyrosine kinase inhibitor in RET-mutant medullary thyroid cancer: a systematic review