Combination Of Kinase Inhibitors Research Articles

In-depth exploration of the focus issues of TKI combined with radiotherapy for EGFR-mutant lung adenocarcinoma patients with brain metastasis: a systematic analysis based on literature metrology, meta-analysis, and real-world observational data

BackgroundThere is a growing interest in utilizing a combination of brain radiotherapy (RT) and tyrosine kinase inhibitors (TKIs) for patients diagnosed with brain metastases (BM) in epidermal growth factor receptor (EGFR) mutation-positive lung adenocarcinoma (LAC). The current status of this treatment strategy remains a subject of debate.MethodsWe initiated our study by conducting a comprehensive literature search using the SCI-expanded database of Web of Science Core Collection (WoSCC). We utilized the VOSPviewer software to analyze various aspects of the research, including the year of publication, authorship, keywords, and country.Subsequently, we performed an extensive and systematic literature search on popular online databases. Our primary outcome measures were overall survival (OS) and intracranial progression-free survival (iPFS), both quantified by hazard ratios (HRs).Additionally, for data verification, we included data from patients in non-small cell lung cancer with brain metastasis who underwent therapeutic intervention at the Cancer Prevention and Treatment Center of Sun Yat-sen University and the Radiotherapy Department of Hanzhong Central Hospital between August 2012 and November 2021.ResultsThe bibliometric analysis revealed an increasing trend in research focused on the combination of RT and TKIs for the management of lung cancer brain metastases over the previous decade. Then, nine studies consistent with the research direction were included for meta-analysis. The meta-analysis showed that the OS (HR = 0.81, 95% confidence interval: 0.69–0.94; P = 0.007) and iPFS (HR = 0.71, 95% confidence interval: 0.61–0.82; P < 0.001) of the combination therapy were significantly prolonged. Finally, 168 EGFR-mutated BM advanced LAC patients in the real world were verified, and the median iPFS of the combination therapy (n = 88 and EGFR-TKIs alone (n = 80) were 16.0 and 9.0 months, respectively, (P < 0.001). The median OS was 29.0 and 27.0 months, respectively, with no dramatic difference (P = 0.188).ConclusionsResearch on EGFR-mutant LAC brain metastasis has turned towards exploring optimal treatment strategies for this condition. Our meta-analysis and real-world data analysis consistently demonstrate that combination therapy offers a substantial improvement in patient survival compared to EGFR-TKI monotherapy. Notably, among patients undergoing salvage radiotherapy (RT), our subgroup analysis reveals that those initially treated with third-generation TKIs experience more significant benefits than those treated with first- or second-generation TKIs.

Fatal Case of Immune-Related Myocarditis and Myositis Due to Treatment with Immune Checkpoint and Tyrosine Kinase Inhibitors.

Immune checkpoint inhibitor and tyrosine kinase inhibitor combinations have become the new standard of care in the first-line treatment of metastatic clear cell renal cell carcinoma. However, there is a growing concern regarding severe immune-related adverse events. A 78-year-old man with metastatic clear cell renal cell carcinoma, treated with pembrolizumab and axitinib, was admitted to the emergency department 30 days after initiating treatment due to rapidly progressive myositis. Myocarditis with severe ventricular dysfunction was identified. Muscular biopsy findings were compatible with inflammatory myopathy associated with immune checkpoint inhibitors. Initial treatment with high-dose corticosteroids showed an insufficient response. Therapeutic escalation on the third day with methylprednisolone, immunoglobulin, and abatacept resulted in clinical improvement. On the eleventh day, a sudden malignant arrhythmia occurred, followed by cardiac arrest. This represents one of the first case reports describing myocarditis and myositis during treatment with pembrolizumab-axitinib. While immune checkpoint inhibitor may play a major role, it is also possible that the tyrosine kinase inhibitor, while attempting to promote immune modulation, also increases severe toxicities.

6850 A Case of Anaplastic Thyroid Carcinoma With a Complete Metabolic Response to Pembrolizumab

Abstract Disclosure: E. Tirthani: None. J.T. Kung: None. Background: Anaplastic thyroid carcinoma (ATC) is an aggressive disease with limited therapeutic options and generally poor prognosis. Post-surgery, most patients are treated with a combination of chemotherapy, radiation, and tyrosine kinase inhibitors +/- immune checkpoint inhibitors. We describe a unique case of ATC with a complete metabolic response to pembrolizumab, a selective PD-1 inhibitor, as evidenced by imaging. Clinical Case: A 69-year-old female presented to the clinic for evaluation of a rapidly enlarging neck mass. The initial ultrasound showed a large mixed cystic-solid right thyroid nodule with irregular margins with micro- and macrocalcifications, which was biopsied. Cytology showed discohesive high-grade malignant tumor cells with enlarged nuclei, nuclear hyperchromasia in the background of necrosis, and dense neutrophilic infiltration concerning for ATC. A CT scan of the neck and chest showed a complex cystic thyroid mass with central necrosis and calcification with paratracheal, supraclavicular, and mediastinal lymphadenopathy. MRI of the brain was negative for metastatic disease. The patient underwent a total thyroidectomy with right and left level 6 and 7 neck dissection. Intra-operatively, gross extrathyroidal extension of the tumor was noted to the right carotid, larynx, right recurrent laryngeal nerve, and esophagus, with residual tumor left behind near the larynx. Pathology confirmed stage IVC ATC, positive for PIK3CA, NF1, p53 mutations, and BRAF negative. 90% of tumor cells showed PD-L1 expression on immunohistochemical staining. The post-surgical PET scan showed two discrete, well-defined foci of very intense FDG uptake, corresponding to the right lower cervical and para-esophageal lymph nodes with no evidence of distant metastasis. Systemic chemotherapy with carboplatin and paclitaxel (5 cycles) was initiated with concurrent intensity modulated radiation therapy (total 60 Gy/40 fractions to thyroid bed and bilateral neck). Repeat imaging showed minimal change in the size of the PET-positive lymph nodes. Immunotherapy was initiated and with just 2 cycles of 400 mg IV pembrolizumab, a repeat PET scan was obtained, which showed a complete metabolic response to therapy. Minimal residual FDG activity in the right supraclavicular region was thought to be secondary to posttreatment changes. The patient was able to resume her activities of daily living and had an improvement in appetite. The plan is to continue 400 mg IV pembrolizumab every 6 weeks while cautiously assessing for adverse effects from immunotherapy. Conclusion: It is rare to see a complete metabolic response to therapy with pembrolizumab without concurrent use of tyrosine kinase inhibitors in patients with ATC. A high tumoral PD-L1 expression may be the key to having this kind of dramatic response. Presentation: 6/3/2024

A Review on Systematic Treatment of Clear Cell Renal Cell Carcinoma Using Nivolumab and Cabozantinib

Since the introduction of anti-angiogenic and targeted therapies a decade ago, the management of advanced clear-cell renal cell carcinoma has seen significant advancements. Currently, the standard of care for colorectal cancer includes combinations of tyrosine kinase inhibitors (TKIs) and immunotherapy regimens like cabozantinib and nivolumab. The first-line treatment for RCC involves the combination of the anti-PD-1 monoclonal antibody nivolumab (OPDIVO®) and the multi-targeted TKI cabozantinib (Cabometyx®). Throughout the trial, the combination of cabozantinib and nivolumab consistently led to an enhanced health-related quality of life. Cabozantinib is used in the treatment of kidney cancer, hepatocellular carcinoma, and renal cell carcinoma. Nivolumab is typically employed when anti-angiogenic therapy proves ineffective. The combination of cabozantinib plus nivolumab, involving medications like sunitinib, ipilimumab, lenvatinib, and axtinib, is primarily utilized for its efficacy and survival benefits. The present review describes cabozantinib and nivolumab which are used for cancer treatment. This review helps people who are suffering from clear cell renal cell carcinoma.

Decitabine, venetoclax, and ponatinib for advanced phase chronic myeloid leukaemia and Philadelphia chromosome-positive acute myeloid leukaemia: a single-arm, single-centre phase 2 trial

Advanced phase Philadelphia chromosome-positive myeloid disease-consisting of chronic myeloid leukaemia in the myeloid blast phase and in the accelerated phase, and Philadelphia chromosome-positive acute myeloid leukaemia-is associated with poor outcomes. Although previous studies have suggested the benefit of chemotherapy and BCR::ABL1 tyrosine kinase inhibitor combinations, the optimal regimen is uncertain and prospective studies for this rare group of diseases are scant. Preclinical and retrospective clinical data suggest possible synergy between the BCL-2 inhibitor venetoclax and BCR::ABL1 tyrosine kinase inhibitors. We therefore aimed to design a study to evaluate the safety and activity of a novel combination of decitabine, venetoclax, and the third-generation BCR::ABL1 tyrosine kinase inhibitor ponatinib in advanced phase Philadelphia chromosome-positive myeloid diseases. For this phase 2 study, patients aged 18 years or older with previously untreated or relapsed or refractory myeloid chronic myeloid leukaemia-blast phase, chronic myeloid leukaemia-accelerated phase, or advanced phase Philadelphia chromosome-positive acute myeloid leukaemia, and an Eastern Cooperative Oncology Group performance status of 0-3 were eligible. Patients were eligible regardless of the number of previous lines of therapy received or previous receipt of ponatinib. Cycle 1 (induction) consisted of a 7-day lead-in of ponatinib 45 mg orally daily (days 1-7), followed by combination therapy with decitabine 20 mg/m2 intravenously on days 8-12, venetoclax orally daily with ramp-up to a maximum dose of 400 mg on days 8-28, and ponatinib 45 mg orally daily on days 8-28. Cycles 2-24 consisted of decitabine 20 mg/m2 intravenously on days 1-5, venetoclax orally 400 mg on days 1-21, and ponatinib orally daily on days 1-28. Response-based dosing of ponatinib was implemented in consolidation cycles, with reduction to 30 mg daily in patients who reached complete remission or complete remission with an incomplete haematological recovery and a reduction to 15 mg daily in patients with undetectable BCR::ABL1 transcripts. The primary endpoint was the composite rate of complete remission or complete remission with incomplete haematological recovery in the intention-to-treat population. Safety was assessed in the intention-to-treat population. This trial was registered with ClinicalTrials.gov (NCT04188405) and is still ongoing. Between July 12, 2020, and July 8, 2023, 20 patients were treated (14 with chronic myeloid leukaemia-blast phase, four with chronic myeloid leukaemia-accelerated phase, and two with advanced phase Philadelphia chromosome-positive acute myeloid leukaemia). The median age was 43 years (IQR 32-58); 13 (65%) patients were male and seven (35%) were female; and 12 (60%) were White, three (15%) were Hispanic, four (20%) were Black, and one (5%) was Asian. 12 (60%) patients had received 2 or more previous BCR::ABL1 tyrosine kinase inhibitors, and 14 (70%) patients had at least one high-risk additional chromosomal abnormality or complex karyotype. The median duration of follow-up was 21·2 months (IQR 14·1-24·2). The complete remission or complete remission with an incomplete haematological recovery rate was 50% (10 of 20 patients); complete remission in one [5%] patient and complete remission with incomplete haematological recovery in nine [45%]). An additional six (30%) patients had a morphologic leukaemia-free state. The most common grade 3-4 non-haematological adverse events were febrile neutropenia in eight (40%) patients, infection in six (30%), and alanine or aspartate transaminase elevation in five (25%). Eight (40%) patients had at least one cardiovascular event of any grade. There were three on-study deaths, none of which was considered related to the study treatment and all from infections in the setting of refractory leukaemia. The combination of decitabine, venetoclax, and ponatinib is safe and shows promising activity in patients with advanced phase chronic myeloid leukaemia, including those with multiple previous therapies or high-risk disease features. Further studies evaluating chemotherapy and venetoclax-based combination strategies using newer-generation BCR::ABL1 tyrosine kinase inhibitors are warranted. Takeda Oncology, the National Institutes of Health, and the National Cancer Institute Cancer Center.

953P Vessels that encapsulate tumor clusters (VETC): A promising prognostic predictor for patients with hepatocellular carcinoma treated with tyrosine kinase inhibitor and immunotherapy combinations

953P Vessels that encapsulate tumor clusters (VETC): A promising prognostic predictor for patients with hepatocellular carcinoma treated with tyrosine kinase inhibitor and immunotherapy combinations

A small secret of big rheumatology

Current recommendations for RA treatment determine the need to reduce the dose and duration of glucocorticoid(GC) use. This is due to the wide spectrum and high frequency (up to 100%) of serious adverse events (AE) during GC treatment. However, in real practice GCs in RA are used very often (in Russia, Western Europe and the USA they are used in about 50% of patients), and often in long-term courses. This is explained by the fact that the combination of disease-modifying antirheumatic drugs (DMARDs), including biologics (bDMARDs) and Janus kinase inhibitors (JAK), with GCs allows to achieve faster improvement of patients’ condition and therefore is very “convenient” for many patients and physicians.However, it is very difficult to ensure dose reduction and (especially!) complete discontinuation of GC administration afterwards. Clinical and observational studies show that 30–40% of patients manage to discontinue the use of GCs during treatment with bDMARDs and JAK. In addition, discontinuation of GCs may significantly increase the risk of RA flare, even with complex pathogenetic therapy.Nevertheless, prolonged use of GCs, including low doses (less than 7.5 mg/day of prednisolone) should be considered as an indicator of the severity of the disease course and inadequacy of the current therapy. Therefore, we should strive for personalization of RA therapy, selection of DMARDs based on the assessment of the disease phenotype and predictors of response to treatment with different drugs, achieving the main goal of therapy – remission/low disease activity and achievement of acceptable quality of life, without the use of GCs.

Treatment Characteristics and Outcomes of Patients With Chronic/Small Lymphocytic Leukemia (CLL) Treated With Venetoclax and Bruton Tyrosine Kinase Inhibitor (BTKi) Combination Therapies

Treatment Characteristics and Outcomes of Patients With Chronic/Small Lymphocytic Leukemia (CLL) Treated With Venetoclax and Bruton Tyrosine Kinase Inhibitor (BTKi) Combination Therapies

CLL-495 Treatment Characteristics and Outcomes of Patients With Chronic/Small Lymphocytic Leukemia (CLL) Treated With Venetoclax and Bruton Tyrosine Kinase Inhibitor (BTKi) Combination Therapies

CLL-495 Treatment Characteristics and Outcomes of Patients With Chronic/Small Lymphocytic Leukemia (CLL) Treated With Venetoclax and Bruton Tyrosine Kinase Inhibitor (BTKi) Combination Therapies

Comparative analysis of dual immune checkpoint inhibitor combination therapy versus immune checkpoint inhibitor plus tyrosine kinase inhibitor combination therapy for renal cell carcinoma with inferior vena cava tumor thrombosis.

Whether immune checkpoint inhibitor (ICI) plus ICI combination therapy or ICI plus tyrosine kinase inhibitor (TKI) combination therapy is useful for renal cell carcinoma (RCC) with inferior vena cava tumor thrombosis (IVCTT) remains unclear. We retrospectively evaluated the therapeutic effects and incidence of treatment-related adverse events (TRAEs) associated with ICI-based combination therapy in 36 patients with advanced RCC with IVCTT. The median age at initiation of treatment was 71years; the IVCTT stages were cT3b in 22 patients and cT3c in 14. The ICI-ICI and ICI-TKI groups comprised 15 and 21 patients, respectively. Median tumor shrinkage at the best response showed that the primary tumor diameter decreased by 1.8cm (22%), and the IVCTT height decreased by 1.5cm (26%). A higher proportion of patients in the ICI-TKI group experienced tumor shrinkage than those in the ICI-ICI group (primary tumor, p = 0.0325; IVCTT, p = 0.0112). Approximately 27% of patients experienced an increase in the IVCTT height with ICI-ICI combination therapy. No significant difference was observed in the relative tumor shrinkage of IVCTT, primary or level-down staging of IVCTT, other treatment effects, incidence of TRAEs, surgical outcomes, or prognosis between the groups. ICI-based combination therapy is effective against IVCTT and primary RCC. Although ICI-ICI is associated with a higher probability of tumor growth compared with ICI-TKI in the frequency of tumor regression, both therapies may be almost equally effective against primary RCC with IVCTT.

58 Tumor immune microenvironment determinants of response to Lenvatinib and aPD-1 blockade in clear cell renal cell carcinoma

Abstract Background Combinations of immune checkpoint blockade (ICB) and anti-angiogenesis tyrosine kinase inhibitors (TKI) are the mainstay of metastatic ccRCC front-line treatment, but heterogenous responses and lack of biomarkers strongly emphasizes the need to understand RCC-specific mechanisms of effective treatment-related anti-tumor immunity. Although prior work consistently highlights tumor associated macrophages (TAMs) in RCC prognosis and treatment response, TAM targeting has yet to experimentally assessed as a viable treatment sensitizer. Methods We therefore assessed the impact of TAM depletion using a clinical-grade colony stimulating factor receptor-1 inhibitor (CSF1Ri) on ICB or TKI sensitivity in a spontaneous mouse model of ccRCC with inducible kidney-specific Vhl, p53 and Rb1 deletions (KVpR). Mice were randomized to receive either no treatment, single agent Lenvatinib (TKI), aPD-1, or combinations with CSF1Ri. We longitudinally monitored a total of 307 tumors from 96 mice using magnetic resonance imaging (MRI) and collected responding and non-responding tumors for single cell RNA sequencing (scRNAseq) to elucidate the underlying mechanisms of response. Results Surprisingly we found that TAM depletion abolished aPD-1 response, with no effect on Lenvatinib response. ScRNAseq analyses suggest that CSF1R selectively depletes antigen presenting TAMs, leading to a striking loss of T cell infiltration. This suggests that TAMs, rather than dendritic cells as shown in other cancer types, may play a dominant role in eliciting T cells during aPD-1 therapy in RCC. On the other hand, Lenvatinib, which elicited a stronger T cell response than aPD-1, was associated with significant increases in cDC1 and plasma cells in responders, together suggesting that these two treatment modalities may operate through distinct antigen-presenting cells. Also unexpectedly, we found that both Lenvatinib and CSF1Ri induced severe intratumor hypoxia, which is typically associated with poor outcomes in most cancers. We identify a hypoxic niche-specific TAM subset that when abundant at baseline is predictive for poor response to ICB/TKI combos across multiple RCC trials, but post-treatment seems to capture hypoxia-mediated tumor cell death in responders in mouse and humans. We therefore wondered whether high levels of existing tumor hypoxia would exacerbate TKI-induced hypoxia leading to worst outcomes and found that in two novel RCC syngeneic models with high-baseline hypoxia, TKI indeed augments metastatic disease. Conclusions Our results offer mechanistic insight into the failure of CSF1R-based TAM depletion approaches in clinical trials and presents cautionary evidence against the use of hypoxia-inducing agents in tumors with high-baseline hypoxia. We show that TKI and ICB-induce distinct TME and hypoxia-related changes which require further study. More generally our study strongly emphasizes the importance of developing mechanism-guided clinical biomarkers. DOD CDMRP Funding: yes

37 Cost-effectiveness of treatment sequences with front-line nivolumab+ipilimumab therapy vs immuno-oncology+tyrosine kinase inhibitor therapies in intermediate/poor-risk metastatic renal cell carcinoma

Abstract Background Immuno-oncology (IO) and vascular endothelial growth factor (VEGF) targeted tyrosine kinase inhibitor (TKI) combinations have transformed the treatment of metastatic renal cell carcinoma (mRCC). However, there is a lack of evidence regarding the most cost-effective sequencing of these systemic therapies. This study aimed to assess the expected health and economic outcomes of various treatment sequences for newly diagnosed patients with intermediate/poor-risk RCC from a US payer perspective. Methods We developed a model using a continuous time micro-simulation framework. First-line treatment options included: nivolumab+ipilimumab, nivolumab+cabozantinib, pembrolizumab+lenvatinib, and pembrolizumab+axitinib. Second-line treatment options included: cabozantinib and everolimus+lenvatinib. In both lines, the source data for the overall survival (OS) and progression-free survival (PFS) distributions were obtained from the registrational randomized controlled trials (RCTs) of each therapy. The analysis included costs associated with drug acquisition in the US wholesale setting, drug administration and monitoring, management of treatment-related adverse events, disease management, and terminal care. Treatment duration for all first-line IO and TKI therapies was capped at 2 years. Quality-adjusted life-years (QALYs) were estimated by multiplying time in each phase of the disease by phase-specific utility values estimated from the CheckMate 214 trial data using US tariffs. The analysis was run 1000 times for cohorts of 100 patients over a 20-year time horizon. All costs and health outcomes were discounted annually at a 3% rate. Results Average per-patient QALYs were estimated for each sequence of interest: nivolumab+ipilimumab followed by cabozantinib (3.59), nivolumab+ipilimumab followed by lenvatinib+everolimus (3.26), pembrolizumab+axitinib followed by cabozantinib (3.14), pembrolizumab+axitinib followed by lenvatinib+everolimus (2.97), pembrolizumab+lenvatinib followed by cabozantinib (3.51), and nivolumab+cabozantinib followed by lenvatinib+everolimus (2.99). Average per-patient costs were estimated for each sequence of interest: nivolumab+ipilimumab followed by cabozantinib ($468,856), nivolumab+ipilimumab followed by lenvatinib+everolimus ($491,259), pembrolizumab+axitinib followed by cabozantinib ($675,714), pembrolizumab+axitinib followed by lenvatinib+everolimus ($700,411), pembrolizumab+lenvatinib followed by cabozantinib ($837,888), nivolumab+cabozantinib followed by lenvatinib+everolimus ($873,377). First-line drug acquisition costs accounted for the majority of costs for all sequences. Conclusions Based upon our model using data from registrational RCTs, first-line nivolumab+ipilimumab followed by cabozantinib represents the dominant treatment strategy for intermediate/poor-risk mRCC patients in the US, offering estimated cost savings of up to 45% when compared to IO+TKI options. Additional studies are needed to elucidate whether these cost savings translate to the real-world setting.

First-line therapy for metastatic renal cell carcinoma: A propensity score-matched comparison of efficacy and safety

PurposeImmune checkpoint inhibitor (ICI)-based combination therapy is a standard systemic treatment for metastatic renal cell carcinoma (mRCC). Although differential pharmacologic action between ICI+ICI and ICI+tyrosine kinase inhibitor (TKI) combinations may affect outcomes, comparative studies using real-world data are few. MethodsWe retrospectively analyzed the records of 447 mRCC patients treated with 1st-line ICI-based combinations at multiple institutions between January 2018 and August 2023, and selected 320 patients diagnosed with clear cell RCC (ccRCC) for further study. Cohorts were matched using one-to-one propensity scores based on IMDC risk classification. Overall survival (OS), progression-free survival (PFS), objective response rates (ORRs), and treatment-related adverse events (TrAE) were compared. ResultsThe matching process yielded 228 metastatic ccRCC patients treated with ICI+ICI (n = 114) or ICI+TKI (n = 114). Median OS was 53 months (95%CI: 33–NA) in patients treated with ICI+ICI and was not reached (95%CI: 43–NA) with ICI+TKI (P = 0.24). Median PFS was significantly shorter for ICI+ICI (13 months, 95%CI: 7–25) than for ICI+TKI (25 months, 95%CI: 13–NA) (P = 0.047). There were no differences in second-line PFS for sequential therapy after 1st-line combinations of ICI+ICI or ICI+TKI (6 vs. 8 months, P = 0.6). There were no differences in ORR between the 2 groups (ICI+ICI: 51% vs. ICI+TKI: 55%, P = 0.8); the progressive disease (PD) rate was significantly higher in patients treated with the ICI+ICI combination (24% vs. 11%, P = 0.029). The rate of any grade TrAE was significantly higher in patients treated with ICI+TKI (71% vs. 85%, P = 0.016), but we found no differences in severe TrAE between the 2 groups (39% vs. 36%, P = 0.8). ConclusionsIn a matched cohort of real-world data, we confirmed comparable OS benefits between ICI+ICI and ICI+TKI combinations. However, differential clinical behaviors in terms of PFS, PD rates, and TrAE between ICI-based combinations may enrich clinical decision-making.

Toxicity of immune checkpoint inhibitors and tyrosine kinase inhibitor combinations in solid tumours: a systematic review and meta-analysis.

https://www.crd.york.ac.uk/prospero/, identifier CRD42022367416.

Immune effect and prognosis of transcatheter arterial chemoembolization and tyrosine kinase inhibitors therapy in patients with hepatocellular carcinoma.

The combination of transcatheter arterial chemoembolization (TACE) and tyrosine kinase inhibitors (TKIs) has shown broad prospects in prolonging the survival of patients with hepatocellular carcinoma (HCC). TACE and TKIs can affect the immune microenvironment in patients with HCC. To determine the overall effects and differences between TACE and different TKIs combinations on the immune microenvironment. Data and immune cell profile test results from 213 HCC patients treated with TACE combined with apatinib, lenvatinib, sorafenib, or donafenib before and after 3 wk of treatment were collected. Monocytes were co-cultured with LM3 liver cancer cells, and their ability to inhibit cancer cell growth was analyzed using the MTT method and a nude mouse subcutaneous tumorigenesis experiment. Simulated combined therapy was done using an in situ liver cancer C57BL/6 male mouse model, and the immune response of tumor tissues was analyzed using immunohistochemistry. Compared to before combination therapy, the proportion of programmed cell death protein 1 (PD-1)+ mononuclear cells and the number of CD4+ T cells decreased in the TACE + apatinib group, while the number of absolute count of CD4+ and CD8+ T cells increased in the TACE + lenvatinib group. Furthermore, the number of regulatory cells decreased in the TACE + donafenib group, whereas the number of CD8+ T and natural killer cells increased. Additionally, monocytes in the TACE combined with donafenib or lenvatinib groups had a stronger ability to inhibit cancer cell growth than those in the other groups. Combining TACE with donafenib or lenvatinib increased CD8+ T cell infiltration into the tumor tissue. In addition, the proportion of PD-1+ in CD8+ cells, absolute CD8+ T lymphocyte count, and regulatory T cells proportion were independent prognostic factors affecting the survival time of patients with HCC. TACE, in combination with different TKIs, produces different immune responses. Specifically, TACE combined with donafenib or lenvatinib may induce strong anti-tumor immune responses.

Which factors help to determine the long-term response to first-line tyrosine kinase inhibitors in patients with metastatic renal cell carcinoma: A Turkish multi-centre study.

Many developing countries lack access to recommended first-line treatments for metastatic renal cell carcinoma (mRCC), such as immune checkpoint inhibitors (ICIs) or ICI-tyrosine kinase inhibitor (TKI) combinations. As a result, predictive markers are necessary to identify patients who may benefit from single-agent TKIs for long-term response. This study aims to identify such parameters. This was a multi-centre, retrospective study of patients with mRCC who were undergoing first-line treatment with sunitinib or pazopanib. Patients who had been diagnosed with mRCC and had not experienced disease progression for 36 months or more were deemed to have achieved a long-term response. Predictive clinical and pathological characteristics of patients who did not experience long-term disease progression were investigated. A total of 320 patients from four hospitals were included in the study. The median age of the patients was 60 years (range 20-89 years). According to the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk classification, 109 patients were classified as having favourable risk and 211 were in the intermediate-poor risk group. The median progression-free survival (PFS) and overall survival (OS) for all patients were 12.5 months and 76.4 months, respectively. In the long-term responder's group, the median PFS was 78.4 months. Among all patients, prior nephrectomy, the Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) <1, and the absence of brain metastasis were predictive factors for long-term response. For patients in the favourable risk group, the lack of brain metastasis was a predictor of long-term response. In the intermediate-poor risk group, prior nephrectomy and ECOG PS <1 were predictive factors for long-term response. Some individuals with mRCC may experience a durable response to TKIs. The likelihood of a long-term response can be determined by factors such as nephrectomy, ECOG PS < 1, and the absence of brain metastases.

Importance of PTM of FLT3 in acute myeloid leukemia.

FMS-like tyrosine kinase 3 (FLT3) is a receptor tyrosine kinase expressed in hematopoietic cells. Internal-tandem duplication domain (ITD) mutation and tyrosine kinase domain (TKD) mutation are the two most common mutations in acute myeloid leukemia (AML). Post-translational modifications (PTMs) of FLT3, such as glycosylation and ubiquitination, have been shown to impact various aspects of the protein in both wild-type (WT) and mutant forms of FLT3. In this review, we describe how the glycosylation status of FLT3 affects its subcellular localization, which significantly impacts the activation of downstream signaling, and the impact of specific ubiquitination on FLT3 function and stability, which may be associated with disease progression. Moreover, potential novel therapeutic strategies involving a combination of FLT3 tyrosine kinase inhibitors and drugs targeting glycosylation or ubiquitination are discussed.

Combination of menin and kinase inhibitors as an effective treatment for leukemia with NUP98 translocations.

Chromosomal translocations of the nucleoporin 98 (NUP98) gene are found in acute myeloid leukemia (AML) patients leading to very poor outcomes. The oncogenic activity of NUP98 fusion proteins is dependent on the interaction between Mixed Lineage Leukemia 1 and menin. NUP98-rearranged (NUP98-r) leukemia cells also rely on specific kinases, including CDK6 and/or FLT3, suggesting that simultaneous targeting of these kinases and menin could overcome limited sensitivity to single agents. Here, we found that combinations of menin inhibitor, MI-3454, with kinase inhibitors targeting either CDK6 (Palbociclib) or FLT3 (Gilteritinib) strongly enhance the anti-leukemic effect of menin inhibition in NUP98-r leukemia models. We found strong synergistic effects of both combinations on cell growth, colony formation and differentiation in patient samples with NUP98 translocations. These combinations also markedly augmented anti-leukemic efficacy of menin inhibitor in Patient Derived Xenograft models of NUP98-r leukemia. Despite inhibiting two unrelated kinases, when Palbociclib or Gilteritinib were combined with the menin inhibitor, they affected similar pathways relevant to leukemogenesis, including cell cycle regulation, cell proliferation and differentiation. This study provides strong rationale for clinical translation of the combination of menin and kinase inhibitors as novel treatments for NUP98-r leukemia, supporting the unexplored combinations of epigenetic drugs with kinase inhibitors.

Efficacy and Safety of Immuno-Oncology Plus Tyrosine Kinase Inhibitors as Late-Line Combination Therapy for Patients with Advanced Renal Cell Carcinoma.

Background/Objectives: Immuno-oncology plus tyrosine kinase inhibitor (IO+TKI) combination therapy is an essential first-line therapy for advanced renal cell carcinoma (RCC). However, reports of its efficacy and safety as late-line therapy are lacking. This study aimed to examine the efficacy and safety of IO+TKI combination therapy as a late-line therapy for patients with RCC. Methods: We retrospectively examined 17 patients with RCC who received IO+TKI combination therapy as a second-line therapy or beyond (pembrolizumab plus axitinib, n = 10; avelumab plus axitinib, n = 5; nivolumab plus cabozantinib, n = 2). Results: The overall response and disease control rates of IO+TKI combination therapy were 29.4% and 64.7%, respectively. The median overall survival was not attained. Progression-free survival was 552 days, and 94.1% of patients (n = 16) experienced adverse effects (AEs) of any grade; moreover, 41.2% of patients (n = 7) experienced grade ≥ 3 immuno-related AEs. Conclusions: IO+TKI combination therapy may be a late-line therapy option for RCC.

Tislelizumab with anlotinib and chemotherapy for second-line treatment of pancreatic ductal adenocarcinoma: A pilot study early result.

e16316 Background: Advanced pancreatic ductal adenocarcinoma is a malignant tumor with poor prognosis. At present, chemotherapy is still the standard treatment, however the efficacy is unsatisfied. The lack of second-line treatment options for pancreatic cancer results in progression-free survival often lasting less than 3 months. For pancreatic cancer is an immune desert type of tumor, immunotherapy has not brought breakthrough therapeutic regimen compared to the remarkable data in other tumors.There is still insufficient therapeutic evidence treated with PD1 antibody in pancreatic cancer. Anlotinib is a tyrosine kinase inhibitor (TKI) with anti-tumor effects. It has been shown the combination of PD1 and multi-target tyrosine kinase inhibitors can increase immunotherapy efficacy. The purpose of this study is to evaluate the efficacy and tolerability of Tislelizumab combined with Anlotinib, as well as chemotherapy (the choice of the investigator) in second-line treatment of patients with pancreatic ductal adenocarcinoma. Methods: In this single arm, phase II, prospective exploratory study, it was planned to recruit 30 adult patients with treated pancreatic ductal adenocarcinoma who have never received any PD (L) 1 and TKI. Eligible patients received Tislelizumab (iv, 200mg, Q3W), Anlotinib (PO, 10mg, QD), and chemotherapy (determined by the researchers) till disease progression or death. The primary endpoint was median progression-free survival (mPFS), the secondary endpoints were objective response rate (ORR), median overall survival(mOS), disease control rate (DCR), and treatment safety profile. Results: 14 eligible patients were recruited till Jan 2024, 12 patients with PFS records were included. Median follow-up time was 208 days (104 days-504 days). mPFS was 106 days, OS is not reached, BOR (best of response) was stable disease. The 3-months DCR rate was 58.3%, 6-months DCR rate was 25%. One patient was observed to have a 20% tumor shrinkage after two cycles of treatment and is still being followed up. The most common treatment-related adverse events(TRAEs) was neutropenia with level ≤grade 3, observed in 8/14 patients. The immune-related adverse event of concern was hypothyroidism(grade 1/2), which occurred in two patients. Two patients experienced grade 4 obstructive jaundice caused by the progression of the disease. Conclusions: The second-line combination regimen of Tislelizumab with Anlotinib based on chemotherapy demonstrated survival improvement trend and no new safety signals identified in pancreatic cancer. These data suggest Tislelizumab + Anlotinib+Chemo may be a promising novel treatment option for patients with pancreatic cancer. Clinical trial information: NCT05681390 .