Tyrosine Kinase Inhibitors Research Articles

Zasocitinib (TAK-279), a Selective, Oral TYK2 Inhibitor, Reduces Body Surface Area Involvement in a Phase 2b Trial in Moderate-to-Severe Plaque Psoriasis

Background: Zasocitinib (TAK-279) is an oral, allosteric, and highly selective inhibitor of tyrosine kinase 2 (TYK2). TYK2 mediates signaling from cytokines involved in the pathogenesis of psoriasis and other immune-mediated inflammatory diseases. In a phase 2b trial in patients with moderate-to-severe plaque psoriasis (NCT04999839), zasocitinib was well tolerated and demonstrated safety and efficacy, with a greater proportion of patients achieving skin clearance at doses ≥5 mg compared with placebo, with the two highest doses (15mg and 30mg) showing the strongest responses at Week 12. This analysis further evaluated the efficacy of the 15mg and 30mg doses of zasocitinib using body surface area (BSA) involvement. Methods: In this randomized, multicenter, double-blind, placebo-controlled trial, patients with moderate-to-severe plaque psoriasis were randomized 1:1:1:1:1 to receive oral zasocitinib (2, 5, 15 or 30mg) or placebo, once daily for 12 weeks. BSA outcome measures assessed at Week 12 were mean change in BSA from baseline, mean percentage change in BSA from baseline and the proportion of patients achieving a BSA threshold of ≤1% by visit. Mean change in BSA from baseline was prespecified. Results: Baseline mean (standard deviation [SD]) percentage BSA was generally consistent across the zasocitinib 15mg (n=53; 18.3 [10.3]), zasocitinib 30mg (n=52; 22.2 [14.3]) and placebo (n=52; 21.3 [13.6]) groups. Mean percentage BSA decreased as early as Week 2 and continued to decrease through to Week 12 in the zasocitinib groups, whereas scores slightly decreased in the placebo group. At Week 12, mean(SD) percentage BSA was 4.4 (5.3) (least-squares [LS] mean change: −14.7; LS mean percentage change: −72.9%) in the 15mg group, 6.5 (12.5) (LS mean change: −15.7; LS mean percentage change: −73.1%) in the 30mg group and 18.2 (13.6) (LS mean change: −4.0; LS mean percentage change: −19.3%) in the placebo group (p<0.001 for both doses versus placebo). From Week 8 onwards, higher proportions of patients achieved a BSA threshold of ≤1% in the zasocitinib 15mg and 30mg groups than in the placebo group (35.8% and 44.2% versus 0% at Week 12, respectively). Conclusion: Patients with moderate-to-severe plaque psoriasis who received the two highest doses of zasocitinib (15mg and 30mg) in the phase 2b trial achieved greater reductions in BSA than those who received placebo over 12 weeks. Further investigation of the efficacy and safety of zasocitinib in phase 3 studies in psoriasis is ongoing (NCT06088043; NCT06108544).

Clinical Relevance of Intensive Laboratory Monitoring With Standard Venetoclax Ramp-Up for Chronic Lymphocytic Leukemia: A Real-World Experience

PURPOSE Venetoclax is the standard of care for chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) but requires intensive monitoring for optimal safety. Clinical relevance of intensive monitoring in practice is unknown, especially for patients with low or intermediate risk for tumor lysis syndrome (TLS). PATIENTS AND METHODS A retrospective review was conducted to determine clinical significance of monitoring for TLS during standard ramp-up for patients with CLL/SLL. Patients receiving abbreviated ramp-up, clinical trials, or concurrent Bruton tyrosine kinase inhibitors were excluded. The primary end point was TLS incidence, with secondary end points describing associated clinical interventions. RESULTS Fifty-five patients met study criteria. The majority of patients received venetoclax as first-line therapy (58%), with anti-CD20 antibody therapy (82%), and were at low risk of TLS (75%). No clinical TLS events occurred, whereas laboratory TLS occurred in only 1.8% of patients. No patients required antihyperuricemic therapy, and few interventions for hyperphosphatemia or hypocalcemia (3.6% of patients) were required. Additional intravenous fluids were uncommonly required (1.8% of patients), and no unplanned hospitalizations were required. CONCLUSION These findings support efforts to reduce intensive monitoring requirements during venetoclax ramp-up for patients with CLL, potentially increasing accessibility of venetoclax.

Abstract C039: The impact of antiangiogenic therapy on blood vessels and CD8 infiltration in renal cancer metastases is space, time, site, dose, and drug dependent

Abstract Clear cell renal cell carcinoma (ccRCC) is the most prevalent renal neoplasm, with bone as a major site for distant spread in 35% to 40% of the patients. These metastases are typically osteolytic, resistant to treatments, hence result in a variety of skeletal-related complications strongly contributing to mortality. A key feature of ccRCC is the loss of function of the von Hippel–Lindau (VHL) protein leading to extensive angiogenesis. Consequently, different anti-angiogenic tyrosine kinase inhibitors (TKIs) are used as the first or subsequent line of treatment for these patients as single agents or in combination with immune checkpoint inhibitors. However, limited data about their efficacy in bone metastasis is available, and their impact on the immune infiltrate, including effector CD8 cells, is unclear. We hypothesized that TKIs, by inhibiting angiogenesis, significantly reprogram the microenvironment and limit immune infiltration in space, time, dose, and drug dependent fashion. To test these hypotheses, we developed an immunocompetent mouse model of bone metastasis by orthotopical intratibial implantation of luciferase-GFP-positive mouse RENCA-VHL- cell line. Interestingly, intratibial injections gave rise to metastases in lungs, creating a unique opportunity to study two metastatic sites. Three different TKIs currently used in patients were tested and compared to control: axitinib (A), cabozantinib (C), and lenvantinib (L). Outcomes were monitored by macroscopic bioluminescence detection in vivo, 3D multiparametric spatial analysis of bones and lungs, in vivo, and ex vivo. Compared to control-treated mice, high doses of A, C, and L significantly reduced tumor progression in both tumor sites. Even though these TKIs are clinically considered equal, significant differences in their efficacy were noted. Spatial analysis of tumor cells and blood vessels showed a significant decrease in blood vessels formation in both an organ- and TKI-specific pattern over time. Additionally, the reduction of neo angiogenesis in treated tumors directly limited the infiltration of CD8 cells, which localized at the interface with tumor free bone/lung tissue. Interestingly, TKI dose reduction significantly improved CD8 infiltration, while controlling tumor size. TKI withdrawal, instead, led to rapid progression of tumor in both sites and significantly shortened mice survival. In conclusion, we established bone and lung metastatic models of ccRCC and characterized and compared the effects of three antiangiogenic TKIs on angiogenesis and CD8 infiltration. TKIs reduced tumor growth and progression, because of blood vessel formation inhibition. Furthermore, TKI treatment reduced the infiltration of effector T cells in tumors in a dose-dependent manner, an outcome that can have a major impact when TKIs are combined with immunotherapy, a preferential therapeutic regimen for ccRCC patients. Overall, we believe our studies provide important insights and efficacy predictions for innovative therapeutic applications in ccRCC bone metastatic patients. Citation Format: Stefan Maksimovic, Nina Costanza Boscolo, Ludovica La Posta, Matthew T. Campbell, Eleonora Dondossola. The impact of antiangiogenic therapy on blood vessels and CD8 infiltration in renal cancer metastases is space, time, site, dose, and drug dependent [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr C039.

Abstract C029: PM2.5-induced drug resistance in lung cancer

Abstract Long-term exposure to PM2.5 air pollution is a significant contributor to lung cancer incidence. Our previous studies have shown that such exposure promotes lung cancer progression by activating the EGFR (epidermal growth factor receptor) and AhR (aryl hydrocarbon Receptor) pathways. We observed that in lung cancer cells with EGFR mutations, prolonged PM2.5 exposure induces EGFR activation, resulting in accelerated tumor cell growth both in vitro and in vivo. This suggests that PM2.5 may play a role in the resistance to EGFR-TKI (tyrosine kinase inhibitor) therapies, raising concerns about treatment efficacy. To explore this, we exposed the EGFR-mutant lung cancer cell line to PM2.5 for 90 days. Our results revealed that long-term exposure not only reduced the therapeutic effect of EGFR-TKIs but also increased the expression of cMyc, a gene linked to poor prognosis and drug resistance. We further confirmed that PM2.5-induced EGFR-TKI resistance is driven by the AhR-cMyc pathway. AhR, activated by environmental toxins in PM2.5, increases cMyc expression, leading to drug resistance. When we administered cMyc inhibitors, the PM2.5-exposed cells regained sensitivity to EGFR-TKI therapy. These findings indicate that targeting the AhR-cMyc pathway could be a promising approach to overcome PM2.5-induced resistance in lung cancer treatment. Further research is needed to explore the broader implications of environmental pollution on cancer therapy and to develop strategies to counteract the effects of pollutants like PM2.5. Citation Format: Chi-Yuan Chen, Chieh-Wen Chan, Tong-Hong Wang. PM2.5-induced drug resistance in lung cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr C029.

Advanced lung adenocarcinoma with EGFR 19-del mutation transforms into squamous cell carcinoma after EGFR tyrosine kinase inhibitor treatment

In this editorial we comment on the article by Ji et al . We focus specifically on the EGFR tyrosine kinase inhibitor (EGFR-TKI) treatment and the development of drug resistance to EGFR-TKIs.

A prophylactic tyrosine kinase inhibitor strategy based on measurable residual disease pre-transplantation for Ph+ acute lymphoblastic leukemia undergoing allogeneic hematopoietic stem cell transplantation: A prospective multicenter cohort study.

Relapse is the major cause of treatment failure in Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). This study aimed to evaluate the effect of a prophylactic tyrosine kinase inhibitor (TKI) strategy on relapse in this population. Patients were assigned to prophylactic or control groups based on measurable residual disease (MRD) pre-transplantation. The primary endpoint was the cumulative incidence of relapse. A total of 110 patients with Ph+ ALL undergoing allo-HSCT were enrolled in this prospective study. Thirty-eight patients with positive MRD pre-transplantation were included in the prophylactic group, and 72 with negative MRD pre-transplantation were included in the control group. The 4-year cumulative incidence of relapse was 25.3% (95% CI: 12.1%-41.0%) and 20.3% (11.6%-30.7%; HR = 1.272, 95% CI: 0.551-2.940, p = .549), and non-relapse mortality was 10.5% (3.3%-22.7%) and 9.7% (4.2%-17.9%; HR = 1.094, 95% CI: 0.320-3.738, p = .928) in the prophylactic and control groups. The 4-year overall survival was 71.8% (53.2%-84.1%) and 84.1% (72.9%-90.9%; HR = 1.746, 95% CI: 0.741-4.112, p = .196), and leukemia-free survival was 64.1% (45.8%-77.7%) and 70.0% (57.6%-79.4%; HR = 1.212, 95% CI: 0.607-2.421, p = .585) in the prophylactic and control groups. Our results suggest that prophylactic TKI post-HSCT in patients with positive MRD pre-transplantation can produce outcomes comparable to negative MRD pre-transplantation without TKI post-HSCT.

Promising PD-1 antagonists for liver cancer: an evaluation of phase II and III results.

Hepatocellular carcinoma (HCC) is the most common primary liver cancer and a significant cause of cancer-related morbidity and mortality. Limited treatment options for advanced stages emphasize the need for effective therapies. This review examines immune checkpoint inhibitors (ICIs), specifically PD-1, PD-L1, and CTLA-4 inhibitors, as novel treatments for advanced HCC. The review includes data from phase II and III clinical trials that evaluate ICI combinations with tyrosine kinase inhibitors (TKIs) and anti-angiogenic agents, as well as locoregional treatments such as Transarterial Chemoembolization (TACE). Clinical outcomes, including progression-free survival and overall response rates, were analyzed along with the incidence and management of immune-related adverse events (irAEs). A systematic literature review method was applied to ensure the inclusion of comprehensive, high-quality studies. ICI-based therapies and their combinations are reshaping the treatment landscape for advanced HCC by providing improved outcomes and potentially extending patient survival. Although promising, these therapies require further refinement to optimize sequencing and treatment selection, especially for patients with different levels of liver function and disease stages. Managing adverse effects effectively is essential for maximizing the benefits of these therapies in clinical practice. Continued research is needed to support the development of personalized approaches that can better tailor these treatments to individual patient needs, ultimately enhancing the overall effectiveness and safety of HCC management.

Contemporary treatment of metastatic clear cell renal cell carcinoma

Renal cell carcinoma is one of the mostcommon malignant tumors in Germany with an increasing incidence. Drug therapy is indicated in relapsed or metastatic disease. The article is based on the content of the recent guidelines and aselective literature search. Combination therapies based on acheckpoint inhibitor are the current standard in first-line treatment of metastatic renal cell carcinoma. The median overall survival could thus be extended to > 50months. The International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) score is used for risk classification. When selecting asuitable combination therapy, it is important to consider the advantages and disadvantages for each individual patient. There is currently no standard for follow-up therapies. So far, combination therapies have not shown any significant advantage in second-line treatment. It is recommended to switch to asubstance that has not yet been used. Currently, one purely immuno-oncology combination and four combinations of one immune checkpoint inhibitor and one tyrosine kinase inhibitor (TKI) are approved for first-line therapy in Germany. The added value of further intensification of therapy, in particular through triple combinations or further combination therapy in the second line, has not yet been proven.

Present and prospect of transarterial chemoembolization combined with tyrosine kinase inhibitor and PD-1 inhibitor for unresectable hepatocellular carcinoma

Present and prospect of transarterial chemoembolization combined with tyrosine kinase inhibitor and PD-1 inhibitor for unresectable hepatocellular carcinoma

Clinical advances and challenges in targeting FGF/FGFR signaling in lung cancer.

Fibroblast growth factors (FGFs) and their receptors regulate numerous cellular processes, such as metabolism and signal transduction, but can also drive tumorigenesis. Specifically, in lung cancer, the overexpression of FGFs, as well as the amplification, mutation and fusion of FGFR genes, are closely linked to the initiation, progression and resistance of the disease, suggesting that targeting FGF/FGFR is an attractive therapeutic strategy for lung cancer treatment. Nintedanib, a multitarget tyrosine kinase inhibitor (TKI) used in combination with docetaxel, has shown some success as a second-line therapy for lung cancer. However, clinical trials evaluating other FGFR inhibitors have yielded mixed results, indicating substantial complexity in targeting aberrant FGF/FGFR signaling. In this review, we describe the aberrations in FGF/FGFR signaling in lung cancer and summarize the clinical efficacy of FGFR inhibitors, such as multitarget TKIs, selective FGFR-TKIs and biological agents. We also discuss various challenges associated with FGFR targeting in lung cancer, including precision patient selection, toxicity and resistance. Finally, we provide perspectives on future directions, namely, developing novel FGFR-targeting drugs, such as FGFR degraders and more specific FGFR-TKIs, adopting combination therapy and targeting FGFs.

Nintedanib attenuates NLRP3 inflammasome-driven liver fibrosis by targeting Src signaling.

Liver injury induces an inflammatory response that activates hepatic stellate cells, which is the initial factor of liver fibrosis. Nintedanib, a multi-targeted tyrosine kinase inhibitor targeting the Src signalling pathway, has been approved for the treatment of idiopathic pulmonary fibrosis. However, it is still not known whether nintedanib ameliorates liver fibrosis by inhibiting inflammasome activation. Here, a carbon tetrachloride (CCl4)-induced liver fibrosis model was used to assess the anti-fibrotic efficacy of nintedanib in vivo. Lipopolysaccharide and ATP were used to activate nucleotide oligomerisation domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasomes in LX-2 cells, and the efficacy of nintedanib on NLRP3 inflammasome activation was evaluated. Moreover, we used Src-overexpressing and Src-downregulating lentiviruses to transfect LX-2 cells to explore the targets of nintedanib. Nintedanib attenuated inflammation and extracellular matrix accumulation in CCl4-induced fibrotic livers and reduced the expression of NLRP3, fibrotic makers, and the phosphorylation of Src, epidermal growth factor receptor (EGFR), AKT, ERK1/2 in LX-2 cells. Furthermore, nintedanib thwarted NLRP3 inflammasome activation by suppressing the phosphorylation of Src and its downstream signalling pathway and reducing reactive oxygen species production. Our study indicates that nintedanib effectively suppresses NLRP3 inflammasome activation and has the potential for the treatment of liver fibrosis.

Reply to: Significance of Up-Front Stereotactic Radiosurgery for Non-Small Cell Lung Cancer Patients With Brain Metastases in the Era of New Generation Tyrosine Kinase Inhibitors.

Reply to: Significance of Up-Front Stereotactic Radiosurgery for Non-Small Cell Lung Cancer Patients With Brain Metastases in the Era of New Generation Tyrosine Kinase Inhibitors.

Locally advanced/metastatic non-small-cell lung cancer in Lebanon: focus on ALK tyrosine kinase inhibitors.

Treatment of non-small-cell lung cancers (NSCLC) has evolved over the last decade. According to studies, the use of targeted therapies has significantly increased the life expectancy of patients. Moreover, ALK-tyrosine kinase inhibitors (ALK-TKIs) have improved clinical outcomes. In Lebanon, translating recommendations into clinical practice remains challenging. A Lebanese expert panel of oncologists was convened to describe the management paradigm and the clinical evidence supporting the optimal use of next-generation TKIs in patients with ALK-rearranged NSCLC and to provide an expert overview of local challenges and recommendations for optimizing the management of advanced NSCLC in Lebanese patients. The experts agreed that these recommendations should be part of a healthcare strategy to be implemented at the national level.

Tertiary lymphoid structures potentially promote immune checkpoint inhibitor response in SMARCB1-deficient medullary renal cell carcinoma.

The WHO's classification of renal cell carcinoma (RCC) has identified loss of SMARCB1 as one of the driven mutations. Despite intensive postoperative interventions, the prognosis for SMARCB1-deficient medullary RCC remains poor, indicating insufficiency in current therapy. Herein, we reported the treatment outcomes of five patients with metastatic SMARCB1-deficient medullary RCC and molecular correlates. Four patients were treated with first-line immune checkpoint inhibitors (ICI) plus tyrosine kinase inhibitors (TKI) combination therapy with a median PFS (mPFS) of 12.3 months. Transcriptomic analysis revealed enrichment of immune-related pathways in SMARCB1-deficient medullary RCC compared to clear-cell and papillary RCC. Multiple immunofluorescence (mIF) revealed the association between the formation of mature tertiary lymphoid structures (TLSs) and the favorable response to ICI-based combination therapy. In conclusion, ICI-based combination therapy showed promising anti-tumor activity in SMARCB1-deficient medullary RCC patients. The presence of mature tertiary TLSs may partially elucidate the mechanism underlying treatment response.

"The End of the Golden Weather": therapeutic strategies for mantle cell lymphoma relapsed or refractory to covalent BTK inhibitors.

Mantle cell lymphoma (MCL) is a subtype of non-Hodgkin lymphoma which is often characterised by a pattern of continued relapse after frontline chemoimmunotherapy. Although patients are usually able to regain durable disease control with covalent Bruton's tyrosine kinase inhibitors (cBTKi) at first relapse, it is now appreciated that such responses are often not sustained and the management of such patients represents a significant area of unmet need. There is an imperative to better understand resistance mechanisms and identify high-risk subsets of patients for whom cBTKi responses may be particularly short. Allogeneic stem cell transplant has an established role in appropriate candidates, however contemporary consensus is to preferentially offer chimeric antigen receptor (CAR) T-cell therapy. In this Review, we consider the available data on both existing and emerging treatment options, including non-covalent BTK inhibitors, bispecific antibodies, antibody-drug conjugates and Bcl-2 inhibitors and propose a treatment strategy prioritising clinical trials where available.

Mebendazole effectively overcomes imatinib resistance by dual-targeting BCR/ABL oncoprotein and β-tubulin in chronic myeloid leukemia cells.

To target the pivotal BCR/ABL oncoprotein in chronic myeloid leukemia (CML) cells, tyrosine kinase inhibitors (TKIs) are utilized as landmark achievements in CML therapy. However, TKI resistance and intolerance remain principal obstacles in the treatment of CML patients. In recent years, drug repositioning provided alternative and promising perspectives apart from the classical cancer therapies, and promoted anthelmintic mebendazole (MBZ) as an effective anti-cancer drug in various cancers. Here, we investigated the role of MBZ in CML treatment including imatinib-resistant CML cells. Our results proved that MBZ inhibited the proliferation and induced apoptosis in CML cells. We found that MBZ effectively suppressed BCR/ABL kinase activity and MEK/ERK signaling pathway by reducing p-BCR/ABL and p-ERK levels with ABL1 targeting ability. Meanwhile, MBZ directly targeted the colchicine-binding site of β-tubulin protein, hampered microtubule polymerization and induced mitosis arrest and mitotic catastrophe. In addition, MBZ increased DNA damage levels and hampered the accumulation of ataxia-telangiectasia mutated and DNA-dependent protein kinase into the nucleus. This work discovered that anthelmintic MBZ exerts remarkable anticancer effects in both imatinib-sensitive and imatinib-resistant CML cells in vitro and revealed mechanisms underlying. From the perspective of drug repositioning and multi-target therapeutic strategy, this study provides a promising option for CML treatment, especially in TKI-resistant or intolerant individuals.

Pyrrolo[2,3-D]Pyrimidines as EGFR and VEGFR Kinase Inhibitors: A Comprehensive SAR Review.

Tyrosine kinases are implicated in a wide array of cellular physiological processes, including cell signaling. The discovery of the BCR-ABL tyrosine kinase inhibitor imatinib and its FDA approval in 2001 paved the way for the development of small molecule chemical entities of diverse structural backgrounds as tyrosine kinase inhibitors for the treatment of various ailments. Two of the most prominent tyrosine kinases as drug targets are the epidermal growth factor receptor (EGFR) and the vascular endothelial growth factor receptor (VEGFR), as evidenced by the clinical success of their many inhibitors in the drug market. Among several other physiological roles, EGFR regulates epithelial tissue development and homeostasis, while VEGFR regulates tumor-induced angiogenesis. The pyrrolo[2,3-d]pyrimidine nucleus represents a deaza-isostere of adenine, the nitrogenous base of ATP. The recent introduction of many pyrrolo[2,3-d]pyrimidines to the drug market as tyrosine kinase inhibitors makes them a hot topic in the medicinal chemistry research area at the present time. This review article comprehensively sheds light on the structure-activity relationship (SAR) of pyrrolo[2,3-d]pyrimidines as EGFR and VEGFR tyrosine kinase inhibitors, aiming to provide help medicinal chemists in the design of future pyrrolopyrimidine kinase inhibitors.

EGFR bypass activation mediates acquired resistance to regorafenib in hepatocellular carcinoma

BackgroundRegorafenib, a tyrosine kinase inhibitor (TKI), is used in the treatment of unresectable hepatocellular carcinoma (HCC). However, the occurrence of acquired resistance limits its antitumor efficacy. While multiple studies have highlighted the crucial role of bypass activation in acquired TKI resistance, few have focused on bypass activation in regorafenib resistance in HCC.MethodsHigh-throughput proteomics was used to identify differential proteins associated with bypass activation between acquired regorafenib-resistant cells and parental cells. The ability of epidermal growth factor receptor (EGFR) bypass inhibition to reverse resistance was evaluated both in vitro and in vivo using direct microscopic observation, the CCK-8 assay, colony formation assay, Annexin V-FITC/propidium iodide double staining, cell cycle analysis, western blotting, and a xenograft model.ResultsThe expression of EGFR, a member of the receptor tyrosine kinase (RTK) family, was significantly increased in acquired regorafenib-resistant HCC cells compared with parental cells. Pharmacological inhibition of EGFR with gefitinib restored the sensitivity of regorafenib-resistant HCC cells to regorafenib. In a xenograft mouse model, gefitinib sensitized resistant tumors to regorafenib. Additionally, levels of RAS, RAF, and P-ERK1/2, components of the downstream EGFR signaling pathway, were positively associated with EGFR expression.ConclusionEGFR overexpression promotes acquired resistance to regorafenib through RAS/RAF/ERK bypass activation in HCC. Inhibition of EGFR restores sensitivity to regorafenib, and the combination of gefitinib and regorafenib demonstrates significant antitumor efficacy both in vivo and in vitro. These findings suggest that this combination could be a potential strategy for patients with advanced HCC.

LC-MS/MS method for quantification of 23 TKIs in Plasma: Assessing the relationship between anlotinib trough concentration and toxicities.

To develop a simple, rapid, and sensitive LC-MS/MS method for quantifying 23 tyrosine kinase inhibitors (TKIs) in plasma samples, and evaluate the relationship between the trough concentration of anlotinib(ANL) and its toxicities. The method was developed in Agilent 1290-6460 UHPLC-MS/MS system. This study prospectively enrolled 55 cancer patients undergoing ANL treatment. Plasma samples were collected at steady-state trough concentration and subsequently analyzed using the method. Patients were recorded for the occurrence of toxicities. Statistical analysis was performed to assess the association of the toxicities with ANL exposure level and patients' characteristics. The LC-MS/MS method was developed and validated for all items required by pharmacopoeia. The results revealed a positive association between the trough concentration of ANL and the incidence of toxicities. The exposure level 17.655 ng/mL (AUC 0.82, p = 0.010) was identified as a predictive threshold value for grade ≥ 3 overall toxicities. In addition, lower platelet count (PLT count < 179 × 109 g/L) was significantly associated with higher occurrence of grade ≥ 3 toxicities (AUC 0.75, p = 0.049). A logistic model incorporating these two factors demonstrated improved diagnostic capacity for predicting ≥ 3 overall toxicities (AUC = 0.90, p = 0.001). This study successfully developed and validated a simple, rapid, and sensitive LC-MS/MS method for quantifying 23 TKIs in plasma samples. Besides, this study found that both Ctrough of ANL and PLT count as independent predictors for ANL-induced ≥ 3 overall toxicities. Moreover, a logistic model including these two factors presents better prediction capacity for ≥ 3 overall toxicities.

Renal microangiopathy induced by lenvatinib in hepatocellular carcinoma: a case report and literature review

Lenvatinib, a multi-target inhibitor of receptor tyrosine kinases, has been increasingly used in the treatment of advanced hepatocellular carcinoma (HCC). However, its association with renal adverse effects, including proteinuria and renal microvascular complications, was not fully understood in HCC patients. We reported a case of a 68-year-old male with a history of hypertension, diabetes mellitus, and hepatitis C virus (HCV) infection, diagnosed with primary HCC in 2015. Despite previous treatments, he was started on lenvatinib due to tumor recurrence. Initially, he had mild proteinuria, which significantly worsened post-lenvatinib initiation, accompanied by fluctuating renal function and severe edema. The diagnosis of lenvatinib-induced renal microvascular damage was confirmed through renal biopsy, which showed glomerular sclerosis, tubulointerstitial changes, and arteriolosclerosis. Discontinuation of lenvatinib led to significant improvements in proteinuria and edema. Subsequent cancer recurrence was managed with microwave ablation and immunotherapy, with satisfactory recovery. The potential for lenvatinib to induce significant renal microvascular disease, as demonstrated in this case, emphasizes the importance of vigilant renal monitoring and personalized therapeutic strategies in patients treated with lenvatinib for HCC. Early intervention and dose adjustment may be crucial in preventing severe renal impairment, highlighting the significance of tailored treatment plans in the management of advanced HCC patients especially with pre-existing risk factors.