Oral Multikinase Inhibitor Research Articles

INTEGRATE IIa Phase III Study: Regorafenib for Refractory Advanced Gastric Cancer.

Treatment options for refractory advanced gastric and esophagogastric junction cancer (AGOC) are limited. Regorafenib, an oral multikinase inhibitor, prolonged progression-free survival (PFS) versus placebo in the INTEGRATE I phase II trial. INTEGRATE IIa was designed to examine whether regorafenib improved overall survival (OS). A double-blind placebo-controlled phase III trial compared regorafenib and best supportive care (BSC) versus placebo and BSC for participants with confirmed evaluable metastatic/advanced AGOC who failed ≥two prior therapies on a 2:1 random assignment, stratified by tumor location, geographic region (Asia v rest of world), and prior vascular endothelial growth factor inhibitors. The primary end point was OS. Treatment efficacy on OS was first tested in the pooled INTEGRATE I + INTEGRATE IIa cohort and, if significant, then in the INTEGRATE IIa cohort. Secondary end points were PFS, objective response rate, safety, and quality of life (QoL). INTEGRATE IIa enrolled 251 participants: 157 from Asia and 94 from rest of world and 169 received regorafenib and 82 received placebo. No significant heterogeneity was observed between INTEGRATE I and INTEGRATE IIa studies on OS. Pooled OS analysis hazard ratio (HR) was 0.70 (95% CI, 0.56 to 0.87; P = .001; 361 events). INTEGRATE IIa alone OS HR was 0.68 (95% CI, 0.52 to 0.90; P = .006; 238 events), the median OS was 4.5 months versus 4.0 months, and 12-month survival rates were 19% and 6%, for regorafenib versus placebo, respectively. After a preplanned adjustment for multiplicity, there were no statistically significant differences across regions or other prespecified subgroups. Regorafenib improved PFS (HR, 0.53 [95% CI, 0.40 to 0.70]; P < .0001) and delayed deterioration in global QoL (HR, 0.68 [95% CI, 0.52 to 0.89]; P = .0043). The toxicity profile was consistent with that of previous reports. Regorafenib improves survival compared with placebo in refractory AGOC.

Schisandrin C prevents Regorafenib-Induced cardiotoxicity by recovering EPHA2 expression in cardiomyocytes.

Regorafenib, an oral multikinase inhibitor of angiogenic, stromal, and oncogenic receptor tyrosine kinases, has been approved for the treatment of metastatic colorectal cancer, gastrointestinal stromal tumors and hepatocellular carcinoma by the US Food and Drug Administration and European Medicines Agency. However, regorafenib-induced cardiotoxicity increases the risk of mortality. Despite reports that regorafenib can cause mitochondrial dysfunction in cardiomyocytes, the molecular mechanism of regorafenib-induced cardiotoxicity is much less known and there is an urgent need for intervention strategies. Here, we treated mice with vehicle or 200 mg/kg regorafenib daily for 42 days by gavage or treated cardiomyocyte lines with 8, 16 or 32 μM regorafenib, and we found that regorafenib could cause apoptosis, mitochondrial injury and DNA damage in cardiomyocytes. Mechanistically, regorafenib can reduce the expression of EPHA2, which inhibits AKT signaling, leading to cardiomyocyte apoptosis and cardiotoxicity. In addition, we showed that recovering EPHA2 expression via plasmid-induced overexpression of EPHA2 or schisandrin C, a natural product, could prevent regorafenib-induced cardiotoxicity. These findings demonstrated that regorafenib causes cardiomyocyte apoptosis and cardiac injury by reducing the expression of EPHA2 and schisandrin C could prevent regorafenib-induced cardiotoxicity by recovering EPHA2 expression, which provides a potential management strategy for regorafenib-induced cardiotoxicity and will benefit the safe application of regorafenib in clinic.

Lenvatinib for the Treatment of Hepatocellular Carcinoma After Liver Transplant

What Is the Issue? Liver transplant is 1 of the main curative therapies for liver cancer; however, hepatocellular carcinoma (HCC) recurrence presents in 10% to 20% of patients after liver transplant. Lenvatinib, an oral multikinase inhibitor drug, was approved for use in Canada as a first-line standard therapy for unresectable HCC, based on a pivotal trial that excluded patients who underwent a prior liver transplant. Data were scarce on the efficacy and safety of lenvatinib for treatment of HCC recurrence in patients who received a liver transplant, and were limited to a few case series and case reports. What Did We Do? We identified and summarized the literature on the evidence of the clinical effectiveness and safety of lenvatinib for the first-line treatment of patients with unresectable HCC recurrence after liver transplant. We searched key resources, including journal citation databases and conducted a focused internet search for relevant evidence published since 2019. One reviewer screened citations for inclusion based on predefined criteria, critically appraised the included studies, and narratively summarized the findings. What Did We Find? We identified a multinational, multicentre, retrospective, single-arm chart review study evaluating the efficacy and safety of lenvatinib in patients with HCC recurrence after liver transplant. Lenvatinib was primarily used as a first-line treatment for most patients (n = 42; 93.3%) and as a second-line treatment for 3 patients (6.7%). The single-arm chart review study showed lenvatinib treatment had an overall response rate (ORR) of 20.0%, a median overall survival of 14.5 months, and a median progression-free survival (PFS) of 7.6 months. These findings were similar to those randomized to lenvatinib in the pivotal phase III REFLECT trial, which excluded patients who had a prior liver transplant. What Does This Mean? The findings of this report suggest that lenvatinib has a potential role as a first-line treatment of patients with HCC recurrence after liver transplant. As the current evidence is limited to a retrospective single-arm chart review study, which had several limitations (e.g., lack of sample size calculation, noncomparative, and retrospective design), further investigations are needed to establish the clinical efficacy and safety of lenvatinib as a first-line treatment for unresectable HCC recurrence after liver transplant.

Neoadjuvant cabozantinib restores CD8+ T cells in patients with locally advanced non-metastatic clear cell renal cell carcinoma: a phase 2 trial.

Cabozantinib is an oral multikinase inhibitor approved for treatment in metastatic renal cell carcinoma (RCC). We hypothesized that neoadjuvant cabozantinib could downstage localized tumors, facilitating partial nephrectomy, and facilitating surgery in patients with locally advanced tumors that would require significant adjacent organ resection. We, therefore, conducted a phase 2, single-arm trial of cabozantinib treatment for 12 weeks in 17 patients with locally advanced biopsy-proven non-metastatic clear cell RCC before surgical resection. Six patients (35%) experienced a partial response, and 11 patients (65%) had stable disease. We identified that plasma cell-free DNA (cfDNA), VEGF, c-MET, Gas6, and AXL were significantly increased while VEGFR2 decreased during cabozantinib treatments. There was a trend towards CD8+ T cells becoming activated in the blood, expressing the proliferation marker Ki67 and activation markers HLA-DR and CD38. Cabozantinib treatment depleted myeloid populations acutely. Importantly, immune niches made up of the stem-like CD8+ T cells and antigen presenting cells were increased in every patient. These data suggest that cabozantinib treatment was clinically active and safe in the neoadjuvant setting in patients with locally advanced non-metastatic clear cell RCC and activated the anti-tumor CD8+ T cell response. The trial is registered at ClinicalTrials.gov under registration no. NCT04022343.

Combined neurokinin-1 receptor antagonist and sorafenib is a promising approach for hepatocellular carcinoma therapy

BackgroundHCC (Hepatocellular carcinoma) is the most common primary malignant cancer in the liver. Treatment options to incurable HCC such as sorafenib, an oral multikinase inhibitor, had numerous side effects and questionable effectiveness. Neurokinin-1 receptor (NK1R) have a major role in inflammation and tumour environment including the resistance to cell death, the induction of angiogenesis and the promotion of cell migration and proliferation. Additionally, NK-1R is over-expressed in human tumour cells including HCC. Moreover, Aprepitant, one of the NK-1R antagonists exerts multiple antitumor activities (antiproliferative, apoptotic, antimigration, and antiangiogenesis) in vivo and in vitro.Study aimTo analyze the effectiveness of combining sorafenib with aprepitant in the management of HCC (experimental).Patients and methodsIn this retrospective experimental study, the human HCC cell line, HepG2, cells were exposed to increasing concentrations of sorafenib alone, aprepitant alone and combination of both sorafenib and aprepitant evaluation of cytotoxicity, apoptosis, MMP-9, VEGF, NF-kB p-65, p-AKT and p-ERK were done. Moreover, The extent of the NK-1 receptor expression was assessed by immunocytochemistry on 50 HCC paraffin blocks of Egyptian HCC patients and another 50 paraffin blocks of liver cirrhosis only as a control.ResultsDecreased levels of MMP-9, VEGF, NF-kB p-65, p-AKT and p-ERK was more substantial in the combination therapy compared to sorafenib alone and aprepitant alone. Moreover, the rate of apoptosis and cytotoxicity were significantly higher in the combination treatment group than the monotherapy groups with more anti inflammatory, anti angiogentic and anti metastatic effects. Also, among the 50 HCC paraffin blocks, the majority (60%) showed a strong NK-1 expression; which significantly (p < 0.05) correlated with the progression free survival (PFS) but not the overall survival (OS) of the patients when applying multivariate analysis.ConclusionHCC had strong expression and immunostaining for NK1R.Therefore, combined aprepitant and sorafenib may be a promising approach in HCC treatment compared to each one alone.

Novel method of phosphorous doped bismuth oxide with carbon aerogel for a selective voltammetry quantification of anti-cancer drug: Regorafenib

Regorafenib (REG) is an oral multikinase inhibitor derived from diphenylureas. This drug is prescribed to treat colorectal and gastrointestinal stromal tumors and hepatocellular carcinoma. Our present study demonstrates the non-enzymatic electrochemical determination of REG in human blood serum at low concentrations by applying phosphorous-doped bismuth oxide (P-BiO) and porous graphene oxide (PGO)/protonated graphitic carbon nitride (PGCN) combined Aerogel form a P-BiO/Aerogel nanohybrids fabricated glassy carbon electrode (GCE). The property of our proposed electrocatalyst was characterized using several spectroscopic techniques. Utilizing cyclic voltammetry and differential pulse voltammetry techniques the electrochemical performance of this designed sensor was analyzed. Our P-BiO/Aerogel/GCE sensor exhibited a lower detection limit (LOD) of 0.1 nM with a high sensitivity of 1.433 µA µM-1cm−2. As a part of the real-time functionality, our fabricated sensor quantified the trace levels of REG in the consumed patient’s blood serum samples at the recovery range of 99–103 %. Therefore, our P-BiO/Aerogel nanohybrid electrocatalyst is a promising electrocatalyst for the real-time monitoring of REG.

Comparative efficacy of systemic sequential regorafenib after TACE combined with first-line targeted drugs (donafenib, sorafenib, or lenvatinib) after treatment failure for advanced hepatocellular carcinoma: A retrospective, single-center, real-world study.

e16190 Background: Donafenib is a novel multikinase inhibitor, which is a 1st-line systemic treatment for advanced hepatocellular carcinoma (HCC) in China. Regorafenib is an oral multikinase inhibitor and has been approved as the 2nd-line systemic treatment for advanced HCC based on the RESORCE trial. However, the efficacy of systemic sequential regorafenib after donafenib treatment failure in advanced HCC patients(pts) remains unclear. Methods: A retrospective analysis was conducted on the clinical data of advanced HCC pts treated with donafenib combined with TACE (Dona-TACE), sorafenib combined with TACE (Sora-TACE) or lenvatinib combined with TACE (Lenva-TACE) at The First Affiliated Hospital of USTC from January 2018 to December 2023. A total of 87 of these pts with advanced HCC who received regorafenib as the 2nd-line treatment. The 1st-line targeted drugs, disease control rate (DCR) (defined by the mRECIST), progression-free survival (PFS) and adverse events (AEs) (defined by the CTCAE version 5.0) were recorded and compared. Results: After screening, 27 pts in the Dona-TACE group ,35 pts in the Sora-TACE group and 31 pts in the Lenva-TACE group were included in this study. The baseline characteristics of the three groups were similar. The median treatment duration of regorafenib was 5.2 months in the Dona-TACE group, 4.8 months in the Sora-TACE group and 3.7 months in the Lenva-TACE group. The overall DCRs of sequential regorafenib after donafenib, sorafenib or lenvatinib treatment failed were 79%, 75% and 71%(P&gt;0.05). There was no significant difference in median PFS of regorafenib (4.8, 3.9, 4.1m) in the Dona-TACE, Sora-TACE and Lenva-TACE groups. Compared with other groups, the Dona-TACE group received regorafenib sequentially had a lowest incidence of grade 3-4 AEs (39.1%, P&lt;0.05). All groups had no treatment-related deaths from regorafenib. Multivariate analysis showed that ECOG PS score, up-to-seven criteria, tumor blood supply and Extrahepatic metastasis were independent prognostic factors affecting PFS (HR, 3.220, 3.019, 2.753, 3.142; P &lt; 0.05). No survival differences were observed between the patients who received 1st-line treatment with or without a combination of immune checkpoint inhibitor(ICI) reagents. Conclusions: This retrospective, single-center, real-world study demonstrated that when donafenib failed the regorafenib could still improve the prognosis of advanced HCC pts with fewer AEs. The study will continue to focus on overall survival(OS) and whether combined ICIs or not in the 1st-line/ 2nd-line treatment could have a positive effect on OS.

A phase II trial of sitravatinib plus nivolumab after progression on prior immune checkpoint inhibitor (ICI) in patients with metastatic clear cell renal cell carcinoma (ccRCC).

4542 Background: Sitravatinib, an oral multi-kinase inhibitor targeting VEGFR, TAM, and MET, has been shown to resensitize the tumor microenvironment to ICI by reducing immune-suppressive myeloid cells in metastatic ccRCC (Msaouel, Sci Transl Med 2022). ICI is the standard first-line (1L) treatment of metastatic ccRCC, and there is unmet need for improved treatment outcomes after progression on ICI. We hypothesized that sitravatinib plus nivolumab would revert an immunosuppressive tumor microenvironment (TME) to improve objective response rate (ORR) and survival in patients with metastatic ccRCC whose disease progressed on or after ICI. Methods: In this investigator-initiated, phase II, multicenter trial (NCT04904302), patients with progressive metastatic ccRCC after 1-2 lines of treatment were enrolled into three cohorts: Cohort A) progression on 1L nivolumab + ipilimumab, Cohort B) progression on 1L pembrolizumab + axitinib or 2L anti-PD-1 therapy after receiving 1L VEGF-targeted monotherapy, Cohort C) progression on 1L or 2L cabozantinib or lenvatinib +/- everolimus either before, after, or in combination with anti-PD-1 ICI. Starting dose of sitravatinib was 100 mg PO daily and nivolumab was 480 mg IV every 4 weeks. The co-primary endpoints were ORR [complete response (CR) + partial response (PR)] and disease control rate [DCR; CR, PR or stable disease (SD) at 24 weeks]. The study was designed to enroll 88 patients with an interim analysis for futility in each cohort using a BOP2 design, but it was terminated early due to discontinuation of sitravatinib development by the sponsor. Results: 14 patients were enrolled with 2 in cohort A, 6 in cohort B and 6 in cohort C. Most patients had IMDC intermediate risk disease (n=11, 78.6%), 7 patients had prior nephrectomy (50%), and sarcomatoid dedifferentiation was present in the tumors of 2 patients (7.1%). Across all cohorts, the ORR was 15.4% (2/13, 1 patient not evaluable) and DCR at 24 weeks was 35.7% (5/14). The 2 patients who experienced a PR were pre-treated with nivolumab + ipilimumab and pembrolizumab + axitinib. DCR at 24 months was 63% for Cohort A+B and 0% for Cohort C. After a median follow up of 11.9 months (mo), 10 patients had discontinued treatment (71.4%), all due to disease progression, and 6 patients had died (42.9%). Median progression free survival was 5.5 mo [ 95% CI 3.8 – not reached (NR)], and median overall survival was 13.3 mo (95% CI 8.77 – NR). Six patients (42.9%) experienced a grade 3-4 adverse event (AE) and 2 patients (14.3%) experienced an immune-mediated AE. Conclusions: In this small phase 2 trial with limited sample size due to early termination, sitravatinib plus nivolumab demonstrated a manageable safety profile and produced modest clinical benefit. The observed responses occurred in patients who did not receive prior treatment with cabozantinib or lenvatinib. Clinical trial information: NCT04904302 .

Lenvatinib rechallenge after failure of lenvatinib and sorafenib in metastatic thyroid cancer.

The oral multikinase inhibitors sorafenib and lenvatinib are currently available as first-line treatment for patients with unresectable or metastatic thyroid cancer. However, treatment options for patients who are refractory to these multikinase inhibitors are limited. This study aimed to evaluate the safety and efficacy of rechallenged lenvatinib after failure of both lenvatinib and sorafenib in patients with metastatic thyroid cancer in the real-world clinical practice. We retrospectively reviewed the data of consecutive 16 patients with metastatic thyroid cancer who received lenvatinib as a rechallenge after failure of initial lenvatinib and sorafenib treatment at Shizuoka Cancer Center between 2016 and 2023. Of these, the initial lenvatinib was discontinued in 12 patients owing to progressive disease, in 3 patients owing to adverse events, and in 1 patient owing to both. The overall response rate was 6.7%, and disease control was achieved by rechallenge with lenvatinib in all patients with the target lesions. The median progression free survival after rechallenging with lenvatinib was 15.0 months. No new signs of toxicity were observed after rechallenging with lenvatinib. Our findings suggest that rechallenge with lenvatinib after failure of both lenvatinib and sorafenib showed manageable safety and modest efficacy in patients with metastatic thyroid cancer in clinical practice. The strategy of lenvatinib rechallenge may provide an alternative option for patients with no targetable driver genes or when selective kinase inhibitors are not indicated.

Long-term response to MEK inhibitor monotherapy in a patient with papillary thyroid carcinoma harboring BRAF V600E mutation.

Solid tumors harboring mutations in the Braf gene (BRAF) are currently treated by combination Braf/MEK inhibitor therapy, and there is an extensive literature on patient response rates. Alternatively, few studies have documented the clinical response of BRAF mutation-positive solid tumors to MEK inhibitor monotherapy. We report the case of a 57-year-old female diagnosed with papillary thyroid carcinoma and progressive lung metastases initially treated by total thyroidectomy and subsequent thyroid-stimulating hormone suppression therapy. Next-generation sequencing revealed that the tumor harbored a BRAF V600E mutation, and the patient was enrolled in a clinical study of the oral MEK1/2 inhibitor binimetinib. Shortly after starting treatment, the patient experienced pneumothorax due to rapid regression of lung metastases, and computed tomography after 6 months of binimetinib treatment revealed a partial sustained response. One year later, the dose was reduced because of an acneiform rash. After 5 years of binimetinib treatment, lung metastases had regrown, and treatment was switched to the oral multikinase inhibitor lenvatinib. This case demonstrates the potential of MEK inhibitor monotherapy as an alternative treatment for BRAF mutation-positive papillary thyroid carcinoma.

Radiological complete response with regorafenib for multiple lung metastases of ascending colon cancer: a case report

BackgroundRegorafenib is an oral diphenylurea multikinase inhibitor and currently approved for use following third-line therapy for metastatic colorectal cancer (CRC) patients. Only one case has previously been reported of metastatic CRC showing a complete response (CR) to regorafenib.Case presentationA 68-year-old Japanese man underwent laparoscopy-assisted ileocecal resection and D3 lymphadenectomy due to his ascending colon cancer. Eighteen months after surgery, a laparoscopic hepatic left lateral segmentectomy was performed due to a liver tumor, and a pathological diagnosis of colorectal liver metastasis was made. Three months after the second surgery, contrast-enhanced computed tomography (CT) revealed multiple lung metastases. The patient had undergone 18 courses of the FOLFOX + bevacizumab chemotherapy regimen as their first-line therapy and 11 courses of the FOLFIRI + ramucirumab chemotherapy regimen as their second-line therapy. As their third-line therapy, the patient was administered the regorafenib chemotherapy regimen. We evaluated the chemotherapy treatment’s effect on the lung tumors by CT after 3, 7, 11, and 17 courses of the regorafenib chemotherapy regimen, finding that the lung tumors had shrunk with time; thus, each tumor was considered a partial response (PR) based on the RECIST guidelines. After 21 courses of the regorafenib chemotherapy regimen, the chemotherapy was discontinued in response to the patient’s wishes. Even at 1 and 3 months after the discontinuation of the chemotherapy, CT revealed that the lung tumors had shrunk, with each considered a PR. Furthermore, 9 months after the discontinuation of the chemotherapy, CT revealed scarring of the lung tumors. This was considered a CR, rather than a PR. The patient remains disease-free 18 months after the discontinuation of chemotherapy.ConclusionsIn this paper, we present the second case of radiological CR with regorafenib for multiple lung metastases of ascending colon cancer. Currently, there is no consensus on a treatment strategy for patients with radiological CR.

A decade of chemotherapy management in hepatocellular carcinoma: A single-center study in Latin America.

524 Background: Hepatocellular carcinoma (HC) is the most common primary tumor of the liver and is a significant health problem worldwide with check-point inhibitors and oral multikinase inhibitors (TKI) as the first-line therapy for advanced diseases. While chemotherapy treatment may not be standardized in current clinical management guidelines, it remains the only available treatment option in numerous Latin American countries. Methods: A retrospective review was carried out, in patients older than 18 years, between January 2011 and December 2020. 127 patients were analyzed and identified, they had received at least one course of chemotherapy at the Instituto Nacional de Enfermedades Neoplásicas in Lima, Perú. Results: The median age was 40 years, 40 female patients (31.5%) and 87 male patients (68.5%). Among the participants, 77 patients (60.62%) were diagnosed with hepatitis B, 2 patients (1.57%) had hepatitis C virus infections, and 48 patients didn´t have viral hepatitis. 72 patients (91.13%) underwent antiretroviral treatment. Non-cirrhotic patients were 118 (92.91%) and 111 (87.4%) had a Child A score. Chemotherapy was administered as first-line treatment to 118 patients (92.91%), with 47.61% receiving 5-FU-based chemotherapy, 11.11% Adriamycin, and 8.7% Gemcitabine-based chemotherapy. A smaller subset, consisting of 8 individuals (6.29%), received sorafenib as their first-line treatment. The overall survival (OS) rates at 12, 36, and 60 months were 74.14%, 20.69%, and 1.72%, respectively. Regarding disease-free survival (DFS) rates at 12, 24, and 48 months were 28.89%, 6.67%, and 2.22%, respectively. Conclusions: In this updated data for advanced hepatocellular carcinoma, we observed a subset of patients with advanced HC achieved favorable outcomes, with a median OS of 20.37 months and a median DFS of 6.6 months. Additional research is necessary to enhance our understanding of the molecular characteristics and resistance pathways of hepatocellular carcinoma in Peru and their correlation with the favorable survival rates observed in response to chemotherapy treatment.

Phase 1 trial of navitoclax and sorafenib in patients with refractory solid tumors with a hepatocellular carcinoma expansion cohort.

507 Background: Navitoclax (ABT-263) is an oral Bcl-2 homology-3 mimetic that binds with high affinity to pro-survival Bcl-2 proteins, resulting in apoptosis. Sorafenib, an oral multi kinase inhibitor inhibits tumor angiogenesis and also promotes apoptosis. The efficacy of either agent alone is limited; however, preclinical studies demonstrate synergy with the combination of navitoclax and sorafenib. Methods: In this phase 1 pharmacokinetic and pharmacodynamic study (NCT01364051), we evaluated the combination of navitoclax and sorafenib in a dose escalation cohort of patients with refractory solid tumors, with an expansion cohort in hepatocellular carcinoma (HCC). The study agents were provided by the Cancer Therapy Evaluation Program at National Cancer Institute under CRADA. Navitoclax and sorafenib were administered continuously on days 1 through 21 of 21-day cycles. The maximum tolerated dose (MTD) was determined using the continual reassessment method. Results: Ten patients were enrolled in the dose escalation cohort and 15 patients with HCC were enrolled in the expansion cohort. Two dose levels were tested, dose level 1 (navitoclax 150 mg daily plus sorafenib 400 mg twice daily) and dose level 2 (navitoclax 200 mg daily plus sorafenib 400 mg twice daily). At dose level 1, one dose limiting toxicity (DLT) [grade 3 aspartate aminotransferase elevation] was observed among 6 patients treated at this dose level. In a cohort of 3 patients treated at dose level 2, two DLTs were observed (grade 3 hypertension, and grade 3 rash), hence dose level 1 was identified as the MTD. Among all patients, the most common grade 3 toxicity was thrombocytopenia (5 patients, 20%): there were no grade 4 or 5 toxicities (Table). Patients received a median of 2 cycles (range 1-36 cycles) and all patients were off study treatment at data cut off. Six patients in the expansion cohort had stable disease, 5 had progressive disease and 4 with unavailable data. There were no partial or complete responses. Drug-drug interaction between navitoclax and sorafenib was not observed. The combination of navitoclax and sorafenib did not increase induction of apoptosis compared with navitoclax alone. Conclusions: Navitoclax plus sorafenib resulted in manageable, but not ideal toxicities for continuous oral administration which precluded dose escalation. The lack of clinical benefit in the HCC expansion cohort does not support further development of this combination for the treatment of advanced HCC. Clinical trial information: NCT01364051 . [Table: see text]

Molecular predictors of response to first-line systemic therapies in advanced hepatocellular carcinoma.

534 Background: With numerous advances in systemic therapy for advanced hepatocellular carcinoma (HCC) over the past several years, there are now multiple first-line treatment options which can be considered. These options include combination atezolizumab with bevacizumab (atezo/bev), programmed cell death protein 1/programmed death ligand 1 (PD-1/PD-L1) targeted agents, and oral multikinase inhibitor monotherapy. However, further guidance is needed to predict which patients will respond to best to each regimen. Methods: We performed a single center, retrospective study to determine the association between responses to first-line therapies in advanced HCC and various molecular alterations. Patients received first-line therapy with either atezo/bev, PD-1/PD-L1 monotherapy, or oral multikinase inhibitor monotherapy with treatment responses determined by imaging. All patients underwent next-generation sequencing (NGS) with testing performed on peripheral blood or tumor tissue. Results: A total of 116 patients with advanced HCC were included in this study. For first-line therapies, 45 (38.8%) patients received atezo/bev, 41 (35.3%) received oral multikinase inhibitor monotherapy, and 30 (25.9%) received PD-1/PD-L1 monotherapy. There was no association between treatment responses and patient ethnicity, age, or underlying cirrhosis etiology for any regimen. However, when analyzing NGS results, atezo/bev recipients with telomerase reverse transcriptase (TERT) promoter alterations had significantly higher rates of disease progression (PD) compared those without TERT promoter alterations (91.7% vs 54.6%, p = 0.03). In addition, in the oral multikinase inhibitor monotherapy group, those with CTNNB1 alterations had significantly greater PD rates compared to patients without these alterations (66.7% vs 31%, p = 0.04). There were no significant correlations between molecular alterations and responses in the PD-1/PD-L1 monotherapy group (Table). Conclusions: In our study, advanced HCC patients who received first-line systemic therapies were found to have significant correlations between TERT promoter and CTNNB1 alterations and responses to atezo/bev and oral multikinase inhibitor monotherapy, respectively. Given the widespread use of these regimens in the HCC treatment paradigm, additional studies are needed to confirm these findings and determine their impact on survival outcomes.[Table: see text]

Entrectinib in the treatment of ROS1-positive lung cancer

The possibilities in the treatment of patients with non–small cell lung cancer are constantly expanding – thanks to high-performance genomic profiling methods, we are discovering new targets in the tumor for drug action, as a result, new targeted drugs appear, some of them have several application points. Multipurpose drugs have a number of advantages and therefore have become the main direction of drug development. Entrectinib is an oral low molecular weight multikinase inhibitor that blocks three targets at once – the receptors of tyrosine kinases ROS1, NTRK1/2/3 and ALK, in 2023 was approved by the Ministry of Health of the Russian Federation for the treatment of adult patients with ROS1-positive metastatic non-small cell lung cancer. This form of lung cancer is classified as a rare orphan disease, which usually occurs in younger people (about 50 years old), more often in women and non-smokers. Until recently , we had the only active targeted drug – crizotinib. It provided a sufficiently high immediate effect and long-term control of the disease. However, his intracranial activity was not evaluated prospectively, and a retrospective analysis showed modest results. Entrectinib is distinguished from its competitor by high intracranial activity, and, as is known, metastatic brain damage in patients with activating mutations is quite common. With comparable indicators of objective response, its duration and time to progression, entrectinib provides a high level of intracranial control and reduces the risks of progression in the central nervous system in patients who did not have brain metastases at the beginning of therapy. In addition, entrectinib demonstrates good tolerability.

Lenvatinib Suppresses Protein Kinase B Signaling and Induces Apoptosis in Osteosarcoma Cells.

Lenvatinib, an oral multikinase inhibitor, has demonstrated promising activity in patients with osteosarcoma (OS). Therefore, it is worth exploring the inhibitory efficacy and mechanism of action of lenvatinib in osteosarcoma. The primary goal of this study was to examine the inhibitory effectiveness and mechanism of lenvatinib on the growth and invasion of OS cells. The effects of lenvatinib on cell viability, apoptosis, protein kinase B (AKT) activation, its downstream effector proteins involved in tumor progression, and invasion capability were assessed using MTT assay, flow cytometry, western blotting, and invasion/migration assay on U-2 OS and MG63 cells. Lenvatinib effectively induced cytotoxicity, apoptosis, as well as extrinsic and intrinsic apoptotic signaling in OS cells. Lenvatinib also significantly decreased the invasion/migration capability, AKT activation, and downstream effector proteins. The anti-OS effect of lenvatinib may be associated with the induction of apoptosis and the inactivation of AKT.

A feedback loop of PPP and PI3K/AKT signal pathway drives regorafenib-resistance in HCC

BackgroundHepatocellular carcinoma (HCC) is a principal type of liver cancer with high incidence and mortality rates. Regorafenib is a novel oral multikinase inhibitor for second-line therapy for advanced HCC. However, resistance to regorafenib is gradually becoming a dilemma for HCC and the mechanism remains unclear. In this study, we aimed to reveal the metabolic profiles of regorafenib-resistant cells and the key role and mechanism of the most relevant metabolic pathway in regorafenib resistance.MethodsMetabolomics was performed to detect the metabolic alteration between drug-sensitive and regorafenib-resistant cells. Colony formation assay, CCK-8 assay and flow cytometry were applied to observe cell colony formation, cell proliferation and apoptosis, respectively. The protein and mRNA levels were detected by western blot and RT-qPCR. Cell lines of Glucose-6-phosphate dehydrogenase(G6PD) knockdown in regorafenib-resistant cells or G6PD overexpression in HCC cell lines were stably established by lentivirus infection technique. G6PD activity, NADPH level, NADPH/NADP+ ratio, the ratio of ROS positive cells, GSH level, and GSH/GSSG ratio were detected to evaluate the anti-oxidative stress ability of cells. Phosphorylation levels of NADK were evaluated by immunoprecipitation.ResultsMetabonomics analysis revealed that pentose phosphate pathway (PPP) was the most relevant metabolic pathway in regorafenib resistance in HCC. Compared with drug-sensitive cells, G6PD enzyme activity, NADPH level and NADPH/NADP+ ratio were increased in regorafenib-resistant cells, but the ratio of ROS positive cells and the apoptosis rate under the conditions of oxidative stress were decreased. Furthermore, G6PD suppression using shRNA or an inhibitor, sensitized regorafenib-resistant cells to regorafenib. In contrast, G6PD overexpression blunted the effects of regorafenib to drug-sensitive cells. Mechanistically, G6PD, the rate-limiting enzyme of PPP, regulated the PI3K/AKT activation. Furthermore, PI3K/AKT inhibition decreased G6PD protein expression, G6PD enzymatic activity and the capacity of PPP to anti-oxidative stress possibly by inhibited the expression and phosphorylation of NADK.ConclusionTaken together, a feedback loop of PPP and PI3K/AKT signal pathway drives regorafenib-resistance in HCC and targeting the feedback loop could be a promising approach to overcome drug resistance.

Cabozantinib inhibits HBV-RNA transcription by decreasing STAT3 binding to the enhancer region of cccDNA.

Precision medicine and customized therapeutics based on the features of each patient are important for maximizing therapeutic effects. Because most cases of HCC occur in the damaged liver through various etiologies, such as hepatitis virus infection, steatohepatitis, and autoimmune hepatitis, there should be a rationale for the choice of therapeutic options based on these etiologies. Although cabozantinib, an oral multikinase inhibitor, has demonstrated clinical effectiveness in advanced HCC, subgroup analyses showed a lower HR for death in HBV-related HCC. This study aimed to determine the therapeutic effects of cabozantinib in HBV-related HCC. Using HBV infection models and gene knockout cells, we determined the crucial signaling axis responsible for the effects of cabozantinib on HBV. A chromatin immunoprecipitation assay was performed to determine the interaction between the signaling molecules and HBV DNA. Agonists and inhibitors were used for confirmation. Cabozantinib inhibited HBV replication through the HGF-mesenchymal-epithelial transition factor-signal transducer and activator of transcription 3 (MET-STAT3) signaling axis. The importance of STAT3 in viral replication has been confirmed using gene-edited STAT3 knockout cells. The chromatin immunoprecipitation assay revealed that the binding levels of phosphorylated STAT3 to enhancer region 1 of HBV covalently closed circular DNA were significantly increased by HGF stimulation. Cabozantinib has favorable therapeutic effects on HBV-related HCC because it inhibits HCC not only directly but also indirectly by means of inhibitory effects on HBV.

Comparative MIP sensor technique: photopolymerization or thermal polymerization for the sensitive determinationof anticancer drug Regorafenib in different matrixes.

Regorafenib (REG) is a diphenylurea derivative oral multikinase inhibitor. It plays an important role in the treatment of colorectal cancer, metastatic gastrointestinal stromal tumors, and hepatocellular carcinoma. Molecularly imprinted polymer (MIP) based glassy carbon electrodes (GCE) were fabricated using photopolymerization (PP) and thermal polymerization (TP) methods. The characterizations of the proposed sensors were investigated by electrochemical techniques, Fourier transform infrared spectroscopy (FT-IR), and scanning electron microscopy (SEM). Several parameters were studied in detail for the optimum conditions of MIP-based sensors, such as dropping volume, photopolymerization and thermal polymerization durations, removal medium and time, and rebinding time. Both sensors' analytical validation and electroanalytical performance comparison were made in different REG concentrations ranging between 0.1 nM and 2.5 nM in standard solution and commercial human serum samples. The limit of detection (LOD) of PP-REG@MIP/GCE and TP-REG@MIP/GCE were 9.13 × 10-12 M and 1.44 × 10-11 M in standard solutions and 2.04 × 10-11 M and 2.02 × 10-11 M in serum samples, respectively. The applicability of the proposed sensors was tested using commercial human serum samples and pharmaceutical form of REG with high recovery values (PP-REG@MIP/GCE and TP REG@MIP/GCE sensors, 99.56-101.59%, respectively). The selectivity of the sensor for REGwas investigatedin the presence of similar molecules: Sorafenib, Sunitinib, Nilotinib, and Imatinib. The developed techniques and sensors checked the possible biological compounds and ions' effects and storage stability.

A phase II study on the efficacy of regorafenib in treating patients with c-KIT-mutated metastatic malignant melanoma that progressed after previous treatment (KCSG-UN-14-13)

Backgroundc-KIT mutations are found in approximately 15% of patients with malignant melanoma in the Asian population. Regorafenib, an oral multikinase inhibitor, acts against both wild-type and mutant KIT. ObjectiveThis multi-institutional, phase II, single-arm study aimed to evaluate the efficacy of regorafenib against metastatic malignant melanoma harbouring c-KIT mutations. MethodsPatients with metastatic melanoma positive for c-KIT mutations, upon progression after at least one line of systemic treatment, were enroled. Patients received oral regorafenib 160 mg once daily for 3 weeks (4-week cycle). The primary endpoint was disease control rate (DCR), and secondary endpoints were safety, overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). ResultsIn total, 23 patients were enrolled. c-KIT mutations were frequently reported in exon 11 (14/23, 60.9%), followed by exons 13, 17, and 9 in 5 (21.7%), 5 (21.7%), and 2 (8.7%) patients, respectively. DCR at 8 weeks was 73.9%, with 2 patients (8.7%) achieving complete response, 5 (21.7%) achieving partial response, and 10 (43.5%) showing stable disease. ORR was 30.4% (7/23). The median follow-up period was 15.7 months (95% confidence interval [CI], 9.6–21.3), and median OS and PFS were 21.5 months (95% CI, 15.1–27.9) and 7.1 months (95% CI, 5.0–9.2), respectively. Circulating tumour DNA analysis in selected patients showed high c-KIT correlation (85.7%) with tissue-based tumour mutational profiles. The most common adverse events (AEs) were skin reactions, including palmar-plantar erythrodysesthesia (52.2%), and grade 3 AEs were reported in 39.1% (9/23) of the patients. ConclusionRegorafenib in second- or later-line settings demonstrated significant activity in patients with metastatic melanoma harbouring c-KIT mutations.