Sintilimab combined with anlotinib and chemotherapy as second-line or later therapy in extensive-stage small cell lung cancer: a phase II clinical trial.

Treatment options for patients with relapsed extensive-stage small cell lung cancer (ES-SCLC) remain scarce. This study aims to evaluate the efficacy and safety of combining anlotinib and sintilimab plus chemotherapy as a second line or later therapy for ES-SCLC patients. This is a phase II clinical trial (ChiCTR2100049390) conducting at Shandong Cancer Hospital. Patients with ES-SCLC and received at least one prior systemic treatment were enrolled. The trial design involved a combination therapy (sintilimab, anlotinib, and nab-paclitaxel) administered over six 21-day cycles, followed by maintenance sintilimab therapy. The primary endpoint was objective response rate (ORR). Circulating tumor DNA sequencing was employed for exploratory analysis. From July 2021 to April 2023, 25 eligible patients were enrolled. The confirmed ORR was 60% (95% CI: 38.7-78.9%) and the DCR was 76% (95% CI: 54.9-90.6%). The mPFS was 6.0 months (95% CI: 5.4-9.7), and the 6-month PFS rate was 49.2%. The mOS was 13.4 months (95% CI: 11.8-NR), with a 12-month survival rate of 62.2%. Treatment-related adverse events (TRAEs) of any grade occurred in 80% of patients, with the most common being fatigue (40%) and nausea (32%). TRAEs of Grade 3 or higher were reported in 12% of patients. ctDNA analysis indicated that low on-treatment blood tumor mutation burden was associated with longer PFS and OS and a potential role of KMT2D mutation in treatment resistance. This combination therapy shows promising efficacy and a manageable safety profile as a second-line or later treatment for ES-SCLC, with genomic insights providing potential biomarkers for treatment response.

Efficacy and safety of rucaparib in patients with recurrent high-grade ovarian carcinoma: A systematic review and meta-analysis.

Ovarian cancer stands as the third most prevalent gynecological malignancy. The advent of PARP inhibitors, particularly rucaparib, has revolutionized the landscape of advanced ovarian cancer treatment, demonstrating notable efficacy with minimal toxicity, especially in patients not previously exposed to PARP inhibitors. Rucaparib's precision-driven approach, targeting specific genetic mutations, disrupts DNA repair mechanisms, resulting in cytotoxic effects on neoplastic cells. This comprehensive review delves into the clinical efficacy and safety profile of rucaparib in recurrent ovarian cancer, showcasing its promising therapeutic approach. A systematic search of studies reporting rucaparib efficacy and safety, up to September 2023, was conducted across various reputable databases and sources. The meta-analysis of seven articles revealed a pooled objective response rate (ORR) of 0.331 (95% CI, 0.221-0.449; I2 = 92.4%), underscoring rucaparib's efficacy, particularly evident in the BRCA-mutated cohort. Rucaparib consistently outperformed controls in progression-free survival (PFS) and overall survival (OS). Safety evaluations indicated that 98.7% of patients experienced treatment-emergent adverse events (TEAEs), with 61% being grade ≥3. Notable TEAEs included nausea (69.0%), fatigue (66.8%), vomiting (37.3%), and constipation (32.1%). Hematological concerns comprised anemia (47.9%), thrombocytopenia, elevated AST/ALT (37.3%), and serum creatinine levels (19.7%). Despite favourable outcomes, the rucaparib group recorded higher event rates across various metrics than controls. The findings underscore the need for meticulous monitoring and dose adjustments to optimize therapeutic outcomes and mitigate the increased risks associated with adverse events. International Prospective Register of Systematic Review Identifier: CRD42023459646.

Nintedanib and miR-29b co-loaded lipoplexes in idiopathic pulmonary fibrosis: formulation, characterization, and in vitro evaluation.

OBJECTIVE: This study was aimed to develop a cationic lipoplex formulation loaded with Nintedanib and miR-29b (LP-NIN-miR) as an alternative approach in the combination therapy of idiopathic pulmonary dibrosis (IPF) by proving its additive anti-fibrotic therapeutic effects through in vitro lung fibrosis model. SIGNIFICANCE: This is the first research article reported that the LP-NIN-MIR formulations in the treatment of IPF. METHODS: To optimize cationic liposomes (LPs), quality by design (QbD) approach was carried out. Optimized blank LP formulation was prepared with DOTAP, CHOL, DOPE, and DSPE-mPEG 2000 at the molar ratio of 10:10:1:1. Nintedanib loaded LP (LPs-NIN) were produced by microfluidization method and were incubated with miR-29b at room temperature for 30 min to obtain LP-NIN-miR. To evaluate the cellular uptake of LP-NIN-miR, NIH/3T3 cells were treated with 20 ng.mL-1 transforming growth factor-ß1 (TGF-ß1) for 96 h to establish the in vitro IPF model and incubated with LP-NIN-miR for 48 h. RESULTS: The hydrodynamic diameter, polydispersity index (PDI), and zeta potential of the LP-NIN-miR were 87.3 ± 0.9 nm, 0.184 ± 0.003, and +24 ± 1 mV, respectively. The encapsulation efficiencies of Nintedanib and miR-29b were 99.8% ± 0.08% and 99.7% ± 1.2%, respectively. The results of the cytotoxicity study conducted with NIH/3T3 cells indicated that LP-NIN-miR is a safe delivery system. CONCLUSIONS: The outcome of the transfection study proved the additive anti-fibrotic therapeutic effect of LP-NIN-miR and suggested that lipoplexes are effective delivery systems for drug and nucleic acid to the NIH/3T3 cells in the treatment of IPF.

Preparation, Characterization and Evaluation of Nintedanib Amorphous Solid Dispersions with Enhanced Oral Bioavailability.

The dissolution and bioavailability challenges posed by poorly water-soluble drugs continue to drive innovation in pharmaceutical formulation design. Nintedanib (NDNB) is a typical BCS class II drug that has been utilized to treat idiopathic pulmonary fibrosis (IPF). Due to the low solubility, its oral bioavailability is relatively low, limiting its therapeutical effectiveness. It is crucial to enhance the dissolution and the oral bioavailability of NDNB. In this study, we focused on the preparation of amorphous solid dispersions (ASD) using hot melt extrusion (HME). The formulation employed Kollidon® VA64 (VA64) as the polymer matrix, blended with the NDNB at a ratio of 9:1. HME was conducted at temperatures ranging from 80 °C to 220 °C. The successful preparation of ASD was confirmed through various tests including polarized light microscopy (PLM), X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), Fourier-transform infrared spectroscopy (FT-IR), and thermogravimetric analysis (TGA). The in-vitro cumulative release of NDNB-ASD in 2 h in a pH 6.8 medium was 8.3-fold higher than that of NDNB (p < 0.0001). In a pH 7.4 medium, it was 10 times higher (p < 0.0001). In the in-vivo pharmacokinetic experiments, the area under curve (AUC) of NDNB-ASD was 5.3-fold higher than that of NDNB and 2.2 times higher than that of commercially available soft capsules (Ofev®) (p < 0.0001). There was no recrystallization after 6 months under accelarated storage test. Our study indicated that NDNB-ASD can enhance the absorption of NDNB, thus providing a promising method to improve NDNB bioavailability in oral dosages.

LRG1-Targeted Nintedanib Delivery for Enhanced Renal Fibrosis Mitigation.

Renal fibrosis lacks effective nephroprotective drugs in clinical settings due to poor accumulation of therapeutic agents in damaged kidneys, underscoring the urgent need for advanced renal-targeted delivery systems. Herein, we exploited the significantly increased expression of the leucine-rich α-2 glycoprotein 1 (LRG1) protein during renal fibrosis to develop a novel drug delivery system. Our engineered nanocarrier, DENNM, preferentially targets fibrotic kidneys via the decorated ET peptide's high affinity for LRG1. Once internalized by damaged renal cells, DENNM releases its encapsulated nintedanib, triggered by the active caspase-3 protease, disrupting the nanomedicine's structural integrity. The released nintedanib effectively reduces the level of expression of the extracellular matrix and impedes the progression of renal fibrosis by inhibiting the transforming growth factor-ß (TGF-ß)-Smad2/3 pathway. Our comprehensive in vitro and in vivo studies validate DENNM's antifibrotic efficacy, emphasizing LRG1's potential in renal targeted drug delivery and introducing an innovative approach to nanomedicine for treating renal fibrosis.

Efficacy and safety of a novel TKI (anlotinib) for the treatment of advanced digestive system neoplasms: a systematic review and meta-analysis.

Objective: To systematically evaluate the efficacy and safety of anlotinib targeted therapy for the treatment of patients with advanced digestive system neoplasms (DSNs). Methods: Clinical trials were extracted from PubMed, the Cochrane Library, Web of Science, Embase, China National Knowledge Infrastructure (CNKI) and the Wanfang database up to October 2023. Outcome measures, including therapeutic efficacy, quality of life (QOL) and adverse events, were extracted and evaluated. Results: Twenty trials, including 1,613 advanced DSNs patients, were included. The results indicated that, compared with conventional treatment alone, the combination of anlotinib targeted therapy with conventional treatment significantly improved the patients' 6-months overall survival (OS, OR=1.76, CI=1.53 to 2.02, P<0.00001), overall response (ORR, OR=1.76, CI=1.53 to 2.02, P<0.00001) and disease control rate (DCR, OR=1.51, 95% CI=1.25 to 1.84, P<0.0001). Moreover, the group that received the combined therapy had higher rates of hypertension (P<0.00001), proteinuria (P<0.00001), fatigue (P<0.00001), diarrhea (P<0.00001), hypertriglyceridemia (P=0.02), alanine aminotransfease (ALT)increased (P=0.004), aspartate transaminase (AST) increased (P=0.006), anorexia (P<0.00001), weight loss (P=0.002), abdominal pain (P=0.0006), hypothyroidism (P=0.02), prolonged QT interval (P=0.04). Analyses of other adverse events, such as gastrointestinal reaction, leukopenia, and neutropenia, did not reveal significant differences (P>0.05). Conclusion: The combination of anlotinib targeted therapy and conventional treatment is more effective for DSNs treatment than conventional treatment alone. However, this combined treatment could lead to greater rates of hypertension, albuminuria and hand-foot syndrome. Therefore, the benefits and risks should be considered before treatment.

Efficacy and safety of PD-1 monoclonal antibody combined with interferon-alpha 1b and anlotinib hydrochloride as the second-line therapy in patients with unresectable advanced melanoma: A retrospective study.

BACKGROUND: Immune-checkpoint inhibitors are now used more commonly in combination than monotherapy as the first-line choice in patients with unresectable advanced melanoma. Nevertheless, for cases that progressed after the initial combination therapy, the subsequent regimen option can be very difficult. Herein, we reported the efficacy and safety of a triple combination regimen in Chinese unresectable advanced melanoma patients who had poor responses to the first-line immune therapy. METHODS: We reviewed the clinical profiles of patients diagnosed with stage IIIC-IV melanoma between June 1, 2020, and September 30, 2023. The patients who failed the prior immune therapies and received anti-PD-1 mono antibody plus interferon(IFN)-alpha 1b and anlotinib hydrochloride as the second-line therapy were enrolled in the retrospective analysis. Additionally, we examined the exhaustion of T-cells using mIHC staining in available tumor samples. RESULTS: Fifty-five patients were included in this study. The median follow-up period was 13.6 months. The objective response rate evaluated by the investigators was 9.1%(1CR, 4PR). The disease control rate was 47.3%. The median overall survival was 17.6 months, and the median progression-free survival was 2.8 months. The adverse events rate of any grade was 100%. Grade 3 or 4 irAEs were observed in 29.1% of cases. Multiplex immunohistochemical staining revealed an increased trend of TIM3 expression on tumor-infiltrating T cells in patients without objective response. CONCLUSION: PD-1 monoclonal antibody plus interferon-alpha 1b plus anlotinib showed acceptable tolerability and anticancer benefits in Chinese metastatic melanoma patients as a second-line therapy.

Key learnings from the INBUILD trial in patients with progressive pulmonary fibrosis.

In a patient with interstitial lung disease (ILD) of known or unknown etiology other than idiopathic pulmonary fibrosis (IPF), progressive pulmonary fibrosis (PPF) is defined by worsening lung fibrosis on high-resolution computed tomography (HRCT), decline in lung function, and/or deterioration in symptoms. The INBUILD trial involved 663 patients with PPF who were randomized to receive nintedanib or placebo. The median exposure to trial medication was approximately 19 months. The INBUILD trial provided valuable learnings about the course of PPF and the efficacy and safety of nintedanib. The relative effect of nintedanib on reducing the rate of forced vital capacity decline was consistent across subgroups based on ILD diagnosis, HRCT pattern, and disease severity at baseline, and between patients who were and were not taking glucocorticoids or disease-modifying anti-rheumatic drugs and/or glucocorticoids at baseline. The adverse events most frequently associated with nintedanib were gastrointestinal, particularly diarrhea, but nintedanib was discontinued in only a minority of cases. The results of the INBUILD trial highlight the importance of prompt detection and treatment of PPF and the utility of nintedanib as a treatment option.

What did we find out from the INBUILD trial about progressive lung fibrosis?Lung fibrosis is a rare disease in which the lung tissue becomes scarred and hardened. This makes it more difficult for the lungs to inflate and for the lungs to exchange oxygen with the blood. In some patients, lung fibrosis gets worse over time. This is known as progressive lung fibrosis. In the INBUILD trial, researchers looked at the effects of a drug called nintedanib in patients with progressive lung fibrosis. In this trial, 663 patients were randomly allocated to receive either nintedanib or a placebo and then followed for approximately 19 months. The patients and the researchers did not know which patients were taking the active drug (nintedanib) and which patients were taking placebo. The results showed that the criteria used to find patients with progressive lung fibrosis to take part in the trial successfully identified patients whose disease would continue to worsen. These criteria were based on a decline in the volume (size) of the lungs, worsening symptoms such as shortness of breath, and worsening of changes seen on a scan of the chest. The trial results also showed that nintedanib slowed down loss of lung function and had a similar benefit in patients with different severities of disease at the start of the trial. The most common side-effects of nintedanib were gastrointestinal problems, particularly diarrhea, but most patients given nintedanib were able to cope with these side-effects without needing to stop treatment. Large trials like the INBUILD trial are important for helping us understand how diseases progress and in which patients particular drugs should be used.

Gefitinib (an EGFR tyrosine kinase inhibitor) plus anlotinib (an multikinase inhibitor) for untreated, EGFR-mutated, advanced non-small cell lung cancer (FL-ALTER): a multicenter phase III trial.

Dual inhibition of vascular endothelial growth factor and epidermal growth factor receptor (EGFR) signaling pathways offers the prospect of improving the effectiveness of EFGR-targeted therapy. In this phase 3 study (ClinicalTrial.gov: NCT04028778), 315 patients with treatment-naïve, EGFR-mutated, advanced non-small cell lung cancer (NSCLC) were randomized (1:1) to receive anlotinib or placebo plus gefitinib once daily on days 1-14 per a 3-week cycle. At the prespecified final analysis of progression-free survival (PFS), a significant improvement in PFS was observed for the anlotinib arm over the placebo arm (hazards ratio [HR] = 0.64, 95% CI, 0.48-0.80, P = 0.003). Particularly, patients with brain metastasis and those harboring EGFR amplification or high tumor mutation load gained significant more benefits in PFS from gefitinib plus anlotinib. The incidence of grade 3 or higher treatment-emergent adverse events was 49.7% of the patients receiving gefitinib plus anlotinib versus 31.0% of the patients receiving gefitinib plus placebo. Anlotinib plus gefitinib significantly improves PFS in patients with treatment-naïve, EGFR-mutated, advanced NSCLC, with a manageable safety profile.

Efficacy and Safety of Anlotinib in EGFR-Positive Patients with Advanced Lung Adenocarcinoma Compared with Chemotherapy: A Retrospective Study.

There are no standard third-line or beyond treatments for patients with driver mutation-positive advanced lung adenocarcinoma (LUAD). Anlotinib was approved as a third-line multitarget drug in China in 2018. Limited data are available regarding the efficacy and safety of anlotinib compared with chemotherapy. To investigate the efficacy and safety of anlotinib compared with traditional chemotherapy in patients with epidermal growth factor receptor (EGFR)-positive advanced LUAD. We conducted a retrospective study of 83 EGFR mutation-positive patients with advanced LUAD between 2011 and 2022. Progression-free survival (PFS) and overall survival (OS) were the primary endpoints, whereas the objective response rate (ORR) and disease control rate (DCR) were the secondary endpoints. Anlotinib-related adverse events (AEs) were recorded to evaluate the safety of anlotinib. 39 patients with LUAD received anlotinib and 44 patients with LUAD received chemotherapy were enrolled in the study. Patients treated with anlotinib exhibited longer PFS (11.2 vs 4.5 months, P < .01) and OS (18.8 vs 15.8 months, P < .05) than patients treated with chemotherapy. There were no significant differences in ORR (7.9% vs 20.5%, P = .129) or DCR (100% vs 93.2%, P = .120) between the two groups. Anlotinib-related AEs grading 3-4 level were observed in 2 (5.1%) patients, no anlotinib-related death was recorded. Cox regression analyses of PFS and OS showed that brain metastases and age < 30 years at diagnosis had negative effects on clinical outcomes. Anlotinib is effective and safe in patients with EGFR-positive advanced LUAD. Patients without brain metastases had better clinical outcomes.

Emerging pharmacological options in the treatment of idiopathic pulmonary fibrosis (IPF).

INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) is a progressive-fibrosing lung disease with a median survival of less than 5 years. Currently, two agents, pirfenidone and nintedanib are approved for this disease, and both have been shown to reduce the rate of decline in lung function in patients with IPF. However, both have significant adverse effects and neither completely arrest the decline in lung function. AREAS COVERED: Thirty experimental agents with unique mechanisms of action that are being evaluated for the treatment of IPF are discussed. These agents work through various mechanisms of action, these include inhibition of transcription nuclear factor k-B on fibroblasts, reduced expression of metalloproteinase 7, the generation of more lysophosphatidic acids, blocking the effects of transforming growth factor ß, and reducing reactive oxygen species as examples of some unique mechanisms of action of these agents. EXPERT OPINION: New drug development has the potential to expand the treatment options available in the treatment of IPF patients. It is expected that the adverse drug effect profiles will be more favorable than current agents. It is further anticipated that these new agents or combinations of agents will arrest the fibrosis, not just slow the fibrotic process.

Evaluation of 3-O-ß-D-galactosylated resveratrol-loaded polydopamine nanoparticles for hepatocellular carcinoma treatment.

In our previous studies, 3-O-ß-D-galactosylated resveratrol (Gal-Res) was synthesized by structural modification and then 3-O-ß-D-galactosylated resveratrol polydopamine nanoparticles (Gal-Res NPs) were successfully prepared to improve the bioavailability and liver distribution of Res. However, the pharmacodynamic efficacy and specific mechanism of Gal-Res NPs on hepatocellular carcinoma remain unclear. Herein, liver cancer model mice were successfully constructed by xenograft tumor modeling. Gal-Res NPs (34.2 mg/kg) significantly inhibited tumor growth of the liver cancer model mice with no significant effect on their body weight and no obvious toxic effect on major organs. Additionally, in vitro cellular uptake assay showed that Gal-Res NPs (37.5 µmol/L) increased the uptake of Gal-Res by Hepatocellular carcinoma (HepG2) cells, and significantly inhibited the cell migration and invasion. The experimental results of Hoechst 33342/propyl iodide (PI) double staining and flow cytometry both revealed that Gal-Res NPs could remarkably promote cell apoptosis. Moreover, the Western blot results revealed that Gal-Res NPs significantly regulated the Bcl-2/Bax and AKT/GSK3ß/ß-catenin signaling pathways. Taken together, the in vitro/in vivo results demonstrated that Gal-Res NPs significantly improved the antitumor efficiency of Gal-Res, which is a potential antitumor drug delivery system.

Oral in vivo biodistribution of fluorescent labelled nano lipid carrier system of erlotinib using real time optical imaging technique.

This study investigates the biodistribution of a nano lipid carrier system (NLCs) containing the hydrophobic drug erlotinib (ERL-NLCs). The system was labelled with the fluorescent dye IR-780 for real-time dynamic imaging. ERL-NLCs were initially developed using the ultrasonication method with oleic acid and stearic acid. In vitro and ex vivo studies were performed to confirm the formation and penetration of NLCs within the intestine. Subsequently, the biological distribution of ERL-NLCs was monitored using a fluorescent dye through the IVIS® fluorescent optical imaging technique in whole live animals. Mice were orally administered blank IR 780 dye solution, ERL suspension, and IR 780 labelled NLCs. Fluorescence images were acquired at different time intervals up to 24 h and then total radiant efficiency was calculated through the region of interest (ROI) of the whole animal at each interval of time for all three groups. To validate the results obtained from in vivo imaging, various organs including lungs, heart, liver, both kidneys, stomach, and intestine were subsequently extracted and examined after 24 h. The ROI was found to be higher in the blank IR 780 dye solution, followed by the drug suspension and IR 780 labelled NLCs. These results confirm that the plain ERL suspension distributes across the body, and its encapsulation in NLCs facilitates passage through the lymphatic intestinal pathway, effectively avoiding first-pass metabolism. The remarkable results indicated that the NLCs formulation effectively circumvents first-pass metabolism by adopting the intestinal lymphatic pathway, thereby enhancing the oral bioavailability of the drug. This observed behaviour underscores the potential of NLCs in optimizing drug delivery and minimizing adverse effects associated with gastrointestinal and metabolic processes.

Tocilizumab plus Nintedanib for progressive interstitial lung disease in systemic sclerosis: a one-year observational study.

Randomized controlled trials have recently shown that both the IL-6 inhibitor Tocilizumab and the antifibrotic Nintedanib are efficacious for Systemic Sclerosis (SSc)-associated progressive interstitial lung disease (ILD). Since real-world clinical data on Tocilizumab/Nintedanib combination are lacking, we report on their long-term safety and efficacy. Consecutive patients who received off-label Tocilizumab for SSc plus Nintedanib for progressive ILD were retrospectively studied. Adverse events, and changes in Forced Vital Capacity (FVC), Diffucing Capacity for Carbon Monoxide (DLCO) and high resolution chest tomography (HRCT) between baseline and 6 and 12 months were assessed. Tocilizumab/Nintedanib combination was well tolerated by all 20 patients [aged 52 ± 13 years (mean ± SD), 14 women, 15 diffuse SSc, disease duration of 5.7 ± 4.9 years]; 7 of 20 patients received concomitant mycophenolate mofetil safely. No serious adverse events or laboratory abnormalities were noted. Five patients developed persistent diarrhea and 2 of them reduced dosage of Nintedanib. Baseline FVC (74%±12%) and DLCO (45%±10%) remained overall stable both at 6 months (73.5%±13% and 46%±11%, respectively) and 12 months (73%±14% and 45%±11%, respectively), regardless of disease duration. The extent of fibrotic reticular pattern in available pairs of HRCTs (n = 12) remained also stable at 12 months, whereas proportion (%) of ground glass opacities decreased from 29%±16 to 21%±14% (p = 0.048); improvement in HRCTs by almost 75% was noted in 2 of these12 patients. Tocilizumab/Nintedanib combination for one year was safe and stabilized lung function in real-world SSc patients with progressive ILD. Additional studies of this combination treatment in SSc-ILD are warranted.

PARP inhibition with rucaparib alone followed by combination with atezolizumab: Phase Ib COUPLET clinical study in advanced gynaecological and triple-negative breast cancers.

BACKGROUND: Combining PARP inhibitors (PARPis) with immune checkpoint inhibitors may improve clinical outcomes in selected cancers. We evaluated rucaparib and atezolizumab in advanced gynaecological or triple-negative breast cancer (TNBC). METHODS: After identifying the recommended dose, patients with PARPi-naive BRCA-mutated or homologous recombination-deficient/loss-of-heterozygosity-high platinum-sensitive ovarian cancer or TNBC received rucaparib plus atezolizumab. Tumour biopsies were collected pre-treatment, during single-agent rucaparib run-in, and after starting combination therapy. RESULTS: The most common adverse events with rucaparib 600 mg twice daily and atezolizumab 1200 mg on Day 1 every 3 weeks were gastrointestinal effects, fatigue, liver enzyme elevations, and anaemia. Responding patients typically had BRCA-mutated tumours and higher pre-treatment tumour levels of PD-L1 and CD8 + T cells. Markers of DNA damage repair decreased during rucaparib run-in and combination treatment in responders, but typically increased in non-responders. Apoptosis signature expression showed the reverse. CD8 + T-cell activity and STING pathway activation increased during rucaparib run-in, increasing further with atezolizumab. CONCLUSIONS: In this small study, rucaparib plus atezolizumab demonstrated acceptable safety and activity in BRCA-mutated tumours. Increasing anti-tumour immunity and inflammation might be a key mechanism of action for clinical benefit from the combination, potentially guiding more targeted development of such regimens. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov (NCT03101280).

Does a postmortem redistribution affect the concentrations of the 7 azaindole-derived synthetic cannabinoid 5F-MDMB-P7AICA in tissues and body fluids following pulmonary administration to pigs?

Many fatal intoxications have been reported in connection with the consumption of newer, highly potent synthetic cannabinoids. Yet, a possible postmortem redistribution (PMR) might complicate reliable interpretation of analytical results. Thus, it is necessary to investigate the PMR-potential of new synthetic cannabinoids. The pig model has already proven to be suitable for this purpose. Hence, the aim of this study was to study the PMR of the synthetic cannabinoid 5F-MDMB-P7AICA and its main metabolite 5F-MDMB-P7AICA-dimethylbutanoic acid (DBA). 5F-MDMB-P7AICA (200 µg/kg body weight) was administered by inhalation to anesthetized and ventilated pigs. At the end of the experiment, the animals were euthanized and stored at room temperature for 3 days. Tissue and body fluid samples were taken daily. Specimens were analyzed after solid phase extraction using a standard addition method and LC-MS/MS, blood was quantified after protein precipitation using a validated method. In perimortem samples, 5F-MDMB-P7AICA was found mainly in adipose tissue, bile fluid, and duodenum contents. Small amounts of 5F-MDMB-P7AICA were found in blood, muscle, brain, liver, and lung. High concentrations of DBA were found primarily in bile fluid, duodenum contents, urine, and kidney/perirenal fat tissue. In the remaining tissues, rather low amounts could be found. In comparison to older synthetic cannabinoids, PMR of 5F-MDMB-P7AICA was less pronounced. Concentrations in blood also appear to remain relatively stable at a low level postmortem. Muscle, kidney, fat, and duodenum content are suitable alternative matrices for the detection of 5F-MDMB-P7AICA and DBA, if blood specimens are not available. In conclusion, concentrations of 5F-MDMB-P7AICA and its main metabolite DBA are not relevantly affected by PMR.

Efficacy and Safety of Multikinase Inhibitors for Patients With Refractory Thyroid Cancer: Systematic Review and Network Meta-Analysis.

CONTEXT: Multikinase inhibitors (MKIs) improve the treatment of refractory thyroid cancer, including radioactive iodine-refractory differentiated thyroid cancer (RAIR-DTC) and advanced medullary thyroid carcinoma (aMTC). OBJECTIVE: This study aims to compare the efficacy of MKIs in improving survival outcomes and safety. DATA SOURCES: Comprehensive database searches of MEDLINE via PubMed, EMBASE, and Cochrane were performed from inception to December 2023. STUDY SELECTION: Three independent authors selected these studies. Randomized controlled trials that compared the use of a MKI to other MKIs or placebo were included. DATA EXTRACTION AND SYNTHESIS: This review followed Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. Risk of bias was analyzed using the Cochrane risk of bias 2 tool. Bayesian network meta-analysis was performed. Treatments were grouped into common nodes based on the type of MKI. MAIN OUTCOMES AND MEASURES: Primary outcomes were progression-free survival (PFS) and overall survival (OS). Secondary outcomes included objective response rate, disease control rate, clinical benefit rate, and adverse events. RESULTS: Cabozantinib 60 mg/day (CAB60) was associated with the highest prolonged PFS in RAIR-DTC patients, followed by lentivatinib 18 or 24 mg/day (LEN18 or LEN24), and apatinib. PFS was also improved in aMTC patients who received CAB 140 mg/day (CAB140), CAB60, or anlotinib. A significantly greater improvement on the performance of OS was seen in CAB60, LEN24, anlotinib, and sorafenib in RAIR-DTC patients, but in aMTC patients there were lack of statistical differences. Compared with the low-dose MKIs, high-dose MKIs such as CAB, LEN, and vandetanib increased the incidence of adverse events. CONCLUSION: CAB60, LEN, and apatinib are promising topical MKIs with statistically significant primary outcomes in RAIR-DTC patients, while CAB and anlotinib are effective in prolonging PFS in aMTC patients.

The efficacy of almonertinib and anlotinib combination therapy for advanced non-small-cell lung cancer patients who continued to experience cancer progression during third-generation EGFR-TKI treatment: a retrospective study.

BACKGROUND: Epidermal growth factor receptor (EGFR) mutations are key drivers in a significant portion of non-small-cell lung cancer (NSCLC) patients. While third-generation EGFR-tyrosine kinase inhibitors (TKIs) such as osimertinib have demonstrated efficacy, the management of patients who continue to experience disease progression during treatment remains challenging. The emergence of drug resistance, including the development of secondary mutations, necessitates exploration of alternative treatment strategies. This study aims to evaluate and observe the efficacy and safety of almonertinib combined with anlotinib in patients after cancer progression during third-generation EGFR-TKI therapy. METHODS: In this retrospective analysis, we included EGFR-mutated NSCLC patients who were resistant to third-generation EGFR-TKIs. All patients were treated with almonertinib combined with anlotinib. The clinical characteristics, treatment history, clinical benefits, and adverse events of these patients were retrospectively collected. RESULTS: A total of 16 eligible patients were included in the analysis. The results revealed that combination therapy with almonertinib and anlotinib was effective in this patient cohort. The overall response rate was 25% and the disease control rate was 93.75%. The 6 and 12 months of PFS rates were 92.9% (95% confidence interval [CI] 80.3%, 100.0%) and 84.4% (95% CI 66.6%, 100.0%), respectively. Moreover, this combination therapy was generally well-tolerated, with manageable adverse events. CONCLUSION: Our retrospective analysis suggests that almonertinib and anlotinib combination therapy may represent a viable option for EGFR-mutated NSCLC patients who have progressed on third-generation EGFR-TKIs, especially for those with posterior lines and no standard treatment options. Further investigation and larger clinical trials are warranted to validate these observations and refine treatment guidelines.