Assessing the effectiveness and safety of surufatinib versus everolimus or sunitinib in advanced neuroendocrine neoplasms: insights from a real-world, retrospective cohort study using propensity score and inverse probability treatment weighting analysis.

Background: While surufatinib, sunitinib, and everolimus have shown efficacy for advanced neuroendocrine neoplasms (NENs) in randomized controlled trials (RCTs), direct comparisons in a real-world setting remain unexplored. This gap highlights the clinical need to understand their comparative effectiveness and safety within the diverse Chinese population. Addressing this, our study provides insights into the real-world performance of these therapies, aiming to inform treatment selection and improve patient outcomes. Methods: A retrospective, observational study was conducted at Fudan University Shanghai Cancer Center, including patients with advanced NENs treated with surufatinib, sunitinib, or everolimus between July 2020 and April 2023. Eligibility criteria focused on histologically confirmed, locally advanced, unresectable, or metastatic NENs, with patients having received at least one month of targeted therapy. We employed inverse probability weighting (IPW) with the propensity score (PS) matching to adjust for the bias of baseline characteristics. The assessment of covariates included age, sex, performance status, primary tumor site, functional status, genetic mutations, tumor differentiation, Ki67 index, tumor grade, metastasis site, and previous therapies. The primary outcome was progression-free survival (PFS), and secondary outcomes included objective response rate (ORR), disease control rate (DCR), and adverse events (AEs). Results: The study enrolled 123, 56, and 68 locally advanced or metastatic NEN patients treated with surufatinib, sunitinib, and everolimus, respectively. Before adjusting for confounding factors, surufatinib was used less frequently as a first-line treatment compared to sunitinib and everolimus in pancreatic NENs (pNENs) (11.1% vs. 22.1%, P=0.057). Significant differences were noted in prior treatments and tumor characteristics between surufatinib and everolimus groups in extrapancreatic NENs (epNENs) (P<0.05). Post-IPW, these disparities were resolved (P>0.05). Surufatinib demonstrated superior median PFS (mPFS) in both pancreatic [8.30 vs. 6.33 months, hazard ratio (HR) 0.592, P<0.001] and epNENs (8.73 vs. 3.70 months, HR 0.608, P<0.001) compared to everolimus or sunitinib. Notably, male gender (HR 1.75, P=0.001), functional status (HR 2.09, P=0.01), Ki67 index >20% (HR 12.7, P=0.004), previous somatostatin analogue (SSA) treatment (HR 1.73, P=0.001), germline mutation (HR 5.62, P<0.001), poor differentiation (HR 7.45, P<0.001), liver metastasis (HR 1.72, P=0.001) and multiple treatment lines (HR 1.62 for 2nd line, P=0.04; HR 1.88 for ≥3rd line, P=0.01) were identified as negative prognostic factors for PFS. Conversely, dose adjustment (HR 0.63, P=0.009) and treatment with surufatinib (HR 0.58 for pNEN, P<0.001; HR 0.62 for epNEN, P=0.002) were correlated with longer PFS. Conclusions: In a real-world Chinese cohort, surufatinib significantly outperformed sunitinib and everolimus in prolonging PFS among advanced NEN patients, with identifiable clinical features impacting survival, and conclusions regarding superiority should be interpreted with caution due to the retrospective design. Our findings underscore the need for prospective studies to further validate these results and explore additional predictive biomarkers for personalized treatment strategies.

CDK4/6 inhibitors in drug-induced liver injury: a pharmacovigilance study of the FAERS database and analysis of the drug-gene interaction network.

Objective: The aim of this study was to investigate the potential risk of drug-induced liver injury (DILI) caused by the CDK4/6 inhibitors (CDK4/6is abemaciclib, ribociclib, and palbociclib by comprehensively analyzing the FDA Adverse Event Reporting System (FAERS) database. Moreover, potential toxicological mechanisms of CDK4/6is-related liver injury were explored via drug-gene network analysis. Methods: In this retrospective observational study, we collected reports of DILI associated with CDK4/6i use from the FAERS dated January 2014 to March 2023. We conducted disproportionality analyses using the reporting odds ratio (ROR) with a 95% confidence interval (CI). Pathway enrichment analysis and drug-gene network analyses were subsequently performed to determine the potential mechanisms underlying CDK4/6i-induced liver injury. Results: We found positive signals for DILI with ribociclib (ROR = 2.60) and abemaciclib (ROR = 2.37). DILIs associated with liver-related investigations, signs, and symptoms were confirmed in all three reports of CDK4/6is. Moreover, ascites was identified as an unlisted hepatic adverse effect of palbociclib. We isolated 189 interactive target genes linking CDK4/6 inhibitors to hepatic injury. Several key genes, such as STAT3, HSP90AA1, and EP300, were revealed via protein-protein analysis, emphasizing their central roles within the network. KEGG pathway enrichment of these genes highlighted multiple pathways. Conclusion: Our study revealed variations in hepatobiliary toxicity among the different CDK4/6 inhibitors, with ribociclib showing the highest risk of liver injury, followed by abemaciclib, while palbociclib appeared relatively safe. Our findings emphasize the need for cautious use of CDK4/6 inhibitors, and regular liver function monitoring is recommended for long-term CDK4/6 inhibitor use.

Ocular adverse events associated with BRAF and MEK inhibitor combination therapy: a pharmacovigilance disproportionality analysis of the FDA adverse event reporting system.

BACKGROUND: BRAF and MEK inhibitor combination therapy have significantly improved the outcome of several BRAF-mutation tumors, but it also confers the risk of drug-induced ocular adverse events (oAEs). However, very few studies focused on this risk. METHODS: The United States Food and Drug Administration Adverse Event Reporting System (FAERS) data from Quarter 1-2011 to Quarter 2-2022 were searched to detect signs of oAEs of three marketed BRAF and MEK inhibitor combination therapies: vemurafenib plus cobimetinib (V + C), dabrafenib plus trametinib (D + T), and encorafenib plus binimetinib (E + B). Disproportionality analyses were performed by calculating the proportional reporting ratio (PRR), χ2 (chi-square), and reporting odds ratios (RORs) with a 95% confidence interval (CI). RESULTS: A series of oAEs were identified, including 42 preferred terms, which could be classified into 8 aspects. In addition to previously reported oAEs, several unexpected oAE signals were detected. Moreover, differences in oAE profiles were found among three combination therapies (V + C, D + T, and E + B). CONCLUSIONS: Our findings support an association between several oAEs and BRAF and MEK inhibitor combination therapies, including several new oAEs. In addition, oAEs profiles may vary across the treatment regimens. Further studies are needed to better quantify these oAEs.

Prediction of tacrolimus and Wuzhi tablet pharmacokinetic interaction magnitude in renal transplant recipients.

AIM: Wuzhi tablets are a dose-sparing agent for tacrolimus (TAC) in China and increase the bioavailability of TAC. The current study aimed to evaluate the pharmacokinetic interaction magnitude of Wuzhi and TAC and explore the potential determinants of this interaction. METHODS: This study performed a retrospective, self-controlled study of 138 renal transplant recipients who were co-administered TAC and Wuzhi. The trough concentration (C0) of TAC at baseline and 3, 7, 14 and 21 days after Wuzhi co-therapy initiation was measured, and the CYP3A5 polymorphism was genotyped. The corresponding clinical factors were recorded. The ratio of dose-adjusted C0 (C0/D) post- and pre-combination therapy (ΔC0/D) indicates the interaction magnitude. Univariate and multivariate analyses were used to identify determinants and establish the prediction model. RESULTS: ΔC0/D reached a steady state within 14 days. The geometrical mean ΔC0/D was 2.91 (range 1.02-9.49, IQR 2.13-3.80). ΔC0/D was blunted in CYP3A5 expressers (estimated effect: -39.8%, P = .001) and affected by hematocrit (Hct) (+24.0% per 10% increase, P = .005) and baseline C0/D (-31.9% per 1 ng·ml-1 ·mg-1 increase, P < .001). The prediction model was ΔC0/D = .319baseline C0/D × 1.398CYP3A5 (expressers = 0/non-expressers = 1) × 1.024Hct × 1.744, and it explained 28.1% of the variability. CONCLUSION: Our study is the first attempt to date to give an assessment of the magnitude of pharmacokinetic interaction between TAC and Wuzhi in a cohort of renal transplant recipients, and CYP3A5 genotypes, baseline C0/D and Hct were identified as determinants of this interaction.

Influence of Polymers on the Physical and Chemical Stability of Spray-dried Amorphous Solid Dispersion: Dipyridamole Degradation Induced by Enteric Polymers.

Amorphous solid dispersions (ASDs) are inherently unstable because of high internal energy. Evaluating physical and chemical stability during the process and storage is essential. Numerous researches have demonstrated how polymers influence the drug precipitation and physical stability of ASDs, while the influence of polymers on the chemical stability of ASDs is often overlooked. Therefore, this study aimed to investigate the effect of polymers on the physical and chemical stability of spray-dried ASDs using dipyridamole (DP) as a model drug. Proper polymers were selected by assessing their abilities to inhibit drug recrystallization in supersaturated solutions. HPMC E5, Soluplus®, HPMCP-55, and HPMCAS-LP were shown to be effective stabilizers. The optimized formulations were further stored at a high temperature (60 °C) and high humidity (40 °C, 75% RH) for 2 months, and their physical and chemical stability was evaluated using polarizing optical microscopy, FTIR, HPLC, and mass spectrometry (MS). In general, crystallization was observed in all samples, which indicated the physical instability under stressed storage conditions. Also, it was noted that the polymers in ASDs rather than physical mixtures, induced a dramatic drug degradation after being exposed to a high temperature (HPMCP-55 > 80% and HPMCAS-LP > 50%) and high humidity (HPMCP-55 > 40% and HPMCAS-LP > 10%). The MS analysis further confirmed the degradation products, which might be generated from the reaction between dipyridamole and phthalic anhydride decomposed from HPMCP-55 and HPMCAS-LP. Overall, the exposure of ASDs to stressed conditions resulted in recrystallization and even the chemical degradation induced by polymers.