The importance of caregivers for patients with advanced basal cell carcinoma treated with hedgehog-pathway inhibitors: an observational prospective study.

Oral targeted therapy with hedgehog pathway inhibitors has revolutionized the standard of care for patients with advanced basal cell carcinoma (BCC). These patients are frail and elderly, have various comorbidities, and receive pharmacological polytherapy. Moreover, adverse events may have a significant impact on therapeutic adherence, which must be managed by the clinician. We evaluated the impact of caregivers on the treatment of patients with advanced BCC in terms of continuation of therapy over time. All patients included in this observational prospective study had histologically confirmed metastatic or locally advanced BCC (LaBCC) and were treated with hedgehog pathway inhibitors from January 2016 to December 2021 at the Department of Dermatology at the University of Florence, Italy. The collected patient data included: age, sex, BCC site and area of spread; number of cycles, dose, duration and tolerability of therapy; marital status (single, divorced, married/living with a partner, widow/widower); and information such as living with someone, and the presence of any caregivers. Of the 34 patients included, 33 had LaBCC and one metastatic BCC. There were 11 females (32.4%) and 23 males (67.6%). Patients who were married or living with a caregiver -tolerated therapy better than single patients who lived alone. Indeed, patients with married/live-in caregivers and/or those with an adequate caregiver experienced greater therapeutic adherence and tolerance of adverse events. Given the greater therapeutic adherence of patients with live-in caregivers as partners, it is essential to consider patients' marital status. It is advisable to involve the caregiver early on, and there should be a training discussion on the various possible adverse events and the best way to mitigate them. Therapeutic success is linked not only to patients being informed but also to training of caregivers.

[A case of crizotinib-associated renal cysts].

Crizotinib-associated renal cysts (CARC) are the development of new renal cysts or pre-existing renal cysts after the treatment with crizotinib. Most CARC disappear after crizotinib is stopped. A few CARC showed aggressive behavior that could go beyond the invasion of the renal cortex into nearby structures, including perirenal space, psoas major muscle, intestine, and abdominal wall. A case of EML4-ALK fusion mutation in invasive lung adenocarcinoma has been reported. Multiple cystic changes occurred repeatedly in both kidneys, right rectus muscle, and psoas major muscle after treatment with crizotinib, and spontaneous absorption and resolution after discontinuation of the drug.

Zolpidem Stimulant Effect and Dependence: A Case Report on Intranasal Use.

Zolpidem is a widely used hypnotic. Dependence on zolpidem due to the induction of euphoria is a rare condition, while intranasal misuse of zolpidem is a rather new phenomenon. We present the first case of a patient who developed zolpidem dependence, which was associated with the prompt onset of euphoria exclusively following intranasal use. Mr. A was a 51-year-old polydrug abuser with antisocial personality disorder and a physical dependence on zolpidem. Over several years, he consumed 500 mg of the drug daily, usually divided into 30 mg doses, exclusively via the nasal route because unlike the oral administration of the same dose of the drug, intranasal administration induced euphoria. Euphoric effects manifested 3-5 minutes after taking the drug, and pronounced withdrawal symptoms (i.e., profuse sweating, tremors, nausea, vomiting, diarrhea, and inability to drink and eat), present 7-8 hours after the use could disappear within 3-5 minutes upon drug re-administration. The dependence was managed through a slow tapering of the zolpidem use. Clinicians should be aware that intranasal use of zolpidem could be associated with euphoric effects and the development of addiction. The potential for misuse of zolpidem via the nasal route may be of interest for future research.

Regorafenib in Patients With Solid Tumors With BRAF Alterations: Results From the Targeted Agent and Profiling Utilization Registry (TAPUR) Study.

PURPOSE: Targeted Agent and Profiling Utilization Registry is a phase II basket trial evaluating the antitumor activity of commercially available targeted agents in patients with advanced cancer with genomic alterations known to be drug targets. Results of a cohort of patients with solid tumors with BRAF alterations treated with regorafenib are reported. METHODS: Eligible patients had measurable disease (RECIST v.1.1), Eastern Cooperative Oncology Group performance status 0-1, adequate organ function, and no standard treatment options. The primary end point was disease control (DC), defined as investigator assessment of patients with complete or partial response (PR) or stable disease of at least 16-weeks duration (SD16+). Low accruing histology-specific cohorts with BRAF alterations treated with regorafenib were collapsed into a single histology-pooled cohort for this analysis. The results were evaluated on the basis of a one-sided exact binomial test with a null DC rate of 15% versus 35% (power, 0.84; α, .10). Secondary end points were objective response (OR), progression-free survival, overall survival, duration of response, duration of stable disease, and safety. RESULTS: Twenty-eight patients with 12 tumor types with BRAF alterations were enrolled from June 2016 to June 2021. All patients were evaluable for efficacy. Two patients with PR and four with SD16+ were observed for DC and OR rates of 21% (90% CI, 12 to 100) and 7% (95% CI, 1 to 24), respectively. The null hypothesis of 15% DC rate was not rejected (P = .24). Eight patients had at least one grade 3 adverse event or serious adverse event at least possibly related to regorafenib. CONCLUSION: Regorafenib did not meet prespecified criteria to declare a signal of activity in patients with solid tumors with BRAF alterations.

Predicting drug-drug interactions in breast cancer patients treated with CDK4/6 inhibitors and forward planning.

INTRODUCTION: Cyclin-dependent kinase (CDK) 4/6 inhibitors are cornerstones in the treatment of Hormone Receptor (HR) positive and Human Epidermal Growth factor (HER2) negative metastatic breast cancer. Given their widespread use in the metastatic setting and emerging use in the adjuvant setting, studying drug-drug interactions (DDI) of these medications is of utmost importance. AREAS COVERED: This review provides key background information on the CDK4/6 inhibitors, palbociclib, ribociclib, and abemaciclib. We discuss drug-drug interactions including those with proton pump inhibitors as well as CYP3A substrates, inhibitors, and inducers. We describe the effect of these drugs on membrane transporters and their substrates as well as those drugs that increase risk of CDK4/6 toxicities. Finally, we explore future directions for strategies to minimize drug-drug interactions. EXPERT OPINION: It is crucial to be mindful of medications that may interfere with drug absorption, such as proton pump inhibitors, as well as those that interfere with drug metabolism, such as CYP3A4 inhibitors and inducers. Additionally, special consideration should be given to populations at higher risk for polypharmacy, such as older patients with greater comorbidities. These interactions and patient characteristics should be considered when developing individual treatment plans with CDK4/6 inhibitors.

A multicenter, open-label long-term safety study of rimegepant for the acute treatment of migraine.

BACKGROUND: The present study evaluated the long-term safety and tolerability of rimegepant, an orally administered small molecule calcitonin gene-related peptide receptor antagonist, in people with migraine. METHODS: This multicenter, long-term, open-label safety study included adults (≥18 years) with ≥1 year history of migraine who were sequentially enrolled into three groups: participants in the first two groups had either 2-8 or 9-14 moderate to severe migraine attacks per month by history and treated as needed (pro re nata [PRN]) with one rimegepant 75 mg oral tablet up to once per calendar day for 52 weeks (PRN 2-8 and PRN 9-14); a third group, included to collect safety data during higher-frequency dosing, had 4-14 moderate to severe migraine attacks per month by history and who took one rimegepant tablet every other day as scheduled dosing plus PRN dosing of one rimegepant tablet for migraine attacks of any severity on nonscheduled dosing days for 12 weeks (every other day (EOD) + PRN). RESULTS: Overall, 1800 participants self-administered rimegepant (PRN 2-8: n = 1033; PRN 9-14: n = 481; EOD + PRN: n = 286). The most common on-treatment adverse events (AEs) were upper respiratory tract infection (8.8%), nasopharyngitis (6.8%) and sinusitis (5.1%). Most AEs were mild or moderate and considered unrelated to rimegepant. Serious AEs considered possibly (n = 1) or unlikely (n = 9) related to rimegepant were reported in ten (0.6%) participants. No signal of drug-induced liver injury because of rimegepant was identified. CONCLUSIONS: Rimegepant 75 mg up to once per day as EOD + PRN for 12 weeks or PRN for up to 52 weeks was safe and well tolerated. No signal of hepatotoxicity, potential drug abuse, or medication-overuse headache was identified.Trial registration: Clinicaltrials.gov: NCT03266588.

The efficiency and safety of low-dose apatinib combined with oral vinorelbine in pretreated HER2-negative metastatic breast cancer.

BACKGROUND: Apatinib is an oral small-molecule tyrosine kinase inhibitor that blocks vascular endothelial growth factor receptor-2. Oral vinorelbine is a semisynthetic chemotherapeutic agent of vinorelbine alkaloids. Apatinib and oral vinorelbine have been proved to be effective in the treatment of metastatic breast cancer (mBC). At present, several small sample clinical trials have explored the efficacy of apatinib combined with oral vinorelbine in the treatment of mBC. METHODS: This retrospective study included 100 human epidermal growth factor receptor-2 (HER2)-negative mBC patients who received low-dose apatinib (250 mg orally per day) plus oral vinorelbine until disease progression or intolerance during February 2017 and March 2023. The progression-free survival (PFS), overall survival (OS), objective response rate (ORR), clinical benefit rate (CBR), disease control rate (DCR), and safety were analyzed by SPSS 26.0 software and GraphPad Prism 8 software. Cox proportional hazards regression model for univariate and multivariate was used to identify factors significantly related to PFS and OS. RESULTS: The median follow-up time for this study was 38.1 months. Among 100 patients with HER2-negative mBC, 66 were hormone receptor (HR)-positive/HER2-negative and 34 were triple-negative breast cancer (TNBC). The median PFS and OS were 6.0 months (95% CI, 5.2-6.8 months) and 23.0 months (95% CI, 19.9-26.1 months). There were no statistical differences in PFS (p = 0.239) and OS (p = 0.762) between the HR-positive /HER2-negative and TNBC subgroups. The ORR, CBR, and DCR were 21.0%, 58.0%, and 78.0%, respectively. Ninety-five patients (95.0%) experienced varying grades of adverse events (AEs) and 38.0% of patients for Grades 3-4. The most common Grades 3-4 AEs that we observed were neutropenia (30.0%) and leukopenia (25.0%). CONCLUSION: Low-dose apatinib combined with oral vinorelbine demonstrates potential efficacy and well tolerated for pretreated HER2-negative mBC.

5-HT1F agonists.

5-Hydroxytryptamine (HT)/serotonin receptor agonism has been a long-recognized property of triptan medications, and more recently, the study and development of medications with selective binding to the 1F receptor subtype have been explored. While the exact mechanism contributing to decreased symptoms of an acute migraine attack remains unclear, selective 5-HT1F agonists have demonstrated clinical efficacy with lasmiditan as the only approved medication from this class to date. Lasmiditan lacks vasoconstrictive properties, giving it utility in specific patient populations in whom triptans should be avoided. Availability, central nervous system (CNS) side effects, and 8-hour driving restriction may affect its clinical use.

Multi-center retrospective review of vitiligo-like lesions in breast cancer patients treated with cyclin-dependent kinase 4 and 6 inhibitors.

PURPOSE: Cutaneous adverse effects from cyclin-dependent 4 and 6 kinase inhibitors (CDK4/6i) used in metastatic breast cancer are prevalent and well described. Vitiligo-like lesions have been reported and are rare. They can negatively impact patients' quality of life and may be associated with survival benefits. We describe the clinical characteristics of vitiligo-like lesions in an international cohort of patients treated with CDK4/6i to help improve recognition and management. METHODS: Retrospective review of patients diagnosed with vitiligo-like lesions from CDK4/6i from five academic institutions in the USA and Europe was performed. Ten patients were included in the study. RESULTS: Median age of our patients was 55 (range 37-86). Median progression-free survival was 24 months in 5 patients. The median time to rash was 10 months. Sun-exposed areas such as the arms and face were the most affected areas. Multiple skin-directed therapies such as topicals, laser, and phototherapy were trialed with minor success. Mild repigmentation was seen in one patient treated with ruxolitinib cream. CDK4/6 treatment was discontinued due to the vitiligo-like lesions in one patient. CONCLUSION: Clinical characteristics are similar to previously reported findings in case reports and series. We add topical ruxolitinib as a potential treatment option for these patients and include data regarding progression-free survival that should continue to be collected. No definitive conclusions can be made regarding survival benefits from our cohort. Clinicians should refer these patients to dermatologists to aid with management.

A comparison between the adverse event profiles of patients receiving palbociclib and abemaciclib: analysis of two real-world databases.

BACKGROUND: Palbociclib and abemaciclib are cyclin-dependent kinase (CDK) 4/6 inhibitors currently used to treat breast cancer. Although their therapeutic efficacies are considered comparable, differences in adverse event (AE) profiles of the two drugs remain unclear. AIM: We analysed two real-world databases, the World Health Organization's VigiBase and the Food and Drug Administration Adverse Event Reporting System (FAERS), to identify differences in AE profiles of palbociclib and abemaciclib. METHOD: Data of patients with breast cancer receiving palbociclib or abemaciclib recorded until December 2022 were extracted from the VigiBase and FAERS databases. In total, 200 types of AEs were analysed. The reporting odds ratios were calculated using a disproportionality analysis. RESULTS: Cytopenia was frequently reported in patients receiving palbociclib, whereas interstitial lung disease and diarrhoea were frequently reported in those receiving abemaciclib. Moreover, psychiatric and nervous system disorders were more common in the palbociclib group, whereas renal and urinary disorders were more common in the abemaciclib group. CONCLUSION: This study is the first to show comprehensively the disparities in the AE profiles of palbociclib and abemaciclib. The findings highlight the importance of considering these differences when selecting a suitable CDK4/6 inhibitor to ensure safe and favourable outcomes for patients with breast cancer.

A Drug-Drug Interaction Study to Evaluate the Impact of Rimegepant on OCT2- and MATE1-Mediated Transport of Metformin in Healthy Participants.

Rimegepant is a calcitonin gene-related peptide receptor antagonist approved for migraine treatment. This phase 1, open-label, single-center, fixed-sequence study evaluated the effect of rimegepant on the pharmacokinetics (PK) of metformin. Twenty-eight healthy participants received metformin 500 mg twice daily from Days 1 to 4 and Days 7 to 10, and once daily on Days 5 and 11. Rimegepant, 75 mg tablet, was administered once daily from Days 9 to 12. At pre-specified time points, plasma metformin concentration, serum glucose levels, and safety and tolerability were evaluated. A 16% increase in the area under the plasma metformin concentration-time curve (AUC) for 1 dosing interval (AUC0-τ,ss), a statistically insignificant increase in maximum and minimum steady-state metformin concentration (Cmax,ss and Cmin,ss), and a decrease in metformin renal clearance were observed on Day 11 following metformin-rimegepant coadministration compared with metformin alone; however, the changes were not clinically relevant. Additionally, coadministration of rimegepant with metformin did not induce clinically meaningful change in the maximum observed glucose concentration (Gmax) or AUCgluc compared with metformin alone. Overall, rimegepant and metformin coadministration did not result in clinically relevant changes in metformin PK, renal clearance, or the antihyperglycemic effects of metformin. Rimegepant is considered safe for use with metformin.

Exposure-response relationship of cabozantinib in patients with metastatic renal cell carcinoma treated in routine care.

BACKGROUND: Interindividual pharmacokinetic variability may influence the clinical benefit or toxicity of cabozantinib in metastatic renal cell carcinoma (mRCC). We aimed to investigate the exposure-toxicity and exposure-response relationship of cabozantinib in unselected mRCC patients treated in routine care. METHODS: This ambispective multicenter study enrolled consecutive patients receiving cabozantinib in monotherapy. Steady-state trough concentration (Cmin,ss) within the first 3 months after treatment initiation was used for the PK/PD analysis with dose-limiting toxicity (DLT) and survival outcomes. Logistic regression and Cox proportional-hazards models were used to identify the risk factors of DLT and inefficacy in patients, respectively. RESULTS: Seventy-eight mRCC patients were eligible for the statistical analysis. Fifty-two patients (67%) experienced DLT with a median onset of 2.1 months (95%CI 0.7-8.2). In multivariate analysis, Cmin,ss was identified as an independent risk factor of DLT (OR 1.46, 95%CI [1.04-2.04]; p = 0.029). PFS and OS were not statistically associated with the starting dose (p = 0.81 and p = 0.98, respectively). In the multivariate analysis of PFS, Cmin, ss > 336 ng/mL resulted in a hazard ratio of 0.28 (95%CI, 0.10-0.77, p = 0.014). By contrast, Cmin, ss > 336 ng/mL was not statistically associated with longer OS. CONCLUSION: Early plasma drug monitoring may be useful to optimise cabozantinib treatment in mRCC patients treated in monotherapy, especially in frail patients starting at a lower than standard dose.

Regorafenib monotherapy or combined with an immune-checkpoint inhibitor as later-line treatment for metastatic colorectal cancer: a multicenter, real-world retrospective study in China.

OBJECTIVE: To evaluate the efficacy and safety of regorafenib monotherapy or in combination with immune-checkpoint inhibitor while treating Chinese patients with metastatic colorectal cancer (mCRC): a real-world study. METHODS: The data of patients with metastatic colorectal cancer who received regorafenib-containing regimen as the third or later line treatment at ten Chinese hospitals from Aug 2017 to Jun 2020 were retrospectively analyzed, including dosing details, survival data as well as adverse events. Survival analysis was further performed for patients administrated with regorafenib monotherapy and combined with an immune-checkpoint inhibitor based on Kaplan-Meier and Cox regression methods. The primary endpoint was overall survival. RESULTS: A total of 537 patients were included with a median age of 61, among whom 376 received regorafenib monotherapy and 245 received regorafenib combined with immune-checkpoint inhibitors. The clinicopathological characteristics of the two groups at baseline were mainly balanced. No significant difference in progression-free survival (PFS) was observed in patients receiving regorafenib monotherapy or combination therapy (3.8 vs. 5.5 months, p = 0.170). In contrast, patients receiving combination therapy had a more prolonged overall survival (OS) than those receiving regorafenib monotherapy (13.5 vs. 10.0 months, p = 0.001). The treatment regimen and regorafenib dosage were significant prognostic factors in the multivariate analysis. Significant benefits in PFS and OS were achieved in KRAS mutant and anti-angiogenesis treatment-naïve subgroups receiving combination therapy compared to monotherapy. No apparent increase was recorded in treatment-related adverse events in patients receiving combination therapy. CONCLUSION: Regorafenib plus an immune-checkpoint inhibitor has already been a widely adopted strategy in the later-line treatment for mCRC in the real world. The combination therapy yielded a significantly prolonged overall survival than regorafenib alone, with a manageable safety profile in Chinese patients, and warrants further investigation. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04835324. Registered 6th April 2021.

Efficacy and safety of the combination of camrelizumab and apatinib in the treatment of liver cancer: a systematic review and single-arm meta-analysis.

OBJECTIVE: To evaluate the efficacy and safety of the combination of camrelizumab and apatinib in the treatment of liver cancer and to furnish clinical recommendations for pharmacological interventions. METHODS: PubMed, Embase, Web of Science and the Cochrane Library were scrutinized for research publications from their inception to 22 December 2023. Bibliographic perusal and data procurement were executed. The quality of the included studies was evaluated employing the MINORS tool. Meta-analysis was conducted utilizing Stata 15.0 software. RESULTS: A total of 10 studies involving 849 patients were included in the meta-analysis. The study revealed that the objective response rate (ORR) of the combined therapy was 28% (95% CI: 23%-34%), the disease control rate (DCR) was 69% (95% CI: 64%-73%), the median progression-free survival (mPFS) was 5.87 months (95% CI: 4.96-6.78), the median overall survival (mOS) was 19.35 months (95% CI: 17.53-21.17), the incidence of any grade adverse events was 90% (95% CI: 85%-95%), and the occurrence of grade 3 or higher adverse events was 49% (95% CI: 27%-71%). CONCLUSION: The combination of camrelizumab and apatinib exhibits commendable effectiveness in the management of liver cancer; nevertheless, vigilance should be exercised concerning potential adverse reactions in clinical applications to enhance the safety of pharmacological interventions.

The Pharmacokinetics, Safety, and Tolerability of Rimegepant 75 mg Are Similar in Elderly and Nonelderly Adults: A Phase 1, Open-Label, Parallel-Group, Single-Dose Study.

Rimegepant is a small-molecule calcitonin gene-related peptide receptor antagonist approved for the acute treatment of migraine ± aura and preventive treatment of migraine in adults. The pharmacokinetics of rimegepant in elderly and nonelderly subjects were evaluated. In an open-label Phase 1 study, 14 elderly (aged 65 years or older) and 14 nonelderly (aged 18 to less than 45 years) subjects each received a single oral dose of rimegepant 75 mg. Blood samples were collected before dosing and through 96 hours after dosing. The pharmacokinetic parameters of rimegepant after a single dose were similar in both age groups. Geometric least-squares mean ratios (elderly/nonelderly) of the natural log-transformed maximum observed plasma concentration and natural log-transformed area under the plasma concentration-time curve from time 0 extrapolated to infinity were 96.6 and 104.6, respectively. Eight (28.6%) subjects (4 elderly, 4 nonelderly) experienced 1 or more adverse events (AEs); all AEs were mild in intensity, and no serious AEs or AEs leading to discontinuation were reported. Following a single 75-mg dose of oral rimegepant, pharmacokinetic parameters were similar in elderly and nonelderly adults; no dose adjustment is warranted in elderly subjects.

Cabozantinib-induced heart failure.

INTRODUCTION: Cabozantinib is a multikinase inhibitor agent used in the treatment of hepatocellular, renal, and thyroid cancers. The development of heart failure after cabozantinib initiation is an extremely rare side effect, with only four case reports published in the literature. We describe a case of cabozantinib-induced cardiac failure in a patient with thyroid cancer refractory to standard treatment. CASE REPORT: Fifty-seven-year-old woman had no history of cardiovascular disease. Echocardiography prior to chemotherapy revealed normal cardiac function. However, she developed pretibial edema and shortness of breath after 2 months of cabozantinib treatment. Ejection fraction was found to be 30% in the echocardiography of the patient, and global hypokinesia was detected in cardiac functions. MANAGEMENT AND OUTCOME: Cabozantinib treatment of the patient was discontinued. After discontinuation of treatment, the patient's cardiac functions did not return to normal. Heart failure due to cabozantinib treatment was thought to be permanent. DISCUSSION: There are only four cases on this subject in the literature. Although the use of cabozantinib rarely causes heart failure, this side effect can have extremely serious consequences. Even if it is a rare condition, cardiological evaluations should be performed before and after cabozantinib therapy because it can be reversible after discontinuation of the treatment.