Real-World Prevalence and Tolerability of Immune-Related Adverse Events in Older Adults with Non-Small Cell Lung Cancer: A Multi-Institutional Retrospective Study.

With cancer diagnosis occurring at older ages, the use of immune checkpoint inhibitors (ICIs) has extended to older adults. However, the safety of immune-related adverse events (irAEs) in this population remains unclear and relies on data extrapolated from younger adults. This multicenter retrospective study aimed to examine irAE prevalence and tolerability in older adults. We included 436 patients with non-small lung cancer undergoing ICI therapy and dichotomized them into two age groups (< or ≥75 years). Incidence of any irAE grade, grade ≥3 irAEs, and steroid usage after irAE occurrence was similar between younger (n = 332) and older groups (n = 104). While the younger patients with irAEs showed prolonged overall survival in the 12-month landmark Kaplan-Meier analysis (Hazard ratio (HR) 0.59, 95% confidence interval (CI) 0.38-0.89, p = 0.013), the older cohort did not (HR 0.80, 95% CI 0.36-1.78, p = 0.588). Although no differences were observed with ICI continuation or re-challenge after irAE onset, the elderly cohort had double the irAE cases that required a transition to best supportive care (BSC) (11.3% vs. 22.4%, p = 0.026). In conclusion, although irAE prevalence remains consistent regardless of age, the increased conversion to BSC post-irAE onset in older adults suggests diminished tolerability and the potential absence of favorable prognosis associated with irAEs in this population.

Localization of Sites of Osimertinib Action in Rat Intestine, Skin, and Lung by Immunohistochemistry.

Osimertinib is a third-generation, irreversible tyrosine kinase inhibitor (TKI) of epidermal growth factor receptor (EGFR) that selectively inhibits both EGFR-TKI-sensitizing and EGFR T790M resistance mutations and has shown efficacy in patients with non-small-cell lung cancer. In this study, we created osimertinib-specific antibodies and developed an immunohistochemistry (IHC) for locating the sites of osimertinib action. Moreover, we located osimertinib-protein conjugates in intestinal, dermal, and lung tissues of rats, thereby using our IHC to visualize the sites of the adverse effects of osimertinib, including diarrhea, skin disorder, and interstitial pneumonia. This report is the first to elucidate the localization of the sites of action of osimertinib in the rat intestine, skin, and lung and is expected to help clarify the mechanism of osimertinib-induced adverse effects.

Development of a Competitive Enzyme-Linked Immunosorbent Assay for the Determination of Sunitinib Unaffected by Light-Induced Isomerization.

Sunitinib is an oral multi-targeted tyrosine kinase inhibitor approved for treating metastatic renal cell carcinoma. This study reports a specific and sensitive competitive enzyme-linked immunosorbent assay (ELISA) for the pharmacokinetic evaluation of sunitinib. Anti-sunitinib serum was obtained from mice by using N-(2-(diethylamino)ethyl)-5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxamide (DFPC) as a hapten, which has the same substructure as sunitinib, in order to avoid the effects of structural changes in the geometrical isomers of sunitinib. Enzyme labeling of sunitinib with horseradish peroxidase was similarly performed using DFPC. Serum sunitinib concentrations below the limit of quantification of 0.52 ng/mL were reproducibly measurable. This ELISA was specific for sunitinib (Z- and E-isomers) and showed very low cross-reactivity (0.094%) with its major metabolite, N-desethyl sunitinib. Its analytical applicability was demonstrated by a kinetic study with human liver microsomes. In addition, the levels of sunitinib measured by ELISA in a kinetic study with human liver microsomes were comparable with those measured by HPLC, and there was a strong correlation between the values determined by both methods (y = 1.065x - 51.2, R2 = 0.9804). The developed ELISA provides for the specific and sensitive quantification of sunitinib without the influence of its major metabolite or light-induced geometric isomers. This ELISA will be a valuable tool in pharmacokinetic studies of sunitinib.

Severity of constipation related to palonosetron during first-line chemotherapy: a retrospective observational study.

PURPOSE: Palonosetron, a long-acting 5-HT3 receptor antagonist, is an effective antiemetic agent for chemotherapy-induced nausea and vomiting; however, it sometimes causes severe constipation. The aim of the present study was to evaluate the severity of palonosetron-related constipation. METHODS: We retrospectively analyzed the incidence and severity of constipation after intravenous administration of 0.75-mg palonosetron in 150 chemotherapy-naïve patients who received first-line chemotherapy at Saga University Hospital. Constipation was classified into grades 1-5 according to the Common Terminology Criteria for Adverse Events version 5.0. Multiple logistic regression analysis was performed to identify factors associated with palonosetron-related worsening of constipation to grade 2 or higher. RESULTS: Palonosetron significantly increased the incidence and severity of constipation (incidence: before vs. after palonosetron, 35.4% vs. 74.0%, p < 0.0001, and severity: before vs. after palonosetron, 26.7% and 8.7% in grades 1 and 2, respectively, vs. 46.7%, 23.3%, and 4.0% in grades 1, 2, and 3, respectively, p < 0.0001). Despite the use of laxatives, 4.0% of patients had grade 3 constipation requiring manual evacuation. Combination treatment with aprepitant (odds ratio (OR), 10.9; 95% confidence interval (CI), 1.3-90.0; p = 0.026) and older age (OR, 1.25; 95% CI, 1.01-1.57; p = 0.039) were factors associated with the severity of constipation. CONCLUSION: Constipation was more severe in patients receiving combination treatment with aprepitant than in those treated with palonosetron alone. Older age was also associated with increased risk of severe palonosetron-related constipation. Identification of risk factors can help target risk-based laxative therapy.

Association of Genetic Polymorphisms With Afatinib-induced Diarrhoea.

BACKGROUND/AIM: Afatinib, a 2nd generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) used in treatment of non-small cell lung cancer (NSCLC), causes diarrhoea in over 90% of patients. The association of genetic background with diarrhoea is poorly understood. PATIENTS AND METHODS: We evaluated the roles of four single nucleotide polymorphisms (SNPs) in ATP binding cassette subfamily B member 1 (ABCB1) and ATP binding cassette subfamily G member 2 (ABCG2) genes-ABCB1 1236 C>T, 2677 G>T/A, and 3435 C>T, and ABCG2 421 C>A-on treatment-induced diarrhoea in 38 patients with NSCLC treated with afatinib. RESULTS: Diarrhoea occurred more frequently in patients with ABCB1 2677 T(A)/T(A) (14/16, 87.5%) than in patients with non-T(A)/T(A) alleles (8/22, 36.4%) (p=0.003). ABCB1 2677 T(A)/T(A) was significantly predictive of diarrhoea (p=0.002) by multivariable regression analysis. CONCLUSION: Afatinib-induced diarrhoea is associated with the SNP ABCB1 2677 T(A)/T(A).

Development of an application for management of drug holidays in perioperative periods.

Before surgery and other invasive treatments, decisions must be made on whether to discontinue drugs and provide appropriate drug holidays especially for antithrombotic drugs, and this is made difficult by the large number of available drugs and associated guidelines. We have therefore developed an online application for perioperative drug discontinuation and resumption management, named Saga Application for Management of Drug Holidays in PeriOperative Periods (SAMPOP).Multidisciplinary medical staff at Saga University Hospital (SUH) worked together to build an evidence-based Perioperative Drug Discontinuation Management Database (PDDMD) and developed the user-friendly SAMPOP online application via preliminary verification at SUH. From September 2018 to February 2020, 420 medical staff at SUH, including physicians, nurses, and pharmacists, installed and tested SAMPOP.Rate per surgical procedure for forgetting to discontinue antithrombotic drugs preoperatively decreased from 0.18% to 0.09% as of August 2019, 12 months after the introduction of SAMPOP (P = .1359). In addition, six months later, it decreased further to 0.03% as of February 2020 (P = .0436). Forgetting to resume antithrombotic drugs postoperatively decreased from 0.20% to 0.02% as of August 2019, 12 months after the introduction of SAMPOP (P = .0008). There was no case of forgetting to resume the medication in the last 6 months.SAMPOP may be useful for management of drug holidays in the clinic and warrants further evaluation of its safety and efficacy.

Development of a competitive enzyme-linked immunosorbent assay for therapeutic drug monitoring of afatinib.

Afatinib is an oral tyrosine kinase inhibitor (TKI) approved for treating advanced non-small cell lung cancer. It is necessary to develop a simple quantification method for TKIs in order to facilitate therapeutic drug monitoring (TDM) in clinical settings. This study sought to develop a simple and sensitive competitive enzyme-linked immunosorbent assay (ELISA) to quantify afatinib in plasma for routine pharmacokinetic applications. An anti-afatinib antibody was obtained using (S)-N-4-(3-chloro-4-fluorophenyl)-7-(tetrahydrofuran-3-yloxy)-quinazoline-4,6-diamine (CTQD), which has the same substructure as afatinib, as a hapten. Enzyme labeling of afatinib with horseradish peroxidase was similarly performed using CTQD. A simple competitive ELISA for afatinib was developed based on the principle of direct competition between afatinib and the enzyme marker for the anti-afatinib antibody, which had been immobilized on the plastic surface of a microtiter plate. Plasma afatinib concentrations below the limit of quantification of 30 pg/mL were reproducibly measurable. Also, the values of plasma afatinib levels measured from 20 patients were comparable with those measured by high-performance liquid chromatography, and there was a strong correlation between the values determined by both methods (Y = 0.976X - 0.207, r = 0.975). As indicated by its specificity and sensitivity, this newly developed ELISA for afatinib is an important tool for TDM and studies of the pharmacokinetics of afatinib.

Anxiety and depression associated with tyrosine kinase inhibitor discontinuation in patients with chronic myeloid leukemia.

BACKGROUND: ABL tyrosine kinase inhibitors (TKIs) significantly changed the prognosis of patients with chronic myeloid leukemia (CML), and clinical trials demonstrated that TKIs can be discontinued in approximately 50% of patients after a period of deep molecular response (DMR). However, in some patients, TKI discontinuation leads to anxiety and depression. Here, we analysed the incidence of anxiety and depression in patients who stop TKI therapy. METHODS: Anxiety and depression were evaluated using the Hospital Anxiety and Depression Scale (HADS) in 32 patients with CML. The survey periods were at TKI discontinuation, at 1, 6, 12, and 24 months and at reintroduction of TKIs. The HADS score at the initial TKI discontinuation was compared between patients within and outside clinical trials. Treatment-free remission (TFR) rates outside clinical trials were evaluated. RESULTS: The HADS scores were significantly higher at TKI reintroduction after molecular relapse than at the initial TKI discontinuation (at the initiation of stopping TKIs vs. at reintroduction of TKIs, 8.47 ± 5.53 vs. 1.67 ± 2.26; p = 0.0003). The TFR rate at 12 months after stopping TKIs outside clinical trials was 55.6%. The HADS score at the initial TKI discontinuation did not differ between patients within and outside clinical trials. CONCLUSION: Stopping TKIs outside clinical trials is feasible if the guidelines for stopping are followed and an adequate monitoring system is available. Discontinuation of TKIs requires adequate management of anxiety and depression.