Budget impact analysis of next-generation sequencing versus sequential single-gene testing in Japanese patients with advanced non-small-cell lung cancer.

BACKGROUND: Identification of genomic alterations (e.g., EGFR, ALK, ROS1, BRAF, NTRK, and MET) is essential for initiating targeted therapy in patients with advanced non-small-cell lung cancer (aNSCLC). This study estimated the budget impact of using the sequential single-gene (SSG) test, which tests for each mutation one at a time, versus next-generation sequencing (NGS), which tests for all mutations at the same time, among newly diagnosed patients with aNSCLC from a Japanese healthcare payer's perspective. METHODS: A budget impact model (BIM) was used to determine the expected budget impact associated with NGS for newly diagnosed aNSCLC in Japan over a 3-year period. The BIM compared the total costs (biopsy, testing, and treatment) and average turnaround time of "future NGS" and "current NGS" versus SSG testing. RESULTS: The adoption of current NGS over SSG testing had a budget impact of -0.24%, but adoption of future NGS over SSG testing had a budget impact of +4.33% across a 3-year time horizon on the Japanese budget for aNSCLC treatment. The adoption of current or future NGS over SSG testing would shorten the average turnaround time for testing. CONCLUSIONS: The adoption of current NGS over SSG testing would slightly decrease the yearly costs. However, the adoption of future or current NGS over SSG testing would shorten the average turnaround time, enabling faster identification of genomic alterations and earlier initiation of treatment for aNSCLC patients in Japan.

Safety and antitumor activity of copanlisib in Japanese patients with relapsed/refractory indolent non-Hodgkin lymphoma: a phase Ib/II study.

The safety, efficacy, and pharmacokinetics of copanlisib were evaluated in this phase Ib/II study in Japanese patients with relapsed/refractory indolent non-Hodgkin lymphoma (NHL). The primary endpoint was safety at the recommended dose; efficacy endpoints included objective response rate (ORR), progression-free survival (PFS), and overall survival. In phase Ib, patients received copanlisib 45 mg intravenously on days 1, 8, and 15 of a 28-day cycle, and when tolerated, consecutive patients received copanlisib 60 mg. As no dose-limiting toxicities occurred at the 45 mg (n = 3) or 60 mg (n = 7) dose in phase Ib, the recommended dose for Japanese patients was determined to be 60 mg, and this dose was used in phase II (n = 15). Although all patients experienced at least one treatment-emergent adverse event (TEAE), with hyperglycemia being the most common AE, no AE-related deaths were reported. The ORR was 68.0% (17/25 patients), median PFS was 302 (95% CI 231-484) days, and the duration of response was 330 (range 65-659) days. The pharmacokinetic properties of copanlisib were similar between Japanese and non-Japanese patients. Overall, copanlisib 60 mg had an acceptable safety profile and showed promising antitumor activity in Japanese patients with relapsed/refractory indolent NHL.

A rapid and durable response to larotrectinib in a patient with NTRK fusion-positive secretory carcinoma originating from the external auditory canal.

For decades, no clear consensus existed on the standard treatment option for malignant tumors of the external auditory canal, an extremely rare disease. Here we report the case of a 55-year-old female patient with secretory carcinoma that originated from the left external auditory canal. Magnetic resonance imaging (MRI) at baseline showed that the tumor had extended to the medulla oblongata despite surgical and radiation treatments for more than 20 years from the initial diagnosis. Based on the results of a next-generation sequencing test of a formalin-fixed paraffin-embedded surgical specimen indicating that the tumor harbored ETV6-NTRK3 fusion, the patient was enrolled in a global basket study of larotrectinib, an oral selective tropomyosin receptor kinase (TRK) inhibitor. Three weeks after the start of larotrectinib treatment, MRI showed only small remnants of the tumor in the medulla oblongata and the patient's headache before the treatment had disappeared. Subsequent MRI after 12 weeks of treatment confirmed the complete disappearance of the tumor. The patient repeated grade 2 flu-like symptoms related to treatment, but did not experience any other grade 2 or worse treatment-related adverse events. TRK inhibitors, such as larotrectinib, exert potent antitumor activity against neurotrophic tyrosine receptor kinase (NTRK) fusion-positive tumors in a tumor-agnostic manner. To the best of our knowledge, this is the first report on NTRK fusion-positive secretory carcinoma of the external auditory canal, and this report provides a valuable insight into the management of the extremely rare but now treatable malignancy.

Effectiveness and safety of sorafenib for renal cell, hepatocellular and thyroid carcinoma: pooled analysis in patients with renal impairment.

PURPOSE: Sorafenib is an oral multikinase inhibitor with regulatory approval in advanced renal cell carcinoma (RCC), hepatocellular carcinoma (HCC) and refractory differentiated thyroid carcinoma (DTC). Vascular endothelial growth factor receptor (VEGFR) inhibitors like sorafenib may cause proteinuria. This study aimed to analyze the effectiveness and safety of sorafenib in RCC, HCC and DTC patients with chronic kidney disease (CKD). METHODS: This retrospective study analyzed integrated data from prospective post-marketing surveillance studies for advanced RCC, HCC and DTC. Background factors considered to affect patients' prognosis were balanced by propensity score matching using eGFR cut-off values of 60 mL/min/1.73 m2. RESULTS: In the combined matched population (N = 2430), sorafenib was equally effective in patients with lower and higher eGFR values. Sorafenib had an overall response rate (ORR: complete + partial responses) of 18.9% and a disease control rate (DCR: complete + partial responses + stable disease) of 67.0%. There were no significant differences between lower and higher eGFR groups for response rates. Renal function was maintained throughout the 12-month study period in the combined population and in each indication. Adverse events (AEs) and serious AEs were reported in 91.6% and 58.2% of propensity score-matched patients, and with no significant differences between lower and higher eGFR groups. CONCLUSION: The effectiveness and safety of sorafenib were similar in patients with eGFR < 60 and ≥ 60 mL/min/1.73 m2 during the 12-month observation period, and without impairing renal function.

Design, synthesis and evaluation of a novel cyclohexanamine class of neuropeptide Y Y1 receptor antagonists.

A novel series of cyclohexanamine derivatives was designed and synthesized as potent and selective human neuropeptide Y Y1 receptor antagonists. Modification of high-throughput screening hit compound 1 resulted in the identification of compound 3i, which displays potent Y1 activity and good selectivity towards hERG K(+) channel and serotonin transporter.

Imidazopyridine derivatives as potent and selective Polo-like kinase (PLK) inhibitors.

A novel class of imidazopyridine derivatives was designed as PLK1 inhibitors. Extensive SAR studies supported by molecular modeling afforded a highly potent and selective compound 36. Compound 36 demonstrated good antitumor efficacy in xenograft nude rat model.

Optimization of a series of 2,4-diaminopyridines as neuropeptide Y Y1 receptor antagonists with reduced hERG activity.

The synthesis and evaluation of a series of 2,4-diaminopyridine-based neuropeptide Y Y1 (NPY Y1) receptor antagonists are described. Compound 1 was previously reported by our laboratory to be a potent and selective Y1 antagonist; however, 1 was also found to have potent hERG inhibitory activity. The main focus of this communication is structure-activity relationship development aimed at eliminating the hERG activity of 1. This resulted in the identification of compound 3d as a potent and selective NPY Y1 antagonist with reduced hERG liability.

Detection of organic free radicals in irradiated Foeniculi fructus by electron spin resonance spectroscopy.

Foeniculi fructus were irradiated with an electron beam and organic free radicals were detected by electron spin resonance (ESR) spectroscopy for the purpose of identifying radio-disinfected and sterilized herbal drugs. An ESR single-line spectrum near g = 2.005 was observed in the sample before irradiation. After irradiation, the intensity of the signal near g = 2.005 increased. In addition, two subsignals derived from cellulose radicals were observed approximately 3 mT to either side of the main signal, at g = 2.023 and g = 1.987. The intensity of the subsignal at g = 2.023 was proportional to the absorbed dose of radiation. The decrease in intensity of the signals was considerable 2 weeks after irradiation, and continued to decrease steadily thereafter. Among the signals, the fading of the subsignal at g = 2.023 was relatively small. The intensity of the subsignal at g = 2.023 was detectable for over 1 year in the sample that had been irradiated to the level of disinfection and sterilization. Therefore, organic free radicals in irradiated Foeniculi fructus can be measured rapidly and with high sensitivity by ESR spectroscopy. The stable signal at g = 2.023 is a promising indicator of the detection of irradiated herbal drugs.

Asymmetric total synthesis of fredericamycin A: an intramolecular cycloaddition pathway.

The asymmetric total synthesis of the potent antitumor antibiotic fredericamycin A ((S)-1) was achieved by the intramolecular [4+2] cycloaddition of the silylene-protected styrene derivative (S)-7 followed by the aromatic Pummerer-type reaction of the sulfoxide (S)-5. Although we had already succeeded in the total synthesis of racemic 1 by the same approach, synthesis of its asymmetric version was more complicated than we had expected due to the difficulties involved in constructing the quaternary carbon center and the tendency of this center to undergo facile racemization. Racemization of this center during the installation of the acetylene moiety on the dione (R)-8 was the most serious aspect. Systematic studies of its DE-ring analogue (R)-25 revealed that racemization of the quaternary carbon center proceeded by a retro-aldol-aldol reaction of the initial adduct, (1R)-39 a-Li, and that the degree of racemization was dependent on the reaction temperature. The racemization process could be completely depressed by keeping the reaction temperature at -78 degrees C. The construction of the stereogenic quaternary carbon center was achieved by the lipase-catalyzed desymmetrization of the prochiral 1,3-diol 9 a bearing the DEF-ring moiety. These studies enabled us to attain the asymmetric total synthesis of (S)-1 while completely retaining the chiral integrity created by the enzymatic reactions.

Enantiodivergent preparation of optically active oxindoles having a stereogenic quaternary carbon center at the C3 position via the lipase-catalyzed desymmetrization protocol: effective use of 2-furoates for either enzymatic esterification or hydrolysis.

Both enantiomers of oxindoles 2a-h, having a stereogenic quaternary carbon center at the C3 position and a different N-protective group, were readily prepared by the lipase-catalyzed desymmetrization protocol. Thus, the transesterification of the prochiral diols 3a-h with 1-ethoxyvinyl 2-furoate 5 was catalyzed by Candida rugosa lipase to give (R)-(+)-2a-h (68-99% ee), in which the use of a mixed solvent, (i)Pr(2)O (diisopropyl ether)-THF, was crucial. The same lipase also effected the enantioselective hydrolysis of the difuroates 4a-h in a mixture of (i)Pr(2)O, THF, and H(2)O to provide the enantiomers (S)-(-)-2a-h (82-99% ee). The products 2 obtained by both methods were stable against racemization. These enzymatic desymmetrization reactions were also applicable for other typical symmetrical difuroates 12b and 15b to provide the racemization-resistant products 13b and 16b.

Efficient lipase-catalyzed enantioselective desymmetrization of prochiral 2,2-disubstituted 1,3-propanediols and meso 1,2-diols using 1-ethoxyvinyl 2-furoate.

An efficient lipase-catalyzed desymmetrization of prochiral 2,2-disubstituted 1,3-propanediols was developed using 1-ethoxyvinyl 2-furoate 1b, for which the well-known method using vinyl or isopropenyl acetate has had limited success due to low reactivity and easy racemization of the products through acyl group migration. The reagent 1b is highly reactive and converts various prochiral 1,3-diols to the monoesters having a chiral quaternary carbon center with 82-99% ee. These products were stable against racemization under acidic conditions, and their furoyl groups were compatible with oxidative conditions. Prolonging the reaction time led to the kinetic resolution of the monoesters resulting in an increase of their optical purity. The similar desymmetrization of meso cis-1,2-cycloalkanediols gave the monoesters with 82-97% ee without racemization.