Varlitinib and Paclitaxel for EGFR/HER2 Co-Expressing Advanced Gastric Cancer: a Multicenter Phase Ib/II Study (K-MASTER-13).

Purpose: Varlitinib is a pan-human epidermal growth (HER) inhibitor targeting epidermal growth factor receptor (EGFR), HER2, and HER4. We present a phase Ib/II study of a combination of varlitinib and weekly paclitaxel as a second-line treatment for patients with EGFR/HER2 co-expressing advanced gastric cancer (AGC). Materials and Methods: Patients whose tumors with EGFR and HER2 overexpression by immunohistochemistry (IHC) (≥1+) were enrolled. Varlitinib and paclitaxel were investigated every 4 weeks. After determining the recommended phase II dose (RP2D) in phase Ib, a phase II study was conducted to evaluate the antitumor activity. Results: RP2D was treated with a combination of varlitinib (300 mg twice daily) and paclitaxel. Among 27 patients treated with RP2D, the median PFS and overall survival (OS) were 3.3 months and 7.9 months, respectively, with a median follow-up of 15.7 months. Among 16 patients with measurable disease, the objective response rate (ORR) and disease control rate were 31% and 88%, respectively. Patients with strong HER2 expression (n=8) had a higher ORR and longer OS, whereas those with strong EGFR expression (n=3) had poorer outcomes. The most common adverse events (AEs) of any grade were neutropenia (52%), diarrhea (27%), AST/ALT elevation (22%), and nausea (19%). No treatment-related deaths or unexpected AEs resulting from treatment cessation were observed in patients with RP2D. Conclusion: A combination of varlitinib and paclitaxel displayed manageable toxicity and modest antitumor activity in patients with EGFR/HER2 co-expressing AGC who progressed after first-line chemotherapy.

Pragmatic nationwide master observational trial based on genomic alterations in advanced solid tumors: KOrean Precision Medicine Networking Group Study of MOlecular profiling guided therapy based on genomic alterations in advanced Solid tumors (KOSMOS)-II study protocol KCSG AL-22-09.

BACKGROUND: Next-generation sequencing (NGS) has been introduced to many Korean institutions to support molecular diagnostics in cancer since 2017, when it became eligible for reimbursement by the National Health Insurance Service. However, the uptake of molecularly guided treatment (MGT) based on NGS results has been limited because of stringent regulations regarding prescriptions outside of approved indications, a lack of clinical trial opportunities, and limited access to molecular tumor boards (MTB) at most institutions. The KOSMOS-II study was designed to demonstrate the feasibility and effectiveness of MGT, informed by MTBs, using a nationwide precision medicine platform. METHODS: The KOSMOS-II trial is a large-scale nationwide master observational study. It involves a framework for screening patients with metastatic solid tumors for actionable genetic alterations based on local NGS testing. It recommends MGT through a remote and centralized MTB meeting held biweekly. MGT can include one of the following options: Tier 1, the therapeutic use of investigational drugs targeting genetic alterations such as ALK, EGFR, ERBB2, BRAF, FH, ROS1, and RET, or those with high tumor mutational burden; Tier 2, comprising drugs with approved indications or those permitted for treatment outside of the indications approved by the Health Insurance Review and Assessment Service of Korea; Tier 3, involving clinical trials matching the genetic alterations recommended by the MTB. Given the anticipated proportion of patients receiving MGT in the range of 50% ± 3.25%, this study aims to enroll 1,000 patients. Patients must have progressed to one or more lines of therapy and undergone NGS before enrollment. DISCUSSION: This pragmatic master protocol provides a mass-screening platform for rare genetic alterations and high-quality real-world data. Collateral clinical trials, translational studies, and clinico-genomic databases will contribute to generating evidence for drug repositioning and the development of new biomarkers. TRIAL REGISTRATION: NCT05525858.

Beyond One-Size-Fits-All: Tailoring Teicoplanin Regimens for Normal Renal Function Patients Using Population Pharmacokinetics and Monte Carlo Simulation.

In patients with normal renal function, significant teicoplanin dose adjustments are often necessary. This study aimed to develop a population pharmacokinetic (PK) model for teicoplanin in healthy adults and use it to recommend optimal dosage regimens for patients with normal renal function. PK samples were obtained from 12 subjects and analyzed using a population approach. The derived parameters informed Monte Carlo simulations for dosing recommendations. The PK profile was best described using a three-compartment model, in which the estimated glomerular filtration rate calculated via the CKD-EPI equation and adjusted for body surface area was identified as a significant covariate affecting total clearance. For pathogens with a minimum inhibitory concentration of 1 mg/L, a loading dose (LD) of 14 mg/kg administered every 12 h for four doses, followed by a maintenance dose (MD) of 16 mg/kg administered every 24 h, is recommended. These findings indicate the need for dosage adjustments, such as increasing the LD and MD or decreasing the dosing interval of MD in patients with normal renal function. Because of the long half-life of teicoplanin and the requirement for long-term administration, therapeutic drug monitoring at strategic intervals is important to avoid nephrotoxicity associated with elevated trough concentrations.

Comparison of Tepotinib, Paclitaxel, or Ramucirumab Efficacy According to the Copy Number or Phosphorylation Status of the MET Gene: Doublet Treatment versus Single Agent Treatment.

Although conventional combination chemotherapies for advanced gastric cancer (GC) increase survival, such therapies are associated with major adverse effects; more effective and less toxic treatments are required. Combinations of different anti-cancer drugs, for example, paclitaxel plus ramucirumab, have recently been used as second-line treatments for advanced GC. This study evaluated how copy number variations of the MET gene, MET mutations, and MET gene and protein expression levels in human GC cells modulate the susceptibility of such cells to single-agent (tepotinib, ramucirumab, or paclitaxel) and doublet (tepotinib-plus-paclitaxel or ramucirumab-plus-paclitaxel treatment regimens. Compared with ramucirumab-plus-paclitaxel, tepotinib-plus-paclitaxel better inhibited the growth of GC cells with MET exon 14 skipping mutations and those lacking MET amplification but containing phosphorylated MET; such inhibition was dose-dependent and associated with cell death. Tepotinib-plus-paclitaxel and ramucirumab-plus-paclitaxel similarly inhibited the growth of GC cells lacking MET amplification or MET phosphorylation, again in a dose-dependent manner, but without induction of cell death. However, tepotinib alone or tepotinib-plus-ramucirumab was more effective against c-MET-positive GC cells (>30 copy number variations) than was ramucirumab or paclitaxel alone or ramucirumab-plus-paclitaxel. These in vitro findings suggest that compared with ramucirumab-plus-paclitaxel, tepotinib-plus-paclitaxel better inhibits the growth of c-MET-positive GC cells, cells lacking MET amplification but containing phosphorylated MET, and cells containing MET mutations. Clinical studies are required to confirm the therapeutic effects of these regimens.

Open-Label, Multicenter, Randomized, Biomarker-Integrated Umbrella Trial for Second-Line Treatment of Advanced Gastric Cancer: K-Umbrella Gastric Cancer Study.

PURPOSE: This study aimed to screen targeted agents as second-line treatment with a standard-of-care (SOC) controlled umbrella trial design in advanced gastric cancer (AGC). PATIENTS AND METHODS: Patients with HER2-negative AGC from eight Korean cancer centers were screened for druggable targets using immunohistochemistry (IHC) and in situ hybridization, and randomly assigned to the biomarker versus control group at a 4:1 ratio. In the biomarker group, patients were treated with specific targeted agent plus paclitaxel: pan-ERBB inhibitor for epidermal growth factor receptor (EGFR) 2+/3+ patients (afatinib; EGFR cohort), PIK3Cß inhibitor for phosphatase and tensin homolog (PTEN) loss/null patients (GSK2636771; PTEN cohort), and anti-PD-1 inhibitor for PD-L1+, deficient mismatch repair/microsatellite instability-high, or Epstein-Barr virus-related cases (nivolumab; NIVO cohort). NONE cohort in the biomarker group without predefined biomarkers and control group received SOC (paclitaxel with or without ramucirumab). The primary end point was progression-free survival (PFS), and the secondary end points were efficacy and safety. RESULTS: A total of 318 patients were randomly assigned into the control (n = 64) and biomarker (n = 254; EGFR, n = 67; PTEN, n = 37; NIVO, n = 48; NONE, n = 102) groups. Median follow-up was 35 months. Median PFS and overall survival (OS) were 3.7 (95% CI, 3.1 to 4.1) and 8.6 (95% CI, 7.6 to 9.8) months in the biomarker group and 4.0 (95% CI, 3.0 to 4.6) and 8.7 (95% CI, 7.1 to 9.9) months in the control group. Afatinib addition led to marginal survival benefits to patients with EGFR 3+ compared with SOC (PFS, 4.0 v 2.2 months; P = .09), but GSK2636771 did not prolong the survival of patients with PTEN loss. Addition of nivolumab showed a durable survival benefit (median OS, 12.0 v 7.6 months; P = .08). CONCLUSION: Although biomarker group did not show better survival than the control group, IHC-based screening and allocation of patients with AGC to the second-line treatment in an umbrella design were feasible for effective early screening of novel agents.

Trastuzumab Combined With Ramucirumab and Paclitaxel in Patients With Previously Treated Human Epidermal Growth Factor Receptor 2-Positive Advanced Gastric or Gastroesophageal Junction Cancer.

PURPOSE: Trastuzumab-containing chemotherapy is the recommended first-line regimen for human epidermal growth factor receptor 2 (HER2)-positive advanced gastric or gastroesophageal junction (G/GEJ) cancer. We evaluated the safety and efficacy of trastuzumab combined with ramucirumab and paclitaxel as second-line treatment for HER2-positive G/GEJ cancer. PATIENTS AND METHODS: Patients with HER2-positive advanced G/GEJ cancer who progressed after first-line treatment with trastuzumab-containing chemotherapy were enrolled from five centers in the Republic of Korea. Patients were administered a 28-day cycle of trastuzumab (once on days 1, 8, 15, and 22: 2 mg/kg followed by 4 mg/kg loading dose), ramucirumab (once on days 1 and 15: 8 mg/kg), and paclitaxel (once on days 1, 8, and 15: dose level 1, 80 mg/m2; or dose level -1, 70 mg/m2). Phase II was conducted with the recommended phase II dose (RP2D). Primary end points were determination of RP2D during phase Ib and investigator-assessed progression-free survival (PFS) in patients treated with RP2D. RESULTS: Dose-limiting toxicity at dose level 1 was not documented during phase Ib, and a full dose combination was selected as the RP2D. Among 50 patients with a median follow-up duration of 27.5 months (95% CI, 17.4 to 37.6), median PFS and overall survival were 7.1 months (95% CI, 4.8 to 9.4) and 13.6 months (95% CI, 9.4 to 17.7), respectively. Objective response rate was 54% (27 of 50, including one complete response), and disease control rate was 96% (48 of 50). Loss of HER2 expression was observed in 34.8% (8 of 23) patients after first-line treatment, and no definite association between HER2 expression and the outcome was revealed. Safety profiles were consistent with previous reports. CONCLUSION: Trastuzumab combined with ramucirumab and paclitaxel showed appreciable efficacy with manageable safety profiles in patients with previously treated HER2-positive G/GEJ cancer.

A Phase 3 Randomized Clinical Trial to Compare Efficacy and Safety between Combination Therapy and Monotherapy in Elderly Patients with Advanced Gastric Cancer (KCSG ST13-10).

PURPOSE: This study evaluated whether combination therapy is more effective than monotherapy in elderly patients with metastatic or recurrent gastric cancer (MRGC) as first-line chemotherapy. MATERIALS AND METHODS: Elderly (≥ 70 years) chemo-naïve patients with MRGC were allocated to receive either combination therapy (group A: 5-fluorouracil [5-FU]/oxaliplatin, capecitabine/oxaliplatin, capecitabine/cisplatin, or S-1/cisplatin) or monotherapy (group B: 5-FU, capecitabine, or S-1). In group A, starting doses were 80% of standard doses, and they could be escalated to 100% at the discretion of the investigator. Primary endpoint was to confirm superior overall survival (OS) of combination therapy vs. monotherapy. RESULTS: After 111 of the planned 238 patients were randomized, enrollment was terminated due to poor accrual. In the full-analysis population (group A [n=53] and group B [n=51]), median OS of combination therapy vs. monotherapy was 11.5 vs. 7.5 months (hazard ratio [HR], 0.86; 95% confidence interval [CI], 0.56 to 1.30; p=0.231). Median progression-free survival (PFS) was 5.6 vs. 3.7 months (HR, 0.53; 95% CI, 0.34 to 0.83; p=0.005). In subgroup analyses, patients aged 70-74 years tended to have superior OS with combination therapy (15.9 vs. 7.2 months, p=0.056). Treatment-related adverse events (TRAEs) occurred more frequently in group A vs. group B. However, among severe TRAEs (≥ grade 3), there were no TRAEs with a frequency difference of > 5%. CONCLUSION: Combination therapy was associated with numerically improved OS, although statistically insignificant, and a significant PFS benefit compared with monotherapy. Although combination therapy showed more frequent TRAEs, there was no difference in the frequency of severe TRAEs.

AZD8186 in Combination With Paclitaxel in Patients With Advanced Gastric Cancer: Results From a Phase Ib/II Study (KCSG ST18-20).

BACKGROUND: Loss of PTEN function leads to increased PI3Kß signaling. AZD8186, a selective PI3Kß/δ inhibitor, has shown anti-tumor activity in PTEN-deficient preclinical models. Although the combination of AZD8186 and paclitaxel was well tolerated, limited clinical efficacy was observed in advanced gastric cancer with PTEN loss. METHODS: In the phase Ib dose-escalation, subjects with advanced solid tumors received oral AZD8186 (60 mg or 120 mg; twice daily (BID); 5 days on/2 days off) plus intravenous paclitaxel (70 mg/m2 or 80 mg/m2; days 1, 8, and 15) every 4 weeks. In the phase II part, MRGC patients with PTEN loss or PTEN/PIK3CB gene abnormality were enrolled and received recommended phase II dose (RP2D) of AZD8186 plus paclitaxel. Primary endpoints were to determine maximum tolerated dose (MTD) and RP2D in phase Ib and 4-month progression-free survival (PFS) rate in phase II. RESULTS: In phase Ib, both MTD and RP2D were determined at paclitaxel 80 mg/m2 and AZD8186 120 mg BID. In phase II, 18 patients were enrolled [PTEN loss (n = 18) and PIK3CB mutation (n = 1)]. The 4-month PFS rate was 18.8% (3 of 16 evaluable patients) and further enrollment stopped due to futility. CONCLUSION: Although the combination of AZD8186 and paclitaxel was well tolerated, limited clinical efficacy was observed.ClinicalTrials.gov Identifier: NCT04001569.

Randomized phase II study of capecitabine plus cisplatin with or without sorafenib in patients with metastatic gastric cancer (STARGATE).

BACKGROUND: In this randomized phase II study, we evaluated the efficacy and safety of sorafenib in combination with capecitabine and cisplatin (XP) as first-line chemotherapy in advanced gastric cancer. PATIENTS AND METHODS: Patients with metastatic gastric or gastroesophageal junction adenocarcinoma were randomized (1:1) to receive either sorafenib plus XP (S + XP) or XP alone. In cases of disease progression in the XP arm, crossover to sorafenib alone was allowed. The primary endpoint was progression-free survival (PFS). The secondary endpoints included overall survival (OS), response rates, safety profiles, and biomarkers, and the response rates and PFS with secondline sorafenib alone after progression in the XP arm. RESULTS: Between Jan 2011 and Feb 2013, a total of 195 patients were accrued (97 in the S + XP arm and 98 in the XP alone arm). The overall response rate was 54% with S + XP, and 52% with XP alone (p = 0.83). With a median follow-up of 12.6 months (range, 0.1-29.2), the median PFS assessed by independent review was 5.6 months in the S + XP arm and 5.3 months in the XP arm (hazard ratio [HR] 0.92, 95% confidence interval [CI] 0.67-1.27, p = 0.61). Overall survival was not different between the two arms (median 11.7 vs. 10.8 months; HR 0.93, 95% CI 0.65-1.31, p = 0.66). Frequencies of grade 3/4 toxicities were similar between the S + XP and XP alone arms, except for neutropenia (21% vs. 37%), anorexia (0% vs. 5%), and hand-foot skin reaction (7% vs. 1%). Among 51 patients who crossed over to sorafenib alone after disease progression in the XP arm, there was no objective response and their median PFS was 1.3 months (95% CI, 1.2-1.7). CONCLUSION: The addition of sorafenib to XP chemotherapy was safe but not more effective than XP alone for first-line treatment of metastatic gastric cancer.

Safety and effectiveness of aflibercept in combination with FOLFIRI in Korean patients with metastatic colorectal cancer who received oxaliplatin-containing regimen.

PURPOSE: To evaluate the safety and effectiveness of aflibercept in combination with fluorouracil, leucovorin, and irinotecan (FOLFIRI) in Korean patients with metastatic colorectal cancer (mCRC) who progressed with oxaliplatin-containing regimen. METHODS: This was a prospective observational study conducted at 22 sites across Korea between February 2018 and September 2019. Patients aged > 19 years with a diagnosis of mCRC who were prescribed aflibercept plus FOLFIRI, after progression with an oxaliplatin-containing regimen were included. Disease assessment was performed every 6 weeks. RESULTS: A total of 185 patients were included (males, 58.9%; right-sided tumors, 23.8%; and ECOG performance factor ≥ 1, 68.6%). A total of 514 adverse events (AEs) occurred in 134 patients, of which 206 (49.2%; 95% CI 42.0%, 56.4%) events were considered as adverse drug reactions (ADRs), 172 unexpected AEs (49.7%; 95% CI 42.5%, 56.9%), and 53 serious AEs (22.2%; 95% CI16.2%, 28.2%). The most common serious ADR was pneumonia (n = 2, 1.6%). The most common all grade hematological AE and non-hematological AE were neutropenia (21.6%) and nausea (16.2%), respectively. Over a median follow-up of 5.6 months, a total of five grade 5 (1.0%) AEs were reported. Median OS was 9.4 months, and median progression-free survival (PFS) was 7.3 months. The overall response rate was 14.6%. Right-sided tumor location and prior bevacizumab treatment were independent factors of poor PFS in multivariate analysis. CONCLUSION: Aflibercept in combination with FOLFIRI was effective and showed an acceptable safety profile in Korean patients with mCRC in daily clinical practice.

Data collection framework for electronic medical record-based real-world data to evaluate the effectiveness and safety of cancer drugs: a nationwide real-world study of the Korean Cancer Study Group.

Background: Electronic medical records (EMRs) have the highest value among real-world data (RWD). The aim of the present study was to propose a data collection framework of EMR-based RWD to evaluate the effectiveness and safety of cancer drugs by conducting a nationwide real-world study based on the Korean Cancer Study Group. Methods: We considered all patients who received ramucirumab plus paclitaxel (RAM/PTX) for gastric cancer and trastuzumab emtansine (T-DM1) for breast cancer at relevant institutions in South Korea. Standard operating procedures for systematic data collection were prospectively developed. Investigator reliability was evaluated using the concordance rate between the recommended input value for representative fictional cases and the input value of each investigator. Reliability of collected data was evaluated twice during the study period at three institutions randomly selected using the concordance rate between the previously collected data and data collected by an independent investigator. The reliability results of the investigators and collected data were used for revision of the electronic data capture system and site training. Results: Between the starting date of medical insurance coverage and December 2018, a total of 1063 patients at 56 institutions in the RAM/PTX cohort and 824 patients at 60 institutions in the T-DM1 cohort were included. Mean investigator reliability in the RAM/PTX and T-DM1 cohorts was 73.5% and 71.9%, respectively. Mean reliability of collected data in the RAM/PTX and T-DM1 cohort was 90.0% for both cohorts in the first analysis and 89.0% and 84.0% in the second analysis, respectively. Mean missing values of the RAM/PTX and T-DM1 cohorts at the time of simulation of fictional cases and final data analysis decreased from 20.7% to 0.46% and from 18.5% to 0.76%, respectively. Conclusion: This real-world study provides a framework that ensures relevance and reliability of EMR-based RWD for evaluating the effectiveness and safety of cancer drugs.

A single arm phase Ib/II trial of first-line pembrolizumab, trastuzumab and chemotherapy for advanced HER2-positive gastric cancer.

In this multi-center phase II trial, we evaluated the efficacy and safety of a quadruplet regimen (pembrolizumab, trastuzumab, and doublet chemotherapy) as first-line therapy for unresectable or metastatic human epidermal growth factor receptor 2 (HER2)-positive advanced gastric cancer (AGC) (NCT02901301). The primary endpoints were recommended phase 2 dose (RP2D) for phase Ib and objective response rate (ORR) for phase II. The secondary endpoints included progression-free survival (PFS), overall survival (OS), duration of response, time to response and safety. Without dose-limiting or unexpected toxicities, the starting dose in the phase Ib trial was selected as RP2D. In 43 patients, the primary endpoint was achieved: the objective response rate was 76.7% (95% confidence interval [CI]: 61.4-88.2), with complete and partial responses in 14% and 62.8% of patients, respectively. The median progression-free survival, overall survival, and duration of response were 8.6 months, 19.3 months, and 10.8 months, respectively. No patients discontinued pembrolizumab because of immune-related adverse events. Programmed death ligand-1 status was not related to survival. Post hoc analyses of pretreatment tumor specimens via targeted sequencing indicated that ERBB2 amplification, RTK/RAS pathway alterations, and high neoantigen load corrected by HLA-B were positively related to survival. The current quadruplet regimen shows durable efficacy and safety for patients with HER2-positive AGC.

Real-world experience of safety and effectiveness of regorafenib for treatment of metastatic colorectal cancer, advanced gastrointestinal stromal tumors, and hepatocellular carcinoma: a post-marketing surveillance study in Korea.

Purpose: This regulatory post-marketing surveillance (PMS) study was performed to evaluate the safety and effectiveness of regorafenib on Korean patients with colorectal cancer (CRC), gastrointestinal stromal tumors (GIST), and hepatocellular carcinoma (HCC) in a real-world clinical setting. Methods: This PMS was conducted as a multi-center, prospective, observational study at 34 centers in Korea from August 2013 to August 2019. The primary objective was to evaluate the safety of regorafenib in real-world practice, with the secondary objective to investigate its effectiveness, including its overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). Results: In total, 301 patients were included in the analysis (254 patients with CRC, 14 patients with GIST, and 33 patients with HCC). The incidence rates of adverse events (AEs) were 85.0%, 78.6%, and 81.8% in patients with CRC, GIST, and HCC, respectively. The most frequent AE related to regorafenib in the three cancer types was palmar-plantar erythrodysesthesia syndrome (PPES). The ORRs of patients with CRC, GIST, and HCC were 4.7%, 0%, and 41.4%, respectively. The median PFS and OS were 2.1 and 6.1 months for CRC, respectively; 9.2 and 16.4 months for GIST, respectively; and 5.5 months and not estimated (NE) for HCC, respectively. Patients who experienced a dose modification or discontinuation of regorafenib showed significantly shorter median PFS and OS (2.2 vs. 2.6 months, respectively, P = 0.0335 for PFS; 5.3 vs. 8.5 months, respectively, P = 0.0010 for OS). Conclusion: This PMS study, which is the largest surveillance study of CRC in Korea, found no newly identified safety concerns for patients who received regorafenib in the real-world setting. Additionally, the results of this study were consisted with those previously reported in phase III trials.

Responses to the Tepotinib in Gastric Cancers with MET Amplification or MET Exon 14 Skipping Mutations and High Expression of Both PD-L1 and CD44.

Both MET exon 14 skipping mutation (METex14SM) and high copy-number variation (CNV) lead to enhanced carcinogenesis; additionally, programmed-death ligand 1 (PD-L1) is often upregulated in cancers. In this study, we characterized the expression of MET (including METex14SM), PD-L1, and CD44 in human gastric cancer (GC) cells as well as the differential susceptibility of these cells to tepotinib. Tepotinib treatments inhibited the growth of five GC cells in a dose-dependent manner with a concomitant induction of cell death. Tepotinib treatments also significantly reduced the expression of phospho-MET, total MET, c-Myc, VEGFR2, and Snail protein in SNU620, MKN45, and Hs746T cells. Notably, tepotinib significantly reduced the expression of CD44 and PD-L1 in METex14SM Hs746T cells. By contrast, tepotinib was only slightly active against SNU638 and KATO III cells. Migration was reduced to a greater extent in the tepotinib-treated group than in the control group. Tepotinib may have therapeutic effects on c-MET-amplified GC, a high expression of both PD-L1 and CD44, and METex14SM. Clinical studies are needed to confirm these therapeutic effects.

Long-term follow-up results of cytarabine-containing chemotherapy for acute promyelocytic leukemia.

BACKGROUND/AIMS: We evaluated the feasibility and long-term efficacy of the combination of cytarabine, idarubicin, and all-trans retinoic acid (ATRA) for treating patients with newly diagnosed acute promyelocytic leukemia (APL). METHODS: We included 87 patients with newly diagnosed acute myeloid leukemia and a t(15;17) or promyelocytic leukemia/retinoic acid receptor alpha (PML-RARα) mutation. Patients received 12 mg/m2/day idarubicin intravenously for 3 days and 100 mg/m2/day cytarabine for 7 days, plus 45 mg/m2/day ATRA. Clinical outcomes included complete remission (CR), relapse-free survival (RFS), overall survival (OS), and the secondary malignancy incidence during a 20-year follow-up. RESULTS: The CR, 10-year RFS, and 10-year OS rates were 89.7%, 94.1%, and 73.8%, respectively, for all patients. The 10-year OS rate was 100% for patients that achieved CR. Subjects were classified according to the white blood cell (WBC) count in peripheral blood at diagnosis (low-risk, WBC < 10,000/mm3; high-risk, WBC ≥ 10,000/mm3). The low-risk group had significantly higher RFS and OS rates than the high-risk group, but the outcomes were not superior to the current standard treatment (arsenic trioxide plus ATRA). Toxicities were similar to those observed with anthracycline plus ATRA, and higher than those observed with arsenic trioxide plus ATRA. The secondary malignancy incidence after APL treatment was 2.7%, among the 75 patients that achieved CR, and 5.0% among the 40 patients that survived more than 5 years after the APL diagnosis. CONCLUSION: Adding cytarabine to anthracycline plus ATRA was not inferior to anthracycline plus ATRA alone, but it was not comparable to arsenic trioxide plus ATRA. The probability of secondary malignancy was low.

Predicting Antibiotic Effect of Vancomycin Using Pharmacokinetic/Pharmacodynamic Modeling and Simulation: Dense Sampling versus Sparse Sampling.

This study aimed to investigate the effect of a structural pharmacokinetic (PK) model with fewer compartments developed following sparse sampling on the PK parameter estimation and the probability of target attainment (PTA) prediction of vancomycin. Two- and three-compartment PK models of vancomycin were used for the virtual concentration-time profile simulation. Datasets with reduced blood sampling times were generated to support a model with a lesser number of compartments. Monte Carlo simulation was conducted to evaluate the PTA. For the two-compartment PK profile, the total clearance (CL) of the reduced one-compartment model showed a relative bias (RBias) and relative root mean square error (RRMSE) over 90%. For the three-compartment PK profile, the CL of the reduced one-compartment model represented the largest RBias and RRMSE, while the steady-state volume of distribution of the reduced two-compartment model represented the largest absolute RBias and RRMSE. A lesser number of compartments corresponded to a lower predicted area under the concentration-time curve of vancomycin. The estimated PK parameters and predicted PK/PD index from models built with sparse sampling designs that cannot support the PK profile can be significantly inaccurate and unprecise. This might lead to the misprediction of the PTA and selection of improper dosage regimens when clinicians prescribe antibiotics.

Oxaliplatin (3 months v 6 months) With 6 Months of Fluoropyrimidine as Adjuvant Therapy in Patients With Stage II/III Colon Cancer: KCSG CO09-07.

PURPOSE: The combination of oxaliplatin and fluoropyrimidine for 6 months is one of the standard options for adjuvant therapy for high-risk stage II and III colorectal cancers (CRCs). The optimal duration of oxaliplatin to diminish neurotoxicity without compromising efficacy needs to be clarified. PATIENTS AND METHODS: This open-label, randomized, phase III, noninferiority trial randomly assigned patients with high-risk stage II and III CRC to 3 and 6 months of oxaliplatin with 6 months of fluoropyrimidine groups (3- and 6-month arms, respectively). The primary end point was disease-free survival (DFS), and the noninferiority margin was a hazard ratio (HR) of 1.25. RESULTS: In total, 1,788 patients were randomly assigned to the 6-month (n = 895) and 3-month (n = 893) arms, and 83.6% in the 6-month arm and 85.7% in the 3-month arm completed the treatment. The neuropathy rates with any grade were higher in the 6-month arm than in the 3-month arm (69.5% v 58.3%; P < .0001). The 3-year DFS rates were 83.7% and 84.7% in the 6-month and 3-month arms, respectively, with an HR of 0.953 (95% CI, 0.769 to 1.180; test for noninferiority, P = .0065) within the noninferiority margin. Among patients with stage III CRC treated by capecitabine plus oxaliplatin, the 3-year DFS of the 3-month arm was noninferior as compared with that of the 6-month arm with an HR of 0.713 (95% CI, 0.530 to 0.959; P = .0009). However, among patients with high-risk stage II and stage III CRC treated by infusional fluorouracil, leucovorin, and oxaliplatin, the noninferiority of the 3-month arm compared with the 6-month arm was not proven. CONCLUSION: This study suggests that adding 3 months of oxaliplatin to 6 months of capecitabine could be considered an alternative adjuvant treatment for stage III CRC (ClinicalTrials.gov identifier: NCT01092481).

Safety and efficacy of nilotinib in adult patients with chronic myeloid leukemia: a post-marketing surveillance study in Korea.

Background: Nilotinib is a tyrosine kinase inhibitor approved by the Ministry of Food and Drug Safety for frontline and 2nd line treatment of Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML). This study aimed to confirm the safety and efficacy of nilotinib in routine clinical practice within South Korea. Methods: An open-label, multicenter, single-arm, 12-week observational post-marketing surveillance (PMS) study was conducted on 669 Korean adult patients with Ph+ CML from December 24, 2010, to December 23, 2016. The patients received nilotinib treatment in routine clinical practice settings. Safety was evaluated by all types of adverse events (AEs) during the study period, and efficacy was evaluated by the complete hematological response (CHR) and cytogenetic response. Results: During the study period, AEs occurred in 61.3% (410 patients, 973 events), adverse drug reactions (ADRs) in 40.5% (271/669 patients, 559 events), serious AEs in 4.5% (30 patients, 37 events), and serious ADRs in 0.7% (5 patients, 8 events). Furthermore, unexpected AEs occurred at a rate of 6.9% (46 patients, 55 events) and unexpected ADRs at 1.2% (8 patients, 8 events). As for the efficacy results, CHR was achieved in 89.5% (442/494 patients), and minor cytogenetic response or major cytogenetic response was achieved in 85.8% (139/162 patients). Conclusion: This PMS study shows consistent results in terms of safety and efficacy compared with previous studies. Nilotinib was well tolerated and efficacious in adult Korean patients with Ph+ CML in routine clinical practice settings.

PWWP2B promotes DNA end resection and homologous recombination.

Genome instability is one of the leading causes of gastric cancers. However, the mutational landscape of driver genes in gastric cancer is poorly understood. Here, we investigate somatic mutations in 25 Korean gastric adenocarcinoma patients using whole-exome sequencing and show that PWWP2B is one of the most frequently mutated genes. PWWP2B mutation correlates with lower cancer patient survival. We find that PWWP2B has a role in DNA double-strand break repair. As a nuclear protein, PWWP2B moves to sites of DNA damage through its interaction with UHRF1. Depletion of PWWP2B enhances cellular sensitivity to ionizing radiation (IR) and impairs IR-induced foci formation of RAD51. PWWP2B interacts with MRE11 and participates in homologous recombination via promoting DNA end-resection. Taken together, our data show that PWWP2B facilitates the recruitment of DNA repair machinery to sites of DNA damage and promotes HR-mediated DNA double-strand break repair. Impaired PWWP2B function might thus cause genome instability and promote gastric cancer development.