The combination of pembrolizumab and axitinib showed antitumor activity in a phase 1b trial involving patients with previously untreated advanced renal-cell carcinoma. Whether pembrolizumab plus ...axitinib would result in better outcomes than sunitinib in such patients was unclear.
In an open-label, phase 3 trial, we randomly assigned 861 patients with previously untreated advanced clear-cell renal-cell carcinoma to receive pembrolizumab (200 mg) intravenously once every 3 weeks plus axitinib (5 mg) orally twice daily (432 patients) or sunitinib (50 mg) orally once daily for the first 4 weeks of each 6-week cycle (429 patients). The primary end points were overall survival and progression-free survival in the intention-to-treat population. The key secondary end point was the objective response rate. All reported results are from the protocol-specified first interim analysis.
After a median follow-up of 12.8 months, the estimated percentage of patients who were alive at 12 months was 89.9% in the pembrolizumab-axitinib group and 78.3% in the sunitinib group (hazard ratio for death, 0.53; 95% confidence interval CI, 0.38 to 0.74; P<0.0001). Median progression-free survival was 15.1 months in the pembrolizumab-axitinib group and 11.1 months in the sunitinib group (hazard ratio for disease progression or death, 0.69; 95% CI, 0.57 to 0.84; P<0.001). The objective response rate was 59.3% (95% CI, 54.5 to 63.9) in the pembrolizumab-axitinib group and 35.7% (95% CI, 31.1 to 40.4) in the sunitinib group (P<0.001). The benefit of pembrolizumab plus axitinib was observed across the International Metastatic Renal Cell Carcinoma Database Consortium risk groups (i.e., favorable, intermediate, and poor risk) and regardless of programmed death ligand 1 expression. Grade 3 or higher adverse events of any cause occurred in 75.8% of patients in the pembrolizumab-axitinib group and in 70.6% in the sunitinib group.
Among patients with previously untreated advanced renal-cell carcinoma, treatment with pembrolizumab plus axitinib resulted in significantly longer overall survival and progression-free survival, as well as a higher objective response rate, than treatment with sunitinib. (Funded by Merck Sharp & Dohme; KEYNOTE-426 ClinicalTrials.gov number, NCT02853331.).
Patients with advanced gastric or gastroesophageal adenocarcinoma need more efficacious and safer treatments than established today. S-1, a contemporary oral fluoropyrimidine, can provide that ...advantage.
This study was conducted in 24 countries and 146 centers. One thousand fifty-three patients were stratified (center, number of metastatic sites, prior adjuvant therapy, and measurable cancer) and randomly assigned. Patients received either S-1 at 50 mg/m(2) divided in two daily doses for 21 days and cisplatin at 75 mg/m(2) intravenously on day 1, repeated every 28 days (527 patients) or infusional fluorouracil at 1,000 mg/m(2)/24 hours for 120 hours and cisplatin at 100 mg/m(2) intravenously on day 1, repeated every 28 days (526 patients). The primary end point was superiority in overall survival (OS) from cisplatin/S-1 compared with cisplatin/infusional fluorouracil in patients with advanced, untreated gastric, or gastroesophageal adenocarcinoma. The secondary end points were response rate, progression-free survival, time to treatment failure, and safety.
The median OS was 8.6 months in the cisplatin/S-1 arm and 7.9 months in the cisplatin/infusional fluorouracil arm (HR, 0.92; 95% CI, 0.80 to 1.05; P = .20). Significant safety advantages were observed in the cisplatin/S-1 arm compared with the cisplatin/infusional fluorouracil arm for the rates of grade 3/4 neutropenia (32.3% v 63.6%), complicated neutropenia (5.0% v 14.4%), stomatitis (1.3% v 13.6%), hypokalemia (3.6% v 10.8%), and treatment-related deaths (2.5% v 4.9%; P < .05).
Cisplatin/S-1 did not prolong OS of patients with advanced gastric or gastroesophageal adenocarcinoma compared with cisplatin/infusional fluorouracil, but it did result in a significantly improved safety profile.
Cetuximab is effective in platinum-resistant recurrent or metastatic squamous-cell carcinoma of the head and neck. We investigated the efficacy of cetuximab plus platinum-based chemotherapy as ...first-line treatment in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck.
We randomly assigned 220 of 442 eligible patients with untreated recurrent or metastatic squamous-cell carcinoma of the head and neck to receive cisplatin (at a dose of 100 mg per square meter of body-surface area on day 1) or carboplatin (at an area under the curve of 5 mg per milliliter per minute, as a 1-hour intravenous infusion on day 1) plus fluorouracil (at a dose of 1000 mg per square meter per day for 4 days) every 3 weeks for a maximum of 6 cycles and 222 patients to receive the same chemotherapy plus cetuximab (at a dose of 400 mg per square meter initially, as a 2-hour intravenous infusion, then 250 mg per square meter, as a 1-hour intravenous infusion per week) for a maximum of 6 cycles. Patients with stable disease who received chemotherapy plus cetuximab continued to receive cetuximab until disease progression or unacceptable toxic effects, whichever occurred first.
Adding cetuximab to platinum-based chemotherapy with fluorouracil (platinum-fluorouracil) significantly prolonged the median overall survival from 7.4 months in the chemotherapy-alone group to 10.1 months in the group that received chemotherapy plus cetuximab (hazard ratio for death, 0.80; 95% confidence interval, 0.64 to 0.99; P=0.04). The addition of cetuximab prolonged the median progression-free survival time from 3.3 to 5.6 months (hazard ratio for progression, 0.54; P<0.001) and increased the response rate from 20% to 36% (P<0.001). The most common grade 3 or 4 adverse events in the chemotherapy-alone and cetuximab groups were anemia (19% and 13%, respectively), neutropenia (23% and 22%), and thrombocytopenia (11% in both groups). Sepsis occurred in 9 patients in the cetuximab group and in 1 patient in the chemotherapy-alone group (P=0.02). Of 219 patients receiving cetuximab, 9% had grade 3 skin reactions and 3% had grade 3 or 4 infusion-related reactions. There were no cetuximab-related deaths.
As compared with platinum-based chemotherapy plus fluorouracil alone, cetuximab plus platinum-fluorouracil chemotherapy improved overall survival when given as first-line treatment in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck. (ClinicalTrials.gov number, NCT00122460.)
Мета статті: висвітлити процес організації та підготовки вчительських кадрів для церковних шкіл у лівобережних українських єпархіях Російської імперії на межі ХІХ – ХХ ст. Зокрема, виявити та ...проаналізувати особливості функціонування церковно-учительських шкіл і курсів підвищення кваліфікації педагогічних кадрів шкіл духовного відомства. З’ясувати специфіку освітянської та культурницько-просвітницької діяльності православного духовенства на зламі ХІХ-ХХ ст.
Наукова новизна: із загальної теми церковної освіти окремим сегментом виділено учительський корпус, що дало змогу розглянути систему підготовки учительських кадрів. Комплексно досліджено специфіку функціонування церковно-учительських шкіл і підвищення кваліфікації у лівобережних українських єпархіях Російської імперії. Простежено механізм комплектування учительського корпусу єпархій, що дало можливість виявити тенденції еволюції складу учительства, розглянуто кадровий склад як окремий складник галузі освіти. Удосконалено та розширено загальну характеристику освітянської активності духовенства.
Висновки. На основі проведеного дослідження зроблено висновок про те, що учительський склад церковнопарафіяльних шкіл, як складник системи початкової освіти, перебував під пильним контролем церковно-шкільної адміністрації єпархій і церковно-управлінських структур. У зазначених географічних рамках лише Полтавська єпархія мала спеціальні два навчальних заклади – церковно-учительські школи (на полі Полтавської битви й у м. Лубни). Харківська губернія була знаним центром церковно-шкільної справи, яка поширювала досвід викладання Закону Божого на інші єпархії. У Чернігівській губернії на належному рівні відбувалося підвищення кваліфікації педагогічних кадрів, оскільки там учительські курси мали свою спеціалізацію: співочу, сільськогосподарську, богословську.
Церковно-вчительське шкільництво на межі ХІХ-ХХ ст. тільки розпочинало свою діяльність, і Перша світова війна та атеїстична радянська пропаганда не дали можливості виявити весь їх потенціал. За своє короткочасне існування церковно-учительські школи не встигли забезпечити належних масштабів підготовки вчителів для шкіл церковного відомства. Значна частина педагогічних кадрів церковних шкіл так і залишилася без фахової педагогічної освіти.
We evaluated whether motesanib (a selective oral inhibitor of vascular endothelial growth factor receptors 1, 2, and 3; platelet-derived growth factor receptor; and Kit) combined with ...carboplatin/paclitaxel improved overall survival (OS) versus chemotherapy alone in patients with nonsquamous non-small-cell lung cancer (NSCLC) and in the subset of patients with adenocarcinoma.
Patients with stage IIIB/IV or recurrent nonsquamous NSCLC (no prior systemic therapy for advanced disease) were randomly assigned 1:1 to carboplatin (area under the curve, 6 mg/ml · min) and paclitaxel (200 mg/m(2)) intravenously for up to six 3-week cycles plus either motesanib 125 mg (arm A) or placebo (arm B) once daily orally. OS was the primary end point. Secondary end points included progression-free survival (PFS), objective response rate (ORR), adverse events (AEs), and association between placental growth factor (PLGF) change and OS.
A total of 1,090 patients with nonsquamous NSCLC were randomly assigned (arms A/B, n = 541 of 549); of those, 890 had adenocarcinoma (n = 448 of 442). Median OS in arms A and B was 13.0 and 11.0 months, respectively (hazard ratio HR, 0.90; 95% CI, 0.78 to 1.04; P = .14); median OS for the adenocarcinoma subset was 13.5 and 11.0 months, respectively (HR, 0.88; 95% CI, 0.75 to 1.03; P = .11). In descriptive analyses (arms A v B), median PFS was 5.6 months versus 5.4 months (P = < .001); ORR was 40% versus 26% (P < .001). There was no association between PLGF change and OS in arm A. The incidence of grade ≥ 3 AEs (arms A and B, 73% and 59%, respectively) and grade 5 AEs (14% and 9%, respectively) was higher with motesanib treatment.
Motesanib plus carboplatin/paclitaxel did not significantly improve OS over carboplatin/paclitaxel alone in patients with advanced nonsquamous NSCLC or in the adenocarcinoma subset.
Purpose
The phase 3 HERITAGE trial demonstrated that the biosimilar trastuzumab-dkst is well tolerated with similar efficacy (measured by overall response rate ORR and progression-free survival PFS) ...compared with originator trastuzumab combined with taxane followed by monotherapy in patients with HER2-positive metastatic breast cancer (MBC). Herein, we present final overall survival (OS) from HERITAGE.
Methods
HERITAGE is a multicenter, double-blind, randomized, parallel-group study. Patients were randomized 1:1 to receive trastuzumab-dkst or trastuzumab plus taxane followed by continued monotherapy until disease progression. Overall survival was to be assessed at 36 months or after 240 deaths, whichever occurred first, as observed from time of randomization of last patient.
Results
At the final analysis (36 months), 242 patients in the intention-to-treat population had died during the study: 116 and 124 in the trastuzumab-dkst and trastuzumab groups, respectively, and 1 untreated patient from each treatment group. Median OS by Kaplan–Meier analysis was 35.0 months with trastuzumab-dkst and 30.2 months with trastuzumab. Evaluation of PFS showed a median of 11.1 months in both treatment groups. No new safety concerns were reported from week 48 until the end of the survival follow-up.
Conclusion
This is the first phase 3 trial of a trastuzumab biosimilar to report long-term survival data similar to originator trastuzumab in patients with MBC. The comparable long-term OS between the trastuzumab-dkst and originator trastuzumab groups further supports the similarity of trastuzumab-dkst with originator trastuzumab and establishes trastuzumab-dkst as a safe and effective treatment option for patients with HER2-positive MBC.
ClinicalTrials.gov NCT02472964; 6/16/2015
Thyroid cancer (TC) demonstrates steady growth in incidence worldwide and remains an urgent problem in oncology. The detection of sentinel lymph nodes (SLN) with a selective dye and further ...histological examination in selecting the proper (personalized) surgical strategy and the volume of surgical intervention for clinically undetermined regional lymph nodes. The purpose of the study is to evaluate the effectiveness and safety of intraoperative detection of SLN with a 1% toluidine blue aqueous solution.
The significant tasks are to identify the pattern of TC metastases to cervical lymph nodes, to establish the prevalence of "skip" metastases, to compare the frequency of complications after total thyroidectomy and central neck dissection and lateral neck dissection with total thyroidectomy and central neck dissection, and to determine the feasibility of the application of lateral neck dissections in patients with papillary and follicular TC without metastases to regional lymph nodes (according to physical examination and ultrasound).
According to our data the SLN identification rate was 97.6%. Sensitivity, specificity, positive predictive value, negative predictive value, and frequency of false negative and false positive results was 89.2, 94.6, 88.03, 95.16, 10.8, and 5.4%, respectively. The most common metastasis was in the central neck compartment (83.7%). Skip metastases were determined in 4.9% of patients.
The low prevalence of "skip" metastases and a significant risk of postoperative complications (wound exudation, lymphorrhagia, inflammation, hypoparathyroidism, paresis of the vocal cords) support the idea that lateral neck dissection is appropriate only in cases of confirmed metastases by physical examination and/or ultrasound at the preoperative stage.
Summary Background The randomised phase 3 First-Line Erbitux in Lung Cancer (FLEX) study showed that the addition of cetuximab to cisplatin and vinorelbine significantly improved overall survival ...compared with chemotherapy alone in the first-line treatment of advanced non-small-cell lung cancer (NSCLC). The main cetuximab-related side-effect was acne-like rash. Here, we assessed the association of this acne-like rash with clinical benefit. Methods We did a subgroup analysis of patients in the FLEX study, which enrolled patients with advanced NSCLC whose tumours expressed epidermal growth factor receptor. Our landmark analysis assessed if the development of acne-like rash in the first 21 days of treatment (first-cycle rash) was associated with clinical outcome, on the basis of patients in the intention-to-treat population alive on day 21. The FLEX study is registered with ClinicalTrials.gov , number NCT00148798. Findings 518 patients in the chemotherapy plus cetuximab group—290 of whom had first-cycle rash—and 540 patients in the chemotherapy alone group were alive on day 21. Patients in the chemotherapy plus cetuximab group with first-cycle rash had significantly prolonged overall survival compared with patients in the same treatment group without first-cycle rash (median 15·0 months 95% CI 12·8–16·4 vs 8·8 months 7·6–11·1; hazard ratio HR 0·631 0·515–0·774; p<0·0001). Corresponding significant associations were also noted for progression-free survival (median 5·4 months 5·2–5·7 vs 4·3 months 4·1–5·3; HR 0·741 0·607–0·905; p=0·0031) and response (rate 44·8% 39·0–50·8 vs 32·0% 26·0–38·5; odds ratio 1·703 1·186–2·448; p=0·0039). Overall survival for patients without first-cycle rash was similar to that of patients that received chemotherapy alone (median 8·8 months 7·6–11·1 vs 10·3 months 9·6–11·3; HR 1·085 0·910–1·293; p=0·36). The significant overall survival benefit for patients with first-cycle rash versus without was seen in all histology subgroups: adenocarcinoma (median 16·9 months, 14·1–20·6 vs 9·3 months 7·7–13·2; HR 0·614 0·453–0·832; p=0·0015), squamous-cell carcinoma (median 13·2 months 10·6–16·0 vs 8·1 months 6·7–12·6; HR 0·659 0·472–0·921; p=0·014), and carcinomas of other histology (median 12·6 months 9·2–16·4 vs 6·9 months 5·2–11·0; HR 0·616 0·392–0·966; p=0·033). Interpretation First-cycle rash was associated with a better outcome in patients with advanced NSCLC who received cisplatin and vinorelbine plus cetuximab as a first-line treatment. First-cycle rash might be a surrogate clinical marker that could be used to tailor cetuximab treatment for advanced NSCLC to those patients who would be most likely to derive a significant benefit. Funding Merck KGaA.
Trastuzumab-dkst is a biosimilar of trastuzumab. The phase 3 HERITAGE trial demonstrated equivalent overall response rate (ORR) with trastuzumab-dkst or originator trastuzumab at 24 weeks in patients ...with HER2-positive metastatic breast cancer receiving chemotherapy. We now present the correlation of ORR with progression-free survival (PFS) for maintenance monotherapy with trastuzumab-dkst vs trastuzumab at 48 weeks of treatment, and the safety, tolerability, and immunogenicity.
HERITAGE is a multicenter, double-blind, randomized, parallel-group, phase 3 study. Patients were randomized 1:1 to receive trastuzumab-dkst or trastuzumab in combination with taxane followed by continued monotherapy until disease progression. The analysis included PFS at 48 weeks to support the primary efficacy endpoint of ORR and safety, tolerability, and immunogenicity of trastuzumab-dkst vs trastuzumab as maintenance monotherapy.
Of 500 randomized patients, 342 entered the monotherapy phase; 214 patients received ≥48 weeks of treatment. There were no statistically significant differences between PFS, ORR, or interim overall survival at week 48 between trastuzumab-dkst and trastuzumab. Week 24 ORR was highly correlated with week 48 PFS (rb = 0.75). Cumulative treatment-emergent adverse events (TEAEs) and serious AEs were similar in both groups, with few grade ≥3 TEAEs. Immunogenicity was low and similar in both groups at 48 weeks.
The correlation between ORR and PFS supports the design of first-line metastatic trials assessing biosimilar trastuzumab. Overall, trastuzumab-dkst and trastuzumab were well tolerated with similar efficacy, including ORR and PFS, in combination with a taxane followed by monotherapy.
•Trastuzumab-dkst is a biosimilar of trastuzumab.•Trastuzumab-dkst and trastuzumab had similar PFS, ORR, and OS at week 48.•Results support therapeutic equivalence between trastuzumab-dkst and trastuzumab.•Week 24 ORR was highly correlated with week 48 PFS.•ORR and PFS correlation supports ORR as a valid endpoint in clinical trials for MBC.
Studies JVDB and JVCZ examined alternative ramucirumab dosing regimens as monotherapy or combined with paclitaxel, respectively, in patients with advanced/metastatic gastric/gastroesophageal junction ...(GEJ) adenocarcinoma. For JVDB, randomized patients (
= 164) received ramucirumab monotherapy at four doses: 8 mg/kg every 2 weeks (Q2W) (registered dose), 12 mg/kg Q2W, 6 mg/kg weekly (QW), or 8 mg/kg on days 1 and 8 (D1D8) every 3 weeks (Q3W). The primary objectives were the safety and pharmacokinetics of ramucirumab monotherapy. For JVCZ, randomized patients (
= 245) received paclitaxel (80 mg/m
-D1D8D15) plus ramucirumab (8 mg/kg- or 12 mg/kg-Q2W). The primary objective was progression-free survival (PFS) of 12 mg/kg-Q2W arm versus placebo from RAINBOW using meta-analysis. Relative to the registered dose, exploratory dosing regimens (EDRs) led to higher ramucirumab serum concentrations in both studies. EDR safety profiles were consistent with previous studies. In JVDB, serious adverse events occurred more frequently in the 8 mg/kg-D1D8-Q3W arm versus the registered dose; 6 mg/kg-QW EDR had a higher incidence of bleeding/hemorrhage. In JVCZ, PFS was improved with the 12 mg/kg plus paclitaxel combination versus placebo in RAINBOW; however, no significant PFS improvement was observed between the 12 mg/kg and 8 mg/kg arms. The lack of a dose/exposure-response relationship in these studies supports the standard dose of ramucirumab 8 mg/kg-Q2W as monotherapy or in combination with paclitaxel as second-line treatment for advanced/metastatic gastric/GEJ adenocarcinoma.
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