214 research outputs found
Biomarker analyses in the phase III ASCENT study of sacituzumab govitecan versus chemotherapy in patients with metastatic triple-negative breast cancer
BRCA; CĂĄncer de mama triple negativo: AntĂgeno 2 de la superficie celular del trofoblastoBRCA; CĂ ncer de mama triple negatiu; Antigen 2 de la superfĂcie cel·lular del trofoblastBRCA; Triple-negative breast cancer; Trophoblast cell-surface antigen 2Background
The pivotal phase III ASCENT trial demonstrated improved survival outcomes associated with sacituzumab govitecan (SG), an anti-trophoblast cell-surface antigen 2 (anti-Trop-2) antibody-drug conjugate linked with the topoisomerase-inhibitor SN-38, over single-agent chemotherapy treatment of physicianâs choice (TPC) in previously treated metastatic triple-negative breast cancer (mTNBC). This prespecified, exploratory biomarker analysis from the ASCENT trial evaluates the association between tumor Trop-2 expression and germline BRCA1/2 mutation status with clinical outcomes.
Patients and methods
Patients with mTNBC refractory to or progressing after two or more prior chemotherapies, with one or more in the metastatic setting, were randomized to receive SG (10 mg/kg intravenously days 1 and 8, every 21 days) or TPC (capecitabine, eribulin, vinorelbine, or gemcitabine) until disease progression/unacceptable toxicity. Biopsy or surgical specimens were collected at study entry to determine Trop-2 expression level using a validated immunohistochemistry assay and histochemical scoring. Germline BRCA1/2 mutation status was collected at baseline.
Results
Of 468 assessable patients, 290 had Trop-2 expression data [64% (n = 151 SG) versus 60% (n = 139 TPC)] and 292 had known BRCA1/2 mutation status [63% (n = 149 SG) versus 61% (n = 143 TPC)]. Median progression-free survival in SG- versus TPC-treated patients was 6.9, 5.6, and 2.7 months versus 2.5, 2.2, and 1.6 months for high, medium, and low Trop-2 expression, respectively. Median overall survival (14.2, 14.9, and 9.3 months versus 6.9, 6.9, and 7.6 months) and objective response rates (44%, 38%, and 22% versus 1%, 11%, and 6%) were numerically higher with SG versus TPC in patients with high, medium, and low Trop-2 expression, respectively. Efficacy outcomes were numerically higher with SG versus TPC in patients with and without germline BRCA1/2 mutations.
Conclusions
SG benefits patients with previously treated mTNBC expressing high/medium Trop-2 compared with standard-of-care chemotherapy and regardless of germline BRCA1/2 mutation status. The small number of patients with low Trop-2 expression precludes definitive conclusions on the benefit of SG in this subgroup.This work was supported by Immunomedics, Inc., a subsidiary of Gilead Sciences, Inc. (no grant number)
Pembrolizumab monotherapy for previously treated metastatic triple-negative breast cancer: cohort A of the phase II KEYNOTE-086 study
Immunoterapia; Pembrolizumab; neoplĂ sies mamĂ ries triple-negativesInmunoterapia; Pembrolizumab; neoplasias mamarias triple-negativasImmunotherapy; Pembrolizumab; triple-negative breast neoplasmsBackground: Treatment options for previously treated metastatic triple-negative breast cancer (mTNBC) are limited. In cohort A of the phase II KEYNOTE-086 study, we evaluated pembrolizumab as second or later line of treatment for patients with mTNBC. Patients and methods: Eligible patients had centrally confirmed mTNBC, ?1 systemic therapy for metastatic disease, prior treatment with anthracycline and taxane in any disease setting, and progression on or after the most recent therapy. Patients received pembrolizumab 200mg intravenously every 3 weeks for up to 2 years. Primary end points were objective response rate in the total and PD-L1âpositive populations, and safety. Secondary end points included duration of response, disease control rate (percentage of patients with complete or partial response or stable disease for ?24 weeks), progression-free survival, and overall survival. Results: All enrolled patients (NÂŒ170) were women, 61.8% had PD-L1âpositive tumors, and 43.5% had received ?3 previous lines of therapy for metastatic disease. ORR (95% CI) was 5.3% (2.7â9.9) in the total and 5.7% (2.4â12.2) in the PD-L1âpositive populations. Disease control rate (95% CI) was 7.6% (4.4â12.7) and 9.5% (5.1â16.8), respectively. Median duration of response was not reached in the total (range, 1.2ĂŸâ21.5ĂŸ) and in the PD-L1âpositive (range, 6.3â21.5ĂŸ) populations. Median PFS was 2.0 months (95% CI, 1.9â2.0), and the 6-month rate was 14.9%. Median OS was 9.0 months (95% CI, 7.6â11.2), and the 6-month rate was 69.1%. Treatment-related adverse events occurred in 103 (60.6%) patients, including 22 (12.9%) with grade 3 or 4 AEs. There were no deaths due to AEs. Conclusions: Pembrolizumab monotherapy demonstrated durable antitumor activity in a subset of patients with previously treated mTNBC and had a manageable safety profile.This work was supported by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA
Pressure dependence of diffusion in simple glasses and supercooled liquids
Using molecular dynamics simulation, we have calculated the pressure
dependence of the diffusion constant in a binary Lennard-Jones Glass. We
observe four temperature regimes. The apparent activation volume drops from
high values in the hot liquid to a plateau value. Near the critical temperature
of the mode coupling theory it rises steeply, but in the glassy state we find
again small values, similar to the ones in the liquid. The peak of the
activation volume at the critical temperature is in agreement with the
prediction of mode coupling theory
LTXâ315, an oncolytic peptide converts "cold" tumors to "hot" in a majority of patients with advanced cancer: results from an ongoing phase I study
Pembrolizumab monotherapy for previously treated metastatic triple-negative breast cancer: cohort A of the phase II KEYNOTE-086 study
ABSTRACT Background Treatment options for previously treated metastatic triple-negative breast cancer (mTNBC) are limited. In cohort A of the phase II KEYNOTE-086 study, we evaluated pembrolizumab as second or later line of treatment for patients with mTNBC. Patients and methods Eligible patients had centrally confirmed mTNBC, â„1 systemic therapy for metastatic disease, prior treatment with anthracycline and taxane in any disease setting, and progression on or after the most recent therapy. Patients received pembrolizumab 200âmg intravenously every 3âweeks for up to 2âyears. Primary end points were objective response rate in the total and PD-L1âpositive populations, and safety. Secondary end points included duration of response, disease control rate (percentage of patients with complete or partial response or stable disease for â„24âweeks), progression-free survival, and overall survival. Results All enrolled patients (N = 170) were women, 61.8% had PD-L1âpositive tumors, and 43.5% had received â„3 previous lines of therapy for metastatic disease. ORR (95% CI) was 5.3% (2.7â9.9) in the total and 5.7% (2.4â12.2) in the PD-L1âpositive populations. Disease control rate (95% CI) was 7.6% (4.4â12.7) and 9.5% (5.1â16.8), respectively. Median duration of response was not reached in the total (range, 1.2+â21.5+) and in the PD-L1âpositive (range, 6.3â21.5+) populations. Median PFS was 2.0âmonths (95% CI, 1.9â2.0), and the 6-month rate was 14.9%. Median OS was 9.0âmonths (95% CI, 7.6â11.2), and the 6-month rate was 69.1%. Treatment-related adverse events occurred in 103 (60.6%) patients, including 22 (12.9%) with grade 3 or 4 AEs. There were no deaths due to AEs. Conclusions Pembrolizumab monotherapy demonstrated durable antitumor activity in a subset of patients with previously treated mTNBC and had a manageable safety profile. Clinical trial registration ClinicalTrials.gov, NCT0244700
LTX-315, an oncolytic peptide, to convert immunogenically 'cold' tumors to 'hot' in patients with advanced or metastatic tumours: Results from an ongoing phase I study
A phase I dose escalation study of intra-tumoral LTX-315 as monotherapy or in combination with either ipilimumab or pembrolizumab in patients with transdermally accessible tumors (NCT01986426)
First-line therapy in atypical hemolytic uremic syndrome: consideration on infants with a poor prognosis.
BackgroundAtypical hemolytic uremic syndrome (aHUS) is a rare and heterogeneous disorder. The first line treatment of aHUS is plasma therapy, but in the past few years, the recommendations have changed greatly with the advent of eculizumab, a humanized monoclonal anti C5-antibody. Although recent recommendations suggest using it as a primary treatment for aHUS, important questions have arisen about the necessity of immediate use of eculizumab in all cases. We aimed to draw attention to a specific subgroup of aHUS patients with rapid disease progression and high mortality, in whom plasma therapy may not be feasible.MethodsWe present three pediatric patients of acute complement-mediated HUS with a fatal outcome. Classical and alternative complement pathway activity, levels of complement factors C3, C4, H, B and I, as well as of anti-factor H autoantibody and of ADAMTS13 activity were determined. The coding regions of CFH, CFI, CD46, THBD, CFB and C3 genes were sequenced and the copy number of CFI, CD46, CFH and related genes were analyzed.ResultsWe found severe activation and consumption of complement components in these patients, furthermore, in one patient we identified a previously not reported mutation in CFH (Ser722Stop), supporting the diagnosis of complement-mediated HUS. These patients were not responsive to the FFP therapy, and all cases had fatal outcome.ConclusionTaking the heterogeneity and the variable prognosis of atypical HUS into account, we suggest that the immediate use of eculizumab should be considered as first-line therapy in certain small children with complement dysregulation
Soluble CD44: quantification and molecular repartition in plasma of patients with colorectal cancer
Improved renal recovery in patients with atypical hemolytic uremic syndrome following rapid initiation of eculizumab treatment
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