Patients with metastatic colorectal cancer with the
V600E mutation have a poor prognosis, with a median overall survival of 4 to 6 months after failure of initial therapy. Inhibition of BRAF alone ...has limited activity because of pathway reactivation through epidermal growth factor receptor signaling.
In this open-label, phase 3 trial, we enrolled 665 patients with
V600E-mutated metastatic colorectal cancer who had had disease progression after one or two previous regimens. Patients were randomly assigned in a 1:1:1 ratio to receive encorafenib, binimetinib, and cetuximab (triplet-therapy group); encorafenib and cetuximab (doublet-therapy group); or the investigators' choice of either cetuximab and irinotecan or cetuximab and FOLFIRI (folinic acid, fluorouracil, and irinotecan) (control group). The primary end points were overall survival and objective response rate in the triplet-therapy group as compared with the control group. A secondary end point was overall survival in the doublet-therapy group as compared with the control group. We report here the results of a prespecified interim analysis.
The median overall survival was 9.0 months in the triplet-therapy group and 5.4 months in the control group (hazard ratio for death, 0.52; 95% confidence interval CI, 0.39 to 0.70; P<0.001). The confirmed response rate was 26% (95% CI, 18 to 35) in the triplet-therapy group and 2% (95% CI, 0 to 7) in the control group (P<0.001). The median overall survival in the doublet-therapy group was 8.4 months (hazard ratio for death vs. control, 0.60; 95% CI, 0.45 to 0.79; P<0.001). Adverse events of grade 3 or higher occurred in 58% of patients in the triplet-therapy group, in 50% in the doublet-therapy group, and in 61% in the control group.
A combination of encorafenib, cetuximab, and binimetinib resulted in significantly longer overall survival and a higher response rate than standard therapy in patients with metastatic colorectal cancer with the
V600E mutation. (Funded by Array BioPharma and others; BEACON CRC ClinicalTrials.gov number, NCT02928224; EudraCT number, 2015-005805-35.).
The most recent version of the European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, treatment and follow-up of gastric cancer (GC) was published in 2016, and ...covered the management and treatment of local, locoregional, locally advanced and metastatic disease. At the ESMO Asia Meeting in November 2017 it was decided by both ESMO and The Japanese Society of Medical Oncology (JSMO) to convene a special guidelines meeting immediately after the JSMO Annual Meeting in 2018. The aim was to adapt the ESMO 2016 guidelines to take into account the ethnic differences associated with the treatment of metastatic GC in Asian patients. These guidelines represent the consensus opinions reached by experts in the treatment of patients with metastatic GC representing the oncological societies of Japan (JSMO), China (CSCO), Korea (KSMO), Malaysia (MOS), Singapore (SSO) and Taiwan (TOS). The voting was based on scientific evidence and was independent of both the current treatment practices and the drug availability and reimbursement situations in the individual participating Asian countries.
Context.
S
TE
P
AR
S
YN
is an automatic code written in Python 3.X designed to infer the stellar atmospheric parameters
T
eff
, log
g
, and Fe/H of FGKM-type stars following the spectral synthesis ...method.
Aims.
We present a description of the S
TE
P
AR
S
YN
code and test its performance against a sample of late-type stars that were observed with the HERMES spectrograph mounted at the 1.2-m
Mercator
Telescope. This sample contains 35 late-type targets with well-known stellar parameters determined independently from spectroscopy. The code is available to the astronomical community in a
GitHub
repository.
Methods.
S
TE
P
AR
S
YN
uses a Markov chain Monte Carlo sampler to explore the parameter space by comparing synthetic model spectra generated on the fly to the observations. The synthetic spectra are generated with an spectral emulator.
Results.
We computed
T
eff
, log
g
, and Fe/H for our sample stars and discussed the performance of the code. We calculated an internal scatter for these targets of −12 ± 117 K in
T
eff
, 0.04 ± 0.14 dex in log
g
, and 0.05 ± 0.09 dex in Fe/H. In addition, we find that the log
g
values obtained with S
TE
P
AR
S
YN
are consistent with the trigonometric surface gravities to the 0.1 dex level. Finally, S
TE
P
AR
S
YN
can compute stellar parameters that are accurate down to 50 K, 0.1 dex, and 0.05 dex for
T
eff
, log
g
, and Fe/H for stars with
v
sin
i
≤ 30 km s
−1
.
The TESS mission has reported a wealth of new planetary systems around bright and nearby stars amenable for detailed characterizations of planet properties and atmospheres. However, not all ...interesting TESS planets orbit around bright host stars. TOI-263 b is a validated ultra-short-period substellar object in a 0.56-day orbit around a faint (
V
= 18.97) M 3.5 dwarf star. The substellar nature of TOI-263 b was explored using multicolor photometry: a true radius of 0.87 ± 0.21
R
J
was determined, establishing TOI-263 b ’s nature as somewhere between an inflated Neptune and a brown dwarf. The orbital period-radius parameter space occupied by TOI-263 b is quite unique, which prompted a further characterization of its true nature. Here, we report radial velocity measurements of TOI-263 obtained with three VLT units and the ESPRESSO spectrograph to retrieve the mass of TOI-263 b. We find that TOI-263 b is a brown dwarf with a mass of 61.6 ± 4.0
M
Jup
. Additionally, the orbital period of the brown dwarf is found to be synchronized with the rotation period of the host star, and the system is found to be relatively active, possibly revealing a star–brown dwarf interaction. All these findings suggest that the system’s formation history might be explained via disk fragmentation and a later migration to close-in orbits. If the system is found to be unstable, TOI-263 will be an excellent target to test the migration mechanisms before the brown dwarf becomes “engulfed” by its parent star.
The most recent version of the European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, treatment and follow-up of oesophageal cancer was published in 2016, and ...covered the management and treatment of local/locoregional disease, limited disease, locally advanced disease and the management of advanced/metastatic disease. At the ESMO Asia Meeting in November 2017 it was decided by both ESMO and the Japanese Society of Medical Oncology (JSMO) to convene a special guidelines meeting immediately after the JSMO Annual Meeting in 2018. The aim was to adapt the ESMO 2016 guidelines to take into account the ethnic differences associated with the treatment of metastatic oesophageal cancer in Asian patients. These guidelines represent the consensus opinions reached by experts in the treatment of patients with metastatic oesophageal cancer representing the oncological societies of Japan (JSMO), China (CSCO), Korea (KSMO), Malaysia (MOS), Singapore (SSO) and Taiwan (TOS). The voting was based on scientific evidence, and was independent of both the current treatment practices and the drug availability and reimbursement situations in the individual participating Asian countries.
First-line treatment of metastatic pancreatic ductal adenocarcinoma (PDAC) includes nab-paclitaxel/gemcitabine. Ibrutinib, a Bruton's tyrosine kinase inhibitor, exhibits antitumor activity through ...tumor microenvironment modulation. The safety and efficacy of first-line ibrutinib plus nab-paclitaxel/gemcitabine treatment in patients with PDAC were evaluated.
RESOLVE (NCT02436668) was a phase III, randomized, double-blind, placebo-controlled study. Patients (histologically-confirmed PDAC; stage IV diagnosis ≥6 weeks of randomization; Karnofsky performance score ≥70) were randomized to once-daily oral ibrutinib (560 mg) or placebo plus nab-paclitaxel (125 mg/m2) and gemcitabine (1000 mg/m2). Primary endpoints were overall survival (OS) and investigator-assessed progression-free survival (PFS); overall response rate and safety were assessed.
In total, 424 patients were randomized (ibrutinib arm, n = 211; placebo arm, n = 213). Baseline characteristics were balanced across arms. After a median follow-up of 25 months, there was no significant difference in OS between ibrutinib plus nab-paclitaxel/gemcitabine versus placebo plus nab-paclitaxel/gemcitabine (median of 9.7 versus 10.8 months; P = 0.3225). PFS was shorter for ibrutinib plus nab-paclitaxel/gemcitabine compared with placebo plus nab-paclitaxel/gemcitabine (median 5.3 versus 6.0 months; P < 0.0001). Overall response rates were 29% and 42%, respectively (P = 0.0058). Patients in the ibrutinib arm had less time on treatment and received lower cumulative doses for all agents compared with the placebo arm. The most common grade ≥3 adverse events for ibrutinib versus placebo arms included neutropenia (24% versus 35%), peripheral sensory neuropathy (17% versus 8%), and anemia (16% versus 17%). Primary reasons for any treatment discontinuation were disease progression and adverse events.
Ibrutinib plus nab-paclitaxel/gemcitabine did not improve OS or PFS for patients with PDAC. Safety was consistent with known profiles for these agents.
•Addition of ibrutinib to nab-paclitaxel/gemcitabine did not improve efficacy outcomes for pancreatic ductal adenocarcinoma.•Primary endpoints—overall survival and investigator-assessed progression-free survival—were not met in this phase III study.•Ibrutinib treatment led to less time on treatment and lower cumulative dose for all agents compared with placebo treatment.•Reported safety was consistent with the known profiles for ibrutinib and nab-paclitaxel/gemcitabine.
Abstract
We present a self-consistent study of cool supergiants (CSGs) belonging to the Magellanic clouds. We calculated stellar atmospheric parameters using LTE KURUCZ and MARCS atmospheric models ...for more than 400 individual targets by fitting a careful selection of weak metallic lines. We explore the existence of a Teff scale and its implications in two different metallicity environments (each Magellanic cloud). Critical and in-depth tests have been performed to assess the reliability of our stellar parameters (i.e. internal error budget, NLTE systematics). In addition, several Monte Carlo tests have been carried out to infer the significance of the Teff scale found. Our findings point towards a unique Teff scale that seems to be independent of the environment.
Tusamitamab ravtansine (SAR408701) is an antibody–drug conjugate composed of a humanized monoclonal antibody that binds carcinoembryonic antigen-related cell adhesion molecule-5 (CEACAM5) and a ...cytotoxic maytansinoid that selectively targets CEACAM5-expressing tumor cells. In this phase I dose-escalation study, we evaluated the safety, pharmacokinetics, and preliminary antitumor activity of tusamitamab ravtansine in patients with solid tumors.
Eligible patients were aged ≥18 years, had locally advanced/metastatic solid tumors that expressed or were likely to express CEACAM5, and had an Eastern Cooperative Oncology Group Performance Status of 0 or 1. Patients were treated with ascending doses of tusamitamab ravtansine intravenously every 2 weeks (Q2W). The first three dose levels (5, 10, and 20 mg/m2) were evaluated using an accelerated escalation protocol, after which an adaptive Bayesian procedure was used. The primary endpoint was the incidence of dose-limiting toxicities (DLTs) during the first two cycles, graded using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.03 criteria.
Thirty-one patients received tusamitamab ravtansine (range 5-150 mg/m2). The DLT population comprised 28 patients; DLTs (reversible grade 3 microcystic keratopathy) occurred in three of eight patients treated with tusamitamab ravtansine 120 mg/m2 and in two of three patients treated with 150 mg/m2. The maximum tolerated dose was identified as 100 mg/m2. Twenty-two patients (71%) experienced ≥1 treatment-related treatment-emergent adverse event (TEAE), seven patients (22.6%) experienced ≥1 treatment-related grade ≥3 TEAE, and three patients (9.7%) discontinued treatment due to TEAEs. The most common TEAEs were asthenia, decreased appetite, keratopathy, and nausea. Three patients had confirmed partial responses. The mean plasma exposure of tusamitamab ravtansine increased in a dose-proportional manner from 10 to 150 mg/m2.
Tusamitamab ravtansine had a favorable safety profile with reversible, dose-related keratopathy as the DLT. Based on the overall safety profile, pharmacokinetic data, and Bayesian model recommendations, the maximum tolerated dose of tusamitamab ravtansine was defined as 100 mg/m2 Q2W.
•Tusamitamab ravtansine (SAR408701) is a humanized monoclonal antibody covalently linked to a cytotoxic maytansinoid.•This potential first-in-class antibody–drug conjugate selectively targets tumor cells expressing CEACAM5.•100 mg/m2 i.v. every 2 weeks is the maximum tolerated dose of tusamitamab ravtansine, with reversible keratopathy as the DLT.•Tusamitamab ravtansine has a favorable safety profile with infrequent hematological toxicities vs that reported for docetaxel.•Signals of antitumor activity were observed during tusamitamab ravtansine dose escalation.
Abstract
Knowledge of stellar atmospheric parameters (
T
eff
,
log
g
, Fe/H) of M dwarfs can be used to constrain both theoretical stellar models and Galactic chemical evolutionary models, and guide ...exoplanet searches, but their determination is difficult due to the complexity of the spectra of their cool atmospheres. In our ongoing effort to characterize M dwarfs, and in particular their chemical composition, we carried out multiband photometric calibrations of metallicity for early- and intermediate-type M dwarfs. The third Gaia data release provides high-precision astrometry and three-band photometry. This information, combined with the 2MASS and CatWISE2020 infrared photometric surveys and a sample of 4919 M dwarfs with metallicity values determined with high-resolution spectroscopy by
The Cannon
and APOGEE spectra, allowed us to study the effect of the metallicity in color–color and color–magnitude diagrams. We divided this sample into two subsamples: we used 1000 stars to train the calibrations with Bayesian statistics and Markov Chain Monte Carlo techniques, and the remaining 3919 stars to check the accuracy of the estimations. We derived several photometric calibrations of metallicity applicable to M dwarfs in the range of −0.45 ≤ Fe/H ≤ + 0.45 dex and spectral types down to M5.0 V that yield uncertainties down to the 0.10 dex level. Lastly, we compared our results with other photometric estimations published in the literature for an additional sample of 46 M dwarfs in wide binary systems with FGK-type primary stars and found a great predictive performance.
Context. STEPAR is an automatic code written in Python 3.X designed to compute the stellar atmospheric parameters Teff, log g, Fe/H, and ξ of FGK-type stars by means of the equivalent width (EW) ...method. This code has already been extensively tested in different spectroscopic studies of FGK-type stars with several spectrographs and against thousands of Gaia-ESO Survey UVES U580 spectra of late-type, low-mass stars as one of its 13 pipelines. Aims. We describe the code that we tested against a library of well characterised Gaia benchmark stars. We also release the code to the community and provide the link for download. Methods. We carried out the required EW determination of Fe I and Fe II spectral lines using the automatic tool TAME. STEPAR implements a grid of MARCS model atmospheres and the MOOG radiative transfer code to compute stellar atmospheric parameters by means of a Downhill Simplex minimisation algorithm. Results. We show the results of the benchmark star test and also discuss the limitations of the EW method, and hence the code. In addition, we find a small internal scatter for the benchmark stars of 9 ± 32 K in Teff, 0.00 ± 0.07 dex in log g, and 0.00 ± 0.03 dex in Fe/H. Finally, we advise against using STEPAR on double-lined spectroscopic binaries or spectra with R < 30 000, S/N < 20, or v sin i > 15 km s−1, and on stars later than K4 or earlier than F6.