•Recently published phase II trials of anti PD1/PD-L1 combination regimens are heterogeneous.•Other immunotherapeutic agents and targeted agents are the more common partners.•Trials design is mainly ...non-randomized, while ORR represents the most used primary endpoint.•Across the different studies, ORRs span from 0 to 91% and G ≥ 3 TEAEs go from 0 to 100%.•Only a minority of these combinations proceed to phase III and eventually receive approval.
A high number of combinations of PD-1/PD-L1 inhibitors with other anti-cancer therapies are in clinical development. The usefulness of phase II trials in evaluating their efficacy and safety is unclear.
We performed a systematic search on PubMed and Cochrane Library for phase II trials of PD-1/PD-L1 inhibitors in combination with other anti-cancer therapies (systemic therapy and/or radiotherapy) published between January 1st 2018 and December 31st 2020. Study design, primary endpoint and main outcomes were registered for each paper.
119 articles reporting on 65 regimens were included in our analysis. Backbone agents were more frequently PD-1 inhibitors (pembrolizumab = 47, nivolumab = 41, camrelizumab = 3) followed by anti-PD-L1 (durvalumab = 19, atezolizumab = 6, avelumab = 3). Therapeutic partners were other immunotherapeutic agents (n = 46), targeted therapies (n = 40), chemotherapy (n = 22) or radiotherapy (n = 11). The majority of articles reported on single-arm trials (n = 87, 73%) and response rate was the most frequent primary endpoint (n = 69, 58%). Objective responses, registered in 109 (92%) articles, ranged between 0% and 91%. The incidence of grade 3 or higher treatment-related adverse events, clearly reported in 97 (82%) articles, spanned from 0 to 100%. Five combinations received regulatory approval by Food and Drug Administration or European Medicine Agency for 9 different indications, based on the results of a phase II trial (n = 3) or on a confirmatory phase III trial (n = 6).
The landscape of phase II trials evaluating PD-1/PD-L1 inhibitors with other anticancer therapies is heterogeneous. Combinations of two immunotherapeutic agents have been the most investigated. Only a minority of indications (8%) granted regulatory approval.
Abstract
We present the first fully simultaneous fits to the near-infrared (NIR) and X-ray spectral slope (and its evolution) during a very bright flare from Sgr A*, the supermassive black hole at ...the Milky Way's centre. Our study arises from ambitious multiwavelength monitoring campaigns with XMM–Newton, NuSTAR and SINFONI. The average multiwavelength spectrum is well reproduced by a broken power law with ΓNIR = 1.7 ± 0.1 and ΓX = 2.27 ± 0.12. The difference in spectral slopes (ΔΓ = 0.57 ± 0.09) strongly supports synchrotron emission with a cooling break. The flare starts first in the NIR with a flat and bright NIR spectrum, while X-ray radiation is detected only after about 103 s, when a very steep X-ray spectrum (ΔΓ = 1.8 ± 0.4) is observed. These measurements are consistent with synchrotron emission with a cooling break and they suggest that the high-energy cut-off in the electron distribution (γmax) induces an initial cut-off in the optical–UV band that evolves slowly into the X-ray band. The temporal and spectral evolution observed in all bright X-ray flares are also in line with a slow evolution of γmax. We also observe hints for a variation of the cooling break that might be induced by an evolution of the magnetic field (from B ∼ 30 ± 8 G to B ∼ 4.8 ± 1.7 G at the X-ray peak). Such drop of the magnetic field at the flare peak would be expected if the acceleration mechanism is tapping energy from the magnetic field, such as in magnetic reconnection. We conclude that synchrotron emission with a cooling break is a viable process for Sgr A*'s flaring emission.
The first St Gallen Advanced Prostate Cancer Consensus Conference (APCCC) Expert Panel identified and reviewed the available evidence for the ten most important areas of controversy in advanced ...prostate cancer (APC) management. The successful registration of several drugs for castration-resistant prostate cancer and the recent studies of chemo-hormonal therapy in men with castration-naïve prostate cancer have led to considerable uncertainty as to the best treatment choices, sequence of treatment options and appropriate patient selection. Management recommendations based on expert opinion, and not based on a critical review of the available evidence, are presented. The various recommendations carried differing degrees of support, as reflected in the wording of the article text and in the detailed voting results recorded in supplementary Material, available at Annals of Oncology online. Detailed decisions on treatment as always will involve consideration of disease extent and location, prior treatments, host factors, patient preferences as well as logistical and economic constraints. Inclusion of men with APC in clinical trials should be encouraged.
Abstract
We present
K
-band interferometric observations of the PDS 70 protoplanets along with their host star using VLTI/GRAVITY. We obtained
K
-band spectra and 100
μ
as precision astrometry of ...both PDS 70 b and c in two epochs, as well as spatially resolving the hot inner disk around the star. Rejecting unstable orbits, we found a nonzero eccentricity for PDS 70 b of 0.17 ± 0.06, a near-circular orbit for PDS 70 c, and an orbital configuration that is consistent with the planets migrating into a 2:1 mean motion resonance. Enforcing dynamical stability, we obtained a 95% upper limit on the mass of PDS 70 b of 10
M
Jup
, while the mass of PDS 70 c was unconstrained. The GRAVITY
K
-band spectra rules out pure blackbody models for the photospheres of both planets. Instead, the models with the most support from the data are planetary atmospheres that are dusty, but the nature of the dust is unclear. Any circumplanetary dust around these planets is not well constrained by the planets’ 1–5
μ
m spectral energy distributions (SEDs) and requires longer wavelength data to probe with SED analysis. However with VLTI/GRAVITY, we made the first observations of a circumplanetary environment with sub-astronomical-unit spatial resolution, placing an upper limit of 0.3 au on the size of a bright disk around PDS 70 b.
The European Society for Medical Oncology (ESMO) consensus conference on testicular cancer was held on 3–5 November 2016 in Paris, France. The conference included a multidisciplinary panel of 36 ...leading experts in the diagnosis and treatment of testicular cancer (34 panel members attended the conference; an additional two panel members CB and K-PD participated in all preparatory work and subsequent manuscript development). The aim of the conference was to develop detailed recommendations on topics relating to testicular cancer that are not covered in detail in the current ESMO Clinical Practice Guidelines (CPGs) and where the available level of evidence is insufficient. The main topics identified for discussion related to: (1) diagnostic work-up and patient assessment; (2) stage I disease; (3) stage II-III disease; (4) post-chemotherapy surgery, salvage chemotherapy, salvage and desperation surgery and special topics; and (5) survivorship and follow-up schemes. The experts addressed questions relating to one of the five topics within five working groups. Relevant scientific literature was reviewed in advance. Recommendations were developed by the working groups and then presented to the entire panel. A consensus vote was obtained following whole-panel discussions, and the consensus recommendations were then further developed in post-meeting discussions in written form. This manuscript presents the results of the expert panel discussions, including the consensus recommendations and a summary of evidence supporting each recommendation. All participants approved the final manuscript.
We report the definite spectroscopic identification of 40 OB supergiants, giants, and main-sequence stars in the central parsec of the Galaxy. Detection of their absorption lines has become possible ...with the high spatial and spectral resolution and sensitivity of the adaptive optics integral field spectrometer SPIFFI/SINFONI on the ESO VLT. Several of these OB stars appear to be helium- and nitrogen-rich. Almost all of the 80 massive stars now known in the central parsec (central arcsecond excluded) reside in one of two somewhat thick (<|h|/R> 0.14) rotating disks. These stellar disks have fairly sharp inner edges (R 1) and surface density profiles that scale as R super(-2). We do not detect any OB stars outside the central 0.5 pc. The majority of the stars in the clockwise system appear to be on almost circular orbits, whereas most of those in the "counterclockwise" disk appear to be on eccentric orbits. Based on its stellar surface density distribution and dynamics, we propose that IRS 13E is an extremely dense cluster (r sub(core) > 3 x 10 super(8) M sub(z) pc super(-3)) that has formed in the counterclockwise disk. The stellar contents of both systems are remarkably similar, indicating a common age of 6 c 2 Myr. The K-band luminosity function of the massive stars suggests a top-heavy mass function and limits the total stellar mass contained in both disks to 1.5 x 10 super(4) M sub(z). Our data strongly favor in situ star formation from dense gas accretion disks for the two stellar disks. This conclusion is very clear for the clockwise disk and highly plausible for the counterclockwise system.
We derive the extinction curve toward the Galactic center (GC) from 1 to 19 Delta *mm. We use hydrogen emission lines of the minispiral observed by ISO-SWS and SINFONI. The extinction-free flux ...reference is the 2 cm continuum emission observed by the Very Large Array. Toward the inner 14'' X 20'', we find an extinction of A 2.166 Delta *mm = 2.62 ? 0.11, with a power-law slope of Delta *a = --2.11 ? 0.06 shortward of 2.8 Delta *mm, consistent with the average near-infrared slope from the recent literature. At longer wavelengths, however, we find that the extinction is grayer than shortward of 2.8 Delta *mm. We find that it is not possible to fit the observed extinction curve with a dust model consisting of pure carbonaceous and silicate grains only, and the addition of composite particles, including ices, is needed to explain the observations. Combining a distance-dependent extinction with our distance-independent extinction, we derive the distance to the GC to be R 0 = 7.94 ? 0.65 kpc. Toward Sgr A* (r < 05), we obtain AH = 4.21 ? 0.10, AKs = 2.42 ? 0.10, and A L' = 1.09 ? 0.13.
Adding abiraterone acetate with prednisolone (AAP) or docetaxel with prednisolone (DocP) to standard-of-care (SOC) each improved survival in systemic therapy for advanced or metastatic prostate ...cancer: evaluation of drug efficacy: a multi-arm multi-stage platform randomised controlled protocol recruiting patients with high-risk locally advanced or metastatic PCa starting long-term androgen deprivation therapy (ADT). The protocol provides the only direct, randomised comparative data of SOC+AAP versus SOC+DocP.
Recruitment to SOC+DocP and SOC+AAP overlapped November 2011 to March 2013. SOC was long-term ADT or, for most non-metastatic cases, ADT for≥2years and RT to the primary tumour. Stratified randomisation allocated pts 2:1:2 to SOC; SOC+docetaxel 75mg/m2 3-weekly×6+prednisolone 10mg daily; or SOC+abiraterone acetate 1000mg+prednisolone 5mg daily. AAP duration depended on stage and intent to give radical RT. The primary outcome measure was death from any cause. Analyses used Cox proportional hazards and flexible parametric models, adjusted for stratification factors. This was not a formally powered comparison. A hazard ratio (HR) <1 favours SOC+AAP, and HR>1 favours SOC+DocP.
A total of 566 consenting patients were contemporaneously randomised: 189 SOC+DocP and 377 SOC+AAP. The patients, balanced by allocated treatment were: 342 (60%) M1; 429 (76%) Gleason 8–10; 449 (79%) WHO performance status 0; median age 66years and median PSA 56ng/ml. With median follow-up 4years, 149 deaths were reported. For overall survival, HR=1.16 (95% CI 0.82–1.65); failure-free survival HR=0.51 (95% CI 0.39–0.67); progression-free survival HR=0.65 (95% CI 0.48–0.88); metastasis-free survival HR=0.77 (95% CI 0.57–1.03); prostate cancer-specific survival HR=1.02 (0.70–1.49); and symptomatic skeletal events HR=0.83 (95% CI 0.55–1.25). In the safety population, the proportion reporting≥1 grade 3, 4 or 5 adverse events ever was 36%, 13% and 1% SOC+DocP, and 40%, 7% and 1% SOC+AAP; prevalence 11% at 1 and 2 years on both arms. Relapse treatment patterns varied by arm.
This direct, randomised comparative analysis of two new treatment standards for hormone-naïve prostate cancer showed no evidence of a difference in overall or prostate cancer-specific survival, nor in other important outcomes such as symptomatic skeletal events. Worst toxicity grade over entire time on trial was similar but comprised different toxicities in line with the known properties of the drugs.
Clinicaltrials.gov: NCT00268476.
In a dynamically relaxed cluster around a massive black hole a dense stellar cusp of old stars is expected to form. Previous observations showed a relative paucity of red giant stars within the ...central 0.5 pc in the Galactic Center. By co-adding spectroscopic observations taken over a decade, we identify new late-type stars, including the first five warm giants (G2-G8III), within the central 1 arcsec2 (0.04 × 0.04 pc2) of the Galaxy. Our findings increase the number of late-type stars to 21, of which we present deep spectra for 16. The updated star count, based on individual spectral classification, is used to reconstruct the surface density profile of giant stars. Our study, for the first time, finds a cusp in the surface number density of the spectroscopically identified old (>3 Gyr) giants population (mK < 17) within 0.02-0.4 pc described by a single power law with an exponent Γ = 0.34 0.04.
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