c-MET (MET) receptor activation is associated with poor prognosis and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) resistance in non-small-cell lung cancer (NSCLC). This ...global, randomized phase II trial examined erlotinib plus tivantinib (ARQ 197; ArQule, Woburn, MA), a novel MET inhibitor.
Previously treated patients with EGFR TKI-naive advanced NSCLC were randomly assigned to receive oral erlotinib (150 mg daily) plus oral tivantinib (360 mg twice daily) or erlotinib plus placebo (EP). The primary end point was progression-free survival (PFS). At the time of progression, cross-over from EP to erlotinib plus tivantinib (ET) was permitted. Archival tumor tissue specimens were required.
One hundred sixty-seven patients were randomly assigned to ET (n = 84) and to EP (n = 83). Median PFS was 3.8 months for ET and 2.3 months for EP (hazard ratio HR, 0.81; 95% CI, 0.57 to 1.16; P = .24). Exploratory analysis revealed that the small cohort with KRAS mutations achieved a PFS HR of 0.18 (95% CI, 0.05 to 0.70; interaction P = .006). Objective responses were seen in 10% of patients on ET, 7% of patients on EP, and in two patients who crossed over from EP to ET, including one with EGFR mutation and MET gene copy number greater than 5. There were no significant differences in adverse events between study arms.
The combination of the MET inhibitor tivantinib and erlotinib is well-tolerated. Although the study did not meet its primary end point, evidence of activity was demonstrated, especially among patients with KRAS mutations. Additional study of tivantinib and erlotinib in patients with NSCLC is planned.
Crizotinib is an oral kinase inhibitor approved for the treatment of ALK-rearranged non-small-cell lung cancer (NSCLC). The clinical benefits of crizotinib in patients with brain metastases have not ...been previously studied.
Patients with advanced ALK-rearranged NSCLC enrolled onto clinical trial PROFILE 1005 or 1007 (randomly assigned to crizotinib) were included in this retrospective analysis. Patients with asymptomatic brain metastases (nontarget or target lesions) were allowed to enroll. Tumor assessments were evaluated every 6 weeks using RECIST (version 1.1).
At baseline, 31% of patients (275 of 888) had asymptomatic brain metastases; 109 had received no prior and 166 had received prior brain radiotherapy as treatment. Among patients with previously untreated asymptomatic brain metastases, the systemic disease control rate (DCR) at 12 weeks was 63% (95% CI, 54% to 72%), the intracranial DCR was 56% (95% CI, 46% to 66%), and the median intracranial time to progression (TTP) was 7 months (95% CI, 6.7 to 16.4). Among patients with previously treated brain metastases, the systemic DCR was 65% (95% CI, 57% to 72%), the intracranial DCR was 62% (95% CI, 54% to 70%), and the median intracranial TTP was 13.2 months (95% CI, 9.9 to not reached). Patients with systemic disease control were also likely to experience intracranial disease control at 12 weeks (correlation coefficient, 0.7652; P < .001). Among patients without baseline brain metastases who developed progressive disease (n = 253) after initiation of crizotinib, 20% were diagnosed with brain metastases.
Crizotinib was associated with systemic and intracranial disease control in patients with ALK-rearranged NSCLC who were ALK inhibitor naive and had brain metastases. However, progression of preexisting or development of new intracranial lesions while receiving therapy was a common manifestation of acquired resistance to crizotinib.
The GALAH+ survey: Third data release Buder, Sven; Sharma, Sanjib; Kos, Janez ...
Monthly notices of the Royal Astronomical Society,
2021, Letnik:
506, Številka:
1
Journal Article
Recenzirano
Odprti dostop
ABSTRACT
The ensemble of chemical element abundance measurements for stars, along with precision distances and orbit properties, provides high-dimensional data to study the evolution of the Milky ...Way. With this third data release of the Galactic Archaeology with HERMES (GALAH) survey, we publish 678 423 spectra for 588 571 mostly nearby stars (81.2 per cent of stars are within <2 kpc), observed with the HERMES spectrograph at the Anglo-Australian Telescope. This release (hereafter GALAH+ DR3) includes all observations from GALAH Phase 1 (bright, main, and faint survey, 70 per cent), K2-HERMES (17 per cent), TESS-HERMES (5 per cent), and a subset of ancillary observations (8 per cent) including the bulge and >75 stellar clusters. We derive stellar parameters Teff, log g, Fe/H, vmic, vbroad, and vrad using our modified version of the spectrum synthesis code Spectroscopy Made Easy (sme) and 1D marcs model atmospheres. We break spectroscopic degeneracies in our spectrum analysis with astrometry from Gaia DR2 and photometry from 2MASS. We report abundance ratios X/Fe for 30 different elements (11 of which are based on non-LTE computations) covering five nucleosynthetic pathways. We describe validations for accuracy and precision, flagging of peculiar stars/measurements and recommendations for using our results. Our catalogue comprises 65 per cent dwarfs, 34 per cent giants, and 1 per cent other/unclassified stars. Based on unflagged chemical composition and age, we find 62 per cent young low-$\alpha$, 9 per cent young high-$\alpha$, 27 per cent old high-$\alpha$, and 2 per cent stars with Fe/H ≤ −1. Based on kinematics, 4 per cent are halo stars. Several Value-Added-Catalogues, including stellar ages and dynamics, updated after Gaia eDR3, accompany this release and allow chrono-chemodynamic analyses, as we showcase.
The allocation and cycling of carbon (C) within forests is an important component of the biospheric C cycle, but is particularly understudied within tropical forests. We synthesise reported and ...unpublished results from three lowland rainforest sites in Amazonia (in the regions of Manaus, Tapajós and Caxiuanã), all major sites of the Large-Scale Biosphere-Atmosphere Programme (LBA). We attempt a comprehensive synthesis of the C stocks, nutrient status and, particularly, the allocation and internal C dynamics of all three sites. The calculated net primary productivities (NPP) are 10.1±1.4 Mg C ha⁻¹ yr⁻¹ (Manaus), 14.4±1.3 Mg C ha⁻¹ yr⁻¹ (Tapajós) and 10.0±1.2 Mg C ha⁻¹ yr⁻¹ (Caxiuanã). All errors bars report standard errors. Soil and leaf nutrient analyses indicate that Tapajós has significantly more plant-available phosphorus and calcium. Autotrophic respiration at all three sites (14.9-21.4 Mg C ha yr⁻¹) is more challenging to measure, with the largest component and greatest source of uncertainty being leaf dark respiration. Comparison of measured soil respiration with that predicted from C cycling measurements provides an independent constraint. It shows general good agreement at all three sites, with perhaps some evidence for measured soil respiration being less than expected. Twenty to thirty percent of fixed C is allocated belowground. Comparison of gross primary productivity (GPP), derived from ecosystem flux measurements with that derived from component studies (NPP plus autotrophic respiration) provides an additional crosscheck. The two approaches are in good agreement, giving increased confidence in both approaches to estimating GPP. The ecosystem carbon-use efficiency (CUEs), the ratio of NPP to GPP, is similar at Manaus (0.34±0.10) and Caxiuanã (0.32±0.07), but may be higher at Tapajós (0.49±0.16), although the difference is not significant. Old growth or infertile tropical forests may have low CUE compared with recently disturbed and/or fertile forests.
Crizotinib has been shown to induce consistent clinical and radiographic responses in patients whose NSCLC harbours ALK rearrangements,1ROS1 rearrangements,2 high-level MET amplification, or MET exon ...14 skipping mutations.3 A series of phase 3 trials4,5 have indisputably shown that crizotinib (at a starting dose of 250 mg twice daily) was superior to traditional cytotoxic chemotherapies at inducing a response in patients with ALK-rearranged lung adenocarcinomas, in the second-line (docetaxel or pemetrexed) or first-line (platinum plus pemetrexed) setting, and improved progression-free survival and quality of life.
exon 20 insertions account for up to 10% of all
mutations in lung adenocarcinomas, representing the third most common cluster of mutations. The management of advanced cancers with these mutations ...remains elusive, without an approved inhibitor.
Preclinical models of a representative set of EGFR exon 20 insertion mutations to evaluate the efficacy of different inhibitors and description of the clinical outcome of an advanced lung cancer.
We show that select first-, second-, and third-generation EGFR inhibitors are unable to deter common EGFR exon 20 insertion mutants in concentrations that spare the wild-type kinase. Nonetheless, EGFR exon 20 insertion mutants associate with the Hsp90 chaperone system. We exploit this vulnerability to show that the nongeldanamycin Hsp90 inhibitor luminespib (formerly AUY922) degrades EGFR exon 20 mutations, downstream targets, and induces apoptosis. In addition, a patient whose EGFR inhibitor-insensitive lung adenocarcinoma harbored an
exon 20 insertion mutation had a confirmed radiographic response to luminespib.
The report confirms that EGFR exon 20 mutations are dependent on Hsp90 and are readily inhibited by the Hsp90 inhibitor luminespib; a treatment strategy that has been pursued in a confirmatory clinical trial (NCT01854034) for this group of lung adenocarcinomas that currently represent an unmet clinical need in precision oncology.
At least one climate model predicts severe reductions of rainfall over Amazonia during this century. Long-term throughfall exclusion (TFE) experiments represent the best available means to ...investigate the resilience of the Amazon rainforest to such droughts. Results are presented from a 7 yr TFE study at Caxiuanã National Forest, eastern Amazonia. We focus on the impacts of the drought on tree mortality, wood production and above-ground biomass. Tree mortality in the TFE plot over the experimental period was 2.5% yr⁻¹ compared with 1.25% yr⁻¹ in a nearby control plot experiencing normal rainfall. Differences in stem mortality between plots were greatest in the largest (> 40 cm diameter at breast height (dbh)) size class (4.1 % yr⁻¹ in the TFE and 1.4% yr⁻¹ in the control). Wood production in the TFE plot was 30% lower than in the control plot. Together, these changes resulted in a loss of 37.8 ± 2.0 Mg carbon (C) ha⁻¹ in the TFE plot (2002-2008), compared with no change in the control. These results are remarkably consistent with those from another TFE (at Tapajós National Forest), suggesting that eastern Amazonian forests may respond to prolonged drought in a predictable manner.
Most clinically available small-molecule kinase inhibitors are multi-targeted and can inhibit multiple kinases. Our driving hypothesis was that one of these multi-targeted tyrosine kinase inhibitors ...(TKIs) would have antiproliferative activity against ROS1 translocated non–small-cell lung cancer (NSCLC).
We selected NSCLC cell lines—A549 (KRAS G12S), NCI-H3255 (EGFR L858R), NCI-H3122 (EML4-ALK E13;A20), and HCC78 (SLC34A2-ROS1)—to evaluate the antiproliferative effects of submicromolar concentrations of the multitargeted TKIs imatinib, sorafenib, erlotinib, and crizotinib.
Imatinib and sorafenib were unable to significantly inhibit proliferation of the aforementioned cell lines. Erlotinib only inhibited EGFR mutated NCI-H3255, as expected. Crizotinib displayed dose-dependent inhibition of anaplastic lymphoma kinase translocated NCI-H3122 and also ROS1-translocated HCC78. The SLC34A2-ROS1 translocated HCC78 cell line had phosphorylated levels of ROS1, AKT, and ERK inhibited by submicromolar doses of crizotinib, and subsequently underwent apoptosis.
The ROS1-translocated HCC78 cell line was sensitive to inhibition by the multitargeted ALK/MET/RON/ROS1 inhibitor crizotinib. Preclinical data supports the clinical development of crizotinib for ROS1-translocated NSCLC.
Intracranial efficacy of first-line crizotinib versus chemotherapy was compared prospectively in the phase III PROFILE 1014 study in ALK-positive non-small-cell lung cancer.
Patients were randomly ...assigned to receive crizotinib (250 mg twice daily; n = 172) or chemotherapy (pemetrexed 500 mg/m(2) plus cisplatin 75 mg/m(2) or carboplatin at area under the curve 5 to 6, every 3 weeks for ≤ six cycles; n = 171). Patients with stable treated brain metastases (tBM) were eligible. Intracranial efficacy was assessed at baseline and every 6 or 12 weeks in patients with or without known brain metastases (BM), respectively; intracranial time to tumor progression (IC-TTP; per protocol) and intracranial disease control rate (IC-DCR; post hoc) were measured. The intent-to-treat population was also assessed.
Of 343 patients in the intent-to-treat population, 23% had tBM at baseline. A nonsignificant IC-TTP improvement was observed with crizotinib in the intent-to-treat population (hazard ratio HR, 0.60; P = .069), patients with tBM (HR, 0.45; P = .063), and patients without BM (HR, 0.69; P = .323). Among patients with tBM, IC-DCR was significantly higher with crizotinib versus chemotherapy at 12 weeks (85% v 45%, respectively; P < .001) and 24 weeks (56% v 25%, respectively; P = .006). Progression-free survival was significantly longer with crizotinib versus chemotherapy in both subgroups (tBM present: HR, 0.40; P < .001; median, 9.0 v 4.0 months, respectively; BM absent: HR, 0.51; P < .001; median, 11.1 v 7.2 months, respectively) and in the intent-to-treat population (HR, 0.45; P < .001; median, 10.9 v 7.0 months, respectively).
Compared with chemotherapy, crizotinib demonstrated a significantly higher IC-DCR in patients with tBM. Improvements in IC-TTP were not statistically significant in patients with or without tBM, although sensitivity to detect treatment differences in or between the two subgroups was low.
Highlights • Brain metastases are frequent in ALK rearranged lung cancers. • Brain metastases are frequent in EGFR mutated lung cancers. • ∼25% of patients at diagnosis and half at 3-years of ...survival have brain metastases.
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