Immunotherapy has revolutionized the treatment of advanced non-small-cell lung cancer (NSCLC). In two phase III trials (CheckMate 017 and CheckMate 057), nivolumab showed an improvement in overall ...survival (OS) and favorable safety versus docetaxel in patients with previously treated, advanced squamous and nonsquamous NSCLC, respectively. We report 5-year pooled efficacy and safety from these trials.
Patients (N = 854; CheckMate 017/057 pooled) with advanced NSCLC, ECOG PS ≤ 1, and progression during or after first-line platinum-based chemotherapy were randomly assigned 1:1 to nivolumab (3 mg/kg once every 2 weeks) or docetaxel (75 mg/m
once every 3 weeks) until progression or unacceptable toxicity. The primary end point for both trials was OS; secondary end points included progression-free survival (PFS) and safety. Exploratory landmark analyses were investigated.
After the minimum follow-up of 64.2 and 64.5 months for CheckMate 017 and 057, respectively, 50 nivolumab-treated patients and nine docetaxel-treated patients were alive. Five-year pooled OS rates were 13.4% versus 2.6%, respectively; 5-year PFS rates were 8.0% versus 0%, respectively. Nivolumab-treated patients without disease progression at 2 and 3 years had an 82.0% and 93.0% chance of survival, respectively, and a 59.6% and 78.3% chance of remaining progression-free at 5 years, respectively. Treatment-related adverse events (TRAEs) were reported in 8 of 31 (25.8%) nivolumab-treated patients between 3-5 years of follow-up, seven of whom experienced new events; one (3.2%) TRAE was grade 3, and there were no grade 4 TRAEs.
At 5 years, nivolumab continued to demonstrate a survival benefit versus docetaxel, exhibiting a five-fold increase in OS rate, with no new safety signals. These data represent the first report of 5-year outcomes from randomized phase III trials of a programmed death-1 inhibitor in previously treated, advanced NSCLC.
Phase 3 clinical data has shown higher proportions of patients with objective response, longer response duration, and longer overall survival with nivolumab versus docetaxel in patients with ...previously treated advanced non-small-cell lung cancer (NSCLC). We aimed to evaluate the long-term benefit of nivolumab and the effect of response and disease control on subsequent survival.
We pooled data from four clinical studies of nivolumab in patients with previously treated NSCLC (CheckMate 017, 057, 063, and 003) to evaluate survival outcomes. Trials of nivolumab in the second-line or later setting with at least 4 years follow-up were included. Comparisons of nivolumab versus docetaxel included all randomised patients from the phase 3 CheckMate 017 and 057 studies. We did landmark analyses by response status at 6 months to determine post-landmark survival outcomes. We excluded patients who did not have a radiographic tumour assessment at 6 months. Safety analyses included all patients who received at least one dose of nivolumab.
Across all four studies, 4-year overall survival with nivolumab was 14% (95% CI 11–17) for all patients (n=664), 19% (15–24) for those with at least 1% PD-L1 expression, and 11% (7–16) for those with less than 1% PD-L1 expression. In CheckMate 017 and 057, 4-year overall survival was 14% (95% CI 11–18) in patients treated with nivolumab, compared with 5% (3–7) in patients treated with docetaxel. Survival subsequent to response at 6 months on nivolumab or docetaxel was longer than after progressive disease at 6 months, with hazard ratios for overall survival of 0·18 (95% 0·12–0·27) for nivolumab and 0·43 (0·29–0·65) for docetaxel; for stable disease versus progressive disease, hazard ratios were 0·52 (0·37–0·71) for nivolumab and 0·80 (0·61–1·04) for docetaxel. Long-term data did not show any new safety signals.
Patients with advanced NSCLC treated with nivolumab achieved a greater duration of response compared with patients treated with docetaxel, which was associated with a long-term survival advantage.
Bristol-Myers Squibb.
Abstract
Background: Historically, 5-y overall survival (OS) with chemotherapy for pts with metastatic lung cancer was ~5%; with the advent of immunotherapy, this has increased to ~15%. CheckMate ...(CM) 017, 057, 063, and 003 are NIVO studies with extensive follow-up in pts with previously treated advanced NSCLC. Using pooled data from these studies, we evaluated the long-term benefit (up to 4 y) of NIVO and impact of early response or disease control on subsequent long-term OS.
Methods: Progression-free survival (PFS) and OS were estimated for pts with NSCLC across histologies treated with NIVO in pooled analyses of CM 017, 057, 063, and 003 (n=664), and for pts randomized to NIVO (n=427) or docetaxel (DOC; n=427) in pooled analyses of CM 017/057. Other analyses for CM 017/057 included estimation of OS in pts alive at 6 mo by response status at 6 mo, and OS in all responders (complete or partial response CR/PR) from time of response.
Results: In pooled analyses of the 4 studies, 4-y OS rates for NIVO in all pts and those with PD-L1 ≥1% and <1% were 14%, 19%, and 11%, respectively. In CM 017/057, the 4-y OS rate in all pts was higher with NIVO vs DOC (14% vs 5%). Pts with either CR/PR or stable disease (SD) at 6 mo had longer subsequent OS with NIVO vs DOC; for pts with PD at 6 mo, 1-y OS rates were higher with NIVO vs DOC, while 2-4 y OS rates were similar (Table). For responders (CR/PR) in CM 017/057, 4-y OS rate from time of response with NIVO vs DOC was 54% vs 12%; median duration of response was 24 mo vs 6 mo, respectively. Overall, the NIVO discontinuation rate due to treatment-related adverse events (AEs) was 8.7%; most common treatment-related select AEs were skin reactions (incidence rate, 38.6 per 100 person-y).
Conclusions: These large pooled analyses show pts with CR/PR or SD with NIVO at 6 mo derived marked OS benefit; this long-term benefit was improved vs pts with DOC with the same response status at 6 mo. The NIVO safety profile was consistent with prior reports.
Table.6-Month Landmark Analysis of OS by Response Status at 6 months in Pooled CM 017/057aPts alive at mo 6Response status at 6 mo, %bPost-landmark 1-y OS rate, %Post-landmark 2-y OS rate, %Post-landmark 3-y OS rate, %Post-landmark 4-y OS rate, %NIVO 3 mg/kg Q2W (n = 280)CR/PR, 2581636158SD, 2458352419PD, 51401384DOC 75 mg/m2 Q3W (n = 264)CR/PR, 1362382612SD, 39351872PD, 48221285aThe 6-month landmark timepoint was used to allow sufficient time for the majority of responses with NIVO to occur, while allowing meaningful time to assess OS post landmark: median time to response, 2.1 mo; 75th quartile, 3.5 mo.b% of pts alive at 6 mo.
Citation Format: Julie Brahmer, Hossein Borghaei, Suresh S. Ramalingam, Leora Horn, Esther Holgado, Adam Pluzanski, Marco A. Burgio, Marina Garassino, Laura Q. Chow, Scott Gettinger, Lucio Crino, David Planchard, Charles Butts, Alexander Drilon, Joanna Wojcik-Tomaszewska, Gregory Otterson, Vinny Hayreh, Ang Li, John R. Penrod, Scott J. Antonia. Long-term survival outcomes with nivolumab (NIVO) in pts with previously treated advanced non-small cell lung cancer (NSCLC): Impact of early disease control and response abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT195.
Caffeine is one of the most widely consumed psychoactive drugs in the world. It easily crosses the blood-brain barrier, and caffeine-interacting adenosine and ryanodine receptors are distributed in ...various areas of the brain, including the hypothalamus and pituitary. Caffeine intake may have an impact on reproductive and immune function. Therefore, in the present study performed on the ewe model, we decided to investigate the effect of peripheral administration of caffeine (30 mg/kg) on the secretory activity of the hypothalamic-pituitary unit which regulates the reproductive function in females during both a physiological state and an immune/inflammatory challenge induced by lipopolysaccharide (LPS; 400 ng/kg) injection. It was found that caffeine stimulated (
< 0.01) the biosynthesis of gonadotropin-releasing hormone (GnRH) in the hypothalamus of ewe under both physiological and inflammatory conditions. Caffeine also increased (
< 0.05) luteinizing hormone (LH) secretion in ewes in a physiological state; however, a single administration of caffeine failed to completely release the LH secretion from the inhibitory influence of inflammation. This could result from the decreased expression of GnRHR in the pituitary and it may also be associated with the changes in the concentration of neurotransmitters in the median eminence (ME) where GnRH neuron terminals are located. Caffeine and LPS increased (
< 0.05) dopamine in the ME which may explain the inhibition of GnRH release. Caffeine treatment also increased (
< 0.01) cortisol release, and this stimulatory effect was particularly evident in sheep under immunological stress. Our studies suggest that caffeine affects the secretory activity of the hypothalamic-pituitary unit, although its effect appears to be partially dependent on the animal's immune status.
The purpose of the paper was to investigate the possibility of obtaining lithium from geothermal water using natural and synthetic zeolites applying poly(acrylic acid). The efficiency of lithium ion ...sorption was determined depending on the type of tested zeolite, pH of the solution and the presence of anionic poly(acrylic acid). It was shown that the adsorption amount on the surface of aluminosilicates depends on their structure (size of specific surface area and porosity). Moreover, it was proved that the amount of adsorbed lithium ions increases with the increasing pH value of the solution. This is due to an increase in the concentration of negatively charged groups on the zeolite surface that capture the lithium cations from the solution effectively. In general, the addition of anionic polymer increases lithium ions sorption from the LiCl solution at pH 9, at which about 100% recovery of Li cations by Na-X zeolite was obtained. Under these conditions the poly(acrylic acid) carboxyl groups are completely dissociated which guarantees effective formation of polymer-metal complexes and results in the increase of amount of adsorbed lithium ions. The important parameter affecting lithium ions sorption amount is the order of adsorbates addition to the system since the polymer adsorption modifies surface properties of the solid thus influencing the ion exchange process of metal cations. The maximum recovery of lithium cations from geothermal water (at the natural pH 5.5) was obtained in the system containing natural clinoptilolite and anionic polymer. It amounted to almost 5 mg/L (with the initial content of Li+ ions in water about 10 mg/L).
Schematic representation of Li+ ions sorption from geothermal water on the clinoptilolite surface in the poly(acrylic acid) presence. Display omitted
•Lithium recovery from geothermal water using zeolites was examined.•Efficiency of lithium ion sorption depends on solution pH and polymer presence.•Synthetic Na-X zeolite was prepared from fly ash on a semi-technical scale.•50% recovery of lithium was obtained for natural clinoptilolite with polymer.•Geothermal water can be potential source of lithium ions.
This study aimed to present the clinical features and results of treatment of patients diagnosed with refractory or relapsed acute myeloid leukaemia (AML) in Polish Paediatric Leukaemia/Lymphoma ...Study Group (PPL/LSG) institutions, treated in accordance with the Protocol Acute Myeloid Leukaemia Berlin-Frankfurt-Munster 2012, as their first-line therapy.
The outcome data of 10 patients with refractory AML (median age 9.5 years) and 30 with relapsed AML (median age 12 years) were analysed retrospectively. Re-induction was usually based on idarubicin, fludarabine, and cytarabine along with allogeneic haematopoietic stem cell transplant (allo-HSCT) in 5 patients with refractory AML and 7 relapsed AML children.
37.5% (3/8) of refractory AML patients achieved second complete remission second complete remission (CRII). One of ten patients (1/10; 10%) was alive and stayed in complete remission for 34 months after the allo-HSCT. The probability of 3-year event-free survival (pEFS) in this group was 0.125 ±0.11. In the group of relapsed AML patients, the CRII was achieved in 9 patients (34%), and the probability of survival was: pEFS = 0.24 ±0.08; probability overall survival (pOS) = 0.34 ±0.09, with significantly better results achieved in patients who underwent allo-HSCT (pOS = 0.54 ±0.14 vs. 0.08 ±0.08,
< 0.0001).
The prognosis of refractory AML and the first AML recurrence in children who were first-line treated in PPL/LSG centres according to Protocol Acute Myeloid Leukaemia Berlin-Frankfurt-Munster 2012 is poor. Failures of re-induction treatment particularly result from difficulties in achieving remission. Allogeneic HSCT improves prognosis in children with refractory and first recurrent AML, under the condition it is performed in complete remission. Novel therapeutic approaches are needed to increase the remission rate and improve the outcomes.
ACL injuries – next to damage to the collateral ligaments, menisci of the knee – are the most common injuries of the knee joint and very often require surgical treatment. The main aim of the ...treatment is to restore normal gait pattern. The objective of this study was to determine the influence of reconstructed ACL on selected gait parameters by using an accelerometer system.
The study involved 34 people aged 18-54 who were divided in two groups. The first group consisted of 20 people after ACL reconstruction, aged 19-54 years old (mean 29). The second group consisted of 14 healthy people between the age of 18-45 (mean 25.36). Gait analysis in normal and fast rate was performed using the CQMotion Electronik System, MEMS type.
Differences in the results were observed in the first group. In 75% of people during normal walking and in 95% during fast walking, a 5% difference between the healthy limb and the limb after ACL reconstruction was observed. The gait rate had influence on acceleration value which was observed in RMS values in both of the groups. The RMS value was different, depending on the gait rate.
Accelerometric gait analysis shows that the differences in comparing rate values between limbs are not so great, however, the gait pace has influence on some gait parameters. parameters.
Serious risks in unrelated hematopoietic stem cell transplantation (HSCT) including graft versus host disease (GvHD) and mortality are associated with HLA disparity between donor and recipient. The ...increased risks might be dependent on disparity in not-routinely-tested multiple polymorphisms in genetically dense MHC region, being organized in combinations of two extended MHC haplotypes (Ehp). We assessed the clinical role of donor-recipient Ehp disparity levels in N = 889 patients by the population-based detection of HLA allele phase mismatch. We found increased GvHD incidences and mortality rates with increasing Ehp mismatch level even with the same HLA mismatch level. In multivariate analysis HLA mismatch levels were excluded from models and Ehp disparity level remained independent prognostic factor for high grade acute GvHD (p = 0.000037, HR = 10.68, 95%CI 5.50–32.5) and extended chronic GvHD (p < 0.000001, HR = 15.51, CI95% 5.36–44.8). In group with single HLA mismatch, patients with double Ehp disparity had worse 5-year overall survival (45% vs. 56%, p = 0.00065, HR = 4.05, CI95% 1.69–9.71) and non-relapse mortality (40% vs. 31%, p = 0.00037, HR = 5.63, CI95% 2.04–15.5) than patients with single Ehp disparity. We conclude that Ehp-linked factors contribute to the high morbidity and mortality in recipients given HLA-mismatched unrelated transplant and Ehp matching should be considered in clinical HSCT.
Background
Since 1983 four consecutive unified regimens: acute myeloid leukemia-Polish pediatric leukemia/lymphoma study group (AML-PPLLSG) 83, AML-PPLLSG 94, AML-PPLLSG 98 and AML-BFM 2004 Interim, ...for AML have been conducted by the Polish Pediatric Leukemia/Lymphoma Study Group (PPLLSG). In this paper, we review four successive studies on the basis of acute myeloid leukemia-Berlin–Frankfurt–Munster (AML-BFM) protocol, in which a stepwise improvement of treatment outcome was observed. Treatment results of the last protocol AML-BFM 2004 Interim are presented in detail.
Methods
Three hundred and three patients with
de novo
AML were treated according to the AML-BFM 2004 Interim at 15 Polish centers from January 1, 2005 to June 30, 2011. A confrontation with previous treatment periods was based upon historical, already published data.
Results
In four consecutive periods, 723 children were eligible for evaluation (208, 83, 195, and 237, respectively). Complete remission rates in consecutive periods were: 71, 68, 81 and 87 %, respectively. The 5-year overall survival rates, event-free survival rates, and relapse-free survival rates were 33, 32, and 45%, respectively for AML-PPLLSG 83 regimen; 38, 36, and 53 % respectively for AML-PPLLSG 94 regimen; 53, 46, and 65 % respectively for AML-PPLLSG 98 regimen, and 63, 52, and 64 % for AML–BFM Interim 2004, respectively. Incidence of early deaths and that due to complications (mainly infections) in the first remission decreased over time from 22 to 4.6 % and from 10 to 5.9 %, respectively.
Conclusions
Despite continuous improvement in the treatment outcome, the number of failures still remains too high. Further progress seemed to be possible due to continued cooperation of oncology centers within large international study groups.
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