The randomized, phase III AVAPERL trial evaluated the safety and efficacy of bevacizumab maintenance with or without pemetrexed in nonsquamous nonsmall-cell lung cancer (nsNSCLC). Progression-free ...survival (PFS) was significantly prolonged with bevacizumab–pemetrexed, but overall survival (OS) data were immature. In this article, we report an independent, updated analysis of survival outcomes in AVAPERL.
Patients with advanced nsNSCLC received first-line bevacizumab (7.5 mg/kg), cisplatin (75 mg/m2), and pemetrexed (500 mg/m2) every 3 weeks (q3w) for four cycles. Nonprogressing patients were randomized to maintenance bevacizumab (7.5 mg/kg) or bevacizumab–pemetrexed (500 mg/m2) q3w until progression or consent withdrawal. The primary end point of the trial was PFS; in this independent OS analysis, participating study centers were contacted to collect survival data on patients still alive at the time of the first analysis.
A total of 376 patients received induction treatment. Disease control was confirmed in 71.9% of patients; 253 patients were randomized to maintenance treatment with bevacizumab (n = 125) or bevacizumab–pemetrexed (n = 128). At a median follow-up of 14.8 months, patients allocated to bevacizumab–pemetrexed had significantly improved PFS versus those on bevacizumab when measured from randomization 7.4 versus 3.7 months, hazard ratio (HR), 0.57, 95% confidence interval (CI) 0.44–0.75); P < 0.0001. OS events occurred in 58% of all patients. OS was numerically longer with bevacizumab–pemetrexed versus bevacizumab when measured from randomization 17.1 versus 13.2 months, HR 0.87 (0.63–1.21); P = 0.29. Second-line therapy was administered in 77% and 70% of patients in the bevacizumab and bevacizumab–pemetrexed arms, respectively. No new adverse events were reported during this updated analysis.
In an unselected population of nsNSCLC patients achieving disease control on platinum-based induction therapy, maintenance with bevacizumab–pemetrexed was associated with a nonsignificant increase in OS over bevacizumab alone.
To assess the efficacy, safety, tolerability and pharmacokinetics of BIBF 1120 in patients with stage IIIB/IV non-small-cell lung cancer (NSCLC).
Patients with locally advanced or metastatic relapsed ...NSCLC in whom first- or second-line platinum-based chemotherapy failed were randomly allocated to daily 250 mg BIBF 1120 b.i.d. or 150 mg BIBF 1120 b.i.d. Primary end points were progression-free survival (PFS) and objective tumour response (RECIST). Incidence and severity of adverse events (AEs) were reported.
Seventy-three patients received BIBF 1120. Median PFS was 6.9 weeks, with no significant difference between treatment arms. Median overall survival (OS) was 21.9 weeks. Eastern Cooperative Oncology Group (ECOG) 0–1 patients (n = 56) had a median PFS of 11.6 weeks and a median OS of 37.7 weeks. Tumour stabilisation was achieved in 46% of patients (ECOG 0–1 patients: 59%), with one confirmed partial response (250 mg b.i.d.). Most commonly reported drug-related AEs were nausea (57.5%), diarrhoea (47.9%), vomiting (42.5%), anorexia (28.8%), abdominal pain (13.7%) and reversible alanine transaminase (13.7%) and aspartate aminotransferase elevations (9.6%). BIBF 1120 displayed dose-linear pharmacokinetic characteristics.
Continuous treatment with BIBF 1120 was well tolerated, with no difference in efficacy between treatment arms. PFS and objective response with single-agent treatment in advanced disease warrants further exploration.
Post-translational modifications (PTMs) of proteins in the adult brain are known to mark activity-dependent processes for complex brain functions such as learning and memory. Multiple PTMs occur in ...nerve cells, and are able to modulate proteins in different subcellular compartments. In synaptic terminals, protein phosphorylation is the primary PTM that contributes to the control of the activity and localization of synaptic proteins. In the nucleus, it can modulate histones and proteins involved with the transcriptional machinery and, in combination with other PTMs such as acetylation, methylation and ubiquitination, acts to regulate chromatin remodelling and gene expression. The combination of histone PTMs is highly complex and is known to be unique to each gene. The ensemble of PTMs in the adult brain, however, remains unknown. Here, we describe a novel proteomic approach that allows the isolation and identification of PTMs on synaptic and nuclear proteins, in particular on histones. Using subcellular fractionation, we identified 2082 unique phosphopeptides from 1062 phosphoproteins, and 196 unique PTM sites on histones H1, H2A, H2B, H3 and H4. A comparison of phosphorylation sites in synaptic and nuclear compartments, and on histones, suggests that different kinases and kinase motifs are involved. Overall, our data demonstrates the complexity of PTMs in the brain and the prevalence of histone PTMs, and reveals potentially important regulatory sites on proteins involved in synaptic plasticity and brain functions.
•Adsorption of mAb monomer/dimer mixtures on CEX resin visualized by CLSM.•Monomer/dimer selectivity varies with salt concentration.•Displacement of monomer by dimer occurs within the resin beads at ...higher salt.•Intraparticle adsorption fronts are consistent with dual shrinking core model.•Low salt monomer/dimer adsorption not predicted by current isotherm models.
Adsorption equilibrium and kinetics are determined for a monoclonal antibody (mAb) monomer and dimer species, individually and in mixtures, on a macroporous cation exchange resin both under the dilute limit of salt gradient elution chromatography and at high protein loads and low salt based on batch adsorption equilibrium and confocal laser scanning microscopy (CLSM) experiments. In the dilute limit and weak binding conditions, the dimer/monomer selectivity in 10mM phosphate at pH 7 varies between 8.7 and 2.3 decreasing with salt concentration in the range of 170–230mM NaCl. At high protein loads and strong binding conditions (0–60mM NaCl), the selectivity in the same buffer is near unity with no NaCl added, but increases gradually with salt concentration reaching high values between 2 and 15 with 60mM added NaCl. For these conditions, the two-component adsorption kinetics is controlled by pore diffusion and is predicted approximately by a dual shrinking core model using parameters based on single component equilibrium and kinetics measurements.
To further characterize survival benefit with first-line nivolumab plus ipilimumab with two cycles of chemotherapy versus chemotherapy alone, we report updated data from the phase III CheckMate 9LA ...trial with a 2-year minimum follow-up.
Adult patients were treatment naïve, with stage IV/recurrent non-small-cell lung cancer, no known sensitizing EGFR/ALK alterations, and an Eastern Cooperative Oncology Group performance status ≤1. Patients were randomized 1 : 1 to nivolumab 360 mg every 3 weeks plus ipilimumab 1 mg/kg every 6 weeks with two cycles of chemotherapy, or four cycles of chemotherapy. Updated efficacy and safety outcomes are reported, along with progression-free survival (PFS) after next line of treatment (PFS2), treatment-related adverse events (TRAEs) by treatment cycle, and efficacy outcomes in patients who discontinued all treatment components in the experimental arm due to TRAEs.
With a median follow-up of 30.7 months, nivolumab plus ipilimumab with chemotherapy continued to prolong overall survival (OS) versus chemotherapy. Median OS was 15.8 versus 11.0 months hazard ratio 0.72 (95% confidence interval 0.61-0.86); 2-year OS rate was 38% versus 26%. Two-year PFS rate was 20% versus 8%. ORR was 38% versus 25%, respectively; 34% versus 12% of all responses were ongoing at 2 years. Median PFS2 was 13.9 versus 8.7 months. Improved efficacy outcomes in the experimental versus control arm were observed across most subgroups, including by programmed death-ligand 1 and histology. No new safety signals were observed; onset of grade 3/4 TRAEs was mostly observed during the first two treatment cycles in the experimental arm. In patients who discontinued all components of nivolumab plus ipilimumab with chemotherapy treatment due to TRAEs (n = 61) median OS was 27.5 months; 56% of responders had an ongoing response ≥1 year after discontinuation.
With a 2-year minimum follow-up, nivolumab plus ipilimumab with two cycles of chemotherapy provided durable efficacy benefits over chemotherapy with a manageable safety profile and remains an efficacious first-line treatment of advanced non-small-cell lung cancer.
•Nivolumab + ipilimumab + two cycles of chemotherapy (chemo) significantly prolonged survival versus chemo in first-line advanced NSCLC.•At 2 years, overall survival benefits were durable with nivolumab + ipilimumab + chemo versus chemo.•Benefits of nivolumab + ipilimumab + chemo were seen across most patient subgroups, including by PD-L1 and histology.•Discontinuing nivolumab + ipilimumab + chemo due to treatment-related AEs did not negatively impact long-term benefits.•Nivolumab + ipilimumab + two cycles of chemo is an efficacious first-line treatment option for advanced non-oncogene-driven NSCLC.
First-line nivolumab plus ipilimumab prolongs survival versus chemotherapy in advanced non-small-cell lung cancer (NSCLC). We further characterized clinical benefit with this regimen in a large ...pooled patient population and assessed the effect of response on survival.
Data were pooled from four studies of first-line nivolumab plus ipilimumab in advanced NSCLC (CheckMate 227 Part 1, 817 cohort A, 568 Part 1, and 012). Overall survival (OS), progression-free survival (PFS), objective response rate, duration of response, and safety were assessed. Landmark analyses of OS by response status at 6 months and by tumor burden reduction in responders to nivolumab plus ipilimumab were also assessed.
In the pooled population (N = 1332) with a minimum follow-up of 29.1-58.9 months, median OS was 18.6 months, with a 3-year OS rate of 35%; median PFS was 5.4 months (3-year PFS rate, 17%). Objective response rate was 36%; median duration of response was 23.7 months, with 38% of responders having an ongoing response at 3 years. In patients with tumor programmed death-ligand 1 (PD-L1) <1%, ≥1%, 1%-49%, or ≥50%, 3-year OS rates were 30%, 38%, 30%, and 48%. Three-year OS rates were 30% and 38% in patients with squamous or non-squamous histology. Efficacy outcomes in patients aged ≥75 years were similar to the overall pooled population (median OS, 20.1 months; 3-year OS rate, 34%). In the pooled population, responders to nivolumab plus ipilimumab at 6 months had longer post-landmark OS than those with stable or progressive disease; 3-year OS rates were 66%, 22%, and 14%, respectively. Greater depth of response was associated with prolonged survival; in patients with tumor burden reduction ≥80%, 50% to <80%, or 30% to <50%, 3-year OS rates were 85%, 72%, and 44%, respectively. No new safety signals were identified in the pooled population.
Long-term survival benefit and durable response with nivolumab plus ipilimumab in this large patient population further support this first-line treatment option for advanced NSCLC.
•Pooled analyses from four 1L NIVO + IPI studies support the durable efficacy of this regimen for advanced NSCLC treatment.•Durable responses and long-term survival benefit with NIVO + IPI were observed across histologies/PD-L1 expression levels.•Patients who had a response at 6 months with 1L NIVO + IPI had improved post-landmark survival benefit.•Responders with higher tumor burden reduction from baseline derived long-term OS benefit.
Variable chemotherapy exposure may cause toxicity or lack of efficacy. This study was initiated to validate pharmacokinetically (PK)-guided paclitaxel dosing in patients with advanced non-small-cell ...lung cancer (NSCLC) to avoid supra- or subtherapeutic exposure.
Patients with newly diagnosed, advanced NSCLC were randomly assigned to receive up to 6 cycles of 3-weekly carboplatin AUC 6 or cisplatin 80 mg/m2 either with standard paclitaxel at 200 mg/m2 (arm A) or PK-guided dosing of paclitaxel (arm B). In arm B, initial paclitaxel dose was adjusted to body surface area, age, sex, and subsequent doses were guided by neutropenia and previous-cycle paclitaxel exposure time above a plasma concentration of 0.05 µM (Tc>0.05) determined from a single blood sample on day 2. The primary end point was grade 4 neutropenia; secondary end points included neuropathy, radiological response, progression-free survival (PFS) and overall survival (OS).
Among 365 patients randomly assigned, grade 4 neutropenia was similar in both arms (19% versus 16%; P = 0.10). Neuropathy grade ≥2 (38% versus 23%, P < 0.001) and grade ≥3 (9% versus 2%, P < 0.001) was significantly lower in arm B, independent of the platinum drug used. The median final paclitaxel dose was significantly lower in arm B (199 versus 150 mg/m2, P < 0.001). Response rate was similar in arms A and B (31% versus 27%, P = 0.405), as was adjusted median PFS 5.5 versus 4.9 months, hazard ratio (HR) 1.16, 95% confidence interval (CI) 0.91–1.49, P = 0.228 and OS (10.1 versus 9.5 months, HR 1.05, 95% CI 0.81–1.37, P = 0.682).
PK-guided dosing of paclitaxel does not improve severe neutropenia, but reduces paclitaxel-associated neuropathy and thereby improves the benefit–risk profile in patients with advanced NSCLC.
NCT01326767 (https://clinicaltrials.gov/ct2/show/NCT01326767).
We show copy number gain in of the PD-L1 gene about 5% NSCLC. This seems to be associated with low differntiation and high expression of the protein. Patiens showing copy number gain of PD-L1 are ...likely to behave differentially under Anti-PD-L1 therapy.
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