A randomised phase II study of osimertinib and bevacizumab versus osimertinib alone as second-line targeted treatment in advanced NSCLC with confirmed EGFR and acquired T790M mutations: the European Thoracic Oncology Platform (ETOP 10-16) BOOSTER trial.

BACKGROUND: While osimertinib, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) is the standard treatment in patients with advanced non-small-cell lung cancer (NSCLC) with sensitising EGFR and acquired T790M mutations, progression inevitably occurs. The angiogenic pathway is implicated in EGFR TKI resistance. PATIENTS AND METHODS: BOOSTER is an open-label randomised phase II trial investigating the efficacy and safety of combined osimertinib 80 mg daily and bevacizumab 15 mg/kg every 3 weeks, versus osimertinib alone, in patients with EGFR-mutant advanced NSCLC and acquired T790M mutations after failure on previous EGFR TKI therapy. Primary endpoint was investigator-assessed progression-free survival (PFS). Secondary endpoints were overall survival (OS), objective response rate (ORR) and adverse events (AEs). RESULTS: Between May 2017 and February 2019, 155 patients were randomised (combination: 78; osimertinib: 77). At data cut-off of 22 February 2021, median follow-up was 33.8 months [interquartile range (IQR): 26.5-37.6 months] and 129 (83.2%) PFS events were reported in the intention-to-treat population. There was no difference in median PFS between the combination [15.4 months; 95% confidence interval (CI) 9.2-18.0 months] and osimertinib arm (12.3 months; 95% CI 6.2-17.2 months; stratified log-rank P = 0.83), [hazard ratio (HR) = 0.96; 95% CI 0.68-1.37]. Median OS was 24.0 months (95% CI 17.8-32.1 months) in the combination arm and 24.3 months (95% CI 16.9-37.0 months) in the osimertinib arm (stratified log-rank P = 0.91), (HR = 1.03; 95% CI 0.67-1.56). Exploratory analysis revealed a significant interaction of smoking history with treatment for PFS (adjusted P = 0.0052) with a HR of 0.52 (95% CI 0.30-0.90) for smokers, and 1.47 (95% CI 0.92-2.33) for never smokers. ORR was 55% in both arms and the median time to treatment failure was significantly shorter in the combination than in the osimertinib arm, 8.2 months versus 10.8 months, respectively (P = 0.0074). Safety of osimertinib and bevacizumab was consistent with previous reports with grade ≥3 treatment-related AEs (TRAEs) reported in 47% and 18% of patients on combination and osimertinib alone, respectively. CONCLUSIONS: No difference in PFS was observed between osimertinib plus bevacizumab and osimertinib alone. Grade ≥3 TRAEs were more common in patients on combination.

Immune-related adverse events predict the therapeutic efficacy of anti-PD-1 antibodies in cancer patients.

BACKGROUND: Cancer immune therapy has shown remarkable benefit in the treatment of a range of cancer types, although it may initiate autoimmune-related disorders in some patients. We have attempted to establish whether the incidence of irAEs after the use of anti-PD-1 antibodies nivolumab or pembrolizumab in advanced malignancies is associated with anti-PD-1 treatment efficacy. PATIENTS AND METHODS: We studied patients treated with single-agent nivolumab or pembrolizumab for advanced cancer. irAEs (immune-related adverse events) were identified clinically and graded as per the Common Terminology Criteria for Adverse Events version 4.0. Efficacy was evaluated with objective response rate (ORR, immune-Response Evaluation Criteria in Solid Tumours [RECIST] criteria) progression-free survival (PFS) and overall survival (OS). Tests were performed to determine the association between irAEs and ORR, PFS or OS. RESULTS: We identified 106 patients. Primary diagnoses were lung cancer (n = 77), melanoma (n = 8), head and neck carcinoma (n = 7), renal carcinoma (n = 5), Hodgkin's lymphoma (n = 3), urothelial carcinoma (n = 3) and gallbladder adenocarcinoma, hepatocellular carcinoma and Merkel cell carcinoma (n = 1 each). IrAEs were observed in 40 patients (37.7%). The most frequent irAEs were hypothyroidism (n = 15), nephritis (n = 5) and hyperthyroidism (n = 4). Objective response was observed in 44 patients (41.5%), and median PFS was 5.5 months (0.5-31 months). Thirty-three of the 40 patients with irAEs had objective response (82.5%) in contrast with 11 of the 66 cases without irAEs (16.6%) (OR 23.5, P < 0.000001). PFS in patients with irAEs was 10 months and 3 months in those without irAEs (HR 2.2, P = 0.016). OS in patients with irAEs was 32 months and 22 in those without irAEs, without statistically significant differences. CONCLUSION: In advanced cancer treated with single-agent anti-PD-1 antibodies, patients with irAEs showed a markedly improved efficacy over patients without irAEs (ORR of 82.5% and PFS of 10 months vs ORR of 16.6% and PFS of 3 months). Future studies of anti-PD-1 immune-therapy should address this association to explore the underlying biological mechanisms of efficacy.

Clinical utility of plasma-based digital next-generation sequencing in patients with advance-stage lung adenocarcinomas with insufficient tumor samples for tissue genotyping.

BACKGROUND: Approximately 30% of tumor biopsies from patients with advanced-stage lung adenocarcinomas yield insufficient tissue for successful molecular subtyping. We have analyzed the clinical utility of next-generation sequencing (NGS) of cell-free circulating tumor DNA (ctDNA) in patients with inadequate tumor samples for tissue genotyping. PATIENTS AND METHODS: We conducted the study in a multi-institutional prospective cohort of clinically unselected patients with advanced-stage lung adenocarcinomas with insufficient tissue for EGFR, ALK or ROS1 genotyping across 12 Spanish institutions (n = 93). ctDNA NGS was carried out by Guardant Health (Guardant360, Redwood City, CA), using a hybrid-capture-based 73-gene panel. Variants were deemed actionable if they were part of the OncoKB precision oncology knowledge database and classified in four levels of actionability based on their clinical or preclinical evidence for drug response. RESULTS: Eighty-three out of 93 patients (89%) had detectable levels of ctDNA. Potentially actionable level 1-4 genomic alterations were detected in 53 cases (57%), of which 13 (14%) had level 1-2A alterations (Food and Drug Administration-approved and standard-care biomarkers according to lung cancer guidelines). Frequencies of each genomic alteration in ctDNA were consistent with those observed in unselected pulmonary adenocarcinomas. The majority of the patients (62%), particularly those with actionable alterations (87%), had more than one pathogenic variant in ctDNA. The median turnaround time to genomic results was 13 days. Twelve patients (13%) received genotype-matched therapies based on ctDNA results, deriving the expected clinical benefit. Patients with co-occurring pathogenic alterations had a significantly shorter median overall survival as compared with patients without co-occurring pathogenic alteration (multivariate hazard ratio = 5.35, P = 0.01). CONCLUSION: Digital NGS of ctDNA in lung cancers with insufficient tumor samples for tissue sequencing detects actionable variants that frequently co-occur with other potentially clinically relevant genomic alterations, allowing timely initiation of genotype-matched therapies.

Long-term survival in advanced non-squamous NSCLC patients treated with first-line bevacizumab-based therapy.

BACKGROUND/AIM: First-line bevacizumab-based therapies have been shown to improve clinical outcomes in patients with non-squamous non-small-cell lung cancer (NSCLC). We aimed to descriptively analyse patients with non-squamous NSCLC who received a long-term period of maintenance bevacizumab. PATIENTS AND METHODS: This retrospective study included 104 patients who had already reached a progression-free survival (PFS) of at least 9 months. RESULTS: Median overall survival and PFS were 30.7 and 15.1 months, respectively. The overall response rate was 83 %. Weight loss ≤5 %, ECOG PS = 0, or low number of metastatic sites seem to be predictive factors of good evolution. The incidence of bevacizumab-related adverse events appeared to be similar as the previous studies. CONCLUSION: Our findings show that there is a long-term survivor group whom the administration of bevacizumab resulted in a relevant prolongation of response without new safety signals. Due to the population heterogeneity, it was not possible to identify the standardised predictive factors.

Learning skills and academic performance in children and adolescents with absence epilepsy.

INTRODUCTION: Although cognitive and learning disorders have been described in patients with epilepsy, very few studies focus on specific disorders such as absence epilepsy. The aim of this study was to evaluate learning skills and academic performance in children and adolescents with absence epilepsy. METHODS: Observational case-control study. Cases were chosen from the Central League against Epilepsy's clinic in Bogotá, Colombia. Controls were selected from a private school and matched with cases by age, school year, and sex. Medical history, seizure frequency, antiepileptic treatment, and academic performance were assessed. Academic abilities were tested with Batería de Aptitudes Diferenciales y Generales (BADyG) (a Spanish-language test of differential and general aptitudes). Data were analysed using Student t-test. RESULTS: The sample consisted of 19 cases and 19 controls aged between 7 and 16. In 15 patients, seizures were controlled; all patients had received antiepileptic medication at some point and 78.9% were actively being treated. Although cases had higher rates of academic failure, a greater incidence of grade retention, and more therapeutic interventions than controls, these differences were not significant. Similarly, there were no significant differences on the BADyG test, except for the immediate memory subcategory on which cases scored higher than controls (P=.0006). CONCLUSION: Children treated pharmacologically for absence epilepsy, whose seizures are controlled, have normal academic abilities and skills for their age.

Randomized, phase III trial of figitumumab in combination with erlotinib versus erlotinib alone in patients with nonadenocarcinoma nonsmall-cell lung cancer.

BACKGROUND: Figitumumab (CP-751,871) is a fully human IgG2 monoclonal antibody that inhibits the insulin-like growth factor 1 receptor. This multicenter, randomized, phase III study investigated the efficacy of figitumumab plus erlotinib compared with erlotinib alone in patients with pretreated, nonsmall-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients (stage IIIB/IV or recurrent disease with nonadenocarcinoma histology) who had previously received at least one platinum-based regimen were randomized to receive open-label figitumumab (20 mg/kg) plus erlotinib 150 mg/day or erlotinib alone every 3 weeks. The primary end point was overall survival (OS). RESULTS: Of 583 patients randomized, 579 received treatment. The study was closed early by an independent data safety monitoring committee due to results crossing the prespecified futility boundary. At the final analysis, median OS was 5.7 months for figitumumab plus erlotinib and 6.2 months for erlotinib alone [hazard ratio (HR) 1.09; 95% confidence interval (CI) 0.91-1.31; P = 0.35]. Median progression-free survival was 2.1 months for figitumumab plus erlotinib and 2.6 months for erlotinib alone (HR 1.08; 95% CI 0.90-1.29; P = 0.43). Treatment-related nonfatal serious adverse events occurred in 18% and 5% of patients in the figitumumab arm or erlotinib alone arm, respectively. There were nine treatment-related deaths (three related to both drugs, four related to erlotinib alone and two related to figitumumab). CONCLUSIONS: The addition of figitumumab to erlotinib did not improve OS in patients with advanced, pretreated, nonadenocarcinoma NSCLC. Clinical development of figitumumab has been discontinued. CLINICAL TRIAL ID: NCT00673049.

Prevalence and management of anaemia in patients with non-myeloid cancer undergoing systemic therapy: a Spanish survey

BACKGROUND: The present study aimed to provide updated data on anaemia prevalence and management in cancer patients undergoing systemic therapy in Spain. METHODS: This was a multicenter, observational, cross-sectional study performed in 2008. Eligible patients were ≥18 years, with non-myeloid malignancies treated with systemic therapy [chemotherapy (CT), hormonal therapy or immunotherapy]. Anaemia was defined according to WHO as haemoglobin (Hb) < 12 g/dL. RESULTS: The study included 214 patients with a median age of 63 years (range 20-91), 58 % women, 73 % with solid tumours, and 79 % with advanced disease. CT was used in 91 % of patients (26 % with platinum compounds), hormonal therapy in 8.5 %, and immunotherapy in 8.5 %. In our study, 48.1 % of patients [95 % confidence interval (CI) 45.2-58.6] showed anaemia (31 % symptomatic): 42.0 % mild (10 ≤ Hb ≤ 11.9 g/dL), 5.6 % moderate (8 ≤ Hb ≤ 9.9 g/dL), and 0.5 % severe (Hb < 8 g/dL). A higher prevalence was observed in patients treated with CT (51 vs. 20 %, p = 0.01), platinum-based CT (70 vs. 47 %, p = 0.01) or palliative CT (61 vs. 39 %, p = 0.003). Anaemia was also more frequent in patients with more than three lines of CT (83 %) and in the fourth or subsequent CT cycle (58 %). Management in the previous 4 weeks in patients with anaemia was: 62 % did not receive treatment (92 % mild), 24 % received erythropoiesis-stimulating agents (ESAs), 14 % received iron and 8.7 % received transfusion. CONCLUSIONS: In Spanish hospitals, about half of patients with non-myeloid malignancies undergoing systemic therapy fulfilled anaemia criteria (87 % mild). Approximately two-third of patients with anaemia do not receive specific treatment and ESA use is below current guidelines (AU)

Cisplatin plus oral vinorelbine as first-line treatment for advanced non-small-cell lung cancer: a prospective study confirming that the day-8 hemogram is unnecessary.

INTRODUCTION: Cisplatin plus oral vinorelbine, one of the standard treatments for metastatic non-small-cell lung cancer (NSCLC), is associated with a high rate of neutropenia, and a hemogram is performed on day 8. We analyzed the oncologists' opinions and the result of the hemogram on day 8 to address the question of whether this hemogram could be avoided. MATERIALS AND METHODS: Fifty-eight chemotherapy-naive, advanced NSCLC patients were included. Each received intravenous doses of 75 mg/m(2) cisplatin on day 1 plus oral vinorelbine [60 mg/m(2) in the first cycle (80 mg/m(2) in subsequent cycles) on days 1 and 8], every 3 weeks, for a maximum of six cycles. RESULTS: Out of 257 cycles analyzed, oral vinorelbine was administered on day 8 in 214 (83.2 %) and the dose was canceled in 6 cycles (2.3 %) due to hematological toxicity. On analyzing the patients to whom chemotherapy had been administered on day 8, based on medical opinion without the doctor knowing the hemogram result, we found that the cycle had been administered with a hemogram showing fewer than 1,500 × 10(6) neutrophils in only 3 of the 185 evaluable cycles [event rate of 1.6 %, with confidence interval 95 % = (0.34-4.67 %)]. CONCLUSION: The hemogram on day 8 can be avoided and oral vinorelbine administered in relative safety in patients with good performance status, when confirmed by the clinician's perception, thereby making this regimen more comfortable for the patient. This is the first prospective study to examine this issue.

Prevalence and management of anaemia in patients with non-myeloid cancer undergoing systemic therapy: a Spanish survey.

BACKGROUND: The present study aimed to provide updated data on anaemia prevalence and management in cancer patients undergoing systemic therapy in Spain. METHODS: This was a multicenter, observational, cross-sectional study performed in 2008. Eligible patients were ≥18 years, with non-myeloid malignancies treated with systemic therapy [chemotherapy (CT), hormonal therapy or immunotherapy]. Anaemia was defined according to WHO as haemoglobin (Hb) < 12 g/dL. RESULTS: The study included 214 patients with a median age of 63 years (range 20-91), 58 % women, 73 % with solid tumours, and 79 % with advanced disease. CT was used in 91 % of patients (26 % with platinum compounds), hormonal therapy in 8.5 %, and immunotherapy in 8.5 %. In our study, 48.1 % of patients [95 % confidence interval (CI) 45.2-58.6] showed anaemia (31 % symptomatic): 42.0 % mild (10 ≤ Hb ≤ 11.9 g/dL), 5.6 % moderate (8 ≤ Hb ≤ 9.9 g/dL), and 0.5 % severe (Hb < 8 g/dL). A higher prevalence was observed in patients treated with CT (51 vs. 20 %, p = 0.01), platinum-based CT (70 vs. 47 %, p = 0.01) or palliative CT (61 vs. 39 %, p = 0.003). Anaemia was also more frequent in patients with more than three lines of CT (83 %) and in the fourth or subsequent CT cycle (58 %). Management in the previous 4 weeks in patients with anaemia was: 62 % did not receive treatment (92 % mild), 24 % received erythropoiesis-stimulating agents (ESAs), 14 % received iron and 8.7 % received transfusion. CONCLUSIONS: In Spanish hospitals, about half of patients with non-myeloid malignancies undergoing systemic therapy fulfilled anaemia criteria (87 % mild). Approximately two-third of patients with anaemia do not receive specific treatment and ESA use is below current guidelines.

Brain metastases from lung cancer responding to erlotinib: the importance of EGFR mutation.

Median survival of patients with brain metastases from nonsmall cell lung cancer (NSCLC) is poor and more effective treatments are urgently needed. We have evaluated the efficacy of erlotinib in this setting and its association with activating mutations in the epidermal growth factor receptor (EGFR) gene. We retrospectively identified patients with NSCLC and brain metastases treated with erlotinib. EGFR mutations in exons 19 and 21 were analysed by direct sequencing. Efficacy and tolerability were compared according to EGFR mutational status. 69 NSCLC patients with brain metastases were identified, 17 of whom harboured EGFR mutations. Objective response rate in patients with EGFR mutations was 82.4%; no responses were observed in unselected patients (p<0.001). Median (95% CI) time to progression within the brain for patients harbouring EGFR mutations was 11.7 (7.9-15.5) months, compared to 5.8 (5.2-6.4) months for control patients whose EGFR mutational status had not been assessed (p<0.05). Overall survival was 12.9 (6.2-19.7) months and 3.1 (2.5-3.9) months (p<0.001), respectively. The toxicity of erlotinib was as expected and no differences between cohorts were observed. Erlotinib is active in brain metastases from NSCLC; this clinical benefit is related to the presence of activating mutations in exons 19 or 21 of the EGFR gene.

Single nucleotide polymorphisms in MDR1 gen correlates with outcome in advanced non-small-cell lung cancer patients treated with cisplatin plus vinorelbine.

UNLABELLED: New therapeutic approaches are being developed based on the findings that several genetic abnormalities underlying NSCLC could influence chemosensitivity. In this study, we assessed whether the presence of polymorphisms in ERCC1, XPD, RRM1 and MDR1 genes can affect the efficacy and the tolerability of cisplatin and vinorelbine in NSCLC patients. MATERIAL AND METHODS: Eligible patients had histological confirmed stage IV or IIIB (with malignant pleural effusion) non-small-cell lung cancer (NSCLC) previously untreated with chemotherapy; World Health Organization performance status (PS) 0-1. Patients received intravenous doses of vinorelbine 25 mg/m² on day 1 and 8 and cisplatin 75 mg/m² on day 1, every 21 days, for a maximum of eight cycles. RESULTS: 94 patients were included. Median age was 61 years; 84% were male; WHO performance status (PS) was 0 in 24%; and 88% of patients had stage IV disease. The median number of cycles was 6. Overall median survival was 10.92 months (95% CI 9.0-12.9). Overall median time to progression was 5.89 months (95% CI 5.2-6.6). Results of the multivariate analysis for time to progression showed that ECOG 0 (hazard ratio [HR] ECOG 1 vs. ECOG 0, 1.74; p=0.036), MDR13435CC (HR CT vs. CC, 2.01; p=0.017; HR TT vs. CC, 1.54; p=0.22), and decreasing age (HR of age, 0.97; p=0.016) were the most powerful prognostic factors significantly related to lower risk of progression. Whereas ECOG 0 was the only prognostic factor for survival (HR ECOG 1 vs. ECOG 0, 3.02; p=0.001). There was no significant association between any of the SNPs analysed and the occurrence of vinorelbine and cisplatin-related toxicity. CONCLUSION: In our results, the most important prognostic factors associated with lower risk of progression were MDR1 3435 CC genotype, PS 0 and younger age.

Biotransformation kinetic of binifibrate and identification of its metabolites.

The metabolism of binifibrate was studied in 10,000 g supernatant fractions from rat liver. Binifibrate was found to be completely biotransformed into clofibric acid and nicotinic acid at 60 min from the start of incubation through a series of intermediate products among which glycerol dinicotinate was identified. The biotransformation constant of binifibrate into its different metabolites proved to be 0.11 +/- 0.025 min-1. The formation of clofibric acid follows a first-order kinetic process characterized by its corresponding rate constant (kc), proving to be 0.043 +/- 0.017 min-1. The amount of clofibrate was 0.78 +/- 0.16 mumol/ml, showing that it is not biotransformed later in the incubation mixture. The formation constant of nicotinic acid (kn) was 0.067 +/- 0.020 min-1 and the amount of substance contained in the incubation mixture (0.94 +/- 0.25 mumol/ml shows that it is later biotransformed in the incubation mixture through the previously described metabolic processes.