Safety of Anti-Angiogenic Drugs in Pediatric Patients with Solid Tumors: A Systematic Review and Meta-Analysis.

Cancer is a clinical condition that can benefit from anti-angiogenic drugs (AADs). Given the low prevalence and the heterogeneity of childhood cancers, information about the safety of these drugs in pediatric patients is partially assessed. The aim of this study was to evaluate the safety of AADs in pediatric patients with solid tumors. Clinical trials and observational studies were searched in PubMed, ISI Web of Science, and ClinicalTrials database For each included study, adverse events (AEs) were extracted. A meta-analysis was conducted by pooling proportions of AEs using a random intercept logistic regression model. Seventy studies were retrieved. Most part were clinical trials (55 out of 70), and only fifteen observational studies were found. Overall, proportion of serious and non-serious AEs of AADs used as monotherapy was 46% and 89%, respectively. Proportions of serious AEs varied among drugs: sunitinib, 79%; lenvatinib, 64%; sorafenib, 48%; ramucirumab, 41%; pazopanib, 30%; and vandetanib, 27%. A higher proportion of non-serious hematological AEs was found in the patients receiving pazopanib with respect to sunitinib and lenvatinib. The safety profile of AADs has been extensively investigated for mostly drugs in phase I and II trials and is limited to acute toxicities. Overall, one out of two patients using AAD drugs in monotherapy experienced a serious AE despite proportions varied per single drugs. When AADs were combined with standard chemotherapy, the proportion of AEs varied in relation to the single combinations.

Development and validation of a case-finding algorithm for the identification of non-small cell lung cancers in a region-wide Italian pathology registry.

PURPOSE: To develop and validate a case-finding algorithm for the identification of Non-Small Cell Lung Cancer (NSCLC) cases in a region-wide Italian pathology registry (PR). MATERIALS AND METHODS: Data collected between 2009 and 2017 in the PR and the Pharmacy Database of the University Hospital of Siena and the PR of Tuscany region were used. A NSCLC-identification algorithm based on free-text keywords and SNOMED morphology and topography codes was designed and tested on data from Siena: indication for drug use (i.e. NSCLC) was the reference standard for sensitivity (SE); positive predictive value (PPV) was estimated through manual review. Algorithm modifications were then tested to improve algorithm performance: PPV was calculated against validated dataset from PR of Siena; a range of SE [min-max] was estimated in PR of Tuscany using analytical formulae that assumed NSCLC incidence equal either to 80% or 90% of overall lung cancer incidence recorded in Tuscany. The algorithm modification with the best performance was chosen as the final version of the algorithm. A random sample of 200 cases was extracted from the PR of Tuscany for manual review. RESULTS: The first version of the algorithm showed a PPV of 74.7% and SE of 79% in PR of Siena. The final version of the algorithm had a SE in PR of Tuscany that grew with calendar time (2009 = [24.7%-28%]; 2017 = [57.9%-65.1%]) and a PPV of 93%. CONCLUSIONS: The final NSCLC-finding algorithm showed with very high PPV. SE was in line with the expected contribution of PR to overall cases captured in the regional Cancer Registry, with a trend of increase over calendar time. Given the promising algorithm validity and the wide use of SNOMED terminology in electronic pathology records, the proposed algorithm is expected to be easily adapted to other electronic databases for (pharmaco)epidemiology purposes.

Clinical impact of STK11 mutation in advanced-stage non-small cell lung cancer.

BACKGROUND: Mutations in STK11/LKB1 gene present a negative impact on tumour immune microenvironment, especially with concomitant activating KRAS mutation. These recent data may explain a decreased response to immunotherapy treatment in STK11 mutant non-small cell lung cancer (NSCLC). OBJECTIVE: The primary objective is to evaluate, in a real-life setting, overall survival (OS) in patients with NSCLC according to the presence of STK11 mutation. The secondary objective is to assess time to treatment failure (TTF) for the first-line chemotherapy or immunotherapy. METHODS: This observational multicentric study was conducted in Nouvelle-Aquitaine (France), for 24 months. Clinical, histopathological and imagery data were collected in each centre while the next-generation sequencing analysis was performed in Bordeaux Hospital University. Patient's data were longitudinally followed from NSCLC diagnosis date to the occurrence of censoring events (therapeutic failure or death, as applicable) or until the study end date. RESULTS: median OS from the first drug administration was significantly longer for STK11wt patients than STK11mut patients (16.2 months [11 - nr] versus 4.7 months [2.5-9.4]; Log-rank test P < 0.001). The Presence of STK11 mutation was significantly associated with shortened OS (RR = 2.26 [1.35-3.79], P = 0.002). First-line TTF was significantly shorter in STK11mut population and the presence of the mutation was significantly associated with an increase in treatment failures (RR = 1.87 [1.21-2.89], P = 0.005). The type of treatment (chemotherapy, immunotherapy) does not influence the amplitude of reduced TTF in patients with STK11mut. CONCLUSION: The presence of STK11 mutation is associated with poor prognosis in NSCLC.

Second-line lurbinectedin as a new treatment option for small-cell lung cancer: Preliminary results in real-clinical practice.

INTRODUCTION: Few strategies exist for treatment of patients with small-cell lung cancer (SCLC) extended-stage after failure of first-line platinum-based chemotherapy. Lurbinectedin is a novel RNA-polymerase-II inhibitor investigated as a second-line therapy for SCLC. However, its efficacy and safety profile in real clinical practice remain to be determined. OBJECTIVE: To determine the efficacy and safety of lurbinectedin in real-life among patients with SCLC previously treated with first-line platinum-based chemotherapy. METHODS: We retrospectively evaluated patients who received at least one dose of lurbinectedin (3.2 mg/m2 ) between March 2020 and November 2021, in the pulmonary department of Bordeaux University Hospital. Endpoints were time to treatment discontinuation, progression-free survival, overall survival, and safety profile. RESULTS: Thirteen patients were included. The median age was 60 years (range: 42-77), seven (54%) were females, nine (69%) having a performance status of 0-1. Lurbinectedin was given as second-line treatment before platinum rechallenge in four (31%) patients. After a mean follow-up of 4.1 months, the objective response rate (ORR) was 17%. The median time to treatment discontinuation (TTD) was 2.3 months (interquartile range [IQR], 1.2-3.6). The median progression-free survival (PFS) and overall survival (OS) were, respectively, 1.9 (IQR, 0.1.8) and 4.1 (IQR, 2.0-3.5) months. No significant difference regarding TTD, PFS or OS was found in the two groups according to treatment history or according to chemotherapy-free intervall (CMI) 〈1 or 〉1 month. The most common adverse events (AEs) were asthenia, nausea, and anemia in nine (70%) patients. Grade 3 AEs were reported, fatigue, vomiting, nausea, anorexia, and neutropenia. CONCLUSIONS: Lurbinectedin in real clinical practice could have had a lower efficacy than in phase II trial, but a better hematological and bioclinical tolerance than previously reported. Early relapse after platinum-based chemotherapy seems to have a lower response to lurbinectedin.

First-Line Pharmacotherapies and Survival among Patients Diagnosed with Non-Resectable NSCLC: A Real-Life Setting Study with Gender Prospective.

(1) Purpose: To describe first-line pharmacotherapy and overall survival in non-resectable non-small cell lung cancer (nrNSCLC) patients by gender. (2) Methods: Incident cases of nrNSCLC recorded between 2009 and 2019 (cohort entry) in the pathology registry of the regional administrative healthcare database of Tuscany were identified. Records of antineoplastic therapies delivered up to 4 months following cohort entry were classified as chemotherapy, target therapies, immunotherapies, and undefined monoclonal antibodies. First-line treatment and survival of patients receiving drug treatment was described. Analyses were stratified according to histology, gender, and cohort entry year. (3) Results: 4393 incident cases of nrNSCLC were included. Women with non-squamous-NSCLC received target-therapy more frequently than men (14.9% vs. 6.5%). Immunotherapy incidence of use varied between 3.8% (2017) and 9.1% (2019). The 2-year survival rate increased over time: for non-squamous-NSCLC, it was 22.3% (2009-2011) and 30.6% (2018-2019), while for squamous-NSCLC, it was 13.5% and 22.5%, respectively. After multivariate analysis, a low reduction in mortality risk in 2018-2019 vs. 2009-2011 was found (non-squamous: HR: 0.95 CI95%: 0.92-0.98; squamous: HR: 0.94 CI95%: 0.90-0.98). Among non-squamous NSCLC, median survival was longer in women than in men (389 vs. 276 days). (4) Conclusion: In light of sex-related biomolecular differences, among non-squamous NSCLC, women received target-therapy more frequently than men. Survival seemed to slightly improve over the study period for both histologies, despite a poor reduction in mortality risk was still observed.

Association of Concomitant Bone Resorption Inhibitors With Overall Survival Among Patients With Metastatic Castration-Resistant Prostate Cancer and Bone Metastases Receiving Abiraterone Acetate With Prednisone as First-Line Therapy.

Importance: Bone resorption inhibitors (BRIs) are recommended by international guidelines to prevent skeletal-related events (SREs) among patients with metastatic castration-resistant prostate cancer (mCRPC) and bone metastases. Abiraterone acetate with prednisone is currently the most common first-line therapy for the treatment of patients with mCRPC; however, the clinical impact of the addition of BRIs to abiraterone acetate with prednisone in this disease setting is unknown. Objective: To evaluate the association of the use of concomitant BRIs with overall survival (OS) and time to first SRE among patients with mCRPC and bone metastases receiving abiraterone acetate with prednisone as first-line therapy. Design, Setting, and Participants: This retrospective cohort study collected data from 745 consecutive patients who began receiving abiraterone acetate with prednisone as first-line therapy for mCRPC with bone metastases between January 1, 2013, and December 31, 2016. Data were collected from 8 hospitals in Canada, Europe, and the US from June 15 to September 15, 2019. Exposures: Patients were classified by receipt vs nonreceipt of concomitant BRIs and subclassified by volume of disease (high volume or low volume, using definitions from the Chemohormonal Therapy Vs Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer [CHAARTED] E3805 study) at the initiation of abiraterone acetate with prednisone therapy. Main Outcomes and Measures: The primary end point was OS. The secondary end point was time to first SRE. The Kaplan-Meier method and Cox proportional hazards models were used. Results: Of the 745 men (median age, 77.6 years [interquartile range, 68.1-83.6 years]; 699 White individuals [93.8%]) included in the analysis, 529 men (71.0%) received abiraterone acetate with prednisone alone (abiraterone acetate cohort), and 216 men (29.0%) received abiraterone acetate with prednisone plus BRIs (BRI cohort). A total of 420 men (56.4%) had high-volume disease, and 276 men (37.0%) had low-volume disease. The median follow-up was 23.5 months (95% CI, 19.8-24.9 months). Patients in the BRI cohort experienced significantly longer OS compared with those in the abiraterone acetate cohort (31.8 vs 23.0 months; hazard ratio [HR], 0.65; 95% CI, 0.54-0.79; P < .001). The OS benefit in the BRI cohort was greater for patients with high-volume vs low-volume disease (33.6 vs 19.7 months; HR, 0.51; 95% CI, 0.38-0.68; P < .001). The BRI cohort also had a significantly shorter time to first SRE compared with the abiraterone acetate cohort (32.4 vs 42.7 months; HR, 1.27; 95% CI, 1.00-1.60; P = .04), and the risk of a first SRE was more than double in the subgroup with low-volume disease (HR, 2.29; 95% CI, 1.57-3.35; P < .001). In the multivariable analysis, concomitant BRIs use was independently associated with longer OS (HR, 0.64; 95% CI, 0.52-0.79; P < .001). Conclusions and Relevance: In this study, the addition of BRIs to abiraterone acetate with prednisone as first-line therapy for the treatment of patients with mCRPC and bone metastases was associated with longer OS, particularly in patients with high-volume disease. These results suggest that the use of BRIs in combination with abiraterone acetate with prednisone as first-line therapy for the treatment of mCRPC with bone metastases could be beneficial.

Real-World Utilization of Target- and Immunotherapies for Lung Cancer: A Scoping Review of Studies Based on Routinely Collected Electronic Healthcare Data.

Routinely collected electronic healthcare data (rcEHD) have a tremendous potential for enriching pre-marketing evidence on target- and immunotherapies used to treat lung cancer (LC). A scoping review was performed to provide a structured overview of available rcEHD-based studies on this topic and to support the execution of future research by facilitating access to pertinent literature both for study design and benchmarking. Eligible studies published between 2016 and 2020 in PubMed and ISI Web of Science were searched. Data source and study characteristics, as well as evidence on drug utilization and survival were extracted. Thirty-two studies were included. Twenty-six studies used North American data, while three used European data only. Thirteen studies linked ≥1 data source types among administrative/claims data, cancer registries and medical/health records. Twenty-nine studies retrieved cancer-related information from medical records/cancer registries and 31 studies retrieved information on drug utilization or survival from medical records or administrative/claim data. Most part of studies concerned non-small-cell-LC patients (29 out of 32) while none focused on small-cell-LC. Study cohorts ranged between 85 to 81,983 patients. Only two studies described first-line utilization of immunotherapies. Results from this review will serve as a starting point for the execution of future rcEHD-based studies on innovative LC pharmacotherapies.

Association between neutropenia and response to ramucirumab and paclitaxel in patients with metastatic gastric cancer.

The aim of this study was to evaluate if the occurrence of neutropenia is correlated with response to ramucirumab plus paclitaxel for metastatic gastric cancer. This is a retrospective study of patients treated with ramucirumab plus paclitaxel. Fifty-three patients were evaluated. Among these, 10 patients (26.5%) developed grade ≥3 neutropenia. Patients with grade ≥3 neutropenia reported a progression-free survival of 6.6 months (95% confidence interval 3.3-8.4) and overall survival of 11 months (95% confidence interval 5.9-13.1) vs. 4.4 months (95% confidence interval 3.9-5.2) and 8.7 months (95% confidence interval 7.8-10.1) respectively in patients' group with lower grade events. Our analysis seems to suggest that the occurrence of neutropenia predicts response to treatment with ramucirumab and paclitaxel.

Immune Checkpoint Inhibitors in Pre-Treated Gastric Cancer Patients: Results from a Literature-Based Meta-Analysis.

Immunotherapy has recently changed the treatment of several cancers. We performed a literature-based meta-analysis of randomised controlled trials to assess the efficacy of the novel immune checkpoint inhibitors (ICIs) in metastatic gastric cancer. The main outcome was overall survival. Based on age (cut-off agreed at 65 years), tumour location (gastric vs. gastro-oesophageal junction), programmed death-ligand 1 (PD-L1) status, sex and Eastern Cooperative Oncology Group (ECOG) status (1 vs. 0), we scheduled a subgroup analysis for the overall survival. Three studies were included in the analysis for a total of 1456 cases (811 cases were in the experimental group and 645 cases in the control group). The pooled analysis showed improved overall survival in the experimental arm in the absence of statistical significance (hazard ratio (HR) = 0.87, 95% CI: 0.64-1.18; p = 0.37). The subgroup of patients with PD-L1-positive tumours (HR = 0.82 vs. 1.04) and gastro-oesophageal junction cancer (HR = 0.82 vs. 1.04) showed a statistically significant advantage of overall survival. This study supports the efficacy of immune checkpoint inhibitors in the subgroup of patients with metastatic gastric cancer with PD-L1-positive and gastro-oesophageal junction tumour location. Future studies are needed with the aim of identifying reliable predictive biomarkers of ICI efficacy.

Poor outcome for patients with gastric cancer and lung metastases treated with ramucirumab and paclitaxel.

The aim of this report is to investigate the activity of ramucirumab in combination with paclitaxel in patients with metastatic gastric cancer (GC) and lung metastases. We retrospectively reviewed clinical data from patients with GC treated in second line with ramucirumab and paclitaxel according to the presence or not of lung metastases. Thirty-one patients were eligible. Five (16.1%) patients had lung metastases. The median progression-free survival was 156 days in patients without lung metastases compared with 54 days in patients with lung metastases. The median survival also showed a trend in favour of patients without lung metastases. Despite the small number of patients and the retrospective nature of the data, our analysis showed relatively poor efficacy of ramucirumab plus paclitaxel as a second-line treatment in patients with lung metastases from GC. Further studies are required to evaluate novel treatments in this subset of patients.

Is there still a place for vinorelbine in advanced metastatic castration resistant prostate cancer?

The aim of this paper was to evaluate the activity and tolerability of oral vinorelbine in patients with advanced castration resistant prostate cancer (CRPC) who progressed after a minimum of three lines including: abiraterone acetate, docetaxel, cabazitaxel, and enzalutamide.Treatment consisted of weekly oral vinorelbine 60 mg/m. Chemotherapy was administered until disease progression or unacceptable toxicity.Twenty-six patients received vinorelbine: their median age was 74 years (range 58-84 years). Twenty-four (92.3%) patients had bone metastases. A decrease in PSA levels ≥50% was observed in 2 patients (7.7%). Among the subjects who were symptomatic at baseline, pain was reduced in 3 patients (13.6%) with a significant decrease in analgesic use. Median progression-free survival was 9 weeks (95% CI: 7 to 11) and median overall survival was 17 weeks (95% CI: 12 to 22). Treatment was well tolerated, and no grade 4 toxicities were observed.Our findings do not suggest the use of oral vinorelbine on a weekly schedule, in CRPC heavily pre-treated.

The influence of prior ramucirumab treatment on the clinical activity of FOLFIRI as third-line therapy in patients with metastatic gastric Cancer.

Purpose Few data described the activity of chemotherapy after ramucirumab plus paclitaxel progression in metastatic gastric cancer patients. The aim of this phase II study is to assess the efficacy and safety of the FOLFIRI regimen as a third-line of treatment. Methods The study enrolled patients with histologically proven metastatic gastric cancer or gastroesophageal junction carcinoma whose disease had progressed after ramucirumab-based second line of treatment. Treatment consisted of biweekly irinotecan 150 mg/m2 as a 1-h infusion on day 1, folinic acid 100 mg/m2 intravenously on days 1-2, and 5-fluorouracil as a 400 mg/m2 bolus and then 600 mg/m2 continuous infusion over 22 h on days 1-2. Primary end-point was tumor response rate (confirmed complete and partial response). Results Twenty-six patients were enrolled. Overall response rate and disease control rate were 11.5% and 38.5%. The median progression free survival (PFS) was 52 days (95% CI:42-74), and the median overall survival was 117 days (95% CI: 94-154). no unexpected adverse events have been observed. A longer PFS and OS were observed in patients who had achieved PFS ≥ 3 months during prior ramucirumab treatment. Conclusions Our findings suggest a poor efficacy of the FOLFIRI regimen in metastatic gastric or gastroesophageal junction cancer patients whose disease progressed during a ramucirumab-based second line of treatment. However, FOLFIRI could be an option for patients who responded to prior ramucirumab.

Association between ramucirumab-related hypertension and response to treatment in patients with metastatic gastric cancer.

PURPOSE: Hypertension (HTN) is frequently associated with the use of angiogenesis inhibitors targeting the vascular endothelial growth factor pathway, such as ramucirumab. The aim of this study was to retrospectively evaluate if occurrence of HTN is correlated with response to second line treatment with ramucirumab+paclitaxel for metastatic gastric cancer. METHODS: Treatment consisted of ramucirumab 8 mg/kg intravenously (iv) on days 1 and 15, plus paclitaxel 80 mg/m2 iv on days 1, 8, and 15 of a 28-day cycle. Patients received study treatment until disease progression, unacceptable toxicity, or withdrawal of consent. RESULTS: Thirty-four patients were retrospectively evaluated. Among these, 6 (17.6%) developed grade 3 ramucirumab-induced HTN. These patients had a better outcome than those with lesser grades events, with a progression-free survival (PFS) of 7.8 months (95% CI 4.4-not reached) versus 4.2 months (95% CI 3.1-5.2) (p=0.001). overall survival (OS) was 11.9 months (95% CI 9.3-not reached) in the grade 3 HTN group, versus 7.2 months (95% CI 5.9-10.1). CONCLUSIONS: Despite the small number of patients and the retrospective nature of the data, our analysis showed that occurrence of ramucirumab-related HTN, in particular G3 HTN, predicts response to treatment with ramucirumab+paclitaxel in patients with metastatic gastric cancer.

Docetaxel, oxaliplatin, 5FU, and trastuzumab as first-line therapy in patients with human epidermal receptor 2-positive advanced gastric or gastroesophageal junction cancer: Preliminary results of a phase II study.

The aim of this study is to report first preliminary results of patients enrolled in a phase II study that will investigate the activity and safety of docetaxel, oxaliplatin, and 5-fluorouracil (DOF) in combination with trastuzumab in human epidermal receptor-2 (HER-2) positive patients with advanced gastric or gastroesophageal junction (GEJ) cancer.Treatment consisted of docetaxel 70 mg/m combined with oxaliplatin 130 mg/m on day 1, and continuous infusion 5-fluorouracil mg/m days 1-5 plus trastuzumab at the standard dose on day 1, every 3 weeks for a maximum of 8 cycles.Fifteen patients were enrolled. The overall response rate was 60%. The median progression-free survival was 9.2 months (95% confidence interval [CI], 4.4-10.1 months) and the median overall survival was 19.4 months (95% CI, 8.9-21.1 months). Grade 3 neutropenia was observed in 3 patients (20%).The DOF plus trastuzumab seems active in HER-2 positive advanced gastric or GEJ cancer, final results of the phase II study are awaited.

Response rate as a potential surrogate for survival and efficacy in patients treated with novel immune checkpoint inhibitors: A meta-regression of randomised prospective studies.

INTRODUCTION: To assess the role of the tumour response rate (RR) after immune checkpoint inhibitors-based therapy as a potential surrogate end-point of progression-free survival (PFS) and overall survival (OS) in patients with solid tumours, we performed a trial-based meta-regression of randomised studies comparing different immune checkpoint inhibitors-based treatments. METHODS: The systematic literature search included the electronic databases and the proceedings of oncologic meetings. Treatment effects on PFS and OS were expressed as hazard ratios (HRs); treatment effects on RR were expressed as odds ratios (ORs). A weighted regression analysis was performed on log-transformed treatment effect estimates to test the association between treatment effects on the surrogate outcome and treatment effects on the clinical outcome. RESULTS: Twenty-four trials, for a total of 11,894 patients, were included in the analysis. Using the complete set of data, the regression of either the log(HR) for PFS or the log(HR) for OS on the log(OR) for RR demonstrated weak associations (R2 = 0.47; 95% confidence interval [CI], 0.03-0.77; P = 0.001; and R2 = 0.32; 95% CI, 0.02-0.76; P = 0.01, respectively). The pre-planned analyses stratifying trials according to different type of disease and different mechanism of action of immune checkpoint inhibitors showed a very weak association of the RR with the OS for non-small cell lung cancer indicated and a modest association of the RR with the PFS for cytotoxic T lymphocyte-associated antigen 4 checkpoint inhibitors. CONCLUSION: The results of the trial-based meta-regression analysis indicated a weak correlation between RR and OS, supporting future investigations to assess the surrogacy of RR in the patient treated with immune checkpoint inhibitors.