Safety profile of avelumab in patients with advanced solid tumors: A pooled analysis of data from the phase 1 JAVELIN solid tumor and phase 2 JAVELIN Merkel 200 clinical trials.

BACKGROUND: Antibodies targeting the programmed death-ligand 1 (PD-L1)/programmed cell death protein 1 (PD-1) checkpoint may cause adverse events (AEs) that are linked to the mechanism of action of this therapeutic class and unique from those observed with conventional chemotherapy. METHODS: Patients with advanced solid tumors who were enrolled in the phase 1 JAVELIN Solid Tumor (1650 patients) and phase 2 JAVELIN Merkel 200 (88 patients) trials received avelumab, a human anti-PD-L1 IgG1 antibody at a dose of 10 mg/kg every 2 weeks. Treatment-related AEs (TRAEs) were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.0). In post hoc analyses, immune-related AEs (irAEs) were identified via an expanded AE list and medical review, and infusion-related reactions (IRRs) occurring ≤2 days after infusion and symptoms occurring ≤1 day after infusion and resolving ≤2 days after onset were identified based on prespecified Medical Dictionary for Regulatory Activities (MedDRA) terms. RESULTS: Of the 1738 patients analyzed, grade ≥3 TRAEs occurred in 177 (10.2%); the most common were fatigue (17 patients; 1.0%) and IRR (10 patients; 0.6%). TRAEs led to discontinuation in 107 patients (6.2%) and death in 4 patients (0.2%). Grade ≥3 irAEs occurred in 39 patients (2.2%) and led to discontinuation in 34 patients (2.0%). IRRs or related symptoms occurred in 439 patients (25.3%; grade 3 in 0.5% [9 patients] and grade 4 in 0.2% [3 patients]). An IRR occurred at the time of first infusion in 79.5% of 439 patients who had an IRR, within the first 4 doses in 98.6% of 439 patients who had an IRR, and led to discontinuation in 35 patients (2.0%). CONCLUSIONS: Avelumab generally was found to be well tolerated and to have a manageable safety profile. A minority of patients experienced grade ≥3 TRAEs or irAEs, and discontinuation was uncommon. IRRs occurred mainly at the time of first infusion, and repeated events were infrequent. Cancer 2018;124:2010-7. © 2018 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

Model-informed approach for risk management of bleeding toxicities for bintrafusp alfa, a bifunctional fusion protein targeting TGF-ß and PD-L1.

PURPOSE: Bintrafusp alfa (BA) is a bifunctional fusion protein composed of the extracellular domain of the transforming growth factor-ß (TGF-ß) receptor II fused to a human immunoglobulin G1 antibody blocking programmed death ligand 1 (PD-L1). The recommended phase 2 dose (RP2D) was selected based on phase 1 efficacy, safety, and pharmacokinetic (PK)-pharmacodynamic data, assuming continuous inhibition of PD-L1 and TGF-ß is required. Here, we describe a model-informed dose modification approach for risk management of BA-associated bleeding adverse events (AEs). METHODS: The PK and AE data from studies NCT02517398, NCT02699515, NCT03840915, and NCT04246489 (n = 936) were used. Logistic regression analyses were conducted to evaluate potential relationships between bleeding AEs and BA time-averaged concentration (Cavg), derived using a population PK model. The percentage of patients with trough concentrations associated with PD-L1 or TGF-ß inhibition across various dosing regimens was derived. RESULTS: The probability of bleeding AEs increased with increasing Cavg; 50% dose reduction was chosen based on the integration of modeling and clinical considerations. The resulting AE management guidance to investigators regarding temporary or permanent treatment discontinuation was further refined with recommendations on restarting at RP2D or at 50% dose, depending on the grade and type of bleeding (tumoral versus nontumoral) and investigator assessment of risk of additional bleeding. CONCLUSION: A pragmatic model-informed approach for management of bleeding AEs was implemented in ongoing clinical trials of BA. This approach is expected to improve benefit-risk profile; however, its effectiveness will need to be evaluated based on safety data generated after implementation.

Evaluation of the potential for QTc prolongation with avelumab.

PURPOSE: To report integrated electrocardiogram (ECG) summary and exposure-QTc analyses for avelumab, a human immunoglobulin G1 monoclonal antibody that binds programmed cell death 1 ligand 1, to assess potential effects on cardiac repolarization. METHODS: Data were pooled from three-phase 1/2 studies of patients with advanced solid tumors who received avelumab monotherapy (22,000 ECGs from 1818 patients). All analyses used 12-lead singlet ECGs taken using local ECG machines before and approximately 2 h after avelumab infusion on prespecified days. The exposure-QTc and outlier analyses used locally read ECGs; since larger variability is known to be associated with local reading, outlier ECGs were subsequently reevaluated by central read. QTc derived from Fridericia's formula (QTcF) and a project-specific formula (QTcP) were analyzed. Multivariable linear mixed-effects models were used to describe the relationship between serum concentration of avelumab and QTc absolute value or change from baseline (ΔQTc). RESULTS: Exposure-QTc models showed that the effect of avelumab on QTc or ΔQTc was minimal and not statistically significant for both QTcP and QTcF. In addition, models including avelumab concentration and diphenhydramine premedication use did not show a clinically meaningful effect on the QT interval. The frequency of QTc outliers in both short and long ranges was overestimated by local reads. Six patients (0.3%) were QTc outliers; all had either received concomitant medication known to cause QT prolongation or had a preexisting cardiac condition. CONCLUSION: Avelumab does not have any clinically relevant effect on cardiac repolarization.

Trends in cervical squamous cell carcinoma incidence in 13 European countries: changing risk and the effects of screening.

Despite there being sufficient evidence for the effectiveness of screening by cytology in preventing cancer of the cervix uteri, screening policies vary widely among European countries, and incidence is increasing in younger women. This study analyzes trends in squamous cell carcinoma (SCC) of the cervix uteri in 13 European countries to evaluate effectiveness of screening against a background of changing risk. Age-period-cohort models were fitted and period and cohort effects were estimated; these were considered as primarily indicative of screening interventions and changing etiology, respectively. A unique set of estimates was derived by fixing age slopes to one of several plausible age curves under the assumption that the relation between age and cervical cancer incidence is biologically determined. There were period-specific declines in cervical SCC in several countries, with the largest decreases seen in northern Europe. A pattern emerged across Europe of escalating risk in successive generations born after 1930. In the western European countries, a decrease followed by a stabilization of risk by cohort was accompanied by period-specific declines. In southern Europe, stable period, but increasing cohort trends, were observed. Substantial changes have occurred in cervical SCC incidence in Europe and well-organized screening programs have been highly effective in reducing the incidence of cervical SCC. Screening and changing sexual mores largely explain the changing period- and cohort-specific patterns, respectively. The increasing risk in recent cohorts is of obvious concern particularly in countries where no screening programs are in place. Further investigation of the effectiveness of opportunistic screening is warranted as is the observation of differing risk patterns in young cohorts in countries with relatively similar societal structures.

Microbiological quality of carbonated drinking water produced with in-home carbonation systems.

The microbiological quality of carbonated water produced with tap water in commercial in-home carbonation systems was determined, the results being discussed in the context of the microbiological quality of the tap water used, the properties of the drink makers, and the procedures of preparation and washing of various parts of the appliance. The last-mentioned data were received from each participant of the study by questionnaire. Escherichia coli, coliforms, fecal streptococci and spore-forming sulphite-reducing anaerobes were used as indicators for the hygienic quality of the water. Tap-water samples were collected according to the usual procedure when filling the carbonating bottle, i.e., without previous flushing and disinfection of the faucet. In 12% of tap-water samples, coliforms could be detected. On the other hand, in 20 of 52 carbonated waters (39%), coliforms as indicators of water pollution were found. By means of fecal streptococci and Pseudomonas aeruginosa, it was possible to establish additional contamination not involving E. coli or coliforms alone. Analysis revealed that, in addition to contaminated tap water, a bacterial biofilm on the inner surface of the re-usable bottles had a predominant influence on the microbiological quality of the carbonated water.

Reduced incidence of infusion-related reactions in metastatic colorectal cancer during treatment with cetuximab plus irinotecan with combined corticosteroid and antihistamine premedication.

BACKGROUND: : The multinational MABEL study of 1147 patients with metastatic colorectal cancer (mCRC) who had recently failed an irinotecan-containing regimen confirmed in a community practice setting the efficacy and safety of cetuximab combined with irinotecan. METHODS: : This report describes a post hoc analysis of the influence of prophylactic premedication on the incidence of infusion-related reactions (IRRs) in the MABEL study. The analysis was focused on the subpopulation of patients premedicated with antihistamines either with (n = 700) or without (n = 422) corticosteroids. Stepwise Cox regression modeling was used to examine the explanatory value of the type of premedication on progression-free survival (PFS) and overall survival (OS) times. RESULTS: : The incidence of IRRs was lower in the group of patients who received antihistamine plus corticosteroid (9.6%) compared with those who received antihistamine alone (25.6%). A similar trend was seen for grade 3 or 4 IRRs (1.0% vs 4.7%, respectively). The 12-week PFS rates (61% vs 60%), median PFS (16.1 vs 13.1 weeks) and OS (9.2 vs 9.0 months) times for patients who received, respectively, antihistamines with and without corticosteroids were similar. Cox regression modeling did not identify any impact of type of premedication used (antihistamine with or without corticosteroids) on the efficacy of treatment in relation to PFS or OS. CONCLUSIONS: : Prophylactically premedicating mCRC patients with both antihistamine and a corticosteroid appeared to reduce the frequency of cetuximab-associated IRRs. Given that this was a post hoc analysis, caution must be exercised in the interpretation of these data, which require formal confirmation in a randomized study. Cancer 2010. (c) 2010 American Cancer Society.

Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer.

PURPOSE: This randomized study assessed whether the best overall response rate (ORR) of cetuximab combined with oxaliplatin, leucovorin, and fluorouracil (FOLFOX-4) was superior to that of FOLFOX-4 alone as first-line treatment for metastatic colorectal cancer. The influence of KRAS mutation status was investigated. PATIENTS AND METHODS: Patients received cetuximab (400 mg/m(2) initial dose followed by 250 mg/m(2)/wk thereafter) plus FOLFOX-4 (oxaliplatin 85 mg/m(2) on day 1, plus leucovorin 200 mg/m(2) and fluorouracil as a 400 mg/m(2) bolus followed by a 600 mg/m(2) infusion during 22 hours on days 1 and 2; n = 169) or FOLFOX-4 alone (n = 168). Treatment was continued until disease progression or unacceptable toxicity. KRAS mutation status was assessed in the subset of patients with assessable tumor samples (n = 233). RESULTS: The confirmed ORR for cetuximab plus FOLFOX-4 was higher than with FOLFOX-4 alone (46% v 36%). A statistically significant increase in the odds for a response with the addition of cetuximab to FOLFOX-4 could not be established (odds ratio = 1.52; P = .064). In patients with KRAS wild-type tumors, the addition of cetuximab to FOLFOX-4 was associated with a clinically significant increased chance of response (ORR = 61% v 37%; odds ratio = 2.54; P = .011) and a lower risk of disease progression (hazard ratio = 0.57; P = .0163) compared with FOLFOX-4 alone. Cetuximab plus FOLFOX-4 was generally well tolerated. CONCLUSION: KRAS mutational status was shown to be a highly predictive selection criterion in relation to the treatment decision regarding the addition of cetuximab to FOLFOX-4 for previously untreated patients with metastatic colorectal cancer.

Cetuximab plus irinotecan in heavily pretreated metastatic colorectal cancer progressing on irinotecan: MABEL Study.

PURPOSE: This large, multinational study aimed to confirm in a community practice setting the efficacy and safety of cetuximab plus irinotecan in patients with epidermal growth factor-expressing metastatic colorectal cancer (mCRC) who had recently failed an irinotecan-containing regimen. PATIENTS AND METHODS: The primary objective was to determine the progression-free survival (PFS) rate at 12 weeks. The initial cetuximab dose was 400 mg/m(2) and was followed weekly by 250 mg/m(2); irinotecan (according to prestudy regimen) was given weekly (125 mg/m(2) weekly for 4 of 6 weeks), every 2 weeks (180 mg/m(2) each), or every 3 weeks (350 mg/m(2) each). RESULTS: The intention-to-treat/safety population comprised 1,147 treated patients who received irinotecan weekly (n = 93); every 2 weeks (n = 670); every 3 weeks (n = 356); or another dose (n = 28). The PFS rate at 12 weeks was 61%, and the median survival was 9.2 months. Treatment was generally well tolerated. The most common treatment-related grades 3 to 4 adverse events were diarrhea (19%), neutropenia (10%), rash (7%), and asthenia (6%). The rate of grades 3 to 4 infusion-related reactions (IRRs; composite adverse event category) was 1% for patients who received both antihistamine and corticosteroid premedication. CONCLUSION Tolerability (except IRR incidence), PFS rate, and overall survival rate were in line with previous results. At 1%, the rate of IRRs in patients who received prophylactic premedication with both antihistamine and corticosteroid is lower than previously reported. MABEL clearly confirms in a community practice setting the efficacy and safety of cetuximab plus irinotecan in the treatment of mCRC.

Geographic and temporal variations in cancer of the corpus uteri: incidence and mortality in pre- and postmenopausal women in Europe.

Corpus uteri cancer is the fourth most common neoplasm in women in Europe and the tenth most common cause of cancer death. We examined geographic and temporal variations in corpus uteri cancer incidence and mortality rates in the age groups 25-49 and 50-74 in 22 European countries. The disease is considerably less common in premenopausal women, with incidence and mortality rates decreasing throughout Europe and mortality declines more marked in western and southern European countries. Incidence rates among postmenopausal women are highest in the Czech Republic, Slovakia, Sweden and Slovenia and lowest in France and the United Kingdom. Increasing incidence trends in this age group are observed in the Nordic countries (except Denmark) and in the United Kingdom. Some increases are also seen in eastern (Slovakia) and southern Europe (Spain and Slovenia), while relatively stable or modestly decreasing trends are observed in Italy and most western European countries. Postmenopausal mortality rates are systematically higher in eastern Europe, with death rates in the Ukraine, Latvia, Czech Republic, Russia and Belarus 2-3 times those seen in western Europe. Declining mortality trends are seen in most populations, though in certain Eastern European countries, the declines began rather recently, during the 1980s. In Belarus and Russia, recent postmenopausal death rates are stable or increasing. The rates are adjusted for misclassification of uterine cancer deaths but remain unadjusted for hysterectomy, and where there is an apparent levelling off of incidence or mortality rates recently, rising prevalence of hysterectomy cannot be discounted as an explanation. However, the trends by age group can be viewed in light of several established risk factors for endometrial cancer that are highly prevalent and most likely changing with time. These are discussed, as are the prospects for preventing the disease.