Bemarituzumab in patients with FGFR2b-selected gastric or gastro-oesophageal junction adenocarcinoma (FIGHT): a randomised, double-blind, placebo-controlled, phase 2 study.

BACKGROUND: Outcomes are poor in patients with HER2-negative, advanced gastric or gastro-oesophageal junction adenocarcinomas. In this study, we investigated efficacy and safety of the first-in-class, afucosylated, humanised IgG1 anti-fibroblast growth factor receptor 2 isoform IIb (FGFR2b) monoclonal antibody bemarituzumab with modified 5-fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) in patients with FGFR2b-selected gastric or gastro-oesophageal junction adenocarcinoma. METHODS: In the randomised, double-blind, placebo-controlled phase 2 trial (FIGHT), patients aged 18 years and older with HER2 non-positive, FGFR2b-selected gastric or gastro-oesophageal junction adenocarcinoma, and an Eastern Cooperative Oncology Group performance status of 0-1 were recruited from 144 clinical sites across 17 countries. Patients with previous treatment with any selective inhibitor of the FGF-FGFR pathway were excluded. Eligible patients were randomly assigned (1:1), using permuted-block randomisation (block size of four) and a central interactive voice-web-based response system, stratified by geographical region, previous treatment with curative intent, and administration of mFOLFOX6 while being screened for FGFR2b status, to either bemarituzumab (15 mg/kg of bodyweight) or matched placebo intravenously every 2 weeks. All patients also received mFOLFOX6 (oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, and 5-fluorouracil as a 400 mg/m2 bolus followed by 2400 mg/m2 over approximately 46 h) intravenously every 2 weeks. Patients were given treatment until disease progression (defined by Response Evaluation Criteria in Solid Tumours [RECIST] version 1.1), unacceptable toxicity, withdrawal of consent, or death. The primary endpoint was progression-free survival in the intention-to-treat population (defined as all patients randomly assigned to treatment). Safety was assessed in all patients who received at least one dose of assigned treatment. This study is registered with ClinicalTrials.gov, NCT03694522, and is now complete. FINDINGS: Between Nov 14, 2017, and May 8, 2020, 910 patients were screened and 155 were randomly assigned to the bemarituzumab (n=77) or placebo group (n=78). Median age was 60·0 years (IQR 51·0-67·0), 44 (28%) participants were women, 111 (72%) were men, 89 (57%) were Asian, and 61 (39%) were White. At the time of the primary analysis and at a median follow-up of 10·9 months (IQR 6·3-14·2), median progression-free survival was 9·5 months (95% CI 7·3-12·9) in the bemarituzumab group and 7·4 months (5·8-8·4) in the placebo group (hazard ratio [HR] 0·68 [95% CI 0·44-1·04; p=0·073). Common grade 3 or worse adverse events were decreased neutrophil count (23 [30%] of 76 in the bemarituzumab group vs 27 [35%] of 77 in the placebo group), cornea disorder (18 [24%] vs none), neutropenia (ten [13%] vs seven [9%]), stomatitis (seven [9%] vs one [1%]), and anaemia (six [8%] vs ten [13%]). Serious treatment-emergent adverse events were reported in 24 (32%) patients in the bemarituzumab group and 28 (36%) in the placebo group. Serious mFOLFOX6 treatment-related adverse events occurred in nine (12%) patients in the bemarituzumab group and in 15 (19%) patients in the placebo group. All-grade corneal events (adverse events of special interest) occurred in 51 (67%) patients in the bemarituzumab group and eight (10%) in the placebo group; grade 3 corneal events were reported only in 18 (24%) patients in the bemarituzumab group. Treatment-related deaths occurred in three patients in the bemarituzumab group (two due to sepsis, one due to pneumonia) and none in the placebo group. INTERPRETATION: In this exploratory phase 2 study, despite no statistically significant improvement in progression-free survival, treatment with bemarituzumab showed promising clinical efficacy. Confirmatory phase 3 trials of bemarituzumab plus mFOLFOX6 powered to demonstrate statistical significance are being investigated in patients with previously untreated, FGFR2b-overexpressing, advanced gastric or gastro-oesophageal junction adenocarcinoma. FUNDING: Five Prime Therapeutics.

Phase 1 dose-escalation study of momelotinib, a Janus kinase 1/2 inhibitor, combined with gemcitabine and nab-paclitaxel in patients with previously untreated metastatic pancreatic ductal adenocarcinoma.

Purpose Preclinical evidence suggests the importance of Janus activating kinase (JAK) and TANK-binding kinase 1 (TBK1) in pancreatic ductal adenocarcinoma (PDAC). We evaluated the safety and efficacy of momelotinib (MMB), a JAK1/2 inhibitor with additional activity against TBK1, plus albumin-bound paclitaxel + gemcitabine (nab-P + G), in patients with previously untreated metastatic PDAC. Experimental Design Patients were enrolled into five cohorts of increasing doses of MMB between 100 and 200 mg administered once or twice daily in combination with nab-P + G in 28-day cycles to determine maximum tolerated dose (MTD). Safety, efficacy, pharmacokinetics, and pharmacodynamics were assessed for all patients. Results Twenty-five patients were enrolled. Dose-limiting toxicities of Grade 3 diarrhea occurred in 1 patient each in the 100 and 200 mg MMB once-daily dose groups. MTD was not reached. The 200 mg MMB twice-daily was the maximum administered dose. Objective response rate was 28% (all partial responses), and 13 (52%) patients had a best response of stable disease. The most common adverse events (AEs) were fatigue (80%), nausea (76%), and anemia (68%). Grade 3 or 4 AEs, most commonly neutropenia (32%), were reported by 88% of patients, of which 44% were considered related to MMB. Pharmacokinetic analyses showed MMB concentrations were too low for TBK1 inhibition. Conclusions MMB was safe and well tolerated in combination with nab-P + G. As no OS or PFS benefit vs nab-P + G was apparent in context of suboptimal engagement of the target TBK1, this study does not support further development of MMB as a first-line therapy in pancreatic cancer.

Effects of health-related quality of life on health service utilisation in patients with colorectal neoplasms.

This study was to assess the impact of HRQOL on health service utilisation using four different count data models. The HRQOL was measured using the Short-Form Six-Dimension instrument and the functional assessment of cancer therapy-colorectal whereas health service utilisation was measured by the number of monthly clinical consultations and the number of monthly hospitalisation. Different count data models (Poisson's regression, negative binomial regression, zero-inflated Poisson's regression and zero-inflated negative binomial regression) were used to assess the association between HRQOL and health service utilisation. A performance comparison was made between the models. Goodness-of-fit statistics (the Pearson's chi-squared test statistic, the Akaike and Bayesian information criteria) were used to determine the best-fitting model. The negative binomial model performed the best in assessing the association between HRQOL measures and health service utilisation in patients with colorectal neoplasm and thus recommended. Physical well-being of patients was negatively and significantly associated with the monthly rate of health service utilisation after controlling for patient demographics. Both physical and function well-beings of patients were negatively and significantly associated with the number of monthly hospitalisations. If the data for the condition-specific FACT-C are not available, SF-6D showed a very strong negative relationship with health service utilisation. Such models can be used to guide the allocation of clinical resources and funding for the care of colorectal cancer patients.

A Phase II, Randomized, Double-Blind, Placebo-Controlled Study of Simtuzumab in Combination with FOLFIRI for the Second-Line Treatment of Metastatic KRAS Mutant Colorectal Adenocarcinoma.

LESSONS LEARNED: The safety profile in the patient groups who received FOLFIRI and simtuzumab did not differ from that in the FOLFIRI and placebo group.The addition of simtuzumab to chemotherapy with FOLFIRI does not improve clinical outcomes in patients with metastatic KRAS mutant colorectal carcinoma. BACKGROUND: Simtuzumab, a humanized IgG4 monoclonal antibody to lysyl oxidase-like 2 (LOXL2), blocks desmoplastic reaction in colorectal carcinoma (CRC) cells in vitro. METHODS: Patients with metastatic Kirsten rat sarcoma viral oncogene homolog (KRAS) mutant CRC were randomized to receive second-line 5-fluorouracil, leucovorin, and irinotecan (FOLFIRI) with either 200 or 700 mg simtuzumab or placebo every 2 weeks in cycles of 28 days. Progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and safety were assessed. RESULTS: In total, 249 patients were randomized and treated with FOLFIRI/simtuzumab 700 mg (n = 84), FOLFIRI/simtuzumab 200 mg (n = 85), and FOLFIRI/placebo (n = 80). After a median follow-up of 5.1, 3.8, and 5.5 months, respectively, median PFS for each of the respective treatment groups was 5.5 months (adjusted HR [95% CI], p value versus placebo; 1.32 [0.92, 1.89]; p = .10), 5.4 months (1.45 [1.01, 2.06]; p = .04), and 5.8 months. Median OS was 11.4 months (1.23 [0.80, 1.91]; p = .25), 10.5 months (1.50 [0.98, 2.30]; p = .06), and 16.3 months, respectively. ORR was 11.9%, 5.9%, and 10%, respectively. Simtuzumab was tolerable in metastatic KRAS mutant CRC patients. CONCLUSION: The addition of simtuzumab to FOLFIRI did not improve clinical outcomes in patients with metastatic KRAS mutant CRC. The Oncologist 2017;22:243-e8.

Tests for detecting overdispersion in models with measurement error in covariates.

Measurement error in covariates can affect the accuracy in count data modeling and analysis. In overdispersion identification, the true mean-variance relationship can be obscured under the influence of measurement error in covariates. In this paper, we propose three tests for detecting overdispersion when covariates are measured with error: a modified score test and two score tests based on the proposed approximate likelihood and quasi-likelihood, respectively. The proposed approximate likelihood is derived under the classical measurement error model, and the resulting approximate maximum likelihood estimator is shown to have superior efficiency. Simulation results also show that the score test based on approximate likelihood outperforms the test based on quasi-likelihood and other alternatives in terms of empirical power. By analyzing a real dataset containing the health-related quality-of-life measurements of a particular group of patients, we demonstrate the importance of the proposed methods by showing that the analyses with and without measurement error correction yield significantly different results.

Improving the mapping of condition-specific health-related quality of life onto SF-6D score.

BACKGROUND: This study sought to improve the predicative performance and goodness-of-fit of mapping models, as part of indirect valuation, by introducing cubic spline smoothing to map a group of health-related quality of life (HRQOL) measures onto a preference-based measure. METHODS: This study was a secondary analysis of a cross-sectional health survey data assessing the HRQOL for patients with colorectal neoplasms. Mapping functions of condition-specific functional assessment of cancer therapy-colorectal (FACT-C) onto preference-based SF-6D measure were developed using a dataset of 553 Chinese subjects with different stages of colorectal neoplasm. The missing values of FACT-C were imputed using multiple imputation. Then three widely applicable models (ordinary least square (OLS), Tobit and two-part models) were employed for the mapping function after applying the cubic spline smoothing on the data. For the evaluation of the effectiveness of cubic spline smoothing and multiple imputation, the goodness-of-fit and prediction performance of each model were compared. RESULTS: Analyses showed that the models fitted with transformed data from cubic spline smoothing offered better performance in goodness-of-fit and prediction than the models fitted with the original data. The values of [Formula: see text] were improved by over 10%, and the root mean square error and the mean absolute error were both reduced. The best goodness-of-fit and performance were achieved by OLS model using transformed data from cubic spline smoothing. CONCLUSIONS: Cubic spline smoothing and multiple imputation were recommended for the mapping of HRQOL measures onto the preference-based measure. Among the three mapping models, the simple-to-use OLS model had the best performance.

Relationship Between Negative Life Events and Depressive Symptoms for Chinese College Students: The Mediating Role of Rumination and Moderating Role of Perceived Social Support and Psychological Capital.

Objective: External events affect individuals through their cognitive process, a model on how and when negative life events are associated with depressive symptoms was tested by considering individuals' internal and external factors based on the conservation of resource theory (COR). Methods: We conducted a survey to test our hypotheses. Participants were college students who were selected with the cluster sampling method and were asked to complete the scales measuring negative life events, perceived social support, psychological capital (PsyCap), rumination, and depressive symptoms in the classroom with a unit of class. A total of 764 questionnaires were distributed and returned, and 703 valid data were obtained finally. Results: The present study found that (1) the relationship between negative life events and depressive symptoms was moderated by perceived social support negatively, such that the relationship was stronger with low perceived social support; (2) the relationship between negative life events and depressive symptoms was mediated by rumination; (3) the relationship between rumination and depressive symptoms was moderated by PsyCap negatively, such that the relationship was stronger with low PsyCap; (4) the indirect relationship between negative life events and depressive symptoms through rumination was moderated by PsyCap negatively, such that the indirect relationship got stronger with low PsyCap. Conclusion: Rumination is an essential process for negative life events to affect depressive symptoms, PsyCap and perceived social support help alleviate the detrimental effect of negative life events from internal and external perspectives, respectively. Our research conclusion has a theoretical and practical implementation for reducing depressive symptoms in college students.

Nomograms for Predicting Hepatocellular Carcinoma Recurrence and Overall Postoperative Patient Survival.

Background: Few studies have focused on the prognosis of patients with hepatocellular carcinoma (HCC) of Barcelona Clinic Liver Cancer (BCLC) stage 0‒C in terms of early recurrence and 5-years overall survival (OS). We sought to develop nomograms for predicting 5-year OS and early recurrence after curative resection of HCC, based on a clinicopathological‒radiological model. We also investigated whether different treatment methods influenced the OS of patients with early recurrence. Methods: Retrospective data, including clinical pathology, radiology, and follow-up data, were collected for 494 patients with HCC who underwent hepatectomy. Nomograms estimating OS and early recurrence were constructed using multivariate Cox regression analysis, based on the random survival forest (RSF) model. We evaluated the discrimination and calibration abilities of the nomograms using concordance indices (C-index), calibration curves, and Kaplan‒Meier curves. OS curves of different treatments for patients who had recurrence within 2 years after curative surgery were depicted and compared using the Kaplan-Meier method and the log-rank test. Results: Multivariate Cox regression revealed that BCLC stage, non-smooth margin, maximum tumor diameter, age, aspartate aminotransferase levels, microvascular invasion, and differentiation were prognostic factors for OS and were incorporated into the nomogram with good predictive performance in the training (C-index: 0.787) and testing cohorts (C-index: 0.711). A nomogram for recurrence-free survival was also developed based on four prognostic factors (BCLC stage, non-smooth margin, maximum tumor diameter, and microvascular invasion) with good predictive performance in the training (C-index: 0.717) and testing cohorts (C-index: 0.701). In comparison to the BCLC staging system, the C-index (training cohort: 0.787 vs. 0.678, 0.717 vs. 0.675; external cohort 2: 0.748 vs. 0.624, 0.729 vs. 0.587 respectively, for OS and RFS; external cohort1:0.716 vs. 0.627 for RFS, all p value<0.05), and model calibration curves all showed improved performance. Patients who underwent surgery after tumor recurrence had a higher reOS than those who underwent comprehensive treatments and supportive care. Conclusions: The nomogram, based on clinical, pathological, and radiological factors, demonstrated good accuracy in estimating OS and recurrence, which can guide follow-up and treatment of individual patients. Reoperation may be the best option for patients with recurrence in good condition.