Betel-nut chewing does not influence PD-L1 expression rates in recurrent/metastatic head and neck squamous cell carcinoma (HNSCC): A prospective biomarker prevalence study.

This study explored the relationship between betel-nut chewing and programmed death-ligand 1 (PD-L1) expression in recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) patients in Taiwan. A total 280 R/M HNSCC patients, predominantly male, were evaluated; 75.4 % of whom chewed betel-nut. The prevalence of PD-L1 expression (combined positive score ≥1) was 94.3 % with similar PD-L1 expression rates between betel-nut-exposed and non-exposed groups. PD-L1 prevalence did not differ in those who received prior first-or second-line systemic therapy. In summary, betel-nut exposure did not notably affect PD-L1 expression rates in R/M HNSCC patients in Taiwan.

Treatment Patterns and Health Resource Utilization in Patients With HR+/ HER2- Locally Advanced or Metastatic Breast Cancer in a Real-World Setting in Taiwan.

OBJECTIVES: This study aimed to understand current treatment patterns and healthcare resource utilization (HRU) of women with locally advanced or metastatic breast cancer (advanced breast cancer [ABC]) in Taiwan overall and within the subgroup of patients who were postmenopausal women with no previous systemic therapy in the ABC setting. METHODS: A chart review of anonymized data on patient characteristics, treatment patterns, and HRU was conducted via an online physician survey including 118 patient charts from women ≥ 18 years old with hormone receptor positive/human epidermal growth receptor negative ABC, diagnosed between 2015 and 2017. RESULTS: The mean age of all patients was 56.6 years (range 29-83). Among the 118 patients, the most common first-line systemic therapy group after diagnosis of ABC was endocrine-based therapy (39.0%) or endocrine therapy (ET) plus chemotherapy (ChT) combinations (38.1%). In the postmenopausal subgroup (n = 56), ET-based therapy was the most common (44.6%). Oncologist visits, at annual rate of 9.20 (95% confidence interval 8.81-9.60), and hospitalizations, at annual rate of 1.08 (95% confidence interval 0.96-1.22), were key drivers of HRU. Of the 118 patients, the 72 with at least one ChT agent in their first-line regimen had an annual hospitalization rate of 1.4 versus 0.45 admissions compared with the 46 patients on first-line ET-based therapy. CONCLUSIONS: Current treatment patterns suggest an unmet need for new medications that lead to reduction in high rate of ChT use. Results can inform future evaluations of new ABC treatments that estimate the health economic impact of their adoption in Taiwan.

Second-line treatment of advanced hepatocellular carcinoma: Time for more individualized treatment options?

Hepatocellular carcinoma (HCC) is the most frequently diagnosed primary tumor of the liver and is usually detected as advanced disease. It is an aggressive disease that often progresses rapidly when it fails to respond to treatment. As such, patients have limited opportunities to try different subsequent-line treatment regimens. In the last 5 years, the number of agents and/or regimens available for the treatment of advanced HCC has significantly increased, which has made treatment choices for this patient population increasingly complex. In the second-line setting, several phase III trials of regorafenib (RESORCE), ramucirumab (REACH/REACH-2), and cabozantinib (CELESTIAL) have demonstrated clinically meaningful survival benefits in patients with the disease. However, the median overall survival of patients with advanced HCC remains unchanged at approximately 12 mo from the start of systemic second-line therapy, with a limited duration of response. Evidence from the REACH/REACH-2 trials demonstrated for the first time that baseline alpha-fetoprotein (AFP) levels can be used as an identification factor to select those who are likely to benefit the most from ramucirumab treatment. Ramucirumab is both well tolerated and efficacious and has a clinically acceptable safety profile. Therefore, it should be considered an option for patients with AFP levels ≥ 400 ng/mL.

Treatment Patterns and Health Resource Utilization in Patients With Hepatocellular Carcinoma After Failure of Sorafenib in Real-World Setting in Taiwan.

OBJECTIVES: This study aimed to characterize current treatment patterns and healthcare resource utilization (HRU) observed among patients with hepatocellular carcinoma (HCC) after the failure of sorafenib in real-world setting in Taiwan. METHODS: A chart review was conducted in 130 patients; the inclusion criteria were patients with HCC who were aged 20 years or older and had received systemic therapy or best supportive care after failure of first-line systemic treatment with sorafenib between 2016 and 2018. Anonymized data on patient characteristics, treatment pathways, and survival were abstracted. RESULTS: The mean age of patients was 61.7 years (range 27-84); of these 130 patients, 103 (79%) were male, 81 (62%) had high alpha-fetoprotein (AFP) levels (≥400 ng/mL), and 96 (78.0%) were deceased at the time of data abstraction. After sorafenib therapy, 60 patients (46%) received systemic therapy, including nivolumab monotherapy (42%) and chemotherapy (25%). Oncologist visits at a semiannual per-patient rate of 3.7 (95% confidence interval [CI] 3.4-4.0) and hospitalizations at rate of 1.1 (95% CI 1.0-1.3) were the key contributors to HRU. Semiannual per-patient hospitalization rate was 1.3 (95% CI 1.1-1.5) in the high-AFP group. Median survival from discontinuation of sorafenib was 6.9 months (95% CI 5.9-9.0). CONCLUSIONS: This real-world evidence research on treatment patterns reflected substantial HRU consistent with the severity of HCC, particularly in the high-AFP group. Findings highlighted continuing high mortality in HCC, underlying a need for new treatments that can lengthen survival. Results can inform future evaluations of new HCC treatments that estimate the health economic impact of their adoption in Taiwan.

Patient Perspectives on Health-Related Quality of Life in Diffuse Large B-Cell Lymphoma Treated with Car T-Cell Therapy: A Qualitative Study.

INTRODUCTION: Chimeric antigen receptor T-cell (CAR T) therapy offers a potentially curative option for patients with relapsed and refractory hematologic malignancies, including diffuse large B-cell lymphoma (DLBCL). Patient-reported experiences with CAR T therapy are limited and have not been well characterized. The purpose of this qualitative study was to explore patient descriptions of key domains of health-related quality of life (HRQoL) in DLBCL patients treated with CAR T therapy. METHODS: A targeted literature review was initially conducted to inform the development of the interview guide comprising predetermined open-ended questions. Two focus groups were conducted with a total of 18 patients with DLBCL identified from patient advisory boards. Focus group sessions were recorded and transcribed verbatim. MAXQDA 18.2.0 qualitative data analysis software was utilized to facilitate a constant-comparative coding process to identify key concepts. RESULTS: Eight domain impairments (social functioning, emotional functioning, fatigue, physical functioning, cognitive functioning, role functioning, sleep, and pain/discomfort) were identified from the qualitative analysis and endorsed by DLBCL patients treated with CAR T. Compared with before CAR T therapy, patients reported increased impairment in every domain during or immediately after CAR T therapy. This impairment improved for each domain 6 months after CAR T therapy except for pain/discomfort. Compared with before CAR T therapy, improvement in impairment for each domain was observed 6 months after CAR T therapy except for fatigue, sleep, and pain/discomfort. CONCLUSION: This study provides meaningful information regarding the impact of CAR T therapy on HRQoL in patients with DLBCL throughout their treatment journey. Health care professionals and investigators can utilize these data in examining existing patient-reported outcome (PRO) measures that are used in DLBCL clinical trials and to better understand the needs of DLBCL survivors.

An Overview of the Treatment Efficacy and Side Effect Profile of Pharmacological Therapies in Asian Patients with Breast Cancer.

Breast cancer (BC) among Asians accounts for ~ 40% of the global BC burden. Differences in BC risk, presentation, tumor biology, and response to treatment exist between Asian and non-Asian patients; however, Asian patients are often under-represented in clinical trials. This narrative review summarizes the efficacy and safety of pharmacological therapies for BC in Asian populations, with a focus on outcomes in Asian versus non-Asian patients treated with chemotherapy, hormone therapy, anti-human epidermal growth factor receptor-2 targeted therapies, cyclin-dependent kinase 4/6 (CDK4/6) inhibitors, mammalian target of rapamycin inhibitors, bone-targeted therapies, poly-ADP ribose polymerase, phosphoinositide 3-kinase, and checkpoint inhibitors. While most therapies have demonstrated comparable efficacy and safety in Asian and non-Asian patients with BC, differences that are largely attributed to pharmacogenetic variations between populations exist. Pharmacogenetic differences may contribute to a reduced clinical benefit of tamoxifen, whereas improved clinical outcomes have been reported with tyrosine kinase inhibitors and CDK4/6 inhibitors in Asian versus non-Asian patients with BC. In particular, Asian patients have an increased incidence of hematological toxicities, including neutropenia, although adverse events can be effectively managed using dose adjustments. Recent trials with CDK4/6 inhibitors have increased efforts to include Asians within study subsets. Future clinical trials enrolling higher numbers of Asian patients, and an increased understanding of differences in patient and tumor genetics between Asians and non-Asians, have the potential to incrementally improve the management of BC in Asian patients.

How May Ramucirumab Help Improve Treatment Outcome for Patients with Gastrointestinal Cancers?

GI cancers are characterized by high recurrence rates and a dismal prognosis and there is an urgent need for new therapeutic approaches. This is a narrative review designed to provide a summary of the efficacy as measured by overall survival, progression free survival, and safety data from phase 3 randomized controlled GI clinical trials of ramucirumab including those from important pre-specified patient subgroups and evidence from real clinical practice worldwide. Quality of life (QOL) is discussed where data are available. Our aim was to summarize the efficacy and safety of ramucirumab in the treatment of GI cancers using these existing published data with a view to demonstrating how ramucirumab may help improve treatment outcome for patients with GI cancers. The data indicate that ramucirumab is efficacious, safe, and tolerable across the intent-to-treat patient populations as a whole and across several pre-specified subgroups, even those whose disease is traditionally more difficult to treat. Furthermore, survival outcomes observed in real-world clinical practice demonstrate similar data from phase 3 clinical trials even in patients with complications, suggesting that the benefits of ramucirumab translate in actual clinical practice.

Safety and Preliminary Efficacy of Ramucirumab in Combination with FOLFOX4 in Patients with Advanced Hepatocellular Carcinoma: A Nonrandomized, Open-Label, Phase Ib Study.

LESSONS LEARNED: The combination of ramucirumab (8 mg/kg intravenous, day 1 every 2 weeks) and FOLFOX4 as first-line treatment in patients with advanced hepatocellular carcinoma (HCC) was not sufficiently tolerated. Preliminary efficacy data suggest that the combination may provide clinical benefit to patients with HCC. Dose modification and patient selection should be considered for the future development of ramucirumab plus FOLFOX chemotherapy for advanced HCC. BACKGROUND: The objective of this study was to investigate the safety, preliminary efficacy, pharmacokinetics, and immunogenicity of ramucirumab plus FOLFOX4 as first-line treatment in patients with advanced hepatocellular carcinoma (HCC). METHODS: Patients received ramucirumab (8 mg/kg) intravenously (IV) on day 1, followed by FOLFOX4 (oxaliplatin 85 mg/m2 IV on day 1, folinic acid 200 mg/m2 IV, bolus fluorouracil [5-FU] 400 mg/m2 , and a continuous infusion of 5-FU 600 mg/m2 over 22 hours, on days 1 and 2) every 2 weeks. The primary endpoint was to assess the safety and tolerability of the combination therapy. RESULTS: Eight patients (6 men, 2 women) were treated; all eight patients experienced at least one treatment-emergent adverse event (TEAE) of grade ≥3. Dose-limiting toxicities occurred in three patients (37.5%): hepatic hemorrhage (grade 4), blood bilirubin increased (grade 3), and febrile neutropenia (grade 3). Two patients discontinued study because of hepatic hemorrhage (grade 4) and blood bilirubin increase (grade 3). Six deaths occurred due to progressive disease, and no deaths due to TEAEs. CONCLUSION: There were no unexpected safety findings with ramucirumab plus FOLFOX4 based on the known safety and toxicity of this regimen. The combination was not sufficiently tolerated in patients with advanced HCC at the specified dose and schedule.

Efficacy and Safety of Ramucirumab in Asian and Non-Asian Patients with Advanced Hepatocellular Carcinoma and Elevated Alpha-Fetoprotein: Pooled Individual Data Analysis of Two Randomized Studies.

OBJECTIVE: REACH-2 and REACH were randomized, placebo-controlled, double-blind, multicenter phase 3 trials which showed survival benefits of ramucirumab treatment in patients with advanced hepatocellular carcinoma (HCC) and elevated alpha-fetoprotein (AFP). We evaluated the efficacy and safety of ramucirumab in Asian and non-Asian patients with AFP ≥400 ng/mL from REACH-2 and REACH. METHODS: We pooled Asian and non-Asian patients from the REACH-2 and REACH trials and performed an individual patient data meta-analysis. Overall survival (OS) and progression-free survival were evaluated using the Kaplan-Meier method. Hazard ratios (HRs) were estimated with a stratified Cox regression model. RESULTS: In the pooled REACH-2 and REACH patient population, 291 Asian patients were randomly assigned to receive ramucirumab (n = 168) or placebo (n = 123), and 251 non-Asian patients received ramucirumab (n = 148) or placebo (n = 103). The median OS was significantly longer in the ramucirumab arm in comparison to the placebo arm for Asian patients (8.08 vs. 4.76 months, stratified HR 0.73 [95% CI 0.56-0.95], p = 0.0189) and non-Asian patients (7.98 vs. 5.22 months, stratified HR 0.65 [95% CI 0.49-0.86], p = 0.0028). The overall response rate (ORR) and disease control rate (DCR) were significantly higher in the ramucirumab arm compared to the placebo arm for Asian patients (ORR: 4.2 vs. 0.8%; DCR: 53.6 vs. 33.3%) and non-Asian patients (ORR: 6.8 vs. 1.0%; DCR: 59.5 vs. 41.7%). The most common grade ≥3 treatment-emergent adverse events reported in the ramucirumab arm were hypertension (7.7%), decreased appetite (1.2%), and ascites (1.2%) for Asian patients and hypertension (16.9%), ascites (8.8%), asthenia (4.7%), and fatigue (5.4%) for non-Asian patients. DISCUSSION AND CONCLUSION: This pooled analysis of the REACH-2/REACH trials demonstrates significant benefits, with a manageable safety profile, of ramucirumab treatment in Asian and non-Asian patients with advanced HCC and baseline AFP ≥400 ng/mL.

Does Pemetrexed Work in Targetable, Nonsquamous Non-Small-Cell Lung Cancer? A Narrative Review.

Pemetrexed is currently mainly considered for the treatment of advanced nonsquamous non-small-cell lung cancer (NSCLC) negative for gene mutations/rearrangements (wild-type disease (WTD)). This narrative review aimed to highlight the role of pemetrexed in the treatment of onco-driven nonsquamous advanced NSCLC by reviewing published clinical studies. For epidermal growth factor receptor (EGFR) mutations, patient survival following first-line pemetrexed-platinum was longer than for WTD. Later-line pemetrexed-based treatment after tyrosine kinase inhibitor (TKI) failure provided greater benefits than non-pemetrexed regimens. First- and later-line pemetrexed-based therapy also provided survival benefits in patients with anaplastic lymphoma kinase (ALK) or ROS proto-oncogene 1 (ROS1) rearrangements. In patients with rearranged during transfection (RET) proto-oncogene rearrangements, survival with pemetrexed was similar to that in ALK- and ROS1-positive patients and longer than that in patients with Kirsten rat sarcoma (KRAS) virus proto-oncogene mutations or WTD, although the available studies were limited. For Erb-b2 receptor tyrosine kinase 2 (ERRB2) mutations, first-line pemetrexed showed outcomes similar to those for EGFR and KRAS alterations. Data on pemetrexed in patients with KRAS mutations or MNNG HOS-transforming (MET) expression were limited. Pemetrexed could be an option for first- and second-line treatment for TKI failure in nonsquamous advanced NSCLC with select targetable driver mutations.

Ramucirumab in the second-line treatment of metastatic colorectal cancer: a narrative review of literature from clinical trials.

The development of new anti-angiogenic agents targeting the vascular endothelial growth factor (VEGF) and epidermal growth factor receptor pathways has greatly expanded the therapeutic options for patients with metastatic colorectal cancer (mCRC). Although these new agents have considerably improved survival outcomes compared with conventional chemotherapeutic regimens, the optimal integration of these drugs into the management of patients with mCRC continues to develop. One particular challenge is the identification of patient subgroups that will benefit from treatment with a specific targeted agent. In RAISE, a phase III randomized, placebo-controlled clinical trial, the VEGF receptor 2 antagonist ramucirumab in combination with fluorouracil plus leucovorin and irinotecan demonstrated efficacy as a second-line treatment for patients with mCRC. Ramucirumab is approved for the treatment of patients with mCRC in Taiwan but, due to lack of reimbursement, is often reserved for use as a third-line or later treatment. This narrative review of prespecified and post-hoc analyses of the RAISE study data, and data from other ramucirumab trials and real-world studies, summarizes the efficacy and tolerability of ramucirumab in the second-line treatment of different subpopulations of patients with mCRC. The aim was to identify patients most likely to benefit from treatment with second-line ramucirumab, with a view to illustrating the potential benefit of integrating this regimen into Taiwanese or Asian treatment practice.

Is ramucirumab and paclitaxel therapy beneficial for second-line treatment of metastatic gastric or junctional adenocarcinoma for patients with ascites? Analysis of RAINBOW phase 3 trial data.

PURPOSE: Second-line treatment with ramucirumab-paclitaxel has demonstrated statistically significant and clinically meaningful survival outcomes compared to paclitaxel-alone in patients with advanced gastric cancer (HR=0.807, 95% CI 0.678-0.962; P=0.017). Post hoc, exploratory analyses of RAINBOW patient data were performed to examine whether ascites impacted the efficacy and safety of ramucirumab-paclitaxel. PATIENTS AND METHODS: Patients were placed in with- or without-ascites subgroups based on baseline information collected on case report forms. The Kaplan-Meier method was used to estimate median progression-free survival (PFS) and overall survival (OS) of the ascites subgroups. HR and 95% CI were calculated using the Cox proportional hazards model. Survival distributions within the two arms in each ascites subgroup were compared using the log-rank test. RESULTS: There were 36% of RAINBOW trial patients (237/665) that had ascites at baseline (with-ascites subgroup); 64% of patients (428/665) had no baseline ascites (without-ascites subgroup). Most baseline characteristics were balanced. The with-ascites subgroup had a higher percentage of patients with peritoneal metastases (91% vs 23%) as expected. Overall survival for the with-ascites subgroup was worse than for the without-ascites subgroup (median OS for placebo-treated patients: 5.2 vs 8.5 months, respectively). However, OS treatment effects did not seem to differ significantly among patients with ascites (OS stratified HR=0.864, 95% CI=0.644-1.161; P=0.3362) vs those without ascites (OS stratified HR=0.745, 95% CI=0.593-0.936; P=0.0115). Similar results were observed for PFS. Ramucirumab treatment was associated with a greater incidence of all-grade vomiting for the with-ascites subgroup vs the without-ascites subgroup (ramucirumab arm: 39.2% vs 18.8%; placebo arm: 23.3% vs 19.5%, respectively). The incidence of adverse events of special interest was not elevated among the ramucirumab-treated ascites subgroup over the without-ascites subgroup. CONCLUSION: The benefit/risk profile of ramucirumab-paclitaxel remains favorable in patients with ascites and is consistent with the findings of the RAINBOW trial.

Ramucirumab Safety in East Asian Patients: A Meta-Analysis of Six Global, Randomized, Double-Blind, Placebo-Controlled, Phase III Clinical Trials.

Purpose Several ramucirumab trials have reported a higher incidence of selected adverse events (AEs) in East Asian (EA) patients with cancer versus non-EA patients. A meta-analysis was conducted across six completed phase III trials to establish the safety parameters of ramucirumab in EA compared with non-EA patients. Materials and Methods Six global, randomized, double-blind, placebo-controlled, phase III registration trials investigating ramucirumab were assessed. Relative risks (RRs) and 95% CIs were calculated for selected all-grade and grade ≥ 3 AEs using fixed-effects and mixed-effects models. Ratio of RR and number needed to harm were calculated for AEs (all grade and grade ≥ 3) between EA and non-EA patients. Results Of 4,996 randomly assigned patients receiving ramucirumab or placebo, 802 (16.1%) were EA (ramucirumab, n = 411; placebo, n = 391) and 4,194 were non-EA (ramucirumab, n = 2,337; placebo, n = 1,857). Patient baseline characteristics were generally balanced between treatment arms in EA and non-EA patients, excluding sex and body weight. Grade ≥ 3 AEs possibly associated with ramucirumab, which were increased in EA versus non-EA patients, included neutropenia (42.1% v 25.5%, respectively) and proteinuria (3.9% v 0.6%, respectively). There was an increase in the RR of several grade ≥ 3 AEs, including hypertension and proteinuria, in ramucirumab-treated EA and non-EA patients compared with placebo. The ratio of RR revealed no significant differences between EA and non-EA patients for all-grade and grade ≥ 3 AEs. Conclusion Despite the enhanced propensity of selected AEs in EA patients relative to non-EA patients, there were no substantial differences in the RR for AEs possibly associated with ramucirumab in these phase III trials.

Antiangiogenic therapy for patients with aggressive or refractory advanced non-small cell lung cancer in the second-line setting.

A majority of patients with advanced or metastatic non-small cell lung cancer (NSCLC) will experience disease progression after first-line therapy. Patients who have advanced NSCLC that is especially aggressive, which is defined as disease that rapidly progresses on first-line treatment or disease that is refractory to first-line treatment, have a critical unmet medical need. These patients have a poor prognosis in the second-line setting. Several studies have recently shown that treatment with an antiangiogenic therapy may benefit these patients. This review summarizes the approved antiangiogenic therapies for the treatment of patients with advanced NSCLC in the second-line setting, specifically focusing on the outcomes from subgroups of patients with rapidly progressing or refractory disease. Several antiangiogenic agents, as monotherapy or in combination with other treatments, have been or are currently being studied in patients with advanced NSCLC. Antiangiogenics that are approved for use in patients with advanced NSCLC are limited to bevacizumab in combination with chemotherapy (nonsquamous NSCLC), ramucirumab in combination with docetaxel (all histologies), and nintedanib in combination with docetaxel (adenocarcinoma histology). This review focuses on the efficacy, safety, and quality of life outcomes in the subpopulation of patients with rapidly progressing or refractory NSCLC treated with approved antiangiogenic therapies in the second-line setting. We also discuss the impact of newly approved immunotherapy agents on the outcomes of patients with aggressive or refractory disease. Studies in progress and planned future research will determine if combination treatment with antiangiogenics and immunotherapies will benefit patients with aggressive, advanced NSCLC.

Subgroup analysis of East Asian patients in REGARD: A phase III trial of ramucirumab and best supportive care for advanced gastric cancer.

AIM: We describe a subgroup analysis assessing the efficacy and safety of ramucirumab monotherapy in East Asian (EA) patients from the REGARD trial. METHODS: Patients with advanced gastric or gastroesophageal junction adenocarcinoma with progressive disease were randomized 2:1 to receive ramucirumab (8 mg/kg) plus best supportive care (BSC) or placebo plus BSC every 2 weeks. Post hoc subset analyses were performed on the EA and non-EA intention-to-treat populations. RESULTS: Of 355 intention-to-treat patients, 26 patients from EA were randomized to ramucirumab (n = 18) or placebo (n = 8). Median overall survival was 6.5 months in the ramucirumab arm and 4.8 months in the placebo arm (hazard ratio [HR] 0.69; 95% confidence interval [CI], 0.27-1.82) for EA patients, and 5.2 months in the ramucirumab arm and 3.8 months in the placebo arm (HR 0.78; 95% CI, 0.60-1.02) for non-EA patients. The rate of disease control was numerically higher in ramucirumab patients versus placebo; 61% versus 38% respectively for EA patients, and 48% versus 22% for non-EA patients. The incidence of grade ≥3 treatment emergent adverse events was higher in the ramucirumab arm compared to placebo (39% vs 13%). CONCLUSION: Despite limitations, this subgroup analysis suggests that ramucirumab monotherapy improves efficacy outcomes with a tolerable safety profile in EA patients with previously treated advanced gastric cancer.

Exposure-response relationship of ramucirumab in East Asian patients from RAINBOW: a randomized clinical trial in second-line treatment of gastric cancer.

BACKGROUND: Ramucirumab is a recombinant human IgG1 neutralizing monoclonal antibody specific for vascular endothelial growth factor receptor-2. Second-line ramucirumab, in conjunction with paclitaxel (ramucirumab 8 mg/kg or placebo in combination with 80 mg/m2 paclitaxel), has been shown to be effective and safe in patients with advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma in RAINBOW, a global phase III randomized clinical trial. We conducted an exploratory exposure-response analysis of efficacy and safety of ramucirumab in East Asian patients from the RAINBOW trial. METHODS: Using sparse pharmacokinetic samples collected in the RAINBOW trial, a population pharmacokinetic analysis was conducted to predict ramucirumab minimum trough concentration at steady state (C min,ss) using a nonlinear mixed-effect modeling approach. Kaplan-Meier and Cox proportional hazards analyses were conducted to evaluate ramucirumab exposure (C min,ss) and efficacy relationship by overall survival and progression-free survival. Exposure-safety relationships were assessed descriptively. RESULTS: Two hundred and twenty-two East Asian patients were included in this exposure-response analysis. Higher ramucirumab C min,ss was associated with longer overall survival (p = 0.0115) and progression-free survival (p = 0.0179) in this patient cohort. Patients with higher ramucirumab C min,ss (≥56.87 ng/ml median) had higher incidences of grade ≥3 leukopenia and neutropenia, but not febrile neutropenia or hypertension. CONCLUSIONS: This exploratory analysis suggests a positive relationship between efficacy and ramucirumab exposure with manageable toxicities in East Asian patients from RAINBOW, consistent with the overall exposure-response analysis from this trial. A regimen with a higher dosage of ramucirumab warrants further consideration for East Asian patients with gastric/GEJ cancer.

Development of the Autosomal Dominant Polycystic Kidney Disease Impact Scale: A New Health-Related Quality-of-Life Instrument.

BACKGROUND: The impact of autosomal dominant polycystic kidney disease (ADPKD) on health-related quality of life (HRQoL) is not well understood due to a lack of instruments specific to the condition. STUDY DESIGN: Content for a new self-administered patient-reported outcome (PRO) questionnaire to assess ADPKD-related HRQoL was developed through clinical expert and patient focus group discussions. The new PRO instrument was administered to study patients with ADPKD to evaluate its reliability and validity. SETTING & PARTICIPANTS: 1,674 adult patients with ADPKD participated in this research: 285 patients in focus groups to generate questionnaire content, 15 patients in debriefing interviews to refine the PRO questionnaire, and 1,374 patients to assess the performance and measurement properties of the PRO questionnaire. OUTCOME: A new PRO questionnaire. RESULTS: The ADPKD Impact Scale (ADPKD-IS), consisting of 14 items representing 3 conceptual domains (physical, emotional, and fatigue) plus 4 additional questions, was developed. The instrument's reliability (regarding internal consistency and test-retest consistency) and validity (content and construct) were supported. LIMITATIONS: Need for more responsiveness testing when more data from clinical use become available over time. Complex concepts such as ADPKD-related pain and impact on a patient's HRQoL need further evaluation. CONCLUSIONS: The ADPKD-IS is a new patient-centric tool that reliably and validly provides a standardized method for assessing HRQoL and overall disease burden in patients with ADPKD.

Age does not influence efficacy of ramucirumab in advanced gastric cancer: Subgroup analyses of REGARD and RAINBOW.

BACKGROUND AND AIM: REGARD and RAINBOW were global, phase 3, randomized, double-blind trials of second-line ramucirumab for metastatic gastric or gastroesophageal junction adenocarcinoma. Exploratory subgroup analyses were described to assess the efficacy and safety of ramucirumab in REGARD and RAINBOW in young (≤ 45 and < 65 years) and elderly (≥ 65, ≥ 70, and ≥ 75 years) patients. METHODS: Patients were randomized 2:1 to receive ramucirumab plus best supportive care or placebo plus best supportive care (REGARD) or 1:1 to ramucirumab plus paclitaxel or placebo plus paclitaxel (RAINBOW). Subpopulation Treatment Effect Pattern Plots assessed efficacy and adverse events by age groups for ramucirumab versus placebo. RESULTS: The hazard ratios (HRs) for overall survival favored treatment with ramucirumab: REGARD ≤ 45 years (HR: 0.59, 95% confidence interval: 0.27-1.26), < 65 years (0.80, 0.59-1.10), ≥ 65 years (0.72, 0.48-1.08), ≥ 70 years (0.73, 0.44-1.23), and ≥ 75 years (0.59, 0.25-1.37); and RAINBOW ≤ 45 years (0.56, 0.33-0.93), < 65 years (0.78, 0.63-0.97), ≥ 65 years (0.88, 0.66-1.18), and ≥ 70 years (0.88, 0.60-1.28). The exception was elderly patients aged ≥ 75 years in RAINBOW (0.97, 0.47-2.01); however, patient numbers were low in this subgroup (n = 36). Similar findings were observed for progression-free survival, for which HRs numerically favored ramucirumab-treated patients. Adverse events (including grade ≥ 3) were not associated with age. CONCLUSIONS: In comparison with placebo, ramucirumab conferred improvements in efficacy across age groups with a tolerable safety profile. Despite some limitations, these exploratory analyses support the use of ramucirumab in advanced gastric cancer, irrespective of age.

The economic burden of advanced gastric cancer in Taiwan.

BACKGROUND: Gastric cancer is one of the leading causes of cancer-related deaths in both sexes worldwide, especially in Eastern Asia. This study aimed to estimate the economic burden of advanced gastric cancer (AGC) in Taiwan. METHODS: The costs of AGC in 2013 were estimated using resource use data from a chart review study (n = 122 with AGC) and national statistics. Annual per-patient costs, where patients' follow-up periods were adjusted for, were estimated with 82 patients who had complete resource use data. The costs were composed of direct medical costs, direct non-medical costs (healthcare travel and caregiver costs), morbidity costs, and mortality costs. Relevant unit costs were retrieved mainly from literature and national statistics, and applied to the resource use data. A broad definition of morbidity and mortality costs was employed to value the productivity loss in patients with unpaid employment, economically inactive and unemployed as well as the life years after the age of retirement. Their narrow definitions were also used in sensitivity analyses, using age- and/or sex-specific employment rates. Forgone future earnings/productivity loss were discounted at 3%. Annual per-patient costs were projected to estimate the total costs of AGC at the national level with an estimated number of patients with AGC (N = 2611) in Taiwan in 2013. RESULTS: The mean age of the 82 patients was 59.3 (SD: 11.9) years, and 67.1% were male. Per-patient costs were US$26,431 for direct medical costs, US$4669 for direct non-medical costs, US$5758 for morbidity costs, and US$145,990 for mortality costs (per death). These per-patient costs were projected to incur total AGC costs of US$423 million at the national-level. Mortality costs accounted for 77.3% of the total costs, followed by direct medical costs (16.3%), morbidity costs (3.6%), and direct non-medical costs (2.9%). CONCLUSION: AGC was found to exert a significant economic burden in Taiwan, incurring US$423 million in 2013. This represents about 0.08% of the Taiwanese economy. Mortality costs appeared to be the single greatest contributor to the burden, followed by direct medical costs. Early detection and providing effective treatments will help to reduce its burden on patients, caregivers and society as a whole. A poster of this study was presented at the 2016 American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium in San Francisco, CA, USA.

Anti-angiogenic Therapy in Patients with Advanced Gastric and Gastroesophageal Junction Cancer: A Systematic Review.

Despite advancements in therapy for advanced gastric and gastroesophageal junction cancers, their prognosis remains dismal. Tumor angiogenesis plays a key role in cancer growth and metastasis, and recent studies indicate that pharmacologic blockade of angiogenesis is a promising approach to therapy. In this systematic review, we summarize current literature on the clinical benefit of anti-angiogenic agents in advanced gastric cancer. We conducted a systematic search of PubMed and conference proceedings including the American Society of Clinical Oncology, the European Society for Medical Oncology, and the European Cancer Congress. Included studies aimed to prospectively evaluate the efficacy and safety of anti-angiogenic agents in advanced gastric or gastroesophageal junction cancer. Each trial investigated at least one of the following endpoints: overall survival, progression-free survival/time to progression, and/or objective response rate. Our search yielded 139 publications. Forty-two met the predefined inclusion criteria. Included studies reported outcomes with apatinib, axitinib, bevacizumab, orantinib, pazopanib, ramucirumab, regorafenib, sorafenib, sunitinib, telatinib, and vandetanib. Second-line therapy with ramucirumab and third-line therapy with apatinib are the only anti-angiogenic agents so far shown to significantly improve survival of patients with advanced gastric cancer. Overall, agents that specifically target the vascular endothelial growth factor ligand or receptor have better safety profile compared to multi-target tyrosine kinase inhibitors.