First-line Use Research Articles

Management of common adverse events related to first-line dacomitinib use in EGFR mutation-positive non-small-cell lung cancer: a pooled safety analysis.

Aim: This pooled safety analysis was conducted to analyze incidence and management of key dacomitinib-associated adverse drug reactions (ADRs). Patients & methods: Patients with EGFR mutation-positive advanced non-small-cell lung cancer who received first-line dacomitinib at the 45 mg/day recommended starting dose were included. ADRs were identified based on reasonable association with EGFR tyrosine kinase inhibitors. Results: Overall, 251/255 patients (98%) experienced ADRs. The most common were diarrhea, rash, stomatitis, nail disorder and dry skin. Dose interruptions and dose reductions were reported in 47 and 52% of patients, respectively. Fewer grade 3 key ADRs were observed following dose reductions. Conclusion: Dacomitinib was generally tolerable. Most reported ADRs were known to be associated with EGFR tyrosine kinase inhibitors and were managed with standard medical management and dose modifications.

First-Line Treatment of Non-Small-Cell Lung Cancer (NSCLC) with ImmuneCheckpoint Inhibitors.

Treatment of advanced-stage or metastatic non-small-cell lung cancers (NSCLCs) without EGFR mutations or ALK rearrangements, which can now be treated with molecularly targeted therapies, had been based on cytotoxic chemotherapy for a long time. Immunecheckpoint inhibitors (ICIs), notably antibodies directed against programmed cell-death protein-1 (PD-1) and its ligand (PD-L1) have transformed therapeutic standards in thoracic oncology. These ICIs are now the reference second-line treatment and numerous phase III trials have examined their efficacy in treatment-naïve patients. First-line pembrolizumab monotherapy was validated for patients with ≥ 50% of tumor cells expressing PD-L1; pembrolizumab, atezolizumab, and nivolumab have obtained good outcomes in combination with chemotherapy or another immunotherapy. However, in this context, other phase III trials yielded negative findings for nivolumab alone (CheckMate-026) or in combination (MYSTIC trial). Biomarkers, such as PD-L1 and the tumor mutation burden (TMB), enable better selection of patients who should benefit the most from first-line ICI use.

Cost-effectiveness of first-line versus delayed use of combination dapagliflozin and metformin in patients with type 2 diabetes

The present study sought to evaluate the cost-effectiveness of first-line (immediate) versus delayed use of combination dapagliflozin and metformin in patients with type 2 diabetes, from the perspective of the Australian healthcare system. We developed a Markov model to simulate the progress of subjects with type 2 diabetes. Decision analysis was applied to assess the cost-effectiveness of first-line combination dapagliflozin and metformin versus first-line metformin monotherapy followed by gradual addition of dapagliflozin over time. Transition probabilities, costs (in Australian dollars) and utility data were derived from published sources. All costs, years of life lived and quality adjusted life years (QALYs) lived were discounted at an annual rate of 5%. Over a 20-year model period, first-line use of combination dapagliflozin and metformin was predicted to reduce the onset of hospitalisation of heart failure, cardiovascular deaths and all cause deaths by 5.5%, 57.6% and 29.6%, respectively. An additional 2.5 years of life (discounted) and 1.9 QALYs (discounted) would be gained per patient, at a cost of AUD $23,367 (discounted) per person. These figures equated to AUD $9,535 per years of life saved (YoLS) and AUD $12,477 per QALYs saved. Sensitivity analyses indicated the results to be robust. Compared to first-line metformin monotherapy followed by gradual addition of dapagliflozin, first-line use of combination dapagliflozin and metformin is likely to be a cost-effective approach to the management of Australians with type 2 diabetes mellitus.

Real-world trends in first-line checkpoint inhibitor use (CPI) in advanced urothelial cell carcinoma (aUC).

392 Background: Standard first-line treatment of aUC is cisplatin-based chemotherapy, with carboplatin-based chemotherapy or CPI reserved for cisplatin-ineligible individuals. However, given their favorable toxicity profile, there may be an indication drift of first-line CPI into cisplatin-eligible patients, despite no approved indication in this population. Methods: Using the Flatiron Health Database, a nationally representative electronic medical record-based dataset, we examined real-world prescribing patterns of first-line systemic therapies among 2090 patients with aUC diagnosed between the first quarter (q) of 2015 and 2018q1. Our analysis of cisplatin-eligible individuals excluded patients with pre-treatment (1) Eastern Cooperative Oncology Group performance status (ECOG PS) ≥ 2, (2) creatinine ≥ 1.5 mg/dL, or (3) diagnostic codes for chronic renal failure, congestive heart failure, hearing loss, or peripheral neuropathy. We used nonparametric tests of trend to describe first-line CPI and chemotherapy use over time. Results: Between 2015 and 2018, the quarterly proportion of patients who received first-line CPI increased from 1.4% to 43%, while the proportion who received platinum-based chemotherapy decreased from 89% to 56% (ptrend< 0.001) Similarly, among cisplatin-eligible patients (n = 1181), the proportion of first-line CPI users increased from 1.0% in 2015q4 to 42% in 2018q1 (ptrend= 0.001), while the proportion of first-line cisplatin users fell from 53% in 2015q4 to 33% in 2018q1 (ptrend= 0.018). First-line CPI initiators were older (median age 76 vs 71) and had worse performance status (PS ≥ 2 17.8% vs 11.4%) relative to platinum initiators (Table). Conclusions: Our analysis suggests a dramatic rise in first-line CPI use, even in patients who may be cisplatin-eligible, for whom first-line CPI is not evidence-based. [Table: see text]

232 - Performance of FDA/EMA approved PD-L1 assays in urothelial carcinoma with emphasis on therapy stratification for first-line use of atezolizumab and pembrolizumab

232 - Performance of FDA/EMA approved PD-L1 assays in urothelial carcinoma with emphasis on therapy stratification for first-line use of atezolizumab and pembrolizumab

Efficacy and Safety of Ribociclib With Letrozole in US Patients Enrolled in the MONALEESA-2 Study

BackgroundIn the Mammary Oncology Assessment of LEE011’s (Ribociclib's) Efficacy and Safety (MONALEESA-2) study, combination treatment with the selective inhibitor of cyclin-dependent kinases 4/6 ribociclib with letrozole significantly improved progression-free survival (PFS) versus letrozole alone in postmenopausal women with hormone receptor-positive HR+/HER2− advanced breast cancer (ABC). Herein we present results from the subset of US patients enrolled in MONALEESA-2. Patients and MethodsPostmenopausal women with HR+/HER2− ABC without previous treatment for advanced disease were randomized (1:1) to ribociclib 600 mg/d (3 weeks on/1 week off) with letrozole 2.5 mg/d (continuous) or placebo with letrozole. The primary end point was locally assessed PFS. ResultsOverall, 213 US patients were enrolled in MONALEESA-2 (ribociclib, n = 100; placebo, n = 113). Baseline characteristics were similar between treatment groups and consistent with the global population. With a median follow-up of 27 months, 38 (38%) and 29 (26%) patients in the ribociclib and placebo groups, respectively, had continued to receive treatment. Median PFS was 27.6 months with ribociclib and 15.0 months with placebo (hazard ratio, 0.53). The most common all-cause adverse events were neutropenia (ribociclib, 72.0% [n = 72]; placebo, 4.6% [n = 5]), nausea (ribociclib, 69.0% [n = 69]; placebo, 44.0% [n = 48]), and fatigue (ribociclib, 60.0% [n = 60]; placebo, 50.5% [n = 55]). Two patients (ribociclib, 2.0%; placebo, 0%) experienced febrile neutropenia. ConclusionIn the US subset of MONALEESA-2, ribociclib with letrozole showed superior efficacy versus letrozole alone. These findings are consistent with the global population and support first-line use of ribociclib with letrozole in patients with HR+/HER2− ABC.

Treatment sequence of lenalidomide and hypomethylating agents and the impact on clinical outcomes for patients with myelodysplastic syndromes

Lenalidomide and hypomethylating agents (HMAs) azacitidine and decitabine are approved for treating myelodysplastic syndromes (MDS), but optimal sequencing is unclear. Adults with MDS were identified from a US payer claims database (Inovalon MORE2 Registry) to compare outcomes with lenalidomide followed by HMA (LEN-HMA) or HMA followed by lenalidomide (HMA-LEN). There were 96 patients who received LEN-HMA and 89 who received HMA-LEN. LEN-HMA-treated patients had a longer time to second treatment discontinuation (29.0 vs. 19.0 months, p=.009; adjusted hazard ratio [HR] 0.52, 95% confidence interval [CI] 0.29–0.91, p=.023). LEN-HMA-treated patients had a longer median time to insurance disenrollment (22.4 vs. 16.1 months, p<.001; adjusted HR 0.64, 95% CI: 0.44–0.92, p=.017), used as a proxy for survival. Longer treatment duration and survival with LEN-HMA support first-line use of lenalidomide in MDS in sequence with HMAs.

Performance of the Food and Drug Administration/EMA-approved programmed cell death ligand-1 assays in urothelial carcinoma with emphasis on therapy stratification for first-line use of atezolizumab and pembrolizumab

BackgroundRecently, the Food and Drug Administration (FDA)/European Medicines Agency (EMA) restricted first-line use of atezolizumab and pembrolizumab in patients with metastasised urothelial carcinoma by defining distinct programmed cell death ligand-1 cut-offs. We analysed the diagnostic performance of all FDA/EMA-approved programmed cell death ligand-1 assays with emphasis on new restrictions for first-line treatment with atezolizumab and pembrolizumab. Patients and methodsTwo hundred fifty-one urothelial carcinomas were analysed on tissue microarrays with four cores of each tumour. Stains were performed in certified laboratories on Ventana Benchmark Ultra and Dako Link 48 autostainers. Stains were read on an assay-by-assay basis by two trained pathologists. Overall percentage agreement (OPA) was calculated across the preset cut-offs. Positive percentage agreement (PPA) and negative percentage agreement (NPA) were calculated across different scoring algorithms. Venn diagrams were constructed to illustrate discordance according to the recent FDA/EMA guidelines. ResultsThe Dako 28-8, 22c3 and the Ventana SP263 assays showed high interassay correlation (r-range 0.83–0.91). Interassay correlation between the Ventana SP142 and the three other assays was moderate (r-range 0.66–0.75). OPA of 93.3% was achieved between the Dako 28-8, 22c3 and Ventana SP263 assays. OPA including the SP142 was 84.1%. Pooled PPA and NPA of different scoring algorithms was 89.4% and 95.3% for the Dako 28-8, 22c3 and the SP263 assays, respectively. With the SP142 assay, pooled PPA was 59.1%. The SP142 assay identifies fewer eligible patients for first-line treatment with atezolizumab/pembrolizumab. ConclusionDako 28-8, 22c3 and SP263 assays show interchangeable performance. The SP142 assay shows divergent staining results. Interassay variability leads to different detection rates of eligible patients for first-line treatment with atezolizumab and pembrolizumab.

Comparison of the Clinical Outcomes of Nilotinib and Dasatinib Therapies in Newly Diagnosed Patients in the Chronic Phase of Chronic Myeloid Leukemia: A Retrospective Analysis

Background and Aim: Treatment with a tyrosine kinase inhibitor (TKI) is the standard of care for patients with chronic myeloid leukemia (CML). Based on the results of the ENESTnd and DASISION studies, the European LeukemiaNet 2013 guidelines now recommend the use of TKIs, imatinib (400 mg once daily), nilotinib (300 mg twice daily), and dasatinib (100 mg once daily) as first-line treatment for patients with CML in the chronic phase (CML-CP). Compared to imatinib, the new generation TKIs, nilotinib and dasatinib, were found to have deeper and faster treatment response rates with acceptable toxicities. However, a direct comparison between nilotinib and dasatinib has never been reported previously. Our study aims to compare the outcomes and molecular responses achieved following the first-line use of these two agents in patients with CML-CP.Patients and Methods: The database of the CML Cooperative Study Group, which includes patients who were initially diagnosed with CML after the introduction of imatinib (April 2001), was reviewed, and patients who were given nilotinib or dasatinib as first-line therapy were identified. The event-free survival (EFS, defined as the loss of treatment efficacy, disease progression, or any cause of death), and rates of cumulative major molecular response (MMR), and deep molecular response (DMR, defined as the depth of MR 4.5) were compared between the nilotinib and dasatinib groups. Further, the predictive ability of the Sokal, Hasford, and European Treatment and Outcome Study (EUTOS) scoring systems for the achievement of molecular responses was also evaluated. For the analysis of molecular responses, patients who switched from their initial treatment agent to another TKI before achievement of MMR or DMR were considered to have no MMR or DMR.Results and Discussion: Out of 361 patients with CML-CP enrolled in our database, 58 and 63 were treated with conventional doses of nilotinib (300 mg twice daily) and dasatinib (100 mg once daily), respectively, as first-line therapy. Patients who had been started on a low dose TKI therapy were excluded from this analysis. The patient demographics, including age, sex, observation periods, and the Sokal, Hasford, and EUTOS scores did not show significant differences between the groups. In total, there were five events during the observation period (1 in the nilotinib group and 4 in the dasatinib group), and all events were deaths unrelated to CML, except for one in a patient in the dasatinib group who showed loss of complete cytogenetic response. The disease did not progress to the accelerated or blastic phase in any of the cases. The EFS did not differ between these two groups (p = 0.214). The MMR rates by 6, 12, 18, and 24 months were 59%, 72%, 74%, and 81%, respectively, in the nilotinib group and 52%, 73%, 81%, and 86%, respectively, in the dasatinib group. The DMR rates by 6, 12, 18, and 24 months was 7%, 17%, 24%, and 28%, respectively, in the nilotinib group and 3%, 16%, 25%, and 29%, respectively, in the dasatinib group. During the first 24 months of treatment, 4 (7%) patients in the nilotinib group and 11 (17%) in the dasatinib group had been switched to other TKIs (p = 0.0983). Among the three scoring systems, only the Hasford score could predict the achievement of DMR, and all of them failed to predict the achievement of MMR in the entire cohort. Our data suggest that both nilotinib and dasatinib have comparable efficacies, with high molecular response rates and promising outcomes. The validity of our findings should be tested in a randomized study, which is currently underway in Japan. DisclosuresTakaku:Bristol-Myers Squibb: Honoraria, Speakers Bureau; Novartis Pharma K.K.: Honoraria, Speakers Bureau. Tokuhira:Mitsubishi Tanabe Pharma Corporation: Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau; AYUMI Pharmaceutical Corporation: Speakers Bureau; Chugai: Speakers Bureau. Asou:Eisai Co., Ltd.: Research Funding; SRL Inc.: Consultancy; Yakult Honsha Co., Ltd.: Speakers Bureau; Kyowa Hakko Kirin Co., Ltd.: Speakers Bureau; Asahi Kasei Pharma Co., Ltd.: Research Funding; Astellas Pharma Inc.: Research Funding; Sumitomo Dainippon Pharma Co., Ltd.: Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding. Kizaki:Nippon Shinyaku,: Research Funding, Speakers Bureau; Celgene: Research Funding, Speakers Bureau; Bristol-Myers Squibb: Research Funding, Speakers Bureau; Novartis: Speakers Bureau. Kawaguchi:Novartis Pharma K.K.: Honoraria, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Speakers Bureau; Alexion: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau.

The Evaluation of Residual Disease By Digital PCR, and TKI Duration Are Critical Predictive Factors for Molecular Recurrence after for Stopping Imatinib First-Line in Chronic Phase CML Patients: Results of the STIM2 Study.

BackgroundTKI discontinuation is now a critical goal of CML management and several studies have demonstrated the feasibility of stopping safely imatinib (IM). A sustained deep molecular response (DMR) on long-term TKI therapy seems critical prior to attempting treatment-free remission (TFR). Results from different studies have been reported recently, but they failed to identify robust and reproducible predictive factors allowing a better selection of candidate patients for successful TFR.AimsWe prospectively asked whether the use of IM first-line in de novo CP-CML patients and a systematic screen of patients with digital droplet quantitative PCR (ddPCR) for BCR-ABL1 would impact on the TFR rates.MethodsIn a national prospective phase II trial (Eudract # NCT01343173), we enrolled newly diagnosed CP-CML patients, in sustained MR4.5 (≥2 yrs on at least 5 consecutive points) according to the ELN criteria, checked centrally. Further molecular follow-up was performed in local laboratories, all ELN standardized and aligned on the international scale (IS). Molecular recurrence was defined as the positivity of BCR-ABL1/ABL1 transcripts with at least 1-log increase between 2 consecutive assessments or as loss of MMR on a single assessment. Duplex ddPCR was performed on screening samples after RT, using EAC primers and probes. Pre-mixes were transferred in aDG8 cartridge, and generation of droplets was made on the QX200 droplet generator. Each emulsion was transferred into a 96 wells ddPCR plate and amplified on the Biorad-C1000 Touch Thermocycler. Each patient was analyzed in duplicate. ddPCR was considered positive when the BCR-ABL1/ABL1 % was ≥3 SD. BCR-ABL1/ABL1 ratios were aligned on the IS, a conversion factor was calculated for the RT-ddPCR as previously described (S. Branford et al., Blood 2008). Impact of variables on the risk of relapse were assessed through univariate and multivariate analyses using SAS program.ResultsThe median follow-up after IM cessation was 23.5 (1-64) Mo. One patient died from unrelated cause, and 107 experienced a loss of MMR. The molecular recurrence-free survival (RFS) was 52% (95%CI: 45-59%) at 6 months, and 50% (95%CI: 43-57%) at 24 months. The Sokal and the EUTOS long-term survival (ELTS) scores failed to discriminate patients but a trend was observed for ELTS score (p=0.0547). Other variables analysed such as gender (p=0.6246), age at diagnosis (p=0.966), age at IM cessation (p=0.6197), interval diagnosis-IM (p=0.9621), interval IM initiation-DMR (p=0.9978) did not impact on the rate of relapse. In contrast, IM and DMR duration before IM cessation significantly impacted on the rate of relapse, as this interval is redundant with IM duration (p=0.008). ddPCR was applied to 174 out of 218 patients at IM cessation. A cut-off of 0.0023%IS ratio (= median of positive ratios) was also associated with a higher risk of relapse. The RFS estimate according to this cut-off is shown in Figure 1. In a multivariate analysis, the duration of IM (≥74.8 months) and ddPCR (≥0.0023%IS) were the two identified significant predictive factors with respectively p=0.0366 [HR=0.635, 95%CI: 0.415-0.972] and p=0.0081 [HR=0.635, 95%CI: 0.415-0.972)].No association was observed between a ddPCR ≥0.0023%IS and gender, Sokal or ELTS score, age at diagnosis, age at IM discontinuation, duration of IM treatment, DMR duration or the time-lapse for obtaining DMR.ConclusionWe conclude that the duration of IM and the residual leukemic cell load as determined by a sensitive technique such as ddPCR are key factors for predicting TFR for de novo CP-CML patients who have been treated with IM front-line. DisclosuresNicolini:Sun Pharma Ltd: Consultancy; BMS: Consultancy, Speakers Bureau; Incyte Biosciences: Consultancy, Speakers Bureau. Dulucq:Incyte: Consultancy; BMS: Consultancy. Etienne:Pfizer: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Speakers Bureau; Incyte: Honoraria, Patents & Royalties, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Mahon:Incyte: Speakers Bureau; Pfizer: Speakers Bureau; Novartis: Speakers Bureau; BMS: Speakers Bureau.

Progression-Free Survival Subset Analysis - Denosumab Vs Zoledronic Acid in Bone Disease Treatment of Newly Diagnosed Multiple Myeloma: An International, Double-Blind, Double-Dummy, Randomized Controlled Phase 3 Study

Introduction: The full primary analysis of the international, double-blind, double-dummy, randomized controlled phase 3 study (20090482) that assessed the efficacy and safety of denosumab vs zoledronic acid for preventing skeletal-related events (SREs) in newly diagnosed patients with multiple myeloma (NDMM) met the primary noninferiority endpoint of time to first on-study SRE (Raje N, et al. Lancet Oncol. 2018). Overall survival, a secondary endpoint, was similar in both arms; however, this result was based on a limited number of events having occurred (denosumab 14.1% vs zoledronic acid 15.0%), which might have affected the ability to detect a difference and also may have been further diluted by multiple subsequent lines of therapy. In addition, results from an exploratory endpoint, progression-free survival (PFS), demonstrated a clinically meaningful 10.7 months median PFS benefit (hazard ratio [HR], 0.82; 95% CI, 0.68-0.99; descriptive P=0.036; Table 1) of denosumab versus zoledronic acid on top of standard of care first-line anti-myeloma treatment. This result provided suggestive clinical evidence of a potential anti-myeloma effect based on RANKL inhibition. Here we present further analysis of PFS according to prespecified subgroups of patients from the 20090482 study.Methods: Adult NDMM patients with ≥1 documented lytic bone lesion were included in this study. Patients received subcutaneous denosumab (120 mg) plus intravenous placebo or intravenous zoledronic acid (4 mg) plus subcutaneous placebo every 4 weeks. Both groups also received investigators' choice of first-line anti-myeloma therapy. The exploratory endpoint PFS (time from randomization to date of first overall disease progression or death due to any cause, investigator identified) was estimated using the Kaplan-Meier method and analyzed using a Cox proportional hazards model stratified by randomization stratification factors and adjusted for baseline covariates. PFS subgroup analyses were conducted according to the novel first-line therapy use (proteasome inhibitor [PI] use, immunomodulatory drug [IMiD] use, PI and IMiD use) and the intent to receive an autologous stem cell transplant (ASCT; yes, no).Results: Overall, 1718 patients (denosumab, n=859; zoledronic acid, n=859) were included in the primary analysis. By the time of the primary analysis cut-off, 219 patients (25.5%) in the denosumab group and 260 patients (30.3%) in the zoledronic acid group had a PFS event. The percentages of patients receiving novel first-line therapy were balanced between the two groups (see Table 1). For patients who had received first-line PI-based therapy, PFS favored denosumab vs zoledronic acid (median, 40.0 vs 35.4 months; HR, 0.74; 95% CI, 0.58-0.95; descriptive P=0.019; Table 1). For patients who had received first-line IMiD only-based therapy, median PFS was not reached with denosumab therapy and was 34.3 months with zoledronic acid therapy (HR, 0.85; 95% CI, 0.53-1.35; descriptive P=0.49). Median PFS was also not reached for either denosumab or zoledronic acid for patients who had received first-line PI plus IMiD therapy (HR, 0.95; 95% CI, 0.62-1.46; descriptive P=0.82). For patients with the intent at baseline to receive an ASCT (54% in each treatment group; Table 1), PFS favored denosumab vs zoledronic acid (median, 46.1 vs 35.7 months; HR, 0.65; 95% CI, 0.49-0.85; descriptive P=0.002).Conclusion: Overall results from this subanalysis indicated PFS impact and benefit of denosumab on top of anti-myeloma therapy, independent from first-line novel therapy which was balanced among treatment arms, mainly in the subgroup of patients receiving PI only-based first-line therapy. In addition, benefit was observed in patients with the intent to receive ASCT, described with an impressive HR of 0.65. [Display omitted] DisclosuresTerpos:Amgen Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grant, steering committee member, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grant, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: member of steering committee, Research Funding; Genesis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grant, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: member of DMC, Research Funding; BMS: Consultancy; Novartis: Consultancy. Willenbacher:Amgen: Honoraria, Other: Steering board, Research Funding; Celgene: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Roche: Honoraria, Research Funding; BMS: Honoraria; Janssen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Merck: Honoraria. Shimizu:Daiichi-Sankyo, Co., Ltd: Consultancy; Fujimoto Pharmacuetical Corp: Consultancy; Amgen Inc.: Other: Non-remunerative Position of Influence, Denosumab 20090482 Global Steering Committee Member. García-Sanz:Hospira: Research Funding; Pharmacyclics: Research Funding; Spanish Government: Research Funding; Gilead: Research Funding; Amgen Inc.: Research Funding; Incyte: Consultancy; BMS: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses. Glennane:Amgen: Employment, Equity Ownership. Guan:Amgen: Employment, Equity Ownership. Niepel:Amgen Inc.: Employment, Equity Ownership. Raje:BMS: Consultancy; Celgene: Consultancy; Janssen: Consultancy; Merck: Consultancy; Takeda: Consultancy; AstraZeneca: Research Funding; Research to Practice: Honoraria; Medscape: Honoraria; Amgen Inc.: Consultancy.

Pazopanib: Evidence review and clinical practice in the management of advanced renal cell carcinoma

BackgroundPazopanib is indicated in the first-line treatment of metastatic renal cell cancer (mRCC). The aim of this study was to review the efficacy, safety, and pharmacokinetics of pazopanib and see how these aspects are linked to clinical practice.MethodsA non-exhaustive systematic review was conducted according to the three topics. No publication restrictions were imposed and the selected languages were Spanish and English. After that, a summary of the main results and findings of the review was presented and discussed during three meetings (one for each topic) with 13 medical oncologists that usually treat mRCC. At these meetings, a questionnaire on the first-line use of pazopanib in clinical practice was also drawn up. After the meetings, the questionnaire was completed by 60 specialist medical oncologists in renal cancer.ResultsThe efficacy and safety of pazopanib have been demonstrated in several clinical trials, and subsequently confirmed in studies in real-world clinical practice. In addition to its clinical benefit and good safety profile, quality of life results for pazopanib, which compare favorably to sunitinib, make it a good option in the first-line treatment of patients. Special populations have been included in studies conducted with pazopanib, and it is safe for use in elderly patients, poor functional status, kidney failure, and mild or moderate hepatic impairment, and in patients with concomitant cardiovascular disease. The results of the questionnaire have shown that pazopanib is perceived as an effective drug, in which quality of life (QoL) outcomes are valued above all.ConclusionsThis paper offers a comprehensive and critical summary of efficacy, tolerability, and pharmacokinetics of pazopanib in the treatment of mRCC. Pazopanib is an effective treatment with an acceptable safety profile. Its QoL and tolerability results offer certain advantages when compared with other therapeutic alternatives, and its use appears to be safe in different patient profiles.

Knowledge and Practice Discordance in Treating Urinary Tract Infections.

Urinary tract infections (UTIs) are a common condition in women. Guidelines have been published on the diagnosis and management of such infections with the twin goals of improved patient safety and avoiding unnecessary health care costs. In this study we evaluated both physicians' knowledge of these guidelines, and whether that knowledge translates to their clinical practice. We performed a retrospective chart review of UTI management before and after an educational intervention in a family medicine residency. Two control sites were also included. We also assessed physicians' knowledge of current UTI management guidelines using an anonymous quiz. At the intervention site, guideline adherence improved following the educational session. Inappropriate culture use decreased from 88% to 68% (P<.005) while first-line antibiotic use increased from 68% to 92% (P<.005). No such benefits were seen at the control sites. The control and intervention site providers did not differ in knowledge of antibiotic choice on the quiz (86% and 88% correct respectively, P=.85), but all control providers felt routine cultures were appropriate, whereas only 38% of the intervention providers did (P<.05). A simple educational intervention made an impact on the management of UTI. Our results also highlighted that knowledge and practice are not always aligned.

New Perspectives in Rheumatology: Implications of the Cardiovascular Safety of Febuxostat and Allopurinol in Patients With Gout and Cardiovascular Morbidities Trial and the Associated Food and Drug Administration Public Safety Alert.

Recently, the US Food and Drug Administration (FDA) issued a public safety alert, responding to the results of the now-published Cardiovascular Safety of Febuxostat and Allopurinol in Patients With Gout and Cardiovascular Morbidities (CARES) trial. The CARES trial showed no significant difference between allopurinol and febuxostat in the primary composite end point of cardiovascular (CV) events in subjects with gout and established CV comorbidities at baseline. However, there was a significantly increased risk of CV and all-cause mortality with febuxostat. Urate-lowering therapy (ULT) is central to the long-term management of gout, and xanthine oxidoreductase inhibitor (XOI) therapy is the consensus first-line approach. Allopurinol is generally the first XOI used, but febuxostat is an effective XOI option, and is commonly used when allopurinol is not tolerated. These data are further relevant since CV comorbidities are common in gout. Here, we examine why the CARES trial was done, and discuss other, ongoing comparative studies of febuxostat and allopurinol whose results are awaited. We assess the strengths and limitations of the CARES trial, and appraise the robustness and biologic plausibility of the results. The CARES trial does not prove that febuxostat raises CV mortality risk, but suggests greater risk with febuxostat than allopurinol. The CARES trial results do not support first-line use of febuxostat ULT, and raise questions about febuxostat placement at various pharmacologic ULT decision tree branches. Alternatives to febuxostat that are frequently effective include allopurinol dose escalation and uricosuric therapy alone or combined with allopurinol. The FDA safety alert highlights the need for shared ULT medical decision-making with gout patients, including discussion of the CV safety of febuxostat.

P3.13-24 Efficacy of EGFR-TKIs Compared with Chemotherapy as First-Line Therapy in Patients with EGFR Rare Mutation Advanced Lung Adenocarcinoma

Clinical activity of epithelial growth factor receptor tyrosine kinase inhibitors or platinum-based chemotherapy as firstline therapy in patients with EGFR rare mutation advanced lung adenocarcinoma remains unknown, This retrospective study assesses the activity and long-term survival of the two treatment regimens. 3856 patients diagnosed with lung adenocarcinoma from Henan Cancer Hospital received EGFR gene detection during January 2, 2012 to November 1, 2017. 1643 patients with EGFR mutation and phase IIIB/IV were identified. Among them, 130 cases (7.9%) with EGFR rare mutations, excluded 64 patients (4 cases of patients coexist with uncommon mutations and common mutations, 17 cases of insertions in exon 20, 42 cases of T790m and T790m complex mutations, and 1 loss of follow-up), 66 cases of EGFR uncommon mutations (G719X, L861Q, S768I and compound mutations) enrolled in the evaluation of efficacy, of whom 34 patients received EGFR-TKIs alone and 32 patients received platinum-based chemotherapy as firstline therapy. All EGFR-TKIs were first-generation drugs, details were gefitinib (250 mg/day), erlotinib (150 mg/day) and eclectinib (125 mg tid/day), all patients received at least 4 weeks of EGFR-TKIs. All chemotherapy drugs were third-generation in combination with platinum, details were pemetrexed (500 mg/m2), vinorelbine (25 mg/m2 d1, 8), or gemcitabine (1000 mg/m2 d 1, 8) platinum-based chemotherapy, every 3 weeks as a treatment cycle. Regardless of whether EGFR-TKIs or chemotherapy, the objective response rate (ORR: 28.6% vs 36% P>0.05) and disease control rate (DCR: 82.1% vs 84% P>0.05) were similar. EGFR-TKIs showed superior progression-free survival than chemotherapy group (7.1 vs 4.9 mts; HR=0.717, P=0.166), but there was not statistically difference. However, compared with chemotherapy, we found that overall survival (OS: 14.6 vs 20.3 mts; HR=1.879, P=0.019) was significantly lower in patients with EGFR-TKIs, which was statistically significant. In multivariate analysis, first-line use of targeted therapy (HR = 0.447 P = 0.006) and smoking history (HR = 3.824 P = 0.003) were found to be a significant independent prognostic factor for OS in lung adenocarcinoma patients with EGFR uncommon mutation. Compared with chemotherapy, first-line use of the first generation of EGFR-TKIs can improve the short-term efficacy of patients with EGFR rare mutation advanced lung adenocarcinoma, but longer survival in patients with first-line platinum-based chemotherapy.

PIN93 - REAL-WORLD TIGECYCLINE USE IN CHINA FOR THE TREATMENT OF COMPLICATED INTRA-ABDOMINAL INFECTIONS (CIAIS)

To describe tigecycline real-world use and compare economic outcomes among patients with cIAIs receiving first-line, later-line, or no tigecycline during hospitalization. This retrospective, observational study included cIAIs patients hospitalized in China at either The Second Affiliated Hospital, Zhejiang University or The First Affiliated Hospital, Sun Yat-sen University from January 1, 2013 to June 30, 2017. Data were obtained for cIAIs patients receiving tigecycline and matched based on age, gender, and Acute Physiologic Assessment and Chronic Health Evaluation II (APACHE II) score to those not receiving tigecycline. Data were collected for 128 patients (tigecycline, n=64; matched, n=64). Mean age was 59.7 years and APACHE II score 16.7; 68.8% were male. The incidence of both extended-spectrum beta-lactamase producing (24.1%) and carbapenem-resistant pathogens (43.8%) was high on initial culture; however, few patients (n=10; 15.6%) received first-line tigecycline. No significant difference in mortality rate was identified among first-line, later-line and no tigecycline users. Of surviving patients, shorter hospital length of stay (days [SD]: 26.0 [15.3] vs 51.6 [31.2] vs 40.9 [26.8]; P=0.025), as well as lower total hospital costs (¥190,992±191,518 vs ¥552,891±908,140 vs ¥216,543±172,470, P=0.001) were observed for patients receiving first- (n=7) vs later-line (n=41) or no tigecycline therapy (n=59), respectively. Of patients admitted to the ICU, ICU days were shorter in patients receiving first- vs later-line or no tigecycline (days [SD]: 9.1[9.5] vs 18.6 [16.8] vs 9.2 [14.0], P=0.0033). First-line tigecycline use was rare in the hospitals providing data for this study. Resistant organisms were commonly cultured from initial specimens. Although these results are limited by small patient numbers and use of data from only 2 hospitals, our results suggest that early tigecycline use may have significant economic benefits with similar mortality. Additional research is warranted to further demonstrate the values of early tigecycline use in patients with cIAIs.

Cost-Effectiveness of Osimertinib in Treating Newly Diagnosed, Advanced EGFR-Mutation-Positive Non-Small Cell Lung Cancer.

The objective of this study was to assess cost and effectiveness of osimertinib in treating newly diagnosed advanced non-small cell lung cancer with an epidermal growth factor receptor (EGFR) mutation from a public payer's perspective in the U.S. and China. Markov models were developed to compare three treatment strategies: first-line use of osimertinib, first-line use of the standard first-generation EGFR-tyrosine kinase inhibitor (EGFR-TKI) followed by the second-line use of osimertinib, and the standard first-generation EGFR-TKI therapy (standard care [SOC]). Clinical data, cost, and utility data were mainly derived from published literatures. Deterministic and probabilistic sensitivity analyses were conducted to assess the robustness of the incremental cost per quality-adjusted life year (QALY) between the treatments. The resultant incremental cost per QALY gained for the first-line osimertinib versus SOC was $312,903 in the U.S. and $41,512 in China. The incremental cost per QALY for the second-line osimertinib versus SOC was $284,532 in the U.S. and $38,860 in China. The probability of the SOC strategy being cost-effective is 1.0 if the willingness to pay threshold is below $150,000/QALY in the U.S. and below $30,000/QALY in China. Osimertinib as first-line treatment could gain more health benefits in comparison with standard EGFR-TKIs or second-line use of osimertinib. However, because of the high cost of treatment, the cost-effectiveness analyses were not in favor of the first-line use of osimertinib from a public payer's perspective in the U.S. and China. Osimertinib as first-line treatment yielded the greatest health outcomes but is not a cost-effective strategy for lung cancer in the U.S. and China. The price of osimertinib has a substantial impact on economic outcomes.

Optimizing cancer pain management in resource-limited settings

PurposeAdequate cancer pain management (CPM) is challenging in resource-limited settings, where current international guideline recommendations are difficult to implement owing to constraints such as inadequate availability and accessibility of opioids, limited awareness of appropriate opioid use among patients and clinicians, and lack of guidance on how to translate the best evidence into clinical practice. The multinational and multidisciplinary CAncer Pain managEment in Resource-limited settings (CAPER) Working Group proposes a two-step initiative to bridge clinical practice gaps in CPM in resource-limited settings.MethodsA thorough review of the literature, a steering committee meeting in February 2017, and post-meeting teleconference discussions contributed to the development of this initiative. As a first step, we developed practical evidence-based CPM algorithms to support healthcare providers (HCPs) in tailoring treatment according to availability of and access to resources. The second part of the initiative proposes a framework to support an effective implementation of the CPM algorithms that includes an educational program, a pilot implementation, and an advocacy plan.ResultsWe developed CPM algorithms for first-line use, breakthrough cancer pain, opioid rotation, and refractory cancer pain based on the National Comprehensive Cancer Network guidelines and expert consensus. Our proposed educational program emphasizes the practical elements and illustrates how HCPs can provide optimal CPM according to evidence-based guidelines despite varied resource limitations. Pilot studies are proposed to demonstrate the effectiveness of the algorithms and the educational program, as well as for providing evidence to support a draft advocacy document, to lobby policymakers to improve availability and accessibility of analgesics in resource-limited settings.ConclusionsThese practical evidence-informed algorithms and the implementation framework represent the first multinational step towards achieving optimal CPM in resource-limited settings.

Perindopril 3.5 mg/amlodipine 2.5 mg versus renin-angiotensin system inhibitor monotherapy as first-line treatment in hypertension: a combined analysis.

Many patients are diagnosed with hypertension each year, making rapid and effective control of blood pressure (BP) crucial. Appropriate first-line treatment is important, and special attention should be paid to the positive effects of lowering BP early. Perindopril 3.5 mg/amlodipine 2.5 mg (P3.5/A2.5) is a single-pill combination suitable for first-line use. The doses of each component of the single-pill combination were selected for a first-line setting. To investigate the effectiveness of the P3.5/A2.5 combination at lowering BP compared with renin-angiotensin system (RAS)-inhibitor monotherapies, after 1 month of treatment. Individual patient data from three randomized controlled trials were used to evaluate the efficacy of P3.5/A2.5 versus RAS-inhibitor monotherapies after 1 month in 5496 patients with hypertension, in a combined analysis. P3.5/A2.5 was well tolerated and significantly more effective at reducing BP after 1 month than RAS-inhibitor monotherapies (perindopril 5 mg, irbesartan 150 mg or valsartan 80 mg). P3.5/A2.5 was associated with a significantly lower SBP (P = 0.002) and DBP (P = 0.005) after 1 month of treatment compared with RAS-inhibitor monotherapies. In a large patient population, early administration of P3.5/A2.5 resulted in a significantly greater BP-lowering effect than perindopril, irbesartan or valsartan monotherapies after 1 month. Reducing BP levels within a month of treatment may reasonably be expected to lead to a reduced risk of cardiovascular events.

Comparative effectiveness of first-line biological monotherapy use in rheumatoid arthritis: a retrospective analysis of the RECord-linkage On Rheumatic Diseases study on health care administrative databases

ObjectiveThese analyses aim to comparatively evaluate the persistence on treatment of different biological disease-modifying antirheumatic drugs (bDMARDs) when administered in monotherapy compared with combination with conventional synthetic disease-modifying antirheumatic drugs...