Ripretinib versus sunitinib in gastrointestinal stromal tumor: ctDNA biomarker analysis of the phase 3 INTRIGUE trial.

INTRIGUE was an open-label, phase 3 study in adult patients with advanced gastrointestinal stromal tumor who had disease progression on or intolerance to imatinib and who were randomized to once-daily ripretinib 150 mg or sunitinib 50 mg. In the primary analysis, progression-free survival (PFS) with ripretinib was not superior to sunitinib. In clinical and nonclinical studies, ripretinib and sunitinib have demonstrated differential activity based on the exon location of KIT mutations. Therefore, we hypothesized that mutational analysis using circulating tumor DNA (ctDNA) might provide further insight. In this exploratory analysis (N = 362), baseline peripheral whole blood was analyzed by a 74-gene ctDNA next-generation sequencing-based assay. ctDNA was detected in 280/362 (77%) samples with KIT mutations in 213/362 patients (59%). Imatinib-resistant mutations were found in the KIT ATP-binding pocket (exons 13/14) and activation loop (exons 17/18). Mutational subgroup assessment showed 2 mutually exclusive populations with differential treatment effects. Patients with only KIT exon 11 + 13/14 mutations (ripretinib, n = 21; sunitinib, n = 20) had better PFS with sunitinib versus ripretinib (median, 15.0 versus 4.0 months). Patients with only KIT exon 11 + 17/18 mutations (ripretinib, n = 27; sunitinib, n = 25) had better PFS with ripretinib versus sunitinib (median, 14.2 versus 1.5 months). The results of this exploratory analysis suggest ctDNA sequencing may improve the prediction of the efficacy of single-drug therapies and support further evaluation of ripretinib in patients with KIT exon 11 + 17/18 mutations. ClinicalTrials.gov identifier: NCT03673501.

Patient-reported outcomes and tolerability in patients receiving ripretinib versus sunitinib after treatment with imatinib in INTRIGUE, a phase 3, open-label study.

PURPOSE: In the INTRIGUE trial, ripretinib showed no significant difference versus sunitinib in progression-free survival for patients with advanced gastrointestinal stromal tumour (GIST) previously treated with imatinib. We compared the impact of these treatments on health-related quality of life (HRQoL). PATIENTS AND METHODS: Patients were randomised 1:1 to once-daily ripretinib 150 mg or once-daily sunitinib 50 mg (4 weeks on/2 weeks off). Patient-reported outcomes were assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire for Cancer-30 (EORTC QLQ-C30) questionnaire at day (D)1, and D29 of all cycles until treatment discontinuation. Change from baseline was calculated. Time without symptoms or toxicity (TWiST) was estimated as the mean number of days without progression, death, or grade ≥3 treatment-emergent adverse events per patient over 1 year of follow-up. RESULTS: Questionnaire completion at baseline was 88.1% (199/226) for ripretinib and 87.7% (199/227) for sunitinib and remained high for enrolled patients throughout treatment. Patients receiving sunitinib demonstrated within-cycle variation in self-reported HRQoL, corresponding to the on/off dosing regimen. Patients receiving ripretinib reported better HRQoL at D29 assessments than patients receiving sunitinib on all scales except constipation. HRQoL was similar between treatments at D1 assessments, following 2 weeks without treatment for sunitinib patients. TWiST was greater for ripretinib patients (173 versus 126 days). CONCLUSION: Patients receiving ripretinib experienced better HRQoL than patients receiving sunitinib during the dosing period and similar HRQoL to patients who had not received sunitinib for 2 weeks for all QLQ-C30 domains except constipation. Ripretinib may provide clinically meaningful benefit to patients with advanced GIST previously treated with imatinib.

Overall survival with oral selinexor plus low-dose dexamethasone versus real-world therapy in triple-class-refractory multiple myeloma.

Triple-class-refractory multiple myeloma (MM) describes MM refractory to proteasome inhibitors, immunomodulatory agents, and anti-CD38 monoclonal antibodies. In the Phase IIb STORM study (NCT02336815), oral selinexor plus low-dose dexamethasone (Sel-dex) demonstrated a 26.2% overall response rate in triple-class-refractory MM. Here, we compare overall survival (OS) of 122 patients with triple-class-refractory MM who received Sel-dex in STORM Part 2 with that of 64 similar patients treated with other available therapies in a Flatiron Health Analytic Database (FHAD) cohort. OS from the date that the patients' MM became triple-class-refractory was longer in STORM versus FHAD, with an unadjusted hazard ratio (HR) of 0.43 (P =  .0002; adjusted HR 0.35 [P  =  .011]). In a subset analysis of highly resistant patients receiving further therapies after their MM first became at least triple-class-refractory (i.e., who received Sel-dex in STORM, n = 64, and non-Sel-dex in FHAD, n = 36), the OS was significantly longer in STORM with an unadjusted HR of 0.52 (P = .0331; adjusted HR 0.33 [P = .041]). Within the limits of this analysis, the OS of patients with at least triple-class-refractory MM was significantly better with Sel-dex versus available therapies, suggesting that Sel-dex may be associated with a meaningful OS benefit in these patients.

A Novel Treatment of Opioid Cravings With an Effect Size of .73 for Unilateral Transcranial Photobiomodulation Over Sham.

BACKGROUND: Opioid use disorders (OUDs) are an epidemic causing catastrophic consequences to individuals, families, and society despite treatments including psychotherapy, substitution therapy or receptor blockers, and psychoeducation. We have developed a novel treatment that combines unilateral transcranial photobiomodulation (t-PBM) to the hemisphere with a more positive valence by Dual Brain Psychology (DBP). METHODS: We used a randomized, double blind, placebo-controlled protocol in which 22 patients with significant opioid cravings and a history of recent or current OUD attended three 1-h weekly sessions. After baseline measures of opioid craving and other psychometrics, subjects received two unilateral t-PBM applications (810 nm CW LED, 250 mW/cm2, 60 J/cm2, 4 min) or a sham (foil-covered LED) at F3 or F4. Prior to any treatment we used two tests to determine which hemisphere was more associated with a negative outlook and cravings and treated that side before the more positive hemisphere. Primary outcome measure was an opioid craving scale (OCS). Secondary outcomes were weekly Hamilton Depression (HDRS) and Anxiety (HARS) Rating Scales prior to treatments and at follow-up. RESULTS: Immediately after treatment the OCS improved significantly for both the sham and active treatments, but one week later the active treatment showed a 51.0% (SD 33.7) decrease in OCS while a week after the sham treatments there was a decrease of only 15.8% (SD 35.0) (by Wilcoxon Sign Rank Test, p = 0.004) and by a mixed model it was p = 0.0071. The effect size for the differences between active and sham was 0.73. For the active treatment from before and after treatment the effect size was 1.51 and for the sham, 0.45. The HDRS improved from a baseline of 15.1 to 8.8 (SD 10.3) a week after the active treatment and to 13.3 (SD 12.9) after the sham (p = 0.0071). HARS improved from 14.7 to 8.0 (SD 13.2) after the active treatments and to 14.3 (SD 16.0) after the sham, p = 0.08. Active treatment of the positive hemisphere after the negative hemisphere significantly improved the OCS, but there was no significant difference after the sham treatment. One patient complained of 2 h of abdominal bloating and dropped out; no other adverse effects were observed. DISCUSSION: Unilateral t-PBM to the hemisphere with a more positive hemispheric emotional valence was an effective and safe treatment for opioid cravings as well as for depression and anxiety. Our results also lend support to the underlying premises of DBP.

Comparative efficacy of brigatinib versus ceritinib and alectinib in patients with crizotinib-refractory anaplastic lymphoma kinase-positive non-small cell lung cancer.

OBJECTIVE: Brigatinib, ceritinib, and alectinib are approved to treat crizotinib-refractory anaplastic lymphoma kinase-positive (ALK+) non-small cell lung cancer (NSCLC), but no trial has compared them head-to-head. A matching-adjusted indirect comparison (MAIC) was conducted to estimate the relative efficacy of these agents in the crizotinib-refractory setting. METHODS: MAIC is a propensity score-type method that adjusts for differences in baseline characteristics between trials to estimate relative efficacy. Analyses were based on patient-level data from the ALTA trial for brigatinib and published summary-level trial data from ASCEND-1 and ASCEND-2 for ceritinib and NP28761 and NP28673 for alectinib. Objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were compared. RESULTS: After matching, all key baseline characteristics were balanced between trials. Compared with ceritinib, brigatinib was associated with longer PFS (ASCEND-1: median 15.7 vs 6.9 months, hazard ratio (HR) [95% confidence interval] = 0.38 [0.26-0.57]; ASCEND-2: median = 18.3 vs 7.2 months, HR = 0.33 [0.20-0.56]) and OS (ASCEND-1: not available; ASCEND-2: median 27.6 vs 14.9 months, HR = 0.33 [0.17-0.63]). Versus alectinib, brigatinib was associated with longer PFS (NP28761: median = 17.6 vs 8.2 months, HR = 0.56 [0.36-0.86]; NP28673: median = 17.6 vs 8.9 months, HR = 0.61 [0.40-0.93]); results for OS were inconclusive (NP28761: median = 27.6 vs 22.7 months, HR = 0.70 [0.42-1.16]; NP28673: median = 27.6 vs 26.0 months, HR = 0.66 [0.39-1.09]). ORR was similar. CONCLUSION: In crizotinib-refractory ALK + NSCLC patients, relative efficacy estimates suggest brigatinib may have prolonged PFS and OS vs ceritinib and prolonged PFS vs alectinib.

Correction to: The Toronto cognitive assessment (TorCA): normative data and validation to detect amnestic mild cognitive impairment.

Upon publication of this article [1], it was brought to our attention that one of the 303 participants in the normative study should have been deleted from the database.

The Toronto Cognitive Assessment (TorCA): normative data and validation to detect amnestic mild cognitive impairment.

BACKGROUND: A need exists for easily administered assessment tools to detect mild cognitive changes that are more comprehensive than screening tests but shorter than a neuropsychological battery and that can be administered by physicians, as well as any health care professional or trained assistant in any medical setting. The Toronto Cognitive Assessment (TorCA) was developed to achieve these goals. METHODS: We obtained normative data on the TorCA (n = 303), determined test reliability, developed an iPad version, and validated the TorCA against neuropsychological assessment for detecting amnestic mild cognitive impairment (aMCI) (n = 50/57, aMCI/normal cognition). For the normative study, healthy volunteers were recruited from the Rotman Research Institute registry. For the validation study, the sample was comprised of participants with aMCI or normal cognition based on neuropsychological assessment. Cognitively normal participants were recruited from both healthy volunteers in the normative study sample and the community. RESULTS: The TorCA provides a stable assessment of multiple cognitive domains. The total score correctly classified 79% of participants (sensitivity 80%; specificity 79%). In an exploratory logistic regression analysis, indices of Immediate Verbal Recall, Delayed Verbal and Visual Recall, Visuospatial Function, and Working Memory/Attention/Executive Control, a subset of the domains assessed by the TorCA, correctly classified 92% of participants (sensitivity 92%; specificity 91%). Paper and iPad version scores were equivalent. CONCLUSIONS: The TorCA can improve resource utilization by identifying patients with aMCI who may not require more resource-intensive neuropsychological assessment. Future studies will focus on cross-validating the TorCA for aMCI, and validation for disorders other than aMCI.

Exploratory Analysis of Brigatinib Activity in Patients With Anaplastic Lymphoma Kinase-Positive Non-Small-Cell Lung Cancer and Brain Metastases in Two Clinical Trials.

Purpose In patients with crizotinib-treated, anaplastic lymphoma kinase gene ( ALK)-rearranged non-small-cell lung cancer (ALK-positive NSCLC), initial disease progression often occurs in the CNS. We evaluated brigatinib, a next-generation ALK inhibitor, in patients with ALK-positive NSCLC with brain metastases. Patients and Methods Patients with ALK-positive NSCLC received brigatinib (90 to 240 mg total daily) in a phase I/II trial (phI/II; ClinicalTrials.gov identifier: NCT01449461) and in the subsequent randomized phase II trial ALTA (ALK in Lung Cancer Trial of AP26113; ClinicalTrials.gov identifier: NCT02094573; patients in arm A received 90 mg once daily; patients in arm B received 180 mg once daily with 7-day lead-in at 90 mg). Primary end points (systemic objective response rates [ORRs]) were previously reported. Independent review committees assessed intracranial efficacy in patients with baseline brain metastases. Results Most patients with ALK-positive NSCLC had baseline brain metastases (50 of 79 [63%], phI/II; 80 of 112 [71%] and 73 of 110 [66%] in ALTA arms A and B, respectively), many of whom had no prior brain radiotherapy (23 of 50 [46%], phI/II; 32 of 80 [40%], ALTA arm A; 30 of 73 [41%], arm B). All patients, except four in phI/II, had received crizotinib. Among patients with measurable (≥ 10 mm) brain metastases, confirmed intracranial ORR was 53% (eight of 15; 95% CI, 27% to 79%) in phI/II, 46% (12 of 26; 95% CI, 27% to 67%) in ALTA arm A, and 67% (12 of 18; 95% CI, 41% to 87%) in arm B. Intracranial ORRs were similar in subsets without prior radiation or progression postradiation. Among patients with any baseline brain metastases, median intracranial progression-free survival (iPFS) was 14.6 months (95% CI, 12.7 to 36.8 months), phI/II; 15.6 months (95% CI, 9.0 to 18.3 months), ALTA arm A; 18.4 months (95% CI, 12.8 months to not reached), ALTA arm B. Conclusion Brigatinib yielded substantial intracranial responses and durable iPFS in ALK-positive, crizotinib-treated NSCLC, with highest iPFS in patients receiving 180 mg once daily (with lead-in).

Healthcare resource utilization and costs by age and joint location among osteoarthritis patients in a privately insured population.

AIMS: To compare healthcare resource utilization and costs between patients aged 18-64 years with osteoarthritis (OA) and matched controls without OA in a privately insured population. METHODS: Patients with OA were selected from de-identified US-based employer claims (Q1:1999-Q3:2011). The index date was defined as the first OA diagnosis indicated by ICD-9-CM codes. One year before and after the index date were defined as the baseline and study periods, respectively. A second OA diagnosis during the study period was also required. Patients with OA were matched one-to-one on age, gender, index date, and minimum length of follow-up to controls without OA. Baseline characteristics and study period resource utilization and costs (2016 USD) were compared between cohorts. RESULTS: This study identified 199,539 patients with OA (knee: 87,271, hip: 19,953, hand: 15,670, spine: 12,496). The average age was 54 years, and 58% were female. OA patients had higher healthcare resource utilization than matched controls in inpatient, emergency room, and outpatient settings (p < .001 for all). Further, patients with OA had 4-times the excess total medical costs of their matched controls ($14,521 vs $3,629; p < .001). Patients with hip OA had the highest medical costs among all joint locations. Outpatient and pharmacy costs were similar among patients with knee, hip, and hand OA, but higher in patients with spine OA. In sub-group analyses, older patients (45-64 years old) had higher costs. LIMITATIONS: This sample, obtained using claims data, only includes patients who were actively seeking care for OA and were likely symptomatic. Asymptomatic patients would likely not be captured in this analysis. CONCLUSIONS: Patients with OA incur greater healthcare resource utilization and costs than patients without OA, with substantial variation by joint location.

Brigatinib in Patients With Crizotinib-Refractory Anaplastic Lymphoma Kinase-Positive Non-Small-Cell Lung Cancer: A Randomized, Multicenter Phase II Trial.

Purpose Most crizotinib-treated patients with anaplastic lymphoma kinase gene ( ALK)-rearranged non-small-cell lung cancer (ALK-positive NSCLC) eventually experience disease progression. We evaluated two regimens of brigatinib, an investigational next-generation ALK inhibitor, in crizotinib-refractory ALK-positive NSCLC. Patients and Methods Patients were stratified by brain metastases and best response to crizotinib. They were randomly assigned (1:1) to oral brigatinib 90 mg once daily (arm A) or 180 mg once daily with a 7-day lead-in at 90 mg (180 mg once daily [with lead-in]; arm B). Investigator-assessed confirmed objective response rate (ORR) was the primary end point. Results Of 222 patients enrolled (arm A: n = 112, 109 treated; arm B: n = 110, 110 treated), 154 (69%) had baseline brain metastases and 164 of 222 (74%) had received prior chemotherapy. With 8.0-month median follow-up, investigator-assessed confirmed ORR was 45% (97.5% CI, 34% to 56%) in arm A and 54% (97.5% CI, 43% to 65%) in arm B. Investigator-assessed median progression-free survival was 9.2 months (95% CI, 7.4 to 15.6) and 12.9 months (95% CI, 11.1 to not reached) in arms A and B, respectively. Independent review committee-assessed intracranial ORR in patients with measurable brain metastases at baseline was 42% (11 of 26 patients) in arm A and 67% (12 of 18 patients) in arm B. Common treatment-emergent adverse events were nausea (arm A/B, 33%/40%), diarrhea (arm A/B, 19%/38%), headache (arm A/B, 28%/27%), and cough (arm A/B, 18%/34%), and were mainly grades 1 to 2. A subset of pulmonary adverse events with early onset (median onset: day 2) occurred in 14 of 219 treated patients (all grades, 6%; grade ≥ 3, 3%); none occurred after escalation to 180 mg in arm B. Seven of 14 patients were successfully retreated with brigatinib. Conclusion Brigatinib yielded substantial whole-body and intracranial responses as well as robust progression-free survival; 180 mg (with lead-in) showed consistently better efficacy than 90 mg, with acceptable safety.

Comparison of real-world outcomes of adalimumab and infliximab for patients with ulcerative colitis in the United States.

OBJECTIVE: We compared the real-world effectiveness of initiating adalimumab and infliximab among patients in the US who were naïve to tumor necrosis factor (TNF) inhibitors. METHODS: A retrospective chart review was conducted to evaluate the real-world effectiveness among adults with ulcerative colitis (UC) initiating adalimumab or infliximab. Charts of patients with UC were abstracted by treating physicians (randomly selected from a nationally representative panel) in April 2014. Patient eligibility criteria included: adalimumab or infliximab initiation on/after 1 October 2012; no prior anti-TNF therapy, history of Crohn's disease, or colectomy; and ≥6 months of follow-up. Information on clinical outcomes (partial Mayo score, remission rate, physician global assessment (PGA), stool frequency, and rectal bleeding) and treatment patterns (dose escalations, discontinuations, switches, and treatment augmentations) were retrospectively reported by treating physicians. Kaplan-Meier curves and multivariate Cox proportional hazards regression models were used to assess the time to clinical outcomes and treatment changes for each therapy. RESULTS: Overall, 170 physicians participated, contributing data on 380 and 424 patients who initiated adalimumab and infliximab, respectively. Baseline clinical characteristics were similar between groups. Both adalimumab- and infliximab-treated patients showed substantial improvements from baseline to follow-up in effectiveness measures; results of these measures were similar between the adalimumab and infliximab cohorts. Time to remission (p = 0.5241), no rectal bleeding (p = 0.7648), normal stool count (p = 0.9941), and normal PGA (p = 0.7697) showed no significant differences between therapies in unadjusted and adjusted comparisons. Unadjusted and adjusted time to event analysis of discontinuation (p = 0.7151), dose escalation (p = 0.6310), treatment augmentation (p = 0.1209), and switching (p = 0.7975) showed no significant differences between the two cohorts. LIMITATIONS: Retrospective, observational design. CONCLUSIONS: Adalimumab and infliximab were similarly effective in the treatment of moderate-to-severe UC in the real-world clinical setting.

Comparative effectiveness of everolimus and axitinib as second targeted therapies for metastatic renal cell carcinoma in the US: a retrospective chart review.

Background Second targeted therapies for metastatic renal cell carcinoma (mRCC) include mammalian target of rapamycin inhibitors (mTORis) and tyrosine kinase inhibitors (TKIs). This observational study compares overall survival (OS) and progression-free survival (PFS) of patients treated with everolimus (an mTORi) and axitinib (a TKI) following first TKI, and assesses the impact of type and duration of first TKI on the relative effectiveness of these second targeted therapies. Methods Retrospective reviews of medical records were conducted by medical oncologists or hematologists/oncologists recruited from a nationwide panel. Included patients with mRCC were required to have discontinued a first TKI (sunitinib, sorafenib, or pazopanib) for medical reasons, and to have initiated everolimus or axitinib as second targeted therapy between February 2012 and January 2013. OS and PFS were compared between patients treated with everolimus vs. axitinib using multivariable Cox proportional hazards regression models. Comparative results were also stratified by type and duration of first TKI. Results Included patients (n = 325 for everolimus and n = 127 for axitinib) had a mean age of 61 years and 31% were female. Sunitinib was the most commonly used first TKI (73%). After adjusting for patient characteristics, no statistically significant differences were observed in OS or PFS between everolimus and axitinib. When stratifying by type and duration of first TKI, there was no statistically significant difference in OS between everolimus and axitinib in all subgroups except for patients with <6 months on sunitinib or sorafenib as first TKI. No significant difference in PFS was observed in any subgroup. Limitations Important limitations include potential missing or inaccurate data in medical charts, and confounding due to unobserved factors. Conclusions In this retrospective chart review, no significant differences were detected in OS or PFS between axitinib and everolimus as second targeted therapy. Longer duration of first TKI was not associated with increased effectiveness of subsequent axitinib compared to everolimus.

Real-World Effectiveness of Everolimus Subsequent to Different First Targeted Therapies for the Treatment of Metastatic Renal Cell Carcinoma: Synthesis of Retrospective Chart Reviews.

BACKGROUND: The effect of first targeted therapy on outcomes with second targeted therapy for metastatic renal cell carcinoma is not well known. The purpose of this study was to compare outcomes for patients receiving a second targeted therapy with everolimus by type of first targeted therapy. PATIENTS AND METHODS: Data were drawn from 3 separate retrospective chart reviews conducted in 2011, 2012, and 2014. Inclusion criteria and study design were similar across the 3 studies. To be included in this analysis, patients had to meet the following criteria: aged ≥ 18 years; received first targeted therapy with pazopanib, sunitinib, or sorafenib; and received second targeted therapy with everolimus. Overall survival, time to treatment failure, and time to treatment discontinuation outcomes were measured from second targeted therapy initiation. Outcomes were compared among treatment groups by Cox proportional hazard models adjusting for demographic and clinical characteristics. Hazard ratios for overall survival, time to treatment failure, and time to treatment discontinuation obtained from the 3 chart reviews were synthesized in meta-analyses. RESULTS: Of 696 patients treated with everolimus as second targeted therapy, 605 patients received first targeted therapy with sunitinib/sorafenib and 91 with pazopanib. After synthesizing the hazard ratios from all studies in meta-analyses, there were no significant differences in study outcomes between patients receiving sunitinib/sorafenib versus those receiving pazopanib as first targeted therapy. CONCLUSION: There were no significant differences among outcomes while receiving second targeted therapy with everolimus for patients treated with pazopanib versus sunitinib/sorafenib as first targeted therapy.

Real-world dosing and drug costs with everolimus or axitinib as second targeted therapies for advanced renal cell carcinoma: a retrospective chart review in the US.

OBJECTIVE: To describe dosing patterns and to compare the drug costs per month spent in progression-free survival (PFS) among patients with advanced renal cell carcinoma (aRCC) treated with everolimus or axitinib following a first tyrosine kinase inhibitor (TKI). METHODS: A medical record retrospective review was conducted among medical oncologists and hematologists/oncologists in the US. Patient eligibility criteria included: (1) age ≥18 years; (2) discontinuation of first TKI (sunitinib, sorafenib, or pazopanib) for medical reasons; (3) initiation of axitinib or everolimus as a second targeted therapy during February 2012-January 2013. Real-world dosing patterns were summarized. Dose-specific drug costs (as of October 2014) were based on wholesale acquisition costs from RED BOOK Online. PFS was compared between everolimus and axitinib using a multivariable Cox proportion hazards model. Everolimus and axitinib drug costs per month of PFS were compared using multivariable gamma regression models. RESULTS: A total of 325 patients received everolimus and 127 patients received axitinib as second targeted therapy. Higher proportions of patients treated with axitinib vs everolimus started on a higher than label-recommended starting dose (14% vs 2%) or experienced dose escalation (11% vs 1%) on second targeted therapy. The PFS did not differ significantly between patients receiving everolimus or axitinib (adjusted hazard ratio (HR) = 1.16; 95% confidence interval [CI] = 0.73-1.82). After baseline characteristics adjustment, axitinib was associated with 17% ($1830) higher drug costs per month of PFS compared to everolimus ($12,467 vs $10,637; p < 0.001). LIMITATIONS: Retrospective observational study design and only drug acquisition costs considered in drug costs estimates. CONCLUSIONS: Patients with aRCC receiving axitinib as second targeted therapy were more likely to initiate at a higher than label-recommended dose and were more likely to dose escalate than patients receiving everolimus. With similar observed durations of PFS, drug costs were significantly higher-by 17% per month of PFS-with axitinib than with everolimus.

Change in forced vital capacity and associated subsequent outcomes in patients with newly diagnosed idiopathic pulmonary fibrosis.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a rare and serious disease characterized by progressive lung-function loss. Limited evidence has been published on the impact of lung-function loss on subsequent patient outcomes. This study examined change in forced vital capacity (FVC) across IPF patients in the 6 months after diagnosis and its association with clinical and healthcare resource utilization (HRU) outcomes in a real-world setting in the U.S. METHODS: A retrospective chart review was conducted of patients diagnosed with IPF by U.S. pulmonologists. Patient eligibility criteria included: 1) 40 years or older with a confirmed date of first IPF diagnosis with high-resolution computed tomography and/or lung biopsy between 01/2011 and 06/2013; 2) FVC results recorded at first diagnosis (±1 month) and at 6 months (±3 months) following diagnosis. Based on relative change in FVC percent predicted (FVC%), patients were categorized as stable (decline <5%), marginal decline (decline ≥5% and <10%), or significant decline (decline ≥10%). Physician-reported clinical and HRU outcomes were assessed from ~6 months post-diagnosis until the last contact date with the physician and compared between FVC% change groups. Multivariable Cox proportional-hazards models were constructed to assess risk of mortality, suspected acute exacerbation (AEx), and hospitalization post-FVC% change. Generalized estimating equations were used to account for multiple patients contributed by individual physicians. RESULTS: The sample included 490 IPF patients contributed by 168 pulmonologists. The mean (SD) age was 61 (11) years, 68% were male, and the mean (SD) baseline FVC% was 60% (26%). 250 (51%) patients were categorized as stable, 98 (20%) as marginal decline, and 142 (29%) as significant decline. The mean (SD) observation time was 583 (287) days. In both unadjusted analysis and multivariable models, significantly worse clinical outcomes and increased HRU were observed with greater lung-function decline. CONCLUSIONS: These findings suggest that nearly half of IPF patients experienced decline in FVC% within ~6 months following IPF diagnosis. Greater FVC% decline was associated with an increased risk of further IPF progression, suspected AEx, mortality, and higher rate of HRU. Management options that slow FVC decline may help improve future health outcomes in IPF.

Association of early suspected acute exacerbations of idiopathic pulmonary fibrosis with subsequent clinical outcomes and healthcare resource utilization.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) may be complicated by episodes of acute exacerbation. This study quantified the association between occurrence of suspected acute exacerbations of IPF (AEx-IPF) in the 6 months post-IPF diagnosis with clinical outcomes and IPF-related healthcare resource utilization (HRU). METHODS: U.S. pulmonologists participated in a retrospective chart review of IPF patients. Patient eligibility criteria included: 1) ≥40 years of age and a confirmed date of first IPF diagnosis with HRCT and/or lung biopsy between January 2011-June 2013; 2) 2 separate FVC results recorded around first diagnosis and 6 months post-diagnosis. Patients with a suspected AEx-IPF within 6 months post-diagnosis were categorized as "early AEx-IPF." Subsequent clinical outcomes and IPF-related HRU were assessed from 6 months post-diagnosis until the latest physician contact date. RESULTS: The sample included 490 IPF patients from 168 pulmonologists; 72 (15%) patients had a suspected early AEx-IPF. At IPF diagnosis, the mean (SD) age was 61 (11) years, 68% were male, and the mean FVC percent predicted was 60% (26%). Compared to patients without a suspected early AEx-IPF, patients with an early AEx-IPF had higher mortality risk (HR = 2.87, p < 0.001) and higher rates of subsequent suspected AEx-IPF (IRR = 3.87, p < 0.001), outpatient visits (IRR = 1.46, p < 0.001), ER visits (IRR = 4.39, p < 0.001), hospitalizations (IRR = 7.96, p < 0.001), and ICU stays (IRR = 9.74, p < 0.001). CONCLUSIONS: Using a large sample of IPF patients from varied practice settings, we found a strong relationship between suspected early AEx-IPF and worse subsequent clinical outcomes and increased IPF-related HRU. This relationship was particularly pronounced for acute resource use.

One-year and long-term molecular response to nilotinib and dasatinib for newly diagnosed chronic myeloid leukemia: a matching-adjusted indirect comparison.

BACKGROUND: Nilotinib and dasatinib have shown superior rates of molecular response (MR) compared to imatinib for the treatment of newly diagnosed chronic myeloid leukemia (CML) in chronic phase (CP). This study indirectly compares MR in patients taking nilotinib 300 mg bid with that in those taking dasatinib 100 mg qd by 12 months and through 48 months. METHODS: Patients in ENESTnd were re-weighted to match published baseline characteristics reported for DASISION using a propensity score model. After matching, differences in rates of major MR (MMR, measured as a 3 log reduction on the International Scale [IS]), MR(4.0) (4 log reduction on IS), and MR(4.5) (4.5 log reduction on IS) relative to imatinib were indirectly compared between nilotinib and dasatinib. Hazard ratios (HRs) were used to indirectly compare MR outcomes between nilotinib and dasatinib through 48 months of follow-up, while rate differences were used to compare progression to AP/BC between nilotinib and dasatinib by 48 months. RESULTS: After matching, rates of MR by 12 months were higher with nilotinib vs dasatinib by 11.7% for MMR (p = 0.045), 8.2% for MR(4.0) (p = 0.029), and 8.5% for MR(4.5) (p < 0.001). Higher rates of MMR (HR = 1.44, p = 0.018) and MR(4.0) (HR = 1.58, p = 0.013) achievement were maintained with nilotinib compared to dasatinib through 48 months of follow-up. No statistically significant differences were observed for MR(4.5) through 48 months or progression to AP/BC by 48 months. LIMITATIONS: LIMITATIONS include comparisons based solely on indirect evidence and HRs for MR(4.0) and MR(4.5) from the DASISION trial being extracted from cumulative incidence curves. CONCLUSIONS: This indirect comparison suggests that nilotinib is associated with higher rates of achieving MMR, MR(4.0), and MR(4.5) by 12 months compared to dasatinib for the treatment of newly diagnosed CML-CP. In addition, higher rates of MR achievement with nilotinib were also maintained through 48 months of follow-up.

Major molecular response during the first year of dasatinib, imatinib or nilotinib treatment for newly diagnosed chronic myeloid leukemia: a network meta-analysis.

OBJECTIVE: No randomized trials have directly compared dasatinib with nilotinib for the treatment of newly diagnosed chronic myeloid leukemia in the chronic phase. The objective of this study was to indirectly compare these therapies using evidence from randomized trials versus imatinib, the current standard of care. METHODS: Randomized trials that included either dasatinib or nilotinib as first-line treatment for chronic myeloid leukemia were identified in a systematic review. Inclusion and exclusion criteria, baseline characteristics and endpoint definitions were compared across trials. The outcome of interest was major molecular response by or at 12 months. A network meta-analysis was conducted to compare rates of major molecular response among therapies while adjusting for measurement of response by or at 12 months. RESULTS: One trial of nilotinib versus imatinib (ENESTnd) and two trials of dasatinib versus imatinib (DASISION and the S0325 Intergroup Trial) were identified. Major molecular response was reported by and at 12 months in ENESTnd, by 12 months in DASISION, and at 12 months in the S0325 Intergroup Trial. In the network meta-analysis, nilotinib had a 97% chance of having the highest rate of major molecular response compared to dasatinib and imatinib, corresponding to absolute rates of major molecular response by month 12 of 55.2%, 44.8% and 26.7%, respectively. CONCLUSIONS: In this network meta-analysis, nilotinib was associated with the highest rate of major molecular response, compared to dasatinib and imatinib, during the first year of treatment in patients with newly diagnosed chronic myeloid leukemia in the chronic phase.

Impact of misspecifying the distribution of a prognostic factor on power and sample size for testing treatment interactions in clinical trials.

BACKGROUND: Interaction in clinical trials presents challenges for design and appropriate sample size estimation. Here we considered interaction between treatment assignment and a dichotomous prognostic factor with a continuous outcome. Our objectives were to describe differences in power and sample size requirements across alternative distributions of a prognostic factor and magnitudes of the interaction effect, describe the effect of misspecification of the distribution of the prognostic factor on the power to detect an interaction effect, and discuss and compare three methods of handling the misspecification of the prognostic factor distribution. METHODS: We examined the impact of the distribution of the dichotomous prognostic factor on power and sample size for the interaction effect using traditional one-stage sample size calculation. We varied the magnitude of the interaction effect, the distribution of the prognostic factor, and the magnitude and direction of the misspecification of the distribution of the prognostic factor. We compared quota sampling, modified quota sampling, and sample size re-estimation using conditional power as three strategies for ensuring adequate power and type I error in the presence of a misspecification of the prognostic factor distribution. RESULTS: The sample size required to detect an interaction effect with 80% power increases as the distribution of the prognostic factor becomes less balanced. Misspecification such that the actual distribution of the prognostic factor was more skewed than planned led to a decrease in power with the greatest loss in power seen as the distribution of the prognostic factor became less balanced. Quota sampling was able to maintain the empirical power at 80% and the empirical type I error at 5%. The performance of the modified quota sampling procedure was related to the percentage of trials switching the quota sampling scheme. Sample size re-estimation using conditional power was able to improve the empirical power under negative misspecifications (i.e. skewed distributions) but it was not able to reach the target of 80% in all situations. CONCLUSIONS: Misspecifying the distribution of a dichotomous prognostic factor can greatly impact power to detect an interaction effect. Modified quota sampling and sample size re-estimation using conditional power improve the power when the distribution of the prognostic factor is misspecified. Quota sampling is simple and can prevent misspecification of the prognostic factor, while maintaining power and type I error.

Estimating the burden of total knee replacement in the United States.

BACKGROUND: In the last decade, the number of total knee replacements performed annually in the United States has doubled, with disproportionate increases among younger adults. While total knee replacement is a highly effective treatment for end-stage knee osteoarthritis, total knee replacement recipients can experience persistent pain and severe complications. We are aware of no current estimates of the prevalence of total knee replacement among adults in the U.S. METHODS: We used the Osteoarthritis Policy Model, a validated computer simulation model of knee osteoarthritis, and data on annual total knee replacement utilization to estimate the prevalence of primary and revision total knee replacement among adults fifty years of age or older in the U.S. We combined these prevalence estimates with U.S. Census data to estimate the number of adults in the U.S. currently living with total knee replacement. The annual incidence of total knee replacement was derived from two longitudinal knee osteoarthritis cohorts and ranged from 1.6% to 11.9% in males and from 2.0% to 10.9% in females. RESULTS: We estimated that 4.0 million (95% confidence interval [CI]: 3.6 million to 4.4 million) adults in the U.S. currently live with a total knee replacement, representing 4.2% (95% CI: 3.7% to 4.6%) of the population fifty years of age or older. The prevalence was higher among females (4.8%) than among males (3.4%) and increased with age. The lifetime risk of primary total knee replacement from the age of twenty-five years was 7.0% (95% CI: 6.1% to 7.8%) for males and 9.5% (95% CI: 8.5% to 10.5%) for females. Over half of adults in the U.S. diagnosed with knee osteoarthritis will undergo a total knee replacement. CONCLUSIONS: Among older adults in the U.S., total knee replacement is considerably more prevalent than rheumatoid arthritis and nearly as prevalent as congestive heart failure. Nearly 1.5 million of those with a primary total knee replacement are fifty to sixty-nine years old, indicating that a large population is at risk for costly revision surgery as well as possible long-term complications of total knee replacement.