Grading of neurological toxicity in patients treated with tisagenlecleucel in the JULIET trial.

Chimeric antigen receptor-T (CAR-T) cell therapy achieves durable responses in patients with relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL), but may be associated with neurological toxicity (NT). We retrospectively assessed differences and concordance among 3 available grading scales (the National Cancer Institute Common Terminology Criteria for Adverse Events v4.03 [CTCAE], modified CAR-T Related Encephalopathy Syndrome [mCRES], and American Society for Transplantation and Cellular Therapy [ASTCT] scales) applied to the same set of NT data from the JULIET (A Phase 2, Single Arm, Multicenter Trial to Determine the Efficacy and Safety of CTL019 in Adult Patients With Relapsed or Refractory DLBCL) trial. Individual patient-level NT data from the phase 2, single-group, global, pivotal JULIET trial (NCT02445248) were retrospectively and independently graded, using CTCAE, ASTCT, and mCRES, by 4 medical experts with experience managing patients with 3 different CD19-targeted CAR constructs. According to the US Food and Drug Administration definition of NT using CTCAE, 62 of 106 patients infused with tisagenlecleucel had NT as of September 2017. Among 111 patients infused with tisagenlecleucel (as of December 2017), the 4 experts identified 50 patients (45%) who had any-grade NT per CTCAE, 19 (17%) per mCRES, and 19 (17%) per ASTCT. Reevaluation according to the mCRES/ASTCT criteria downgraded 31 events deemed NT by CTCAE to grade 0. This is the first study to retrospectively apply CTCAE, mCRES, and ASTCT criteria to the same patient data set. We conclude that CTCAE v4.03 was not designed for, and is suboptimal for, grading CAR-T cell therapy-associated NT. The CRES and ASTCT scales, which measure immune effector cell-associated neurotoxicity syndrome, offer more accurate assessments of NT after CAR-T cell therapy.

Grading and management of cytokine release syndrome in patients treated with tisagenlecleucel in the JULIET trial.

Chimeric antigen receptor T-cell (CAR-T) therapy yields durable responses in patients with relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL). Cytokine release syndrome (CRS) is a CAR-T therapy-related adverse event. To date, clinical trials of different CAR-T products have not been aligned on CRS grading scales and management algorithms. We assessed concordance between the Penn, Lee, and American Society for Transplantation and Cellular Therapy (ASTCT) grading systems by retrospectively regrading CRS events in the JULIET (A Phase 2, Single Arm, Multicenter Trial to Determine the Efficacy and Safety of CTL019 in Adult Patients With Relapsed or Refractory DLBCL) trial. Four medical experts with experience treating patients with 3 different CAR-T products independently regraded individual patient-level CRS events from the phase 2, global, pivotal JULIET trial (#NCT02445248). As of 8 December 2017, a total of 111 patients with r/r DLBCL underwent infusion with tisagenlecleucel. Sixty-four patients had CRS events graded per the Penn scale; on retrospective review, 63 and 61 patients had CRS events regraded per the Lee and ASTCT criteria, respectively. The Lee scale yielded concordance for 39, lower grade for 20, and higher grade for 5 events compared with the Penn scale. The ASTCT criteria provided concordance for 37, lower grade for 23, and higher grade for 4 events compared with the Penn scale. Sixteen (14%) of 111 patients in the JULIET trial received tocilizumab, all for severe events (Penn grade 3/4 CRS). This study is the first to assess concordance between 3 CRS grading scales using the same patient data set and to compare tocilizumab use according to the Lee scale in the JULIET trial and the ZUMA-1 (Long-Term Safety and Activity of Axicabtagene Ciloleucel in Refractory Large B-Cell Lymphoma) trial. This analysis describes key differences between grading scales and may inform CRS management practices.

Elotuzumab plus lenalidomide and dexamethasone in relapsed/refractory multiple myeloma: Extended 4-year follow-up and analysis of relative progression-free survival from the randomized ELOQUENT-2 trial.

BACKGROUND: The randomized phase 3 ELOQUENT-2 study (NCT01239797) evaluated the efficacy and safety of elotuzumab plus lenalidomide and dexamethasone (ELd) versus lenalidomide and dexamethasone (Ld) in relapsed/refractory multiple myeloma (RRMM), and to date, has the longest follow-up of any monoclonal antibody in patients with RRMM. METHODS: In this extended 4-year follow-up of the ELOQUENT-2 trial, the coprimary endpoints of progression-free survival (PFS) and overall response rate as well as the secondary endpoint of overall survival were assessed. In the absence of head-to-head trials comparing Ld-based triplet regimens to guide treatment selection, 4 randomized controlled trials-ELOQUENT-2, ASPIRE, TOURMALINE-MM1, and POLLUX-were indirectly compared to provide insight into the relative efficacy of these regimens in RRMM. RESULTS: Data at 4 years were consistent with 2- and 3-year follow-up data: ELd reduced the risk of disease progression/death by 29% versus Ld (hazard ratio, 0.71) while maintaining safety. The greatest PFS benefit among the assessed subgroups was observed in patients at the median time or further from diagnosis (≥3.5 years) with 1 prior line of therapy, who had a 44% reduction in the risk of progression/death, and in patients in the high-risk category, who had a 36% reduction in favor of ELd. This regimen also showed a relative PFS benefit that was maintained beyond 50 months. CONCLUSIONS: The sustained PFS benefit and long-term safety of ELd at 4 years, similar to those observed at 2 and 3 years, support ELd as a valuable therapeutic option for the long-term treatment of patients with RRMM.

Comparative Effectiveness of nab-Paclitaxel Plus Gemcitabine vs FOLFIRINOX in Metastatic Pancreatic Cancer: A Retrospective Nationwide Chart Review in the United States.

INTRODUCTION: nab-Paclitaxel plus gemcitabine (nab-P + G) and FOLFIRINOX (FFX) are among the most common first-line (1L) therapies for metastatic adenocarcinoma of the pancreas (MPAC), but real-world data on their comparative effectiveness are limited. METHODS: This retrospective cohort study compared the efficacy and safety of 1L nab-P + G versus FFX, overall and under specific treatment sequences. Medical records were reviewed by 215 US physicians who provided information on MPAC patients who initiated 1L therapy with nab-P + G or FFX between April 1, 2015 and December 31, 2015. Study outcomes were overall survival (OS) and tolerability. OS was compared using Kaplan-Meier curves and adjusted Cox proportional hazards models. RESULTS: In total, 654 medical records were reviewed, including those of 337 and 317 patients initiated on nab-P + G and FFX as 1L MPAC therapy, respectively. nab-P + G-initiated patients were older, less likely to have ECOG ≤ 1, and had more comorbidities than FFX-initiated patients. Median OS (mOS) was 12.1 and 13.8 months for nab-P + G- and FFX-initiated patients, respectively (HR = 0.99, P = 0.96). Among patients with ECOG ≤ 1, mOS was 14.1 and 13.7 months, respectively (HR = 1.00, P = 0.99). Among patients with 1L nab-P + G and FFX, 36.1% and 41.3% received 2L therapy and experienced mOS of 16.3 and 16.6 months, respectively (HR = 1.04, P = 0.76). The rates of diarrhea, fatigue, mucositis, and nausea and vomiting were significantly higher in the FFX than nab-P + G cohort. CONCLUSION: The real-world survival was similar between patients receiving 1L nab-P + G or FFX both overall and among patients who received active 2L treatments. In addition, nab-P + G was associated with significantly lower rates of common AEs compared with FFX. FUNDING: Celgene.

Identifying a subpopulation with higher likelihoods of early response to treatment in a heterogeneous rare disease: a post hoc study of response to teduglutide for short bowel syndrome.

PURPOSE: Teduglutide, a glucagon-like peptide-2 analog, has demonstrated efficacy in reducing parenteral support (PS) among patients with short bowel syndrome with intestinal failure (SBS-IF). This study aims to identify a subpopulation of SBS-IF patients for whom teduglutide has an especially pronounced effect. PATIENTS AND METHODS: Data were from a 24-week, Phase III trial (Study of Teduglutide Effectiveness in Parenteral Nutrition-Dependent SBS Subjects; NCT00798967) that randomized SBS-IF patients with PS dependency to receive teduglutide (n=43) or placebo (n=43). Two prediction models (1 for each arm) were developed for response, defined as 20% reduction in weekly PS at Weeks 20 and 24. Potential predictors included demographics, disease characteristics, and concomitant medications. Patients were then ranked based on the effect score, an individualized predicted response rate difference with teduglutide versus placebo. A subpopulation of patients with a pronounced benefit from teduglutide versus placebo was identified. Baseline characteristics and clinical outcomes were compared between patients included versus those not included in the subpopulation. RESULTS: Six predictors of response to teduglutide were selected: older age, volvulus as the cause of major intestinal resection, baseline PS volume >6 L per week, longer time since start of PS dependency, absence of ileocecal valve, and lower percentage of colon remaining. Higher percentage of colon remaining and volvulus were the selected predictors for response to placebo. A subpopulation of patients more likely to respond to teduglutide was identified as those with the top 60% effect scores. The difference in response rate between teduglutide and placebo was 62% in the subpopulation, which was substantially higher than the difference of 33% in the overall population. Mean PS day reduction was also significantly higher for teduglutide compared to placebo in the subpopulation. CONCLUSION: Pretreatment characteristics as predictors of response to teduglutide versus placebo within 24 weeks were identifiable in the clinical trial population of SBS-IF patients.

Number needed to treat and costs per responder among biologic treatments for moderate-to-severe psoriasis: a network meta-analysis.

BACKGROUND: The clinical benefits of biologic therapies for moderate-to-severe psoriasis are well established, but wide variations exist in patient response. OBJECTIVES: To determine the number needed to treat (NNT) to achieve a 75% and 90% reduction in the Psoriasis Area and Severity Index (PASI-75/90) with FDA-approved agents and evaluate the incremental cost per PASI-75 or PASI-90 responder. METHODS: The relative probabilities of achieving PASI-75 and PASI-90, as well as NNTs, were estimated using a network meta-analysis. Costs (2017 USD) included drug acquisition and administration. The incremental cost per PASI-75 or PASI-90 responder for each treatment was estimated for the clinical trial period, and annually. RESULTS: Compared with supportive care, the NNT to achieve PASI-75 was 1.18 for ixekizumab, 1.29 for secukinumab 300 mg, 1.37 for infliximab, 1.48 for adalimumab, 1.53 for secukinumab 150 mg, 1.58 for ustekinumab, 2.25 for etanercept, and 3.71 for apremilast. The one-year incremental cost per PASI-75 responder relative to supportive care was $59,830 for infliximab, $88,775 for secukinumab 300 mg, $91,837 for adalimumab, $95,898 for ixekizumab, $97,363 for ustekinumab, $105,131 for secukinumab 150 mg, $129,665 for apremilast, and $159,328 for etanercept. Results were similar for PASI-90. CONCLUSION: The NNT and incremental cost per responder are meaningful ways to assess comparative effectiveness and cost effectiveness among psoriasis treatments.

Comparison of Adalimumab and Etanercept for the Treatment of Moderate to Severe Psoriasis: An Indirect Comparison Using Individual Patient Data from Randomized Trials.

OBJECTIVES: To compare outcomes between adalimumab and etanercept in the treatment of moderate to severe plaque psoriasis. METHODS: Study groups included patients randomized to adalimumab or placebo (REVEAL and CHAMPION trials) and those randomized to etanercept or placebo (M10-114 and M10-315 trials). Week 12 outcomes were compared between patients receiving adalimumab and those receiving etanercept after adjusting for cross-trial differences in patient characteristics using propensity score weighting and after subtracting effects of placebo. Outcomes included proportion of patients achieving 75% or more, 90% or more, and 100% reductions from baseline in the Psoriasis Area and Severity Index (PASI75, PASI90, PASI100, respectively), symptom resolution (pruritus = 0; psoriatic pain = 0), lesion resolution (minimal scores for plaque signs erythema, desquamation, and induration, and by body regions head, upper limbs, trunk, and lower limbs), absence of skin-related quality-of-life impact (Dermatology Life Quality Index [DLQI] = 0), "complete disease control" (patient's global assessment [PtGA] = 0), and adverse events. RESULTS: After adjustment, baseline characteristics were balanced among study groups (adalimumab = 875 vs. placebo = 427; etanercept = 260 vs. placebo = 130). Compared with etanercept, adalimumab was associated with significantly better placebo-adjusted outcomes (PASI75: 62.3% vs. 42.6%; PASI90: 35.9% vs. 12.1%; PASI100: 13.1% vs. 4.9%; pruritus: 24.7% vs. 13.0%; psoriatic pain: 27.4% vs. 8.7%; DLQI: 27.7% vs. 11.7%; and PtGA: 16.4% vs. 10.6%; all P < 0.05), except for similar rates of adverse events and head-specific lesion resolution. CONCLUSIONS: Compared with etanercept, adalimumab treatment for moderate to severe plaque psoriasis was associated with greater PASI reduction, higher rates of resolution of skin signs and symptoms, and greater improvements in dermatological life quality.

Poor early response to methotrexate portends inadequate long-term outcomes in patients with moderate-to-severe psoriasis: Evidence from 2 phase 3 clinical trials.

BACKGROUND: Most methotrexate-treated psoriasis patients do not achieve a long-term PASI75 (75% reduction from baseline Psoriasis Area and Severity Index score) response. Indications of nonresponse can be apparent after only 4 weeks of treatment. OBJECTIVE: To develop a prediction rule to identify patients unlikely to respond adequately to methotrexate. METHODS: Patient-level data from CHAMPION (NCT00235820, N = 110) was used to construct a prediction model for week 16 PASI75 by using patient baseline characteristics and week 4 PASI25. A prediction rule was determined on the basis of the sensitivity and specificity and validated in terms of week 16 PASI75 response in an independent validation sample from trial M10-255 (NCT00679731, N = 163). RESULTS: PASI25 achievement at week 4 (odds ratio = 8.917) was highly predictive of response with methotrexate at week 16. Patients with a predicted response probability <30% were recommended to discontinue methotrexate. The rates of week 16 PASI75 response were 65.8% and 21.1% (P < .001) for patients recommended to continue and discontinue methotrexate, respectively. LIMITATIONS: The CHAMPION trial excluded patients previously treated with biologics, and the M10-255 trial had no restrictions. CONCLUSION: A prediction rule was developed and validated to identify patients unlikely to respond adequately to methotrexate. The rule indicates that 4 weeks of methotrexate might be sufficient to predict long-term response with limited safety risk.

Patterns of Disease Monitoring and Treatment Among Patients With Tuberous Sclerosis Complex-related Angiomyolipomas.

OBJECTIVE: To use the tuberous sclerosis complex (TSC) Natural History Database to describe monitoring and treatment patterns among patients with TSC-related angiomyolipomas (AMLs). METHODS: This study used the TSC Natural History Database, which contains demographics, affected areas, diagnosis, and treatments for more than 1300 patients with TSC enrolled in 16 participating clinics during 2006-2013. Patient characteristics, AML monitoring tests, and AML treatments were assessed. RESULTS: Among the 621 patients with TSC-related AMLs, 54% were female; 77% were Caucasian. Median age at TSC diagnosis was <1 year, whereas median age at AML diagnosis was 9.8 years. Most patients (84%) had at least 1 monitoring test following AML diagnosis. The most commonly used tests were magnetic resonance imaging (MRI; 65% of patients), ultrasound (62%), and computed tomography (41%). Between 2000 and 2012, MRI made up an increasingly large proportion of the total number of monitoring tests. Once diagnosed, 155 (25%) of patients received treatment for AML. The median time from diagnosis to first treatment was 3.8 years. The most common treatments were embolization (10%), everolimus (9%), sirolimus (6%), and nephrectomy (6%). The rate of nephrectomies declined over time, with none conducted during 2011 and 2012. No subsequent surgeries were reported among the 71 patients who received mTOR inhibitor as first-line therapy. CONCLUSION: The use of MRIs increased between 2000 and 2012 among patients with TSC-AML. The majority of these patients did not receive treatment for AML. Use of nephrectomy decreased over the study period and was particularly rare in patients who received an mTOR inhibitor.

Patterns of care among patients receiving sequential targeted therapies for advanced renal cell carcinoma: A retrospective chart review in the USA.

OBJECTIVES: To assess real-world treatment patterns of targeted therapies after failure of first-line tyrosine kinase inhibitors in patients with advanced renal cell carcinoma. METHODS: A large, retrospective review of medical charts of patients with advanced renal cell carcinoma in the USA was carried out. Descriptive statistics were used to summarize physicians' and patients' characteristics, treatment sequences, and reasons for treatment choices. P-values were calculated using χ2 -tests for categorical variables and Wilcoxon rank-sum tests for continuous variables. A descriptive comparison was carried out between current results and those of a previous treatment pattern study conducted in 2012 to identify changes in treatment patterns over time. RESULTS: Sunitinib and everolimus remained the most commonly-used first and second targeted therapies, respectively. Among patients who continued to a third targeted therapy, everolimus and axitinib were the most commonly-used treatments after second targeted therapy with a tyrosine kinase inhibitor and a mammalian target of rapamycin inhibitor, respectively. The use of pazopanib as first targeted therapy, and of axitinib and sorafenib as second targeted therapies, increased over time. Efficacy, treatment guidelines and a different mechanism of action were the main reasons given by physicians for choosing among second targeted therapies after failure of a first tyrosine kinase inhibitor. CONCLUSIONS: The results of the present study document patterns of care during a period of rapid and ongoing therapeutic advancement in advanced renal cell carcinoma. Sequencing of therapies warrants ongoing analysis in light of new agents entering the advanced renal cell carcinoma treatment landscape.

Effectiveness and healthcare costs among stabilised rheumatoid arthritis patients with dose reduction of adalimumab or etanercept in real world.

OBJECTIVES: We assessed the level of maintained effectiveness and associated healthcare costs in stabilised rheumatoid arthritis (RA) patients who reduced doses of adalimumab or etanercept. METHODS: Eligible patients were identified from a U.S. commercial insurance database using the following criteria: adults with ≥2 RA diagnoses; effectively treated on standard dose of adalimumab or etanercept for a 6-month baseline period; and ≥3 months of dose reduction within a 6-month assessment period following the index date (date of the first reduced dose). Effectiveness was estimated using a validated claims-based algorithm. Multivariate regression models were used to assess maintained effectiveness and healthcare costs in the short-term (months 7-12) and long-term (months 13-24) following the index date, while adjusting for baseline characteristics. Cost per patient maintaining effective treatment (CPME) was calculated as the average total healthcare costs divided by the proportion of patients with maintained effectiveness. RESULTS: Both groups (etanercept=375; adalimumab=610) had 70% females and a mean age of 48 years. Adjusted rates of maintained effectiveness for etanercept vs. adalimumab were 57.5% vs. 64.7% (p=0.028) in the short-term and 44.3% vs. 51.9% (p=0.047) in the long-term. Adjusted healthcare costs were similar for etanercept- and adalimumab-treated patients (short-term: $15,043 vs. $15,041; long-term: $31,461 vs. $30,449). The CPME was $2,915 higher with etanercept-treated patients in short-term and $12,349 higher in long-term compared with adalimumab-treated patients. CONCLUSIONS: Among stabilised RA patients who reduced biologic dosing, a greater proportion of adalimumab-treated patients maintained effectiveness than etanercept-treated patients. Adalimumab was associated with a lower total CPME than etanercept.

Comparative efficacy of long-acting ß2-agonists as monotherapy for chronic obstructive pulmonary disease: a network meta-analysis.

PURPOSE: Long-acting ß2-agonists (LABAs) have demonstrated efficacy in patients with COPD in clinical trials. The purpose of this study was to assess the comparative efficacy of all available dosages of all LABA monotherapies using a network meta-analysis. METHODS: A systematic literature review identified 33 randomized controlled trials of LABA monotherapies (salmeterol 50 µg twice daily [BID]; formoterol 12 µg BID; indacaterol 75, 150, and 300 µg once daily [OD]; olodaterol 5 and 10 µg OD, and vilanterol 25 µg OD). Clinical efficacy was evaluated at 12 and 24 weeks in terms of trough forced expiratory volume in 1 second (FEV1), transition dyspnea index focal score, St George's Respiratory Questionnaire total score, and rate of COPD exacerbations. The relative effectiveness of all LABA monotherapies was estimated by Bayesian network meta-analysis. RESULTS: At 12 and 24 weeks, indacaterol 300 and 150 µg OD were associated with statistically significant improvement in trough FEV1 compared to all other LABA monotherapies; vilanterol 25 µg OD was superior to formoterol 12 µg BID. At 12 weeks, indacaterol 75 µg OD was associated with significant improvement in trough FEV1 compared to formoterol 12 µg BID and olodaterol (5 and 10 µg OD); salmeterol 50 µg BID was superior to formoterol 12 µg BID and olodaterol 5 µg OD. Indacaterol 300 µg OD was also associated with significant improvement in transition dyspnea index focal score compared to all other LABAs at 12 or 24 weeks. Indacaterol 150 µg OD had significantly better results in exacerbation rates than olodaterol 5 µg and olodaterol 10 µg OD. CONCLUSION: Indacaterol 300 µg, followed by 150 and 75 µg, were the most effective LABA monotherapies for moderate to severe COPD.

Comparative efficacy and incremental cost per responder of methotrexate versus apremilast for methotrexate-naïve patients with psoriasis.

BACKGROUND: To our knowledge, no clinical trials directly compare apremilast with methotrexate (the standard of care for initial systemic treatment of psoriasis). OBJECTIVE: We sought to compare apremilast's relative efficacy with that of methotrexate for moderate to severe psoriasis. METHODS: An anchor-based indirect comparison was conducted for 75% improvement in Psoriasis Area and Severity Index score from baseline to week 16 (PASI 75) rates for systemic-naïve patients from Efficacy and Safety Trial Evaluating the Effects of apreMilast in psoriasis (ESTEEM) 1 and 2 (apremilast vs placebo) and Comparative study of HumirA vs. Methotrexate vs Placebo In psOriasis patieNts (CHAMPION) (adalimumab vs methotrexate vs placebo) trials. The difference-in-difference in PASI 75 response rates was calculated as the difference between the ESTEEM apremilast and placebo rates and the CHAMPION methotrexate versus placebo rates. Number needed to treat and incremental drug cost per responder were also estimated. RESULTS: No statistically significant difference was found between apremilast and methotrexate in PASI 75 (risk difference 13.1%; 95% confidence interval -1.8% to 28.0%; P = .09). Number needed to treat with apremilast versus methotrexate to gain 1 additional PASI 75 responder was 7.6. Annual incremental drug cost of this responder was estimated at $187,888.33. LIMITATIONS: Few trials compare systemic-naïve patients. Only direct medication costs were considered. CONCLUSIONS: There was no statistical evidence of greater efficacy for apremilast versus methotrexate. The $187,888 incremental cost per PASI 75 may exceed what payers are willing to pay.

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.

An indirect comparison and cost per responder analysis of adalimumab, methotrexate and apremilast in the treatment of methotrexate-naïve patients with psoriatic arthritis.

OBJECTIVE: Apremilast was recently approved for the treatment of active psoriatic arthritis (PsA). However, no studies compare apremilast with methotrexate or biologic therapies, so its relative comparative efficacy remains unknown. This study compared the response rates and incremental costs per responder associated with methotrexate, apremilast, and biologics for the treatment of active PsA. METHODS: A systematic literature review was performed to identify phase 3 randomized controlled clinical trials of approved biologics, methotrexate, and apremilast in the methotrexate-naïve PsA population. Using Bayesian methods, a network meta-analysis was conducted to indirectly compare rates of achieving a ≥20% improvement in American College of Rheumatology component scores (ACR20). The number needed to treat (NNT) and the incremental costs per ACR20 responder (2014 US$) relative to placebo were estimated for each of the therapies. RESULTS: Three trials (MIPA for methotrexate, PALACE-4 for apremilast, and ADEPT for adalimumab) met all inclusion criteria. The NNTs relative to placebo were 2.63 for adalimumab, 6.69 for apremilast, and 8.31 for methotrexate. Among methotrexate-naïve PsA patients, the 16 week incremental costs per ACR20 responder were $3622 for methotrexate, $26,316 for adalimumab, and $45,808 for apremilast. The incremental costs per ACR20 responder were $222,488 for apremilast vs. methotrexate. CONCLUSION: Among methotrexate-naive PsA patients, adalimumab was found to have the lowest NNT for one additional ACR20 response and methotrexate was found to have the lowest incremental costs per ACR20 responder. There was no statistical evidence of greater efficacy for apremilast vs. methotrexate. A head-to-head trial between apremilast and methotrexate is recommended to confirm this finding.

Physician experiences and preferences in the treatment of HR+/HER2- metastatic breast cancer in the United States: a physician survey.

Sequential endocrine therapy (ET) is recommended for postmenopausal women with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (mBC) and without visceral symptoms. Chemotherapy (CT) can be considered after sequential ETs, but is associated with adverse side effects. We assessed physicians' preferences and self-reported prescribing patterns for ET and CT in the treatment of HR+/HER2- mBC at community practices in the United States. Community-based oncologists/hematologists from a nationwide online panel who treated postmenopausal women with HR+/HER2- mBC were invited to complete a survey, blinded to the identity of study sponsor. Treatment preferences were collected by treatment class of ET-based regimens versus CT and by agent for postmenopausal HR+/HER2- mBC patients after prior nonsteroidal aromatase inhibitor use in the adjuvant or mBC setting. Among 213 physicians who completed the survey, 78% were male, 71% were based in small/intermediate practices (2-9 oncologists/subspecialists), 55% had >10 years of experience, and 58% referred to the National Comprehensive Cancer Network Guidelines when treating mBC. Among first-line ETs, anastrozole was the most frequently used treatment (35%), followed by everolimus-based (EVE, 34%) and fulvestrant-based (FUL, 15%) therapy. After first-line ET, the most preferred second- and third-line treatments were ET monotherapy (48% and 39%), ET combination therapy (31% and 19%), and CT monotherapy (13% and 30%). Comparing EVE versus FUL, physicians preferred EVE in all lines but first line. Efficacy was the most important consideration for treatment choice. Physicians prescribed CT in early lines mainly because of visceral symptoms. This survey of treatment patterns for HR+/HER2- mBC in community practice suggested that after first-line ET, ET mono- or combination therapy was commonly used for the second- and third-line treatments and CT monotherapy for third- or later line treatments. CTs were used in early lines for patients with visceral symptoms.

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.

Clinical Outcomes with First-line Endocrine Therapy or Chemotherapy in Postmenopausal HR+/HER2- Metastatic Breast Cancer.

OBJECTIVE: To describe patient profiles and clinical outcomes associated with first-line endocrine monotherapy (ET) and chemotherapy (CT) for postmenopausal HR+/HER2- metastatic breast cancer (mBC) patients. METHODS: This is a retrospective chart review of 139 postmenopausal HR+/HER2- mBC patients initiating first-line ET monotherapy or CT. Overall survival (OS) was described using Kaplan-Meier curves. Exploratory comparative proportional hazards regression was conducted. RESULTS: Patients on first-line CT had significantly more frequent liver metastases than patients on first-line ET monotherapy at baseline. The median OS was 35.5 months [95% confidence interval (CI), 22.7-41.2 months] for patients on first-line ET monotherapy and 22.2 months (95% CI, 13.6-25.9 months) for those on first-line CT (P = 0.021). Adjusting for baseline characteristics, the OS between first-line ET monotherapy and CT was not significantly different. CONCLUSIONS: Patients who were prescribed CT as first-line treatment had evidence of more advanced disease at baseline and shorter OS than those who received ET monotherapy as first-line treatment, suggesting a need for additional safe and effective treatment options for these patients.

Brain MRI lesions and atrophy are associated with employment status in patients with multiple sclerosis.

Multiple sclerosis (MS) commonly affects occupational function. We investigated the link between brain MRI and employment status. Patients with MS (n = 100) completed a Work Productivity and Activity Impairment (WPAI) (general health version) survey measuring employment status, absenteeism, presenteeism, and overall work and daily activity impairment. Patients "working for pay" were considered employed; "temporarily not working but looking for work," "not working or looking for work due to age," and "not working or looking for work due to disability" were considered not employed. Brain MRI T1 hypointense (T1LV) and T2 hyperintense (T2LV) lesion volumes were quantified. To assess lesional destructive capability, we calculated each subject's ratio of T1LV to T2LV (T1/T2). Normalized brain parenchymal volume (BPV) assessed brain atrophy. The mean (SD) age was 45.5 (9.7) years; disease duration was 12.1 (8.1) years; 75 % were women, 76 % were relapsing-remitting, and 76 % were employed. T1LV, T1/T2, Expanded Disability Status Scale (EDSS) scores, and activity impairment were lower and BPV was higher in the employed vs. not employed group (Wilcoxon tests, p < 0.05). Age, disease duration, MS clinical subtype, and T2LV did not differ between groups (p > 0.05). In multivariable logistic regression modeling, adjusting for age, sex, and disease duration, higher T1LV predicted a lower chance of employment (p < 0.05). Pearson correlations showed that EDSS was associated with activity impairment (p < 0.05). Disease duration, age, and MRI measures were not correlated with activity impairment or other WPAI outcomes (p > 0.05). We report a link between brain atrophy and lesions, particularly lesions with destructive potential, to MS employment status.