Omalizumab response in patients with asthma by number and type of allergen.

BACKGROUND: The anti-immunoglobulin E therapy, omalizumab, improves asthma control and reduces exacerbations in patients with moderate-to-severe allergic asthma. However, it has been suggested that omalizumab should be reserved for highly allergic patients with multiple allergen sensitivities or perennial-only sensitivities. OBJECTIVE: To examine impact of allergy burden, including number and type of allergen sensitivities, on omalizumab response in a real-world setting. METHODS: This post hoc analysis evaluated a subset of omalizumab-treated patients from the Prospective Observational Study to Evaluate Predictors of Clinical Effectiveness in Response to Omalizumab (NCT01922037) who had completed 13 allergen assessments (N=478). Patients were classified by allergen burden (nonsensitized, 1, 2-4, or ≥5 allergen sensitivities) and type of allergen (nonsensitized, seasonal, perennial, or both). Outcome measures included exacerbation rate vs previous year and improvements in lung function and Asthma Quality of Life Questionnaire (AQLQ). RESULTS: Comparable adjusted exacerbation rates were observed after omalizumab initiation, regardless of number or type of allergen sensitizations (0.56-0.85/y). Improvements in forced expiratory volume in 1 second from baseline at months 6 (0.03-0.09 L) and 12 (-0.08 to 0.08 L) were also similar across subgroups. Least squares mean change in AQLQ from baseline at months 6 (1.0-1.2) and 12 (1.1-1.4) was comparable across patient subgroups, and similar percentages of patients achieved AQLQ minimal clinically important difference of at least a 0.5-point improvement at month 6 (71%-75%), which was maintained or improved to month 12 (71%-89%). In all analyses, 95% confidence intervals overlapped. CONCLUSION: Overall findings suggest that patients with allergic asthma achieved comparable improvements across distinct outcome measures after omalizumab therapy in a real-world setting, regardless of number and type of allergen sensitizations. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01922037.

No difference in omalizumab efficacy in patients with asthma by number of asthma-related and allergic comorbidities.

BACKGROUND: Comorbidities are common in asthma and may complicate treatment response. OBJECTIVE: To examine response to omalizumab in patients with moderate-to-severe allergic asthma by asthma-related and allergic comorbidities. METHODS: Patients aged 12 years or more from placebo-controlled 008/009 (n = 1071), EXTRA (n = 848), and INNOVATE (n = 419), and single-armed PROSPERO (n = 801) omalizumab studies were included. Poisson regression/analysis of covariance models were used to estimate adjusted exacerbation rates and forced expiratory volume in 1 second (FEV1) change from baseline after omalizumab initiation for subgroups by number of comorbidities (0, 1 [008/009]; 0, 1, ≥2 [EXTRA and INNOVATE]; 0, 1, 2, ≥3 [PROSPERO]). Self-reported comorbidities included allergic rhinoconjunctivitis, chronic rhinosinusitis, recurrent acute sinusitis, nasal polyps, atopic and contact dermatitis, urticaria, food allergy, anaphylaxis, other allergies, gastroesophageal reflux disease, eosinophilic esophagitis, and eosinophilic granulomatosis with polyangiitis. RESULTS: In the EXTRA and INNOVATE studies, no consistent pattern was observed for placebo-corrected relative rate reduction in normalized asthma exacerbations among omalizumab-treated comorbidity subgroups. In PROSPERO, on-study exacerbation rates in the comorbidity subgroups were similar (0, 0.68; 1, 0.70; 2, 0.77; ≥3, 0.80). FEV1 improvements were observed throughout the study for omalizumab vs placebo for all comorbidity subgroups. There were no consistent differences in FEV1 improvements among comorbidity subgroups in 008/009, EXTRA, or INNOVATE. Similarly, no among-group differences were observed for FEV1 change from baseline at month 12 in PROSPERO (0, 0.05 L; 1, 0.08 L; 2, 0.00 L; ≥3, 0.04 L). The 95% confidence intervals overlapped substantially in all instances. CONCLUSION: In these analyses of placebo-controlled/single-armed studies, on-study exacerbation rates and FEV1 improvements with omalizumab treatment were similar irrespective of comorbidity burden. TRIAL REGISTRATION: ClinicalTrials.gov identifiers are as follows: EXTRA, NCT00314574 (https://clinicaltrials.gov/ct2/show/NCT00314574); INNOVATE, NCT00046748 (https://clinicaltrials.gov/ct2/show/NCT00046748); and PROSPERO, NCT01922037 (https://clinicaltrials.gov/ct2/show/NCT01922037).

Assessing the discordance rate between local and central HER2 testing in women with locally determined HER2-negative breast cancer.

BACKGROUND: The importance of human epidermal growth factor receptor 2 (HER2) as a prognostic and predictive marker in invasive breast cancer is well established. Accurate assessment of HER2 status is essential to determine optimal treatment options. METHODS: Breast cancer tumor tissue samples from the VIRGO observational cohort tissue substudy that were locally HER2-negative were retested centrally with both US Food and Drug Administration (FDA)-approved immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) assays, using FDA-approved assay cutoffs; results were compared. RESULTS: Of the 552 unique patient samples centrally retested with local HER2-negative results recorded, tumor samples from 22 (4.0%) patients were determined to be HER2-positive (95% confidence interval [CI] = 2.5%-5.7%). Of these, 18 had been tested locally by only one testing methodology; 15 of 18 were HER2-positive after the central retesting, based on the testing methodology not performed locally. Compared with the 530 patients with centrally confirmed HER2-negative tumors, the 22 patients with centrally determined HER2-positive tumors were younger (median age 56.5 versus 60.0 years) and more likely to have ER/PR-negative tumors (27.3% versus 22.3%). These patients also had shorter median progression-free survival (6.4 months [95% CI = 3.8-15.9 months] versus 9.1 months [95% CI = 8.3-10.3 months]) and overall survival (25.9 months [95% CI = 13.8-not estimable] versus 27.9 months [95% CI = 25.0-32.9 months]). CONCLUSIONS: This study highlights the limitations of employing just one HER2 testing methodology in current clinical practice. It identifies a cohort of patients who did not receive potentially efficacious therapy because their tumor HER2-positivity was not determined by the test initially used. Because of inherent limitations in testing methodologies, it is inadvisable to rely on a single test to rule out potential benefit from HER2-targeted therapy.

Treatment patterns and clinical outcomes for patients with de novo versus recurrent HER2-positive metastatic breast cancer.

Improvements in screening and adjuvant therapy for breast cancer are associated with decreased recurrence, which may have the effect of increasing the proportion of patients presenting with first-line de novo versus recurrent metastatic breast cancer (MBC). Here, we describe and compare patients with de novo versus recurrent human epidermal growth factor 2 (HER2)-positive MBC. registHER was a prospective observational cohort study (late 2003-early 2006) of 1,023 patients with HER2-positive MBC. Baseline characteristics, treatment patterns, and clinical outcomes were examined in patients with newly diagnosed de novo (n = 327) compared with recurrent HER2-positive MBC after prior treatment for early-stage disease (n = 674). Patients with de novo HER2-positive MBC were less likely to have lung metastases, more likely to have lymph node, bone, and/or liver metastases and >4 sites of metastases and more likely to receive combined or concurrent chemotherapy and hormonal therapy with or without trastuzumab than those with recurrent HER2-positive MBC. Median follow-up was 29 months. Median progression-free survival was 12.1 versus 9.3 months [hazard ratio = 0.716 (95 % confidence interval (CI) 0.617-0.831)], and overall survival was 41.7 versus 32.8 months [hazard ratio = 0.766 (95 % CI 0.633-0.928)] for patients with de novo versus recurrent HER2-positive MBC, respectively. Patients with recurrent HER2-positive MBC had similar outcomes regardless of whether they received prior adjuvant therapy, excluding hormonal therapy. Despite presenting with more advanced-stage disease and higher tumor burdens, patients with de novo HER2-positive MBC have more favorable clinical outcomes than those with recurrent HER2-positive MBC. These differences may be due to effects of prior drug exposure and could have implications for designing and interpreting clinical trials.

The SystHERs registry: an observational cohort study of treatment patterns and outcomes in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer.

BACKGROUND: Amplification of the human epidermal growth factor receptor 2 (HER2) gene occurs in approximately 20% of invasive breast cancer cases and is associated with a more aggressive disease course than HER2-negative breast cancer. HER2-targeted therapies have altered the natural history of HER2-positive breast cancer, a trend that will likely further improve with the recent approval of new agents. A prospective, observational cohort study was designed and initiated to provide real-world insights into current treatment patterns, long-term survival, and patients' experiences with initial and subsequent treatments for HER2-positive metastatic breast cancer (MBC). METHODS/DESIGN: The Systematic Therapies for HER2-positive Metastatic Breast Cancer Study (SystHERs) is a US-based prospective observational cohort study enrolling patients ≥18 years of age with recently diagnosed HER2-positive MBC not previously treated with systemic therapy in the metastatic setting. The primary objective of the study is to identify treatment patterns and clinical outcomes in recently diagnosed patients in a variety of practice settings. Secondary objectives include comparative efficacy, safety, and patient-reported outcomes (PROs). Healthcare resource utilization is an exploratory end point. Tumor tissue and blood sample collection is optional.The SystHERs registry will enroll approximately 1000 patients over a 3-year period, after which the study will continue for ≥5 years, allowing for a maximum follow-up of 8 years. The treating physician will determine all care and the frequency of visits. PRO measures will be completed at study enrollment and every 90 days. Clinical data will be abstracted quarterly from patient records. The first patient was enrolled in June 2012, and preliminary descriptive data based on 25% to 30% of the final study population are expected at the end of 2013, and as of April 25, 2014, 386 patients are enrolled. DISCUSSION: SystHERs is expected to provide in-depth data on demographic, clinicopathological, and treatment patterns and their associations with clinical outcomes, PROs, and healthcare resource utilization. Tumor tissue and DNA repositories will also be established for use in future translational research. TRIAL REGISTRATION NUMBER: NCT01615068 (ClinicalTrials.gov identifier).

First-line treatment patterns and clinical outcomes in patients with HER2-positive and hormone receptor-positive metastatic breast cancer from registHER.

BACKGROUND: Limited data are available describing the natural history of patients with HER2-positive and hormone receptor (HR)-positive metastatic breast cancer (MBC). We examined first-line treatment patterns and clinical outcomes in patients with HER2-positive, HR-positive MBC in a real-world setting. METHODS: registHER is a prospective, observational cohort of 1,023 patients with HER2-positive MBC diagnosed within 6 months of enrollment and followed until death, disenrollment, or June 2009 (median follow-up time: 27 months). Demographics, first-line treatment patterns, and clinical outcomes were examined for 530 HER2-positive, HR-positive patients. Progression-free survival (PFS) and overall survival (OS) times were examined. Multivariate analyses adjusted for baseline demographic and prognostic factors. RESULTS: HER2-positive, HR-positive patients receiving first-line trastuzumab plus hormonal therapy had significantly longer PFS times than patients who received hormonal therapy only (13.8 vs. 4.8 months; adjusted hazard ratio [HR]: 0.37, 95% confidence interval [CI]: 0.22-0.60); a nonsignificant reduction in OS time was observed (adjusted HR: 0.55, 95% CI: 0.27-1.14). Compared with patients who received first-line trastuzumab plus chemotherapy, patients who received first-line trastuzumab plus chemotherapy and hormonal therapy had longer median PFS times (20.4 months vs. 9.5 months; adjusted HR: 0.53, 95% CI: 0.42-0.68); a statistically significant reduction in risk of death was observed (adjusted HR: 0.50, 95% CI: 0.36-0.70). Sequential use of chemotherapy and hormonal therapy was associated with improved OS times when compared with concurrent use (adjusted PFS HR: 0.81, 95% CI: 0.54-1.21; adjusted OS HR: 0.48, 95% CI: 0.26-0.89). CONCLUSIONS: These real-world data in patients with HER2-positive/HR-positive MBC provide evidence that, with or without chemotherapy, dual targeting of HRs and HER2 receptors is associated with significantly prolonged PFS and OS times.

Racial disparities in treatment patterns and clinical outcomes in patients with HER2-positive metastatic breast cancer.

Data characterizing demographics, treatment patterns, and clinical outcomes in black patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) are limited. registHER is a large, observational cohort study of patients (n = 1,001) with HER2-positive MBC diagnosed ≤6 months of enrollment and followed until death, disenrollment, or June 2009 (median follow-up of 27 months). Demographics, treatment patterns, and clinical outcomes were described for black (n = 126) and white patients (n = 793). Progression-free survival (PFS) following first-line therapy and overall survival (OS) were examined. Multivariate analyses adjusted for baseline and treatment factors. Black patients were more likely than white patients to be obese (body mass index ≥30), to have diabetes, and to have a history of cardiovascular disease; they were also less likely to have estrogen receptor or progesterone receptor positive disease. In patients treated with trastuzumab, the incidence of cardiac safety events (grade ≥3) was higher in black patients (10.9 %) than in white patients (7.9 %). Unadjusted median OS and PFS (months) were significantly lower in black patients than in white patients (OS: black: 27.1, 95 % confidence interval [CI] 21.3-32.1; white: 37.3, 95 % CI 34.6-41.1; PFS: black: 7.0, 95 % CI 5.7-8.2; white: 10.2, 95 % CI 9.3-11.2). The adjusted OS hazard ratio (HR) for black patients compared with white patients was 1.29 (95 % CI 1.00-1.65); adjusted PFS HR was 1.29 (95 % CI 1.05-1.59). This real-world evaluation of a large cohort of patients with HER2-positive MBC shows poorer prognostic factors and independently worse clinical outcomes in black versus white patients. Further research is needed to identify potential biologic differences that could have predictive impact for black patients or that could explain these differences.

Defining the Efficacy of Omalizumab in Nasal Polyposis: A POLYP 1 and POLYP 2 Subgroup Analysis.

BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a heterogeneous disease with variable underlying pathophysiologies. Numerous patient factors have been linked to differences in disease severity, control, and response to treatment, including asthma status, aspirin sensitivity, previous sinonasal surgery, and blood eosinophil levels. OBJECTIVE: The present study examines the efficacy of the anti-immunoglobulin E therapy, omalizumab, versus placebo in patients with CRSwNP from the replicate POLYP 1 (NCT03280550) and POLYP 2 (NCT03280537) trials, grouped by inherent patient characteristics to determine the response to therapy. METHODS: Patients in prespecified subgroups from POLYP 1 and POLYP 2 (studies pooled for analysis) were examined. Subgroups included blood eosinophil count at baseline (>300 or ≤300 cells/µL), previous sinonasal surgery (yes or no), asthma status (yes or no), and aspirin sensitivity status (yes or no). Subgroups were examined for subgroup-specific adjusted mean difference (95% confidence interval [CI]) (omalizumab-placebo) in change from baseline at week 24 in Nasal Congestion Score (NCS), Nasal Polyp Score (NPS), Sino-Nasal Outcome Test-22 (SNOT-22), Total Nasal Symptom Score (TNSS), and University of Pennsylvania Smell Identification Test (UPSIT). RESULTS: Adjusted mean difference (95% CI) (omalizumab-placebo) in NCS, NPS, SNOT-22, TNSS, and UPSIT change from baseline at week 24 consistently favored omalizumab treatment over placebo in patients with blood eosinophil count >300 and ≤300 cells/µL, with or without previous sinonasal surgery, asthma, and aspirin sensitivity. CONCLUSION: Together, these data suggest broad efficacy of omalizumab across clinical and patient-reported outcomes in patients with CRSwNP, independent of the underlying patient factors examined, including those with high eosinophil levels and those who have undergone previous surgery, which are associated with high recurrence. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifiers: POLYP 1: ClinicalTrials.gov identifier NCT03280550 (https://clinicaltrials.gov/ct2/show/NCT03280550); POLYP 2: ClinicalTrials.gov identifier NCT03280537 (https://clinicaltrials.gov/ct2/show/NCT03280537).

Omalizumab in Asthma with Fixed Airway Obstruction: Post Hoc Analysis of EXTRA.

BACKGROUND: Although asthma is typically characterized by bronchodilator responsiveness (BDR), fixed airflow obstruction (FAO) occurs in ∼50% of patients with severe asthma. OBJECTIVE: Do FAO/BDR associate with efficacy of omalizumab, a monoclonal antibody that targets IgE? METHODS: In EXTRA, patients aged 12-75 years with inadequately controlled severe allergic asthma despite high-dose inhaled corticosteroids plus long-acting ß2-agonists were randomized to omalizumab (n = 427) or placebo (n = 423) for 48 weeks of treatment. In this post hoc analysis, high/low BDR were defined as ≥12%/<12% increases in baseline forced expiratory volume in 1 second (FEV1) after bronchodilator administration, respectively. FAO presence (+)/absence (-) were defined as baseline postbronchodilator FEV1/forced vital capacity <70%/≥70%, respectively. Poisson regression/analysis of covariance models were used to estimate exacerbation relative rate reductions (RRRs)/least-squares mean changes in FEV1, respectively. RESULTS: In patients with high BDR, omalizumab reduced exacerbations more than placebo over the 48-week treatment period regardless of FAO status (RRR [95% confidence interval (CI)]: FAO+, 59.8% [17.7-80.4%]; FAO-, 44.3% [16.6-62.8%]). Omalizumab improved FEV1 compared with placebo in the FAO-, high BDR subgroup (FEV1 change from baseline [95% CI] for omalizumab vs placebo, 0.065 L [-0.071 to 0.201 L] to 0.236 L [0.112-0.359 L]) across 48 weeks. This was not observed in patients with low BDR, irrespective of FAO. CONCLUSION: Omalizumab was more efficacious than placebo at reducing exacerbations in patients with high, but not low, BDR, regardless of the presence of FAO. Lung function improvement primarily occurred in FAO-, high BDR patients, suggesting that asthma with low BDR may represent a difficult-to-treat phenotype.

Response to Omalizumab in Black and White Patients with Allergic Asthma.

BACKGROUND: Higher asthma burden is more likely to be experienced by Black than White patients. In clinical research, underrepresentation of minority populations is observed. OBJECTIVE: To estimate response to omalizumab in Black and White patients in North America with moderate to severe asthma. METHODS: Data from placebo-controlled (EXTRA) and single-armed (PROSPERO) omalizumab studies were used for this post hoc analysis. We used a Poisson regression model to examine exacerbation rates. An analysis of covariance model was used to estimate placebo-corrected change in FEV1 and Asthma Quality of Life Questionnaire (AQLQ) by racial group. RESULTS: This analysis included 631 White and 176 Black patients from EXTRA and 567 White and 130 Black patients from PROSPERO. In EXTRA, placebo-corrected exacerbation rate reductions (relative rate change [95% confidence interval], 22.6% [2.0-38.9%] vs 22.0% [-18.0% to 48.4%]) and FEV1 improvements were similar for White and Black patients. There was a trend toward greater AQLQ improvements for Black versus White patients (least squares mean treatment differences: 0.0 vs 0.3, 0.6 vs 0.4, and 0.6 vs 0.2 at weeks 16, 32, and 48, respectively) throughout the study. In PROSPERO, on-study exacerbation rates (0.76 [0.65-0.88] vs 0.77 [0.56-1.10]) and AQLQ improvements (least squares mean change from baseline: 1.2 vs 1.2 and 1.3 vs 1.2 at month 6 and end of study, respectively) were similar for White versus Black patients. A trend toward greater FEV1 improvement was observed in White versus Black patients throughout the study. CONCLUSIONS: This analysis of EXTRA and PROSPERO suggests that Black and White patients with moderate to severe asthma experience similar improvements in exacerbations, FEV1, and AQLQ with omalizumab.

The impact of dichotomization in longitudinal data analysis: a simulation study.

In this paper, a simulation study is conducted to systematically investigate the impact of dichotomizing longitudinal continuous outcome variables under various types of missing data mechanisms. Generalized linear models (GLM) with standard generalized estimating equations (GEE) are widely used for longitudinal outcome analysis, but these semi-parametric approaches are only valid under missing data completely at random (MCAR). Alternatively, weighted GEE (WGEE) and multiple imputation GEE (MI-GEE) were developed to ensure validity under missing at random (MAR). Using a simulation study, the performance of standard GEE, WGEE and MI-GEE on incomplete longitudinal dichotomized outcome analysis is evaluated. For comparisons, likelihood-based linear mixed effects models (LMM) are used for incomplete longitudinal original continuous outcome analysis. Focusing on dichotomized outcome analysis, MI-GEE with original continuous missing data imputation procedure provides well controlled test sizes and more stable power estimates compared with any other GEE-based approaches. It is also shown that dichotomizing longitudinal continuous outcome will result in substantial loss of power compared with LMM.

Impact of missing data on type 1 error rates in non-inferiority trials.

In this paper, a simulation study is conducted to systematically investigate the impact of different types of missing data on six different statistical analyses: four different likelihood-based linear mixed effects models and analysis of covariance (ANCOVA) using two different data sets, in non-inferiority trial settings for the analysis of longitudinal continuous data. ANCOVA is valid when the missing data are completely at random. Likelihood-based linear mixed effects model approaches are valid when the missing data are at random. Pattern-mixture model (PMM) was developed to incorporate non-random missing mechanism. Our simulations suggest that two linear mixed effects models using unstructured covariance matrix for within-subject correlation with no random effects or first-order autoregressive covariance matrix for within-subject correlation with random coefficient effects provide well control of type 1 error (T1E) rate when the missing data are completely at random or at random. ANCOVA using last observation carried forward imputed data set is the worst method in terms of bias and T1E rate. PMM does not show much improvement on controlling T1E rate compared with other linear mixed effects models when the missing data are not at random but is markedly inferior when the missing data are at random.

Treatment Benefit with Omalizumab in Children by Indicators of Asthma Severity.

BACKGROUND: Greater severity in childhood asthma negatively impacts functioning and quality of life. Omalizumab is effective in children aged 6 years or older with moderate to severe persistent asthma, but predicting responsiveness in severe disease requires further study. OBJECTIVE: To assess response to omalizumab treatment among children using indicators of asthma severity. METHODS: Post hoc analyses of randomized placebo-controlled studies of omalizumab (Inner-City Anti-IgE Therapy for Asthma [ICATA], IA05, and Preventative Omalizumab or Step-up Therapy for Fall Exacerbations [PROSE]) stratified by body mass index, eosinophil count, fractional exhaled nitric oxide levels, and baseline severity indicators (baseline percent predicted FEV1, previous hospitalizations, asthma exacerbations). Poisson regression analysis examined exacerbation rate reductions for body mass index, biomarkers, and severity indicators. RESULTS: Children aged 6 to 11 years in IA05 (N = 576; 56% white, 17% black, 26% other/missing), ICATA (N = 237; 55% black, 43% Hispanic), and PROSE (N = 342; 59% black, 35% Hispanic) were included. Trends indicative of greater exacerbation rate change ([omalizumab - placebo]/placebo) were observed for low baseline lung function (IA05 percent predicted FEV1: <90%, 36% reduction, 95% CI, -53.3 to -13.5; ≥90%, 22% reduction, 95% CI, -52.1 to 27.5), previous hospitalizations (ICATA: 46% reduction with, 95% CI, -69.7 to -3.9; 24% reduction without, 95% CI, -48.1 to 10.3), frequent baseline exacerbations (IA05: ≥3, 42% reduction, 95% CI, -60.4 to -14.1; <3, 20% reduction, 95% CI, -45.2 to -15.9), and high baseline eosinophil count (IA05: ≥300 cells/µL, 39% reduction, 95% CI, -56.4 to -14.7; <300 cells/µL, 5% reduction, 95% CI, -40.6 to 52.1). CONCLUSIONS: Omalizumab reduces exacerbations in children with moderate to severe persistent allergic asthma, and may provide greater benefit in children with more severe asthma subtypes.

Targeted Therapy for Advanced Solid Tumors on the Basis of Molecular Profiles: Results From MyPathway, an Open-Label, Phase IIa Multiple Basket Study.

Purpose Detection of specific molecular alterations in tumors guides the selection of effective targeted treatment of patients with several types of cancer. These molecular alterations may occur in other tumor types for which the efficacy of targeted therapy remains unclear. The MyPathway study evaluates the efficacy and safety of selected targeted therapies in tumor types that harbor relevant genetic alterations but are outside of current labeling for these treatments. Methods MyPathway ( ClinicalTrials.gov identifier: NCT02091141) is a multicenter, nonrandomized, phase IIa multiple basket study. Patients with advanced refractory solid tumors harboring molecular alterations in human epidermal growth factor receptor-2, epidermal growth factor receptor, v-raf murine sarcoma viral oncogene homolog B1, or the Hedgehog pathway are treated with pertuzumab plus trastuzumab, erlotinib, vemurafenib, or vismodegib, respectively. The primary end point is investigator-assessed objective response rate within each tumor-pathway cohort. Results Between April 1, 2014 and November 1, 2016, 251 patients with 35 different tumor types received study treatment. The efficacy population contains 230 treated patients who were evaluated for response or discontinued treatment before evaluation. Fifty-two patients (23%) with 14 different tumor types had objective responses (complete, n = 4; partial, n = 48). Tumor-pathway cohorts with notable objective response rates included human epidermal growth factor receptor-2-amplified/overexpressing colorectal (38% [14 of 37]; 95% CI, 23% to 55%) and v-raf murine sarcoma viral oncogene homolog B1 V600-mutated non-small-cell lung cancer (43% [six of 14]; 95% CI, 18% to 71%). Conclusion The four currently approved targeted therapy regimens in the MyPathway study produced meaningful responses when administered without chemotherapy in several refractory solid tumor types not currently labeled for these agents.

HER2-Positive Metastatic Breast Cancer Patients Receiving Pertuzumab in a Community Oncology Practice Setting: Treatment Patterns and Outcomes.

BACKGROUND: Pertuzumab (Perjeta®), a HER2/neu receptor antagonist, was approved by the US Food and Drug Administration in June 2012 for use in the first-line setting for patients with HER2-positive metastatic breast cancer (mBC). OBJECTIVE: This retrospective study investigated the clinical and demographic characteristics, treatment patterns, safety, and clinical outcomes for patients with HER2-positive mBC who received pertuzumab in the first-line setting in US community oncology practices. METHODS: Patients with HER2-positive mBC, who initiated pertuzumab within 60 days of mBC diagnosis between June 2012 and June 2014, followed through December 2014, had ≥2 visits within the McKesson Specialty Health/US Oncology Network, and were not on clinical trials during the study period, were eligible. This study utilized iKnowMed electronic health records, Claims Data Warehouse, and Social Security Death Index. Progression-free survival (PFS) was assessed by Kaplan-Meier methods. RESULTS: A total of 266 patients met the selection criteria. A vast majority of the patients (249/266, 93.6%) received a trastuzumab + pertuzumab + taxane (H + P + T) regimen. The number of patients with prior adjuvant/neoadjuvant therapy was higher than the CLEOPATRA trial, but age (median 57 years) and percentage of visceral disease (74.8%) were similar. The most common adverse events were fatigue (50.8%), diarrhea (44.7%), nausea (35.3%), peripheral neuropathy (33.5%), neutropenia (24.9%), and rash (24.4%). The median PFS was 16.9 months (95% CI 14.2-19.7). CONCLUSIONS: In this retrospective study of patients with HER2-positive mBC receiving pertuzumab in the first-line setting, most patients were treated with H + P + T. The safety and PFS of H + P + T were consistent with those observed in the pivotal trial.

Blood pressure as an independent prognostic factor in acute ischemic stroke.

BACKGROUND AND PURPOSE: Blood pressure is elevated in most patients during acute ischemic stroke, but the prognostic significance of this is unclear as the current data yield conflicting results. METHODS: Admission blood pressure from the 1281 patients in the Trial of ORG 10172 in Acute Stroke Treatment (TOAST) was analyzed for prognostic significance as well as the risk of hemorrhagic transformation. We also examined weighted-average blood pressure over seven days, and the impact of a 30% change in blood pressure in 24 hours. Patients with severe hypertension were excluded from the TOAST trial. RESULTS: Increasing systolic blood pressure (SBP) on admission, but not diastolic (DBP) or mean arterial pressure (MAP) was predictive of poor outcome, but this effect was not significant after adjustment for other know prognostic factors. Increasing weighted-average SBP and MAP over seven days were predictive for poor outcome, but a 30% change in blood pressure over 24 hours was not. CONCLUSIONS: Admission blood pressure is not an independent prognostic factor in acute ischemic stroke, but the weighted-average of SBP and MAP over seven days probably does have predictive value with higher values having a worse prognosis. A prospective trial of blood pressure control during acute stroke is needed.