Summary Background Nivolumab has shown improved survival in the treatment of advanced non-small-cell lung cancer (NSCLC) previously treated with chemotherapy. We assessed the safety and activity of ...combination nivolumab plus ipilimumab as first-line therapy for NSCLC. Methods The open-label, phase 1, multicohort study (CheckMate 012) cohorts reported here were enrolled at eight US academic centres. Eligible patients were aged 18 years or older with histologically or cytologically confirmed recurrent stage IIIb or stage IV, chemotherapy-naive NSCLC. Patients were randomly assigned (1:1:1) by an interactive voice response system to receive nivolumab 1 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks, nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 12 weeks, or nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks until disease progression, unacceptable toxicities, or withdrawal of consent. Data from the latter two cohorts, which were considered potentially suitable for further clinical development, are presented in this report; data from the other cohort (as well as several earlier cohorts) are described in the appendix . The primary outcome was safety and tolerability, assessed in all treated patients. This ongoing study is registered with ClinicalTrials.gov , number NCT01454102. Findings Between May 15, 2014, and March 25, 2015, 78 patients were randomly assigned to receive nivolumab every 2 weeks plus ipilimumab every 12 weeks (n=38) or nivolumab every 2 weeks plus ipilimumab every 6 weeks (n=40). One patient in the ipilimumab every-6-weeks cohort was excluded before treatment; therefore 77 patients actually received treatment (38 in the ipilimumab every-12-weeks cohort; 39 in the ipilimumab every-6-weeks cohort). At data cut-off on Jan 7, 2016, 29 (76%) patients in the ipilimumab every-12-weeks cohort and 32 (82%) in the ipilimumab every-6-weeks cohort had discontinued treatment. Grade 3–4 treatment-related adverse events occurred in 14 (37%) patients in the ipilimumab every-12-weeks cohort and 13 (33%) patients in the every-6-weeks cohort; the most commonly reported grade 3 or 4 treatment-related adverse events were increased lipase (three 8% and no patients), pneumonitis (two 5% and one 3% patients), adrenal insufficiency (one 3% and two 5% patients), and colitis (one 3% and two 5% patients). Treatment-related serious adverse events were reported in 12 (32%) patients in the ipilimumab every-12-weeks cohort and 11 (28%) patients in the every-6-weeks cohort. Treatment-related adverse events (any grade) prompted treatment discontinuation in four (11%) patients in the every-12-weeks cohort and five (13%) patients in the every-6-weeks cohort. No treatment-related deaths occurred. Confirmed objective responses were achieved in 18 (47% 95% CI 31–64) patients in the ipilimumab every-12-weeks cohort and 15 (38% 95% CI 23–55) patients in the ipilimumab every-6-weeks cohort; median duration of response was not reached in either cohort, with median follow-up times of 12·8 months (IQR 9·3–15·5) in the ipilimumab every-12-weeks cohort and 11·8 months (6·7–15·9) in the ipilimumab every-6-weeks cohort. In patients with PD-L1 of 1% or greater, confirmed objective responses were achieved in 12 (57%) of 21 patients in the ipilimumab every-12-weeks cohort and 13 (57%) of 23 patients in the ipilimumab every-6-weeks cohort. Interpretation In NSCLC, first-line nivolumab plus ipilimumab had a tolerable safety profile and showed encouraging clinical activity characterised by a high response rate and durable response. To our knowledge, the results of this study are the first suggestion of improved benefit compared with anti-PD-1 monotherapy in patients with NSCLC, supporting further assessment of this combination in a phase 3 study. Funding Bristol-Myers Squibb.
Summary Background The irreversible ErbB family blocker afatinib and the reversible EGFR tyrosine kinase inhibitor gefitinib are approved for first-line treatment of EGFR mutation-positive ...non-small-cell lung cancer (NSCLC). We aimed to compare the efficacy and safety of afatinib and gefitinib in this setting. Methods This multicentre, international, open-label, exploratory, randomised controlled phase 2B trial (LUX-Lung 7) was done at 64 centres in 13 countries. Treatment-naive patients with stage IIIB or IV NSCLC and a common EGFR mutation (exon 19 deletion or Leu858Arg) were randomly assigned (1:1) to receive afatinib (40 mg per day) or gefitinib (250 mg per day) until disease progression, or beyond if deemed beneficial by the investigator. Randomisation, stratified by EGFR mutation type and status of brain metastases, was done centrally using a validated number generating system implemented via an interactive voice or web-based response system with a block size of four. Clinicians and patients were not masked to treatment allocation; independent review of tumour response was done in a blinded manner. Coprimary endpoints were progression-free survival by independent central review, time-to-treatment failure, and overall survival. Efficacy analyses were done in the intention-to-treat population and safety analyses were done in patients who received at least one dose of study drug. This ongoing study is registered with ClinicalTrials.gov , number NCT01466660. Findings Between Dec 13, 2011, and Aug 8, 2013, 319 patients were randomly assigned (160 to afatinib and 159 to gefitinib). Median follow-up was 27·3 months (IQR 15·3–33·9). Progression-free survival (median 11·0 months 95% CI 10·6–12·9 with afatinib vs 10·9 months 9·1–11·5 with gefitinib; hazard ratio HR 0·73 95% CI 0·57–0·95, p=0·017) and time-to-treatment failure (median 13·7 months 95% CI 11·9–15·0 with afatinib vs 11·5 months 10·1–13·1 with gefitinib; HR 0·73 95% CI 0·58–0·92, p=0·0073) were significantly longer with afatinib than with gefitinib. Overall survival data are not mature. The most common treatment-related grade 3 or 4 adverse events were diarrhoea (20 13% of 160 patients given afatinib vs two 1% of 159 given gefitinib) and rash or acne (15 9% patients given afatinib vs five 3% of those given gefitinib) and liver enzyme elevations (no patients given afatinib vs 14 9% of those given gefitinib). Serious treatment-related adverse events occurred in 17 (11%) patients in the afatinib group and seven (4%) in the gefitinib group. Ten (6%) patients in each group discontinued treatment due to drug-related adverse events. 15 (9%) fatal adverse events occurred in the afatinib group and ten (6%) in the gefitinib group. All but one of these deaths were considered unrelated to treatment; one patient in the gefitinib group died from drug-related hepatic and renal failure. Interpretation Afatinib significantly improved outcomes in treatment-naive patients with EGFR -mutated NSCLC compared with gefitinib, with a manageable tolerability profile. These data are potentially important for clinical decision making in this patient population. Funding Boehringer Ingelheim.
Background Increased incidence and prevalence of asthma have been documented for perinatally HIV-infected youth 10 to 21 years of age compared with HIV-exposed uninfected (HEU) youth. Objective We ...sought to perform objective pulmonary function tests (PFTs) in HIV-infected and HEU youth with and without diagnosed asthma. Method Asthma was determined in 370 participants (218 HIV-infected and 152 HEU participants) by means of chart review and self-report at 13 sites. Interpretable PFTs (188 HIV-infected and 132 HEU participants) were classified as obstructive, restrictive, or normal, and reversibility was determined after bronchodilator inhalation. Values for HIV-1 RNA, CD4 and CD8 T cells, eosinophils, total IgE, allergen-specific IgE, and urinary cotinine were measured. Adjusted prevalence ratios (PRs) of asthma and PFT outcomes were determined for HIV-infected participants relative to HEU participants, controlling for age, race/ethnicity, and sex. Results Current asthma was identified in 75 (34%) of 218 HIV-infected participants and 38 (25%) of 152 HEU participants (adjusted PR, 1.33; P = .11). The prevalence of obstructive disease did not differ by HIV status. Reversibility was less likely in HIV-infected youth than in HEU youth (17/183 9% vs 21/126 17%; adjusted PR, 0.47; P = .020) overall and among just those with obstructive PFT results (adjusted PR, 0.46; P = .016). Among HIV-infected youth with current asthma, serum IgE levels were inversely correlated with CD8 T-cell counts and positively correlated with eosinophil counts and not associated with CD4 T-cell counts. HIV-infected youth had lower association of specific IgE levels to several inhalant and food allergens compared with HEU participants and significantly lower CD4/CD8 T-cell ratios (suggesting immune imbalance). Conclusion Compared with HEU youth, HIV-infected youth demonstrated decreased reversibility of obstructive lung disease, which is atypical of asthma. This might indicate an early stage of chronic obstructive pulmonary disease. Follow-up into adulthood is warranted to further define their pulmonary outcomes.
Abstract Background & Objectives Palliative systemic therapy is frequently underutilsed in patients with advanced non-small cell lung cancer, for many reasons. The aim of this study was to identify ...patient-reported factors that may predict for treatment decisions and survival in advanced NSCLC, using the Edmonton Symptom Assessment Scale (ESAS), which is a self-reported questionnaire that quantifies symptom burden by asking patients to rate the severity of 9 common symptoms. Methods With ethics approval, we analysed ESAS scores at initial oncology consultation for 461 patients with advanced NSCLC seen at The Ottawa Hospital Cancer Centre (TOHCC) from 2009 to 2012. Subgroup analysis was performed to determine if treatment strategies or overall survival (OS) were related to the total symptom burden, as defined by the sum of the individual ESAS symptom scores. Results The severity of the ESAS total symptom burden score was positively correlated with ECOG performance status (PS) (R=0.48, p<0.0001). Furthermore, patients with a higher symptom burden were less likely to receive systemic chemotherapy than those with fewer symptoms (43% versus 66%, p<0.0001), and had a significantly reduced OS (5.5 versus 9.9 months, p<0.0001). A higher ESAS symptom burden score was also associated with reduced OS by univariate analysis (HR1.78, 95% CI 1.45-2.18, p<0.0001), although multivariate analysis showed only a trend towards significance (HR1.27, 95% CI 0.99-1.62, p=0.06). Conclusions Overall, this demonstrates a novel role for the ESAS as a prognostic tool that could complement existing patient assessment models, such as ECOG PS, in the development of optimal treatment plans and estimation of survival, in patients with advanced lung cancer.
Pulmonary graft-versus-host disease (GVHD) after hematopoietic cell transplant (HCT) and allograft rejection after lung transplant are parallel immunologic processes that lead to significant ...morbidity and mortality. Our murine model of pulmonary GVHD after inhaled lipopolysaccharide (LPS) suggests that innate immune activation potentiates pulmonary transplant-related alloimmunity. We hypothesized that the chemokine (C-X-C motif) receptor 3 (CXCR3) receptor is necessary for the development of LPS-induced pulmonary GVHD.
Recipient mice underwent allogeneic or syngeneic HCT, followed by inhaled LPS. CXCR3 inhibition was performed by using CXCR3-knockout donors or by systemic anti-CXCR3 antibody blockade. Pulmonary histopathology, cellular sub-populations, cytokine proteins, and transcripts were analyzed.
Compared with the lungs of LPS-unexposed and syngeneic controls, lungs of LPS-exposed allogeneic HCT mice demonstrated prominent lymphocytic peri-vascular and peri-bronchiolar infiltrates. This pathology was associated with increased CD4(+) and CD8(+) T cells as well as an increase in CXCR3 expression on T cells, a 2-fold upregulation of CXCR3 transcript, and a 4-fold increase in its ligand CXCL10/Interferon gamma-induced protein 10 kDa (IP-10). CXCR3 inhibition using gene-knockout strategy or antibody blockade did not change the severity of pulmonary pathology, with a mean pathology score of 6.5 for sufficient vs 6.5 for knockout (p = 1.00) and a mean score of 6.8 for antibody blockade vs 7.4 for control (p = 0.46). CXCR3 inhibition did not prevent CD3 infiltration or prevent production of interleukin-12p40 or significantly change other Th1, Th2, or Th17 cytokines in the lung.
In the setting of allogeneic HCT, innate immune activation by LPS potentiates pulmonary GVHD through CXCR3-independent mechanisms. Clinical strategies focused on inhibition of CXCR3 may prove insufficient to ameliorate transplant-related lung disease.
Acute perivascular rejection (AR) is common in lung recipients and increases the risk for chronic lung allograft dysfunction (CLAD). Hyaluronan (HA), an extracellular matrix constituent, accumulates ...in experimental AR and can act as an innate immune agonist, breaking tolerance and potentiating alloimmunity. We previously demonstrated HA accumulates in CLAD after human-lung transplantation. We sought to determine if HA accumulates in the bronchoalveolar lavage fluid (BALF) concurrent with AR in lung recipients.
The cohort consisted of 126 first adult lung recipients at 5 transplant centers with a total of 373 BALF samples collected within the first posttransplant year. All samples were paired with a lung biopsy from the same bronchoscopy. BALF HA (ng/mL) was quantified by ELISA and log-transformed for analysis. Linear-mixed effect models, adjusted for potential confounders, were used to estimate the association between BALF HA concentration and the presence of AR on biopsy. The association between early posttransplant BALF HA levels and the development of CLAD was explored utilizing tertiles of maximum BALF HA level observed within the first 6 months of transplant.
In analyses adjusted for potential confounders, BALF HA concentration was significantly increased in association with AR (change in means on log-scale 0.31; 95% CI, 0.01-0.60;
= 0.044). When considered on the original scale (ng/mL), BALF HA concentrations were 1.36 times (36%) higher, on average, among samples with, versus without, AR. The cumulative incidence of CLAD was numerically higher in individuals in the highest tertiles of BALF HA level within the first 6 months after transplant, as compared with those in the lowest tertile; however, this difference was not statistically significant (
= 0.32).
These results demonstrate accumulation of HA in clinical AR and suggest a mechanism by which innate and adaptive immune activation might interact in the development of AR and CLAD.
Purpose We examined symptom variability in men and women with urological chronic pelvic pain syndrome. We describe symptom fluctuations as related to early symptom regression and its effect on ...estimated 1-year symptom change. We also describe a method to quantify patient specific symptom variability. Materials and Methods Symptoms were assessed biweekly in 424 subjects with urological chronic pelvic pain syndrome during 1 year. To evaluate the impact of early symptom regression subjects were classified as improved, no change or worse according to the rate of change using 1) all data, 2) excluding week 0 and 3) excluding weeks 0 and 2. Patient specific, time varying variability was calculated at each interval using a sliding window approach. Patients were classified as high, medium or low variability at each time and ultimately as high or low variability overall based on the variability for the majority of contacts. Results Prior to excluding early weeks to adjust for early symptom regression 25% to 38% and 5% to 6% of patients were classified as improved and worse, respectively. After adjustment the percent of patients who were improved or worse ranged from 15% to 25% and 6% to 9%, respectively. High and low variability phenotypes were each identified in 25% to 30% of participants. Conclusions Patients with urological chronic pelvic pain syndrome show symptom variability. At study enrollment patients had worse symptoms on average, resulting in a regression effect that influenced the estimated proportion of those who were improved or worse. Prospective studies should include a run-in period to account for regression to the mean and other causes of early symptom regression. Further, symptom variability may be quantified and used to characterize longitudinal symptom profiles of urological chronic pelvic pain syndrome.
Neurological complications are common after lung transplantation. However, no large cohort studies have examined the incidence, predictors, and clinical significance of neurological events sustained ...by lung transplant recipients.
We conducted a retrospective cohort analysis of a consecutive series of lung transplant recipients, transplanted at Duke University Medical Center between May 2014 and February 2017 (n = 276). Early neurological complications (ie, occurring during the first week after transplant) were documented by transplant mental health specialists and included delirium, ischemic injury, and posterior reversible encephalopathy syndrome. Analyses accounted for age, native disease, sex, type of transplant, lung allocation score, and primary graft dysfunction. The objectives of the study were to characterize the prevalence and predictors of early neurological sequelae (NSE), occurring during the first week posttransplant, and the association between NSE and subsequent clinical outcomes, including length of stay and mortality.
Neurological sequelae were common, occurring in 123 (45%) patients. Fifty-seven patients died over a follow-up interval of 2.1 years. The most common NSE were postoperative delirium (n = 110 40%) and posterior reversible encephalopathy syndrome (n = 12 4%), followed by stroke/transient ischemic attack and neurotoxicity. Higher lung allocation score was the strongest predictor of delirium. The presence of a NSE was associated with longer length of hospital stay (32 days vs 17 days,
< 0.001) and greater mortality (hazard ratio, 1.90; 95% confidence interval, 1.09-3.32,
= 0.024), with the greatest mortality risk occurring approximately 2 years after transplantation.
Neurological events are relatively common after lung transplantation and associated with adverse clinical outcomes.
Background Disease heterogeneity in patients with severe asthma and its relationship to inflammatory mechanisms remain poorly understood. Objective We aimed to identify and replicate ...clinicopathologic endotypes based on analysis of blood and sputum parameters in asthmatic patients. Methods One hundred ninety-four asthmatic patients and 21 control subjects recruited from 2 separate centers underwent detailed clinical assessment, sputum induction, and phlebotomy. One hundred three clinical, physiologic, and inflammatory parameters were analyzed by using topological data analysis and Bayesian network analysis. Results Severe asthma was associated with anxiety and depression, obesity, sinonasal symptoms, decreased quality of life, and inflammatory changes, including increased sputum chitinase 3–like protein 1 (YKL-40) and matrix metalloproteinase (MMP) 1, 3, 8, and 12 levels. Topological data analysis identified 6 clinicopathobiologic clusters replicated in both geographic cohorts: young, mild paucigranulocytic; older, sinonasal disease; obese, high MMP levels; steroid resistant TH 2 mediated, eosinophilic; mixed granulocytic with severe obstruction; and neutrophilic, low periostin levels, severe obstruction. Sputum IL-5 levels were increased in patients with severe particularly eosinophilic forms, whereas IL-13 was suppressed and IL-17 levels did not differ between clusters. Bayesian network analysis separated clinical features from intricately connected inflammatory pathways. YKL-40 levels strongly correlated with neutrophilic asthma and levels of myeloperoxidase, IL-8, IL-6, and IL-6 soluble receptor. MMP1, MMP3, MMP8, and MMP12 levels were associated with severe asthma and were correlated positively with sputum IL-5 levels but negatively with IL-13 levels. Conclusion In 2 distinct cohorts we have identified and replicated 6 clinicopathobiologic clusters based on blood and induced sputum measures. Our data underline a disconnect between clinical features and underlying inflammation, suggest IL-5 production is relatively steroid insensitive, and highlight the expression of YKL-40 in patients with neutrophilic inflammation and the expression of MMPs in patients with severe asthma.
Randomized clinical trials, which aim to determine the efficacy and safety of drugs and medical devices, are a complex enterprise with myriad challenges, stakeholders, and traditions. Although the ...primary goal is scientific discovery, clinical trials must also fulfill regulatory, clinical, and ethical requirements. Innovations in clinical trials methodology have the potential to improve the quality of knowledge gained from trials, the protection of human subjects, and the efficiency of clinical research. Adaptive clinical trial methods represent a broad category of innovations intended to address a variety of long-standing challenges faced by investigators, such as sensitivity to previous assumptions and delayed identification of ineffective treatments. The implementation of adaptive clinical trial methods, however, requires greater planning and simulation compared with a more traditional design, along with more advanced administrative infrastructure for trial execution. The value of adaptive clinical trial methods in exploratory phase (phase 2) clinical research is generally well accepted, but the potential value and challenges of applying adaptive clinical trial methods in large confirmatory phase clinical trials are relatively unexplored, particularly in the academic setting. In the Adaptive Designs Accelerating Promising Trials Into Treatments (ADAPT-IT) project, a multidisciplinary team is studying how adaptive clinical trial methods could be implemented in planning actual confirmatory phase trials in an established, National Institutes of Health–funded clinical trials network. The overarching objectives of ADAPT-IT are to identify and quantitatively characterize the adaptive clinical trial methods of greatest potential value in confirmatory phase clinical trials and to elicit and understand the enthusiasms and concerns of key stakeholders that influence their willingness to try these innovative strategies.
PDF
