Safety and clinical activity of atezolizumab plus erlotinib in patients with non-small-cell lung cancer.

BACKGROUND: Acquired resistance limits long-term epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) efficacy in patients with EGFR mutation-positive non-small-cell lung cancer (NSCLC) in whom anti-programmed death-ligand 1 (PD-L1) efficacy is also limited. We hypothesized that combining atezolizumab with erlotinib could enhance antitumor immunity and extend efficacy in these patients. PATIENTS AND METHODS: This open-label phase Ib trial was conducted in adults aged ≥18 years who had advanced, unresectable NSCLC. Stage 1 (safety evaluation) enrolled EGFR TKI-naive patients regardless of EGFR status. Stage 2 (expansion) enrolled patients with EGFR-mutant NSCLC treated with ≤1 prior non-EGFR TKI therapy. Patients received 150 mg erlotinib orally once daily. After a 7-day erlotinib run-in, atezolizumab 1200 mg was administered intravenously every 3 weeks. The primary endpoint was the safety and tolerability of the combination in all patients; secondary endpoints included antitumor activity per RECIST 1.1 in stage 2 patients. RESULTS: At the data cut-off on 7 May 2020, 28 patients (8 in stage 1, 20 in stage 2) were assessable for safety. No dose-limiting toxicities or grade 4 or 5 treatment-related adverse events occurred. Grade 3 treatment-related adverse events occurred in 46% of patients; the most common were increased alanine aminotransferase, diarrhea, pyrexia, and rash (each in 7% of patients). Serious adverse events occurred in 50% of patients. Pneumonitis (grade 1) was reported in a single patient (4%). The objective response rate was 75% [95% confidence interval (CI) 50.9% to 91.3%]), median response duration was 18.9 months (95% CI 9.5-40.5 months), median progression-free survival was 15.4 months (95% CI 8.4-39.0 months), and median overall survival was not estimable (NE) (95% CI 34.6-NE). CONCLUSIONS: Atezolizumab combined with erlotinib demonstrated a tolerable safety profile and encouraging, durable clinical activity in patients with advanced EGFR mutation-positive NSCLC.

APOBEC mutagenesis, kataegis, chromothripsis in EGFR-mutant osimertinib-resistant lung adenocarcinomas.

BACKGROUND: Studies of targeted therapy resistance in lung cancer have primarily focused on single-gene alterations. Based on prior work implicating apolipoprotein b mRNA-editing enzyme, catalytic polypeptide-like (APOBEC) mutagenesis in histological transformation of epidermal growth factor receptor (EGFR)-mutant lung cancers, we hypothesized that mutational signature analysis may help elucidate acquired resistance to targeted therapies. PATIENTS AND METHODS: APOBEC mutational signatures derived from an Food and Drug Administration-cleared multigene panel [Memorial Sloan Kettering Cancer Center Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT)] using the Signature Multivariate Analysis (SigMA) algorithm were validated against the gold standard of mutational signatures derived from whole-exome sequencing. Mutational signatures were decomposed in 3276 unique lung adenocarcinomas (LUADs), including 93 paired osimertinib-naïve and -resistant EGFR-mutant tumors. Associations between APOBEC and mechanisms of resistance to osimertinib were investigated. Whole-genome sequencing was carried out on available EGFR-mutant lung cancer samples (10 paired, 17 unpaired) to investigate large-scale genomic alterations potentially contributing to osimertinib resistance. RESULTS: APOBEC mutational signatures were more frequent in receptor tyrosine kinase (RTK)-driven lung cancers (EGFR, ALK, RET, and ROS1; 25%) compared to LUADs at large (20%, P < 0.001); across all subtypes, APOBEC mutational signatures were enriched in subclonal mutations (P < 0.001). In EGFR-mutant lung cancers, osimertinib-resistant samples more frequently displayed an APOBEC-dominant mutational signature compared to osimertinib-naïve samples (28% versus 14%, P = 0.03). Specifically, mutations detected in osimertinib-resistant tumors but not in pre-treatment samples significantly more frequently displayed an APOBEC-dominant mutational signature (44% versus 23%, P < 0.001). EGFR-mutant samples with APOBEC-dominant signatures had enrichment of large-scale genomic rearrangements (P = 0.01) and kataegis (P = 0.03) in areas of APOBEC mutagenesis. CONCLUSIONS: APOBEC mutational signatures are frequent in RTK-driven LUADs and increase under the selective pressure of osimertinib in EGFR-mutant lung cancer. APOBEC mutational signature enrichment in subclonal mutations, private mutations acquired after osimertinib treatment, and areas of large-scale genomic rearrangements highlights a potentially fundamental role for APOBEC mutagenesis in the development of resistance to targeted therapies, which may be potentially exploited to overcome such resistance.

COVID-19 in patients with lung cancer.

BACKGROUND: Patients with lung cancers may have disproportionately severe coronavirus disease 2019 (COVID-19) outcomes. Understanding the patient-specific and cancer-specific features that impact the severity of COVID-19 may inform optimal cancer care during this pandemic. PATIENTS AND METHODS: We examined consecutive patients with lung cancer and confirmed diagnosis of COVID-19 (n = 102) at a single center from 12 March 2020 to 6 May 2020. Thresholds of severity were defined a priori as hospitalization, intensive care unit/intubation/do not intubate ([ICU/intubation/DNI] a composite metric of severe disease), or death. Recovery was defined as >14 days from COVID-19 test and >3 days since symptom resolution. Human leukocyte antigen (HLA) alleles were inferred from MSK-IMPACT (n = 46) and compared with controls with lung cancer and no known non-COVID-19 (n = 5166). RESULTS: COVID-19 was severe in patients with lung cancer (62% hospitalized, 25% died). Although severe, COVID-19 accounted for a minority of overall lung cancer deaths during the pandemic (11% overall). Determinants of COVID-19 severity were largely patient-specific features, including smoking status and chronic obstructive pulmonary disease [odds ratio for severe COVID-19 2.9, 95% confidence interval 1.07-9.44 comparing the median (23.5 pack-years) to never-smoker and 3.87, 95% confidence interval 1.35-9.68, respectively]. Cancer-specific features, including prior thoracic surgery/radiation and recent systemic therapies did not impact severity. Human leukocyte antigen supertypes were generally similar in mild or severe cases of COVID-19 compared with non-COVID-19 controls. Most patients recovered from COVID-19, including 25% patients initially requiring intubation. Among hospitalized patients, hydroxychloroquine did not improve COVID-19 outcomes. CONCLUSION: COVID-19 is associated with high burden of severity in patients with lung cancer. Patient-specific features, rather than cancer-specific features or treatments, are the greatest determinants of severity.

Clinical and molecular correlates of PD-L1 expression in patients with lung adenocarcinomas.

BACKGROUND: Programmed death-ligand 1 (PD-L1) expression is the only FDA-approved biomarker for immune checkpoint inhibitors (ICIs) in patients with lung adenocarcinoma, but sensitivity is modest. Understanding the impact of molecular phenotype, clinical characteristics, and tumor features on PD-L1 expression is largely unknown and may improve prediction of response to ICI. PATIENTS AND METHODS: We evaluated patients with lung adenocarcinoma for whom PD-L1 testing and targeted next-generation sequencing (using MSK-IMPACT) was performed on the same tissue sample. Clinical and molecular features were compared across PD-L1 subgroups to examine how molecular phenotype associated with tumor PD-L1 expression. In patients treated with anti-PD-(L)1 blockade, we assessed how these interactions impacted efficacy. RESULTS: A total of 1586 patients with lung adenocarcinoma had paired PD-L1 testing and targeted next-generation sequencing. PD-L1 negativity was more common in primary compared to metastatic samples (P < 0.001). The distribution of PD-L1 expression (lymph nodes enriched for PD-L1 high; bones predominantly PD-L1 negative) and predictiveness of PD-L1 expression on ICI response varied by organ. Mutations in KRAS, TP53, and MET significantly associated with PD-L1 high expression (each P < 0.001, Q < 0.001) and EGFR and STK11 mutations associated with PD-L1 negativity (P < 0.001, Q = 0.01; P = 0.001, Q < 0.001, respectively). WNT pathway alterations also associated with PD-L1 negativity (P = 0.005). EGFR and STK11 mutants abrogated the predictive value of PD-L1 expression on ICI response. CONCLUSION: PD-L1 expression and association with ICI response vary across tissue sample sites. Specific molecular features are associated with differential expression of PD-L1 and may impact the predictive capacity of PD-L1 for response to ICIs.

Ultra-deep next-generation sequencing of plasma cell-free DNA in patients with advanced lung cancers: results from the Actionable Genome Consortium.

BACKGROUND: Noninvasive genotyping using plasma cell-free DNA (cfDNA) has the potential to obviate the need for some invasive biopsies in cancer patients while also elucidating disease heterogeneity. We sought to develop an ultra-deep plasma next-generation sequencing (NGS) assay for patients with non-small-cell lung cancers (NSCLC) that could detect targetable oncogenic drivers and resistance mutations in patients where tissue biopsy failed to identify an actionable alteration. PATIENTS AND METHODS: Plasma was prospectively collected from patients with advanced, progressive NSCLC. We carried out ultra-deep NGS using cfDNA extracted from plasma and matched white blood cells using a hybrid capture panel covering 37 lung cancer-related genes sequenced to 50 000× raw target coverage filtering somatic mutations attributable to clonal hematopoiesis. Clinical sensitivity and specificity for plasma detection of known oncogenic drivers were calculated and compared with tissue genotyping results. Orthogonal ddPCR validation was carried out in a subset of cases. RESULTS: In 127 assessable patients, plasma NGS detected driver mutations with variant allele fractions ranging from 0.14% to 52%. Plasma ddPCR for EGFR or KRAS mutations revealed findings nearly identical to those of plasma NGS in 21 of 22 patients, with high concordance of variant allele fraction (r = 0.98). Blinded to tissue genotype, plasma NGS sensitivity for de novo plasma detection of known oncogenic drivers was 75% (68/91). Specificity of plasma NGS in those who were driver-negative by tissue NGS was 100% (19/19). In 17 patients with tumor tissue deemed insufficient for genotyping, plasma NGS identified four KRAS mutations. In 23 EGFR mutant cases with acquired resistance to targeted therapy, plasma NGS detected potential resistance mechanisms, including EGFR T790M and C797S mutations and ERBB2 amplification. CONCLUSIONS: Ultra-deep plasma NGS with clonal hematopoiesis filtering resulted in de novo detection of targetable oncogenic drivers and resistance mechanisms in patients with NSCLC, including when tissue biopsy was inadequate for genotyping.

PD-L1 expression, tumor mutational burden, and response to immunotherapy in patients with MET exon 14 altered lung cancers.

Background: MET exon 14 alterations are actionable oncogenic drivers. Durable responses to MET inhibitors are observed in patients with advanced MET exon 14-altered lung cancers in prospective trials. In contrast, the activity of immunotherapy, PD-L1 expression and tumor mutational burden (TMB) of these tumors and are not well characterized. Patients and methods: Patients with MET exon 14-altered lung cancers of any stage treated at two academic institutions were identified. A review of clinicopathologic and molecular features, and an analysis of response to single-agent or combination immune checkpoint inhibition were conducted. PD-L1 immunohistochemistry was carried out and TMB was calculated by estimation from targeted next-generation sequencing panels. Results: We identified 147 patients with MET exon 14-altered lung cancers. PD-L1 expression of 0%, 1%-49%, and ≥50% were 37%, 22%, and 41%, respectively, in 111 evaluable tumor samples. The median TMB of MET exon 14-altered lung cancers was lower than that of unselected non-small-cell lung cancers (NSCLCs) in both independently evaluated cohorts: 3.8 versus 5.7 mutations/megabase (P < 0.001, n = 78 versus 1769, cohort A), and 7.3 versus 11.8 mutations/megabase (P < 0.001, n = 62 versus 1100, cohort B). There was no association between PD-L1 expression and TMB (Spearman's rho=0.18, P = 0.069). In response-evaluable patients (n = 24), the objective response rate was 17% (95% CI 6% to 36%) and the median progression-free survival was 1.9 months (95% CI 1.7-2.7). Responses were not enriched in tumors with PD-L1 expression ≥50% nor high TMB. Conclusion: A substantial proportion of MET exon 14-altered lung cancers express PD-L1, but the median TMB is lower compared with unselected NSCLCs. Occasional responses to PD-1 blockade can be achieved, but overall clinical efficacy is modest.

Paediatric European Network for Treatment of AIDS (PENTA) guidelines for treatment of paediatric HIV-1 infection 2015: optimizing health in preparation for adult life.

The 2015 Paediatric European Network for Treatment of AIDS (PENTA) guidelines provide practical recommendations on the management of HIV-1 infection in children in Europe and are an update to those published in 2009. Aims of treatment have progressed significantly over the last decade, moving far beyond limitation of short-term morbidity and mortality to optimizing health status for adult life and minimizing the impact of chronic HIV infection on immune system development and health in general. Additionally, there is a greater need for increased awareness and minimization of long-term drug toxicity. The main updates to the previous guidelines include: an increase in the number of indications for antiretroviral therapy (ART) at all ages (higher CD4 thresholds for consideration of ART initiation and additional clinical indications), revised guidance on first- and second-line ART recommendations, including more recently available drug classes, expanded guidance on management of coinfections (including tuberculosis, hepatitis B and hepatitis C) and additional emphasis on the needs of adolescents as they approach transition to adult services. There is a new section on the current ART 'pipeline' of drug development, a comprehensive summary table of currently recommended ART with dosing recommendations. Differences between PENTA and current US and World Health Organization guidelines are highlighted and explained.

Phase 1 study of twice weekly pulse dose and daily low-dose erlotinib as initial treatment for patients with EGFR-mutant lung cancers.

Background: Patients with EGFR-mutant lung cancers treated with EGFR tyrosine kinase inhibitors (TKIs) develop clinical resistance, most commonly with acquisition of EGFR T790M. Evolutionary modeling suggests that a schedule of twice weekly pulse and daily low-dose erlotinib may delay emergence of EGFR T790M. Pulse dose erlotinib has superior central nervous system (CNS) penetration and may result in superior CNS disease control. Methods: We evaluated toxicity, pharmacokinetics, and efficacy of twice weekly pulse and daily low-dose erlotinib. We assessed six escalating pulse doses of erlotinib. Results: We enrolled 34 patients; 11 patients (32%) had brain metastases at study entry. We observed 3 dose-limiting toxicities in dose escalation: transaminitis, mucositis, and rash. The MTD was erlotinib 1200 mg days 1-2 and 50 mg days 3-7 weekly. The most frequent toxicities (any grade) were rash, diarrhea, nausea, fatigue, and mucositis. 1 complete and 24 partial responses were observed (74%, 95% CI 60-84%). Median progression-free survival was 9.9 months (95% CI 5.8-15.4 months). No patient had progression of an untreated CNS metastasis or developed a new CNS lesion while on study (0%, 95% CI 0-13%). Of the 18 patients with biopsies at progression, EGFR T790M was identified in 78% (95% CI 54-91%). Conclusion: This is the first clinical implementation of an anti-cancer TKI regimen combining pulse and daily low-dose administration. This evolutionary modeling-based dosing schedule was well-tolerated but did not improve progression-free survival or prevent emergence of EGFR T790M, likely due to insufficient peak serum concentrations of erlotinib. This dosing schedule prevented progression of untreated or any new central nervous system metastases in all patients.

Antibody-mediated thyroid dysfunction during T-cell checkpoint blockade in patients with non-small-cell lung cancer.

Background: Programmed cell death protein-1 (PD-1) blockade therapies have demonstrated durable responses and prolonged survival in a variety of malignancies. Treatment is generally well tolerated although immune-related adverse events (irAEs) can occur. Autoimmune thyroid dysfunction is among the most common irAE, but an assessment of the clinical, mechanistic, and immunologic features has not been previously described. Patient and methods: Patients with advanced non-small-cell lung cancer (NSCLC) treated with pembrolizumab at Memorial Sloan Kettering Cancer Center (n = 51) as part of KEYNOTE-001 (NCT01295827) were included. Thyroid function test and anti-thyroid antibodies were assessed prospectively at each study visit, beginning before the first treatment. Frequency of development of thyroid dysfunction, association with anti-thyroid antibodies, clinical course, and relationship with progression-free survival and overall survival to treatment with pembrolizumab was evaluated. Results: Of 51 patients treated, 3 were hypothyroid and 48 were not at baseline. Ten of 48 [21%, 95% confidence interval (CI) 10% to 35%] patients developed thyroid dysfunction requiring thyroid replacement. Anti-thyroid antibodies were present in 8 of 10 patients who developed thyroid dysfunction, compared with 3 of 38 who did not (80% versus 8%, P < 0.0001). Thyroid dysfunction occurred early (median, 42 days) in the pembrolizumab course, and a majority (6 of 10 patients) experienced brief, transient hyperthyroidism preceding the onset of hypothyroidism; no persistent hyperthyroidism occurred. Both hyperthyroidism and hypothyroidism were largely asymptomatic. Overall survival with pembrolizumab was significantly longer in subjects who developed thyroid dysfunction (hazard ratio, 0.29; 95% CI 0.09-0.94; P = 0.04). Conclusions: Thyroid dysfunction during pembrolizumab treatment of NSCLC is common and is characterized by early-onset, frequently preceded by transient hyperthyroidism, closely associated with anti-thyroid antibodies, and may be associated with improved outcomes. The presence of antibody-mediated toxicity in T-cell-directed therapy suggests an under-recognized impact of PD-1 biology in modulating humoral immunity.

Postnatal retention in HIV care: insight from the Swiss HIV Cohort Study over a 15-year observational period.

OBJECTIVES: The aim of this study was to quantify loss to follow-up (LTFU) in HIV care after delivery and to identify risk factors for LTFU, and implications for HIV disease progression and subsequent pregnancies. METHODS: We used data on pregnancies within the Swiss HIV Cohort Study from 1996 to 2011. A delayed clinical visit was defined as > 180 days and LTFU as no visit for > 365 days after delivery. Logistic regression analysis was used to identify risk factors for LTFU. RESULTS: A total of 695 pregnancies in 580 women were included in the study, of which 115 (17%) were subsequent pregnancies. Median maternal age was 32 years (IQR 28-36 years) and 104 (15%) women reported any history of injecting drug use (IDU). Overall, 233 of 695 (34%) women had a delayed visit in the year after delivery and 84 (12%) women were lost to follow-up. Being lost to follow-up was significantly associated with a history of IDU [adjusted odds ratio (aOR) 2.79; 95% confidence interval (CI) 1.32-5.88; P = 0.007] and not achieving an undetectable HIV viral load (VL) at delivery (aOR 2.42; 95% CI 1.21-4.85; P = 0.017) after adjusting for maternal age, ethnicity and being on antiretroviral therapy (ART) at conception. Forty-three of 84 (55%) women returned to care after LTFU. Half of them (20 of 41) with available CD4 had a CD4 count < 350 cells/µL and 15% (six of 41) a CD4 count < 200 cells/µL at their return. CONCLUSIONS: A history of IDU and detectable HIV VL at delivery were associated with LTFU. Effective strategies are warranted to retain women in care beyond pregnancy and to avoid CD4 cell count decline. ART continuation should be advised especially if a subsequent pregnancy is planned.

Increases in Condomless Sex in the Swiss HIV Cohort Study.

Condomless sex is a key driver of sexually transmitted diseases. In this study, we assess the long-term changes (2000-2013) of the occurrence of condomless sex among human immunodeficiency virus (HIV)-infected individuals enrolled in the Swiss HIV Cohort study. The frequencies with which HIV-infected individuals reported condomless sex were either stable or only weakly increasing for 2000-2008. For 2008-2013, these rates increased significantly for stable relationships among heterosexuals and men who have sex with men (MSM) and for occasional relationships among MSM. Our results highlight the increasing public health challenge posed by condomless sex and show that condomless sex has been increasing even in the most recent years.

DNA methylation in small cell lung cancer defines distinct disease subtypes and correlates with high expression of EZH2.

Small cell lung cancer (SCLC) is an aggressive malignancy characterized by early metastasis, rapid development of resistance to chemotherapy and genetic instability. This study profiles DNA methylation in SCLC, patient-derived xenografts (PDX) and cell lines at single-nucleotide resolution. DNA methylation patterns of primary samples are distinct from those of cell lines, whereas PDX maintain a pattern closely consistent with primary samples. Clustering of DNA methylation and gene expression of primary SCLC revealed distinct disease subtypes among histologically indistinguishable primary patient samples with similar genetic alterations. SCLC is notable for dense clustering of high-level methylation in discrete promoter CpG islands, in a pattern clearly distinct from other lung cancers and strongly correlated with high expression of the E2F target and histone methyltransferase gene EZH2. Pharmacologic inhibition of EZH2 in a SCLC PDX markedly inhibited tumor growth.

Age and sex differences in the incidence of esophageal adenocarcinoma: results from the Surveillance, Epidemiology, and End Results (SEER) Registry (1973-2008).

Risk factors driving sex disparity in esophageal cancer are unclear. Recent molecular evidence suggests hormonal factors. We conducted a national descriptive epidemiological study to assess the hypothesis that estrogen exposure could explain the male predominance in observed esophageal adenocarcinoma incidence. We analyzed the esophageal cancer incidence trends by histology and sex from 1973 to 2008 in nine population-based cancer registries of the Surveillance, Epidemiology, and End Results (SEER) 9 Registry Database. We used age as a proxy for estrogen exposure in females. The collective age groups annual percentage change in esophageal adenocarcinoma for females is positive (0.03%; 95% confidence interval: 0.02, 0.03%) during the study period. Interestingly, the esophageal adenocarcinoma annual percentage change in incidence rates for females during the same time period is significantly negative from ages 50-54 to ages 60-64. Even though the incidence of esophageal adenocarcinoma rises in both males and females, the male-to-female ratio across age peaks in the 50-54 years then decreases. Furthermore, the esophageal adenocarcinoma age-adjusted incidence rate in postmenopausal females age 80 and above increases with age unlike their male counterparts. Taken together, these data support the hypothesis that the endocrine milieu in pre- and perimenopausal females serves as a protective factor against esophageal adenocarcinoma, and with loss of estrogen or because of the increasing time period away from estrogen exposure, the rate of esophageal adenocarcinoma incidence increases in the older postmenopausal female. Because females comprise the largest portion of the elderly population with esophageal adenocarcinoma, these findings are significant.

Obesity Trends and Body Mass Index Changes After Starting Antiretroviral Treatment: The Swiss HIV Cohort Study.

BACKGROUND: The factors that contribute to increasing obesity rates in human immunodeficiency virus (HIV)-positive persons and to body mass index (BMI) increase that typically occurs after starting antiretroviral therapy (ART) are incompletely characterized. METHODS: We describe BMI trends in the entire Swiss HIV Cohort Study (SHCS) population and investigate the effects of demographics, HIV-related factors, and ART on BMI change in participants with data available before and 4 years after first starting ART. RESULTS: In the SHCS, overweight/obesity prevalence increased from 13% in 1990 (n = 1641) to 38% in 2012 (n = 8150). In the participants starting ART (n = 1601), mean BMI increase was 0.92 kg/m(2) per year (95% confidence interval, .83-1.0) during year 0-1 and 0.31 kg/m(2) per year (0.29-0.34) during years 1-4. In multivariable analyses, annualized BMI change during year 0-1 was associated with older age (0.15 [0.06-0.24] kg/m(2)) and CD4 nadir <199 cells/µL compared to nadir >350 (P < .001). Annualized BMI change during years 1-4 was associated with CD4 nadir <100 cells/µL compared to nadir >350 (P = .001) and black compared to white ethnicity (0.28 [0.16-0.37] kg/m(2)). Individual ART combinations differed little in their contribution to BMI change. CONCLUSIONS: Increasing obesity rates in the SHCS over time occurred at the same time as aging of the SHCS population, demographic changes, earlier ART start, and increasingly widespread ART coverage. Body mass index increase after ART start was typically biphasic, the BMI increase in year 0-1 being as large as the increase in years 1-4 combined. The effect of ART regimen on BMI change was limited.

A multicenter phase 1 study of PX-866 in combination with docetaxel in patients with advanced solid tumours.

BACKGROUND: This phase I, dose-finding study determined the safety, maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D), pharmacokinetics, and antitumour activity of PX-866, a phosphatidylinositol 3-kinase inhibitor, combined with docetaxel in patients with incurable solid tumours. METHODS: PX-866 was administered at escalating doses (4-8 mg daily) with docetaxel 75 mg m⁻² intravenously every 21 days. Archived tumour tissue was assessed for potential predictive biomarkers. RESULTS: Forty-three patients were enrolled. Most adverse events (AEs) were grade 1 or 2. The most frequent study drug-related AE was diarrhoea (76.7%), with gastrointestinal disorders occurring in 79.1% (docetaxel-related) and 83.7% (PX-866-related). No dose-limiting toxicities were observed. The RP2D was 8 mg, the same as the single-agent MTD. Co-administration of PX-866 and docetaxel did not affect either drug's PKs. Best responses in 35 evaluable patients were: 2 partial responses (6%), 22 stable disease (63%), and 11 disease progression (31%). Eleven patients remained on study for >180 days, including 8 who maintained disease control on single-agent PX-866. Overall median progression-free survival (PFS) was 73.5 days (range: 1-569). A non-significant association between longer PFS for PIK3CA-MUT/KRAS-WT vs PIK3CA-WT/KRAS-WT was observed. CONCLUSION: Treatment with PX-866 and docetaxel was well tolerated, without evidence of overlapping/cumulative toxicity. Further investigation with this combination is justified.

Dasatinib, nilotinib and standard-dose imatinib for the first-line treatment of chronic myeloid leukaemia: systematic reviews and economic analyses.

BACKGROUND: Nilotinib and dasatinib are now being considered as alternative treatments to imatinib as a first-line treatment of chronic myeloid leukaemia (CML). OBJECTIVE: This technology assessment reviews the available evidence for the clinical effectiveness and cost-effectiveness of dasatinib, nilotinib and standard-dose imatinib for the first-line treatment of Philadelphia chromosome-positive CML. DATA SOURCES: Databases [including MEDLINE (Ovid), EMBASE, Current Controlled Trials, ClinicalTrials.gov, the US Food and Drug Administration website and the European Medicines Agency website] were searched from search end date of the last technology appraisal report on this topic in October 2002 to September 2011. REVIEW METHODS: A systematic review of clinical effectiveness and cost-effectiveness studies; a review of surrogate relationships with survival; a review and critique of manufacturer submissions; and a model-based economic analysis. RESULTS: Two clinical trials (dasatinib vs imatinib and nilotinib vs imatinib) were included in the effectiveness review. Survival was not significantly different for dasatinib or nilotinib compared with imatinib with the 24-month follow-up data available. The rates of complete cytogenetic response (CCyR) and major molecular response (MMR) were higher for patients receiving dasatinib than for those with imatinib for 12 months' follow-up (CCyR 83% vs 72%, p < 0.001; MMR 46% vs 28%, p < 0.0001). The rates of CCyR and MMR were higher for patients receiving nilotinib than for those receiving imatinib for 12 months' follow-up (CCyR 80% vs 65%, p < 0.001; MMR 44% vs 22%, p < 0.0001). An indirect comparison analysis showed no difference between dasatinib and nilotinib for CCyR or MMR rates for 12 months' follow-up (CCyR, odds ratio 1.09, 95% CI 0.61 to 1.92; MMR, odds ratio 1.28, 95% CI 0.77 to 2.16). There is observational association evidence from imatinib studies supporting the use of CCyR and MMR at 12 months as surrogates for overall all-cause survival and progression-free survival in patients with CML in chronic phase. In the cost-effectiveness modelling scenario, analyses were provided to reflect the extensive structural uncertainty and different approaches to estimating OS. First-line dasatinib is predicted to provide very poor value for money compared with first-line imatinib, with deterministic incremental cost-effectiveness ratios (ICERs) of between £256,000 and £450,000 per quality-adjusted life-year (QALY). Conversely, first-line nilotinib provided favourable ICERs at the willingness-to-pay threshold of £20,000-30,000 per QALY. LIMITATIONS: Immaturity of empirical trial data relative to life expectancy, forcing either reliance on surrogate relationships or cumulative survival/treatment duration assumptions. CONCLUSIONS: From the two trials available, dasatinib and nilotinib have a statistically significant advantage compared with imatinib as measured by MMR or CCyR. Taking into account the treatment pathways for patients with CML, i.e. assuming the use of second-line nilotinib, first-line nilotinib appears to be more cost-effective than first-line imatinib. Dasatinib was not cost-effective if decision thresholds of £20,000 per QALY or £30,000 per QALY were used, compared with imatinib and nilotinib. Uncertainty in the cost-effectiveness analysis would be substantially reduced with better and more UK-specific data on the incidence and cost of stem cell transplantation in patients with chronic CML. FUNDING: The Health Technology Assessment Programme of the National Institute for Health Research.

[Possible aggravation of a Henoch Schoenlein purpura by isotretinoin]. / Mögliche Aggravation einer Purpura Schönlein-Henoch durch Isotretinoin.

We report on a 16 year old patient with a hemorrhagic bullous form of a Henoch-Schönlein purpura. The cause for the event could not be determined, but the patient recovered without complications. Since he had begun a therapy with isotretinoin due to an acne inversa 3 weeks before, a possible association between the event and the treatment could not be excluded, and the case was reported to Swissmedic. In the comment, we discuss the pharmacology of isotretinoin, drug-induced vasculitis, and its pathomechanisms. As a general reminder, the criteria for the causality assessment of adverse drug reactions as well as the reporting system of adverse drug reactions in Switzerland are discussed.

Impaired antibody memory to varicella zoster virus in HIV-infected children: low antibody levels and avidity*.

OBJECTIVE: HIV-infected children have impaired antibody responses after exposure to certain antigens. Our aim was to determine whether HIV-infected children had lower varicella zoster virus (VZV) antibody levels compared with HIV-infected adults or healthy children and, if so, whether this was attributable to an impaired primary response, accelerated antibody loss, or failure to reactivate the memory VZV response. METHODS: In a prospective, cross-sectional and retrospective longitudinal study, we compared antibody responses, measured by enzyme-linked immunosorbent assay (ELISA), elicited by VZV infection in 97 HIV-infected children and 78 HIV-infected adults treated with antiretroviral therapy, followed over 10 years, and 97 age-matched healthy children. We also tested antibody avidity in HIV-infected and healthy children. RESULTS: Median anti-VZV immunoglobulin G (IgG) levels were lower in HIV-infected children than in adults (264 vs. 1535 IU/L; P<0.001) and levels became more frequently unprotective over time in the children [odds ratio (OR) 17.74; 95% confidence interval (CI) 4.36-72.25; P<0.001]. High HIV viral load was predictive of VZV antibody waning in HIV-infected children. Anti-VZV antibodies did not decline more rapidly in HIV-infected children than in adults. Antibody levels increased with age in healthy (P=0.004) but not in HIV-infected children. Thus, antibody levels were lower in HIV-infected than in healthy children (median 1151 IU/L; P<0.001). Antibody avidity was lower in HIV-infected than healthy children (P<0.001). A direct correlation between anti-VZV IgG level and avidity was present in HIV-infected children (P=0.001), but not in healthy children. CONCLUSION: Failure to maintain anti-VZV IgG levels in HIV-infected children results from failure to reactivate memory responses. Further studies are required to investigate long-term protection and the potential benefits of immunization.