Subcutaneous versus intravenous formulation of trastuzumab for HER2-positive early breast cancer: updated results from the phase III HannaH study.

BACKGROUND: HannaH (NCT00950300) was a phase III, randomized, international, open-label study that compared pharmacokinetics (PK), efficacy, and safety of two different trastuzumab formulations [subcutaneous (s.c.) and intravenous (i.v.)] in HER2-positive, operable, locally advanced, or inflammatory breast cancer in the neoadjuvant/adjuvant setting. The co-primary end points, to show noninferiority of s.c. versus i.v. trastuzumab in terms of serum concentration (Ctrough) and pathologic complete response (pCR) were met; safety profiles were comparable at 12 months' median follow-up. Secondary end points included safety and tolerability, PK profile, immunogenicity, and event-free survival (EFS). We now report updated safety and efficacy data after a median follow-up of 20 months. PATIENTS AND METHODS: Patients (N = 596) were treated with eight cycles of neoadjuvant chemotherapy, administered concurrently with 3-weekly s.c. trastuzumab (fixed dose of 600 mg) or the standard weight-based i.v. method. Following surgery, patients continued trastuzumab treatment to complete 1 year of therapy. Updated analyses of PK, efficacy, safety, and immunogenicity data were carried out. RESULTS: s.c. trastuzumab was generally well tolerated and the incidence of adverse events (AEs), including grade 3 or 4 AEs, between treatment groups was comparable. A slightly higher incidence of serious AEs (SAEs), mainly due to infections, was reported with s.c. treatment {64 [21.5%; 95% confidence interval (CI) 17.0%-26.7%] versus 42 (14.1%; 95% CI 10.4%-18.6%) in the i.v. group}; however, the differences were small and often based on rare events, with no observable pattern across reported events. An early analysis of EFS showed rates of 95% in both groups 1 year postrandomization. Exploratory analyses did not reveal an association between toxicity and body weight or exposure. CONCLUSIONS: Overall, the safety profile of s.c. trastuzumab was consistent with the previously published data from HannaH and the known safety profile of i.v. trastuzumab. EFS rates were comparable between the i.v. and s.c. groups. CLINICAL TRIAL NUMBER: NCT00950300.

Phase II, randomized, biomarker identification trial (MARK) for erlotinib in patients with advanced pancreatic carcinoma.

BACKGROUND: A prospective, randomized phase II study, with mandatory tumor sampling at current disease stage, aimed to identify biomarkers predictive of improved progression-free survival (PFS) in patients with pancreatic cancer treated with erlotinib. PATIENTS AND METHODS: Patients with histologically/cytologically confirmed, unresectable, locally advanced/metastatic pancreatic cancer, who had failed on or were unsuitable for first-line chemotherapy, underwent a tumor biopsy and were then randomized to receive once-daily erlotinib 150 mg or placebo. The primary end point was identification of biomarkers predicting improved PFS with erlotinib. Secondary end points included PFS, overall survival, response and toxicity. RESULTS: At data cut-off, 207 patients were enrolled and analyzed. Prespecified biomarker analyses of EGFR protein expression, EGFR gene copy number/mutations/polymorphisms and KRAS mutations did not identify any subgroups with a detrimental effect or a strong benefit for PFS with erlotinib. In the primary analysis, the median PFS was 6.1 versus 5.9 weeks in the erlotinib and placebo arms, respectively [hazard ratio (HR) 0.83; 95% confidence interval (CI) 0.63-1.10; P = 0.1909]. However, observed baseline imbalances indicated worse prognosis in the erlotinib arm. After adjustment for baseline characteristics, a significant PFS benefit for erlotinib was observed (HR 0.68; 95% CI 0.50-0.91; P = 0.0102). Exploratory biomarker analyses showed patients with high baseline serum amphiregulin levels might benefit from erlotinib. CONCLUSION: This study in patients with inoperable pancreatic cancer did not identify any prespecified biomarkers predictive of PFS benefit with erlotinib. Exploratory analyses suggested high amphiregulin might predict PFS benefit from erlotinib. CLINICALTRIALSGOV NUMBER: NCT00674973.

A multicentre phase II gene expression profiling study of putative relationships between tumour biomarkers and clinical response with erlotinib in non-small-cell lung cancer.

BACKGROUND: Identification of appropriate markers for predicting clinical benefit with erlotinib in non-small-cell lung cancer (NSCLC) may be able to guide patient selection for treatment. This open-label, multicentre, phase II trial aimed to identify genes with potential use as biomarkers for clinical benefit from erlotinib therapy. METHODS: Adults with stage IIIb/IV NSCLC in whom one or more chemotherapy regimen had failed were treated with erlotinib (150 mg/day). Tumour biopsies were analysed using gene expression profiling with Affymetrix GeneChip microarrays. Differentially expressed genes were verified using quantitative RT-PCR (qRT-PCR). RESULTS: A total of 264 patients were enrolled in the study. Gene expression profiles found no statistically significant differentially expressed genes between patients with and without clinical benefit. In an exploratory analysis in responding versus nonresponding patients, three genes on chromosome 7 were expressed at higher levels in the responding group [epidermal growth factor receptor (EGFR), phosphoserine phosphatase (PSPH) and Rap guanine nucleotide exchange factor 5 (RAPGEF5)]. Independent quantification using qRT-PCR validated the association between EGFR and PSPH overexpression, but not RAPGEF5 overexpression, and clinical outcome. CONCLUSIONS: This study supports the use of erlotinib as an alternative to chemotherapy for patients with relapsed advanced NSCLC. Genetic amplification of the EGFR region of chromosome 7 may be associated with response to erlotinib therapy.

Lung function testing: the dilemma of predicted values in relation to the individual variability.

Quantitated lung function parameters are usually interpreted in relation to so-called "normal ranges' obtained from healthy study groups. The aim of this paper is the critical review of formulas and the evaluation of intraindividual variation in modern lung function testing. To which extent is the total variation of lung function parameters in cross-sectional studies (usually serving as basis for the normal range) attributed to the intraindividual variation between repeated measurements? This question raises a further question: are lung function values in the normal range really normal? To assess spirometric and body plethysmographic parameters 26 healthy subjects from three medical centers underwent 30-72 measurements over a period of 2 months for the determination of variations due to (1) intraindividual variation over time and (2) interindividual variation. For each subject, predicted values of different lung function parameters published by Quanjer et al. [Eur Respir J 1993; 6:5-40.1], of intrathoracic gas volume by Ulmer et al. [Die Lungenfunktion; Stuttgart, Thieme, 1991] and of total airway resistance by Ruehle and Matthys [Pneumologie 1976;153:223] were applied. When converted into percent predicted and adjusted for differences in medical centers, the intraindividual standard deviation was estimated to be about half of the interindividual standard deviation. We conclude that the normal range of lung function parameters derived from the standard deviation within populations is too wide for the assessment of individual values. Interpretation of individual lung function measurements should primarily be based on the "individual normal range' derived from former lung function measurements of the individual and only secondly on the "predicted value'.

[Measuring single breath diffusing capacity in a patient sample with healthy lungs--comparison with the European Coal and Steel Community standard values]. / Messungen der Single-Breath-Diffusionskapazität in einem lungengesunden Kollektiv--Vergleich mit den EGKS-Sollwertformeln.

The measurement values of the diffusion parameters TLCO (diffusion capacity) and KCO (transfer coefficient) of 107 healthy subjects not suffering from pulmonary diseases were compared with the EC/European Community for Coal and Steel (ECCS) standard value formulas (2-5). The diffusion parameter KCO is markedly better described by the 1993 standard value formula than by the 1983 ECCS version. Men yield higher measured values than predicted by the 1993 EC formulas. The diffusion parameters of smokers are significantly lower than those of non-smokers.

[Pilot project for evaluation of lung function reference values]. / Pilotprojekt zur Uberprüfung von Lungenfunktionssollwerten.

Lung function tests were performed in this study on 139 adults (mean age 36 years), as well as on 91 female persons between 16 and 18 years of age (the latter just starting on their professional careers), the lungs being healthy in each case in both groups. The findings were compared with the currently accepted reference value formulae after Quanjer et al., and Zapletal as well as further developed reference value formulae after Brändli et al., Most of the measurement data obtained by spirometry for the BGFA group of probands are between the two recommended reference values for adults with better coincidence with Brändli's predictions (exceptions being MMEF25-75 MEF 50 and MEF 25). In our studies we obtained higher values than the reference median values after Quanjer and Zapletal for IVC, FVC, FEV1 and PEF by 6-8% and 5-15%, respectively, whereas the values for adults differ from the predictions made by Brändli et al. by -4% to +5%. The flow data MMEF 75-25, MEF 50 and especially MEF 25 are set at too low levels (by 5-23%) by Zapletal's and Brändli's values. Comparatively, the values predicted by Quanjer et al. for the above mentioned flow-volume parameters (with the exception of MEF 75) are too high by 4% to 12%. There are also considerable differences in respect of the reference values for IGV to the tune of +15% in the BGFA group compared to Quanjer et al.; in the BAFAM group the values differ from those of Zapletal et al. by +17%. RV yields results in the BGFA group which are higher by 11% than according to Quanjer's formulae, whereas in the BAFAM group they are higher by 15% compared to Zapletal's predictions. In respect of Rt there are differences to the predictions by Rühle and Matthys by +16% (BGFA group) and +13% (BAFAM group), respectively. The BAFAM group differs from Zapletal's predictions by +11%. Looking at the reference limit values the overall impression is confirmed that the predictions after Quanjer et al. and mostly also those by Zapletal are too low in respect of the abovementioned lung function parameters (in the majority of cases not 5% of the examined probands, as expected, are below those levels, but only about 2%). Females, who had been underrepresented in the previous healthy proband groups, show larger deviations than males in respect of most of the parameters.(ABSTRACT TRUNCATED AT 400 WORDS)