Julie Hill

Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial

BACKGROUND Trastuzumab, a monoclonal antibody against human epidermal growth factor receptor 2 (HER2; also known as ERBB2), was investigated in combination with chemotherapy for first-line treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer. METHODS ToGA (Trastuzumab for Gastric Cancer) was an open-label, international, phase 3, randomised controlled trial undertaken in 122 centres in 24 countries. Patients with gastric or gastro-oesophageal junction cancer were eligible for inclusion if their tumours showed overexpression of HER2 protein by immunohistochemistry or gene amplification by fluorescence in-situ hybridisation. Participants were randomly assigned in a 1:1 ratio to receive a chemotherapy regimen consisting of capecitabine plus cisplatin or fluorouracil plus cisplatin given every 3 weeks for six cycles or chemotherapy in combination with intravenous trastuzumab. Allocation was by block randomisation stratified by Eastern Cooperative Oncology Group performance status, chemotherapy regimen, extent of disease, primary cancer site, and measurability of disease, implemented with a central interactive voice recognition system. The primary endpoint was overall survival in all randomised patients who received study medication at least once. This trial is registered with ClinicalTrials.gov, number NCT01041404. FINDINGS 594 patients were randomly assigned to study treatment (trastuzumab plus chemotherapy, n=298; chemotherapy alone, n=296), of whom 584 were included in the primary analysis (n=294; n=290). Median follow-up was 18.6 months (IQR 11-25) in the trastuzumab plus chemotherapy group and 17.1 months (9-25) in the chemotherapy alone group. Median overall survival was 13.8 months (95% CI 12-16) in those assigned to trastuzumab plus chemotherapy compared with 11.1 months (10-13) in those assigned to chemotherapy alone (hazard ratio 0.74; 95% CI 0.60-0.91; p=0.0046). The most common adverse events in both groups were nausea (trastuzumab plus chemotherapy, 197 [67%] vs chemotherapy alone, 184 [63%]), vomiting (147 [50%] vs 134 [46%]), and neutropenia (157 [53%] vs 165 [57%]). Rates of overall grade 3 or 4 adverse events (201 [68%] vs 198 [68%]) and cardiac adverse events (17 [6%] vs 18 [6%]) did not differ between groups. INTERPRETATION Trastuzumab in combination with chemotherapy can be considered as a new standard option for patients with HER2-positive advanced gastric or gastro-oesophageal junction cancer. FUNDING F Hoffmann-La Roche.

Tolerability of beta-blockers in elderly patients with chronic heart failure: The COLA II study

Beta‐blockers are recommended therapy for patients with chronic heart failure (CHF). However, there remains concern regarding tolerability of these agents in the elderly, which has contributed to the limited uptake of these agents in clinical practice.

Quality of Life in the Trastuzumab for Gastric Cancer Trial

BACKGROUND The Trastuzumab for Gastric Cancer phase III trial demonstrated that combining trastuzumab with chemotherapy significantly improved overall survival compared with chemotherapy alone in HER2-positive advanced gastric or gastroesophageal junction cancer. We report health-related quality of life (HRQoL) and quality-adjusted time without symptoms of disease or toxicity (Q-TWiST) results from this trial. PATIENTS AND METHODS Patients were randomized to receive six cycles of chemotherapy given every 3 weeks (capecitabine or fluorouracil, plus cisplatin) either alone or combined with administration of trastuzumab every 3 weeks until disease progression. At each clinical visit, HRQoL was assessed using two European Organization for Research and Treatment of Cancer quality of life questionnaires, QLQ-C30 and QLQ-STO22. Q-TWiST methodology was applied retrospectively using the clinical data and utility coefficients. RESULTS Trastuzumab plus chemotherapy prolonged time to 10% definitive deterioration in all QLQ-C30 and QLQ-STO22 scores, including QLQ-C30 global health status versus chemotherapy alone, from 6.4 months to 10.2 months. In addition, trastuzumab plus chemotherapy extended Q-TWiST by 2.42 months compared with chemotherapy alone. CONCLUSION Compared with chemotherapy alone, trastuzumab plus chemotherapy prolongs time to deterioration of HRQoL and increases quality-adjusted survival in patients with HER2-positive gastric or gastroesophageal junction cancer.

Randomised controlled trial to determine the efficacy and safety of prescribed water intake to prevent kidney failure due to autosomal dominant polycystic kidney disease (PREVENT-ADPKD)

Introduction Maintaining fluid intake sufficient to reduce arginine vasopressin (AVP) secretion has been hypothesised to slow kidney cyst growth in autosomal dominant polycystic kidney disease (ADPKD). However, evidence to support this as a clinical practice recommendation is of poor quality. The aim of the present study is to determine the long-term efficacy and safety of prescribed water intake to prevent the progression of height-adjusted total kidney volume (ht-TKV) in patients with chronic kidney disease (stages 1–3) due to ADPKD. Methods and analysis A multicentre, prospective, parallel-group, open-label, randomised controlled trial will be conducted. Patients with ADPKD (n=180; age ≤65 years, estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2) will be randomised (1:1) to either the control (standard treatment+usual fluid intake) or intervention (standard treatment+prescribed fluid intake) group. Participants in the intervention arm will be prescribed an individualised daily fluid intake to reduce urine osmolality to ≤270 mOsmol/kg, and supported with structured clinic and telephonic dietetic review, self-monitoring of urine-specific gravity, short message service text reminders and internet-based tools. All participants will have 6-monthly follow-up visits, and ht-TKV will be measured by MRI at 0, 18 and 36 months. The primary end point is the annual rate of change in ht-TKV as determined by serial renal MRI in control vs intervention groups, from baseline to 3 years. The secondary end points are differences between the two groups in systemic AVP activity, renal disease (eGFR, blood pressure, renal pain), patient adherence, acceptability and safety. Ethics and dissemination The trial was approved by the Human Research Ethics Committee, Western Sydney Local Health District. The results will inform clinicians, patients and policy-makers regarding the long-term safety, efficacy and feasibility of prescribed fluid intake as an approach to reduce kidney cyst growth in patients with ADPKD. Trial registration number ANZCTR12614001216606.

The impact of baseline HR and BP on the tolerability of carvedilol in the elderly: the COLA (Carvedilol Open Label Assessment) II Study.

BackgroundThe COLA (Carvedilol Open Label Assessment) II Study prospectively evaluated the tolerability of carvedilol in 1030 patients >70 years of age with chronic heart failure (CHF). Tolerability, defined as patients receiving ≥3 months of carvedilol and achieving a maintenance dosage ≥12.5mg/day, was 80%. In a multivariate analysis, advanced age, low DBP, left ventricular ejection fraction, obstructive airways disease, and a presence of diabetes mellitus were predictors of tolerability. The aim of this analysis was to evaluate further the relationship between baseline HR, SBP, DBP and tolerability in COLA II.MethodsBaseline HR, SBP and DBP data were available in 1009 patients (98%). These data were analyzed as both continuous and categorical variables. For the latter analysis, the following categories were created: HR <70, 70 ≤ HR <90, HR ≥90 bpm; SBP <120, 120 ≤ SBP <160, SBP ≥160mm Hg; DBP <70, 70 ≤ DBP <90, DBP ≥90mm Hg.ResultsBaseline HR did not differ between patients who tolerated carvedilol (T) and those who did not (non-T) [81 ± 16 vs 79 ± 16 bpm]. However, SBP and DBP were significantly lower in the non-T versus the T group (131 ± 20 vs 139 ± 22mm Hg for SBP [p<0.001] and 77 ± 11 vs 81 ± 12mm Hg for DBP [p<0.001]). Seventy-four percent of patients in the lowest category for baseline HR (<70 bpm tolerated carvedilol versus 82% and 79% of those in the higher categories (p = not significant). Seventy percent of patients in the lowest category of baseline SBP (<120mm Hg) tolerated carvedilol versus 80% and 89% of those in the upper categories (p<0.001). Similarly, 73% of patients in the lowest category for DBP (<70mm Hg) tolerated carvedilol versus 78% and 87% of those in the upper categories (p<0.005).ConclusionsCarvedilol is generally well tolerated by elderly patients with CHF, even in those with low baseline BP or HR. However, a low baseline SBP or DBP does identify patients who are less likely to tolerate the drug. Baseline HR does not appear to significantly affect tolerability in this population.

Trastuzumab for gastric cancer treatment – Authors' reply

1 Bang YJ, Van Cutsem E, Feyereislova A, et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for HER2-positive advanced gastric or gastrooesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet 2010; 376: 687–97. 2 Okines AFC, Cunningham D. Trastuzumab in gastric cancer. Eur J Cancer 2010; 46: 1939–59. 3 Munro AJ, Niblock PG. Cancer research in the global village. Lancet 2010; 376: 659–60. 4 Ma BBY, Hui EP, Mok TSK. Population-based diff erences in treatment outcome following anticancer drug therapies. Lancet Oncol 2010; 11: 75–84. 5 Koizumi W, Narahara H, Hara T, et al. S-1 plus cisplatin versus S-1 alone for fi rst-line treatment of advanced gastric cancer (SPIRITS trial): a phase III trial. Lancet Oncol 2008; 9: 215–21. Trastuzumab for gastric cancer treatment

Human epidermal growth factor receptor 2 status of breast cancer patients in Asia: Results from a large, multicountry study.

Current estimates of the human epidermal growth factor receptor 2 (HER2)‐positivity rate in breast cancer are largely based on studies from the United States, Europe and Australia, and might not reflect the rate among breast cancer patients in Asia. The primary aim of this study was to conduct a clinical audit of laboratories across eight countries in Asia to determine the incidence of HER2‐positive breast cancer in this region.

Exploratory biomarker assessment in the Trastuzumab for Gastric Cancer (ToGA) study.

e21029 Background: The global, randomized, Phase III ToGA study showed that trastuzumab (H) plus capecitabine or 5-fluorouracil and cisplatin (XP/FP) significantly improves overall survival (OS) vs XP/FP alone (median: 13.8 vs 11.1 mo, hazard ratio [HR] 0.74, P=0.0046) in patients with HER2-positive advanced gastric or gastroesophageal junction (aGC/GEJ) cancer. To explore prognostic and/or predictive biomarkers, optional tumor tissue and blood sampling was implemented for subsequent correlative research. METHODS Tumor tissue samples were collected from 4-25% of the ToGA overall study population, and successfully assessed by immunohistochemistry (IHC) for PTEN (N=108), IGF-1R (N=106), HER3 (N=126), and EGFR (N=95). A total immunoreactivity score (IRS) and IRS per cell membrane, cytoplasm, and nucleus was derived for each IHC analysis. Mutational analyses of KRAS (N=87) and PIK3CA (N=86) on tumor-derived DNA were explored by Sanger sequencing. Genotyping to assess polymorphisms in FcγR (N=130) was conducted on whole blood samples by kinetic thermocycling. All translational research data were correlated to efficacy parameters, including OS and progression-free survival. RESULTS Patients expressing PTEN showed a trend toward OS benefit in the H+XP/FP arm, as indicated by an HR of 0.66 (95% CI 0.34-1.27). An OS benefit was gained with H+XP/FP regardless of IGF-1R levels or cutoffs applied. Data from the HER3 subgroup were difficult to interpret due to inconsistent results across cell compartments. EGFR expression levels were generally low and did not allow appropriate interpretation. Mutations known to result in constitutively active KRAS were detected in 5 samples (2 [5%] for XP/FP; 3 [6%] for H+XP/FP) in exons 2 and 3; codons 12 and 61. Activating hot spot mutations of PIK3CA were detected in 2 samples in exon 9; codons 542 and 545. As the sample size for FcγR analyses was small, it was not feasible to interpret the impact of polymorphism. CONCLUSIONS This is the first report of exploratory biomarker panel data from a global Phase III study in HER2-positive aGC/GEJ cancer. While limited by the small number of tissue samples, observed trends are of interest for hypothesis generation and warrant further investigation.