Radka Obermannová

Oesophageal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up†

Oesophageal cancer is the 19th most common cancer in the European Union (EU), with cca 45 900 new cases diagnosed in 2012 (1% of the total). In the EU, the highest age-standardised incidence rates for oesophageal cancer are in the Netherlands for men and the UK for women [1]. Variation between countries is high and may reflect different prevalence of risk factors, use of screening and diagnostic methods.

Safety and activity of alisertib, an investigational aurora kinase A inhibitor, in patients with breast cancer, small-cell lung cancer, non-small-cell lung cancer, head and neck squamous-cell carcinoma, and gastro-oesophageal adenocarcinoma: a five-arm phase 2 study

BACKGROUND Alisertib is an investigational, oral, selective inhibitor of aurora kinase A. We aimed to investigate the safety and activity of single-agent alisertib in patients with predefined types of advanced solid tumours. METHODS We did a multicentre phase 1/2 study at 40 centres in four countries (Czech Republic, France, Poland, and the USA). Here, we report results from phase 2; enrolment for the study began on Feb 16, 2010, and ended on May 3, 2013. Adult patients were eligible for the study if they had either breast cancer, small-cell lung cancer, non-small-cell lung cancer, head and neck squamous-cell carcinoma, or gastro-oesophageal adenocarcinoma that had relapsed or was refractory to chemotherapy. Patients had to have undergone two or fewer previous cytotoxic regimens (four or fewer for breast cancer patients), not including adjuvant or neoadjuvant treatments. Enrolment followed a two-stage design: to proceed to the second stage, two or more objective responses were needed in the first 20 response-assessable patients in each of the five tumour cohorts. Alisertib was administered orally in 21-day cycles at the recommended phase 2 dose of 50 mg twice daily for 7 days followed by a break of 14 days. The protocol-specified primary endpoint was the proportion of patients with an objective response, assessed by Response Evaluation Criteria In Solid Tumors version 1.1 in the response-assessable population (ie, patients with measurable disease who received at least one dose of alisertib and had undergone at least one post-baseline tumour assessment). This completed trial is registered with ClinicalTrials.gov, NCT01045421. FINDINGS By May 31, 2013, 249 patients had been treated, 53 with breast cancer, 60 with small-cell lung cancer, 26 with non-small-cell lung cancer, 55 with head and neck squamous-cell carcinoma, and 55 with gastro-oesophageal adenocarcinoma. Among response-assessable patients, an objective response was noted in nine (18%, 95% CI 9-32) of 49 women with breast cancer, ten (21%, 10-35) of 48 participants with small-cell lung cancer, one (4%, 0-22) of 23 patients with non-small-cell lung cancer, four (9%, 2-21) of 45 people with head and neck squamous-cell carcinoma, and four (9%, 2-20) of 47 individuals with gastro-oesophageal adenocarcinoma; all were partial responses. Adverse events were similar across tumour types. The most frequent drug-related grade 3-4 adverse events included neutropenia (n=107 [43%]), leukopenia (53 [21%]), and anaemia (26 [10%]). Serious drug-related adverse events were reported in 108 (43%) patients. INTERPRETATION These data support further clinical assessment of alisertib in patients with solid tumours, particularly those with breast cancer and small-cell lung cancer. FUNDING Millennium Pharmaceuticals, Inc, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited.

Subgroup analysis in RAISE: a randomized, double-blind phase III study of irinotecan, folinic acid, and 5-fluorouracil (FOLFIRI) plus ramucirumab or placebo in patients with metastatic colorectal carcinoma progression

The RAISE phase III trial demonstrated ramucirumab + FOLFIRI improved survival compared with placebo + FOLFIRI for second-line metastatic colorectal carcinoma patients previously treated with first-line bevacizumab, oxaliplatin, and a fluoropyrimidine. Analyses reported here found similar efficacy and safety in patients regardless of KRAS mutational status, time to first-line progression, and age.

Analysis of angiogenesis biomarkers for ramucirumab efficacy in patients with metastatic colorectal cancer from RAISE, a global, randomized, double-blind, phase III study

Abstract Background The phase III RAISE trial (NCT01183780) demonstrated that the vascular endothelial growth factor (VEGF) receptor (VEGFR)-2 binding monoclonal antibody ramucirumab plus 5-fluororuracil, leucovorin, and irinotecan (FOLFIRI) significantly improved overall survival (OS) and progression-free survival (PFS) compared with placebo + FOLFIRI as second-line metastatic colorectal cancer (mCRC) treatment. To identify patients who benefit the most from VEGFR-2 blockade, the RAISE trial design included a prospective and comprehensive biomarker program that assessed the association of biomarkers with ramucirumab efficacy outcomes. Patients and methods Plasma and tumor tissue collection was mandatory. Overall, 1072 patients were randomized 1 : 1 to the addition of ramucirumab or placebo to FOLFIRI chemotherapy. Patients were then randomized 1 : 2, for the biomarker program, to marker exploratory (ME) and marker confirmatory (MC) groups. Analyses were carried out using exploratory assays to assess the correlations of baseline marker levels [VEGF-C, VEGF-D, sVEGFR-1, sVEGFR-2, sVEGFR-3 (plasma), and VEGFR-2 (tumor tissue)] with clinical outcomes. Cox regression analyses were carried out for each candidate biomarker with stratification factor adjustment. Results Biomarker results were available from >80% (n = 894) of patients. Analysis of the ME subset determined a VEGF-D level of 115 pg/ml was appropriate for high/low subgroup analyses. Evaluation of the combined ME + MC populations found that the median OS in the ramucirumab + FOLFIRI arm compared with placebo + FOLFIRI showed an improvement of 2.4 months in the high VEGF-D subgroup [13.9 months (95% CI 12.5–15.6) versus 11.5 months (95% CI 10.1–12.4), respectively], and a decrease of 0.5 month in the low VEGF-D subgroup [12.6 months (95% CI 10.7–14.0) versus 13.1 months (95% CI 11.8–17.0), respectively]. PFS results were consistent with OS. No trends were evident with the other antiangiogenic candidate biomarkers. Conclusions The RAISE biomarker program identified VEGF-D as a potential predictive biomarker for ramucirumab efficacy in second-line mCRC. Development of an assay appropriate for testing in clinical practice is currently ongoing. Clinical trials registration NCT01183780.

Insights into next developments in advanced gastric cancer

Purpose of review The purpose of the review is to delineate novel approaches for biology-based treatment in advanced gastric cancer. We reviewed the latest translational and clinical research articles and congress presentations. Recent findings A new molecular classification of gastric cancer based on histology, genetic and proteomic alterations has evolved. It provides a roadmap for development of new drugs and combinations and for patient stratification. Anti-HER2 treatment, which is an effective strategy in metastatic gastric cancer, is now also being studied in the perioperative setting. However, resistance mechanisms in advanced disease are poorly understood and optimal patient selection remains challenging. Targeting angiogenesis is an emerging concept in the management of advanced gastric cancer, and ramucirumab has prolonged survival in the second line either as a monotherapy or in combination with paclitaxel. Biomarkers for selecting patients who benefit from ramucirumab are still lacking. Immune checkpoint blockade and inhibition of cancer stemness targets are other emerging directions for the medical treatment of gastric cancer. Large-scale international studies are ongoing. Summary Promising biology-based treatment strategies are evolving. But tumor heterogeneity which is an inherent feature of gastric cancer challenges the development of molecularly targeted and personalized treatment strategies.

Current challenges in optimizing systemic therapy for patients with pancreatic cancer: expert perspectives from the Australasian Gastrointestinal Trials Group (AGITG) with invited international faculty

ABSTRACT Introduction: Despite recent progress, the outlook for most patients with pancreatic cancer remains poor. There is variation in how patients are managed globally due to differing interpretations of the evidence, partly because studies in this disease are challenging to undertake. This article collates the evidence upon which current best practice is based and offers an expert opinion from an international faculty on how latest developments should influence current treatment paradigms. Areas covered: Optimal chemotherapy for first and subsequent lines of therapy; optimal management of locally advanced, non-metastatic cancer including the role of neoadjuvant chemo(radio)therapy, current evidence for adjuvant chemotherapy, major advances in pancreatic cancer genomics and challenges in supportive care particularly relevant to patients with pancreatic cancer. For each section, literature was reviewed by comprehensive search techniques, including clinical trial websites and abstracts from international cancer meetings. Expert commentary: For each section, a commentary is provided. Overall the challenges identified were: difficulties in diagnosing pancreatic cancer early, challenges for performing randomised clinical trials in all stages of the disease, some progress in systemic therapy with new agents and in identifying molecular subtypes that may be clinically relevant and move towards personalized therapy, but still, pancreatic cancer remains a very poor prognosis cancer with significant palliative care needs.

Tumor Expression ofmiR-10b, miR-21, miR-143andmiR-145Is Related to Clinicopathological Features of Gastric Cancer in a Central European Population

Background/Aim: In Western countries, most patients with gastric cancer (GC) present in advanced stages. Therefore, there is imminent clinical need for novel diagnostic and prognostic biomarkers. Deregulation of microRNAs has been reported as a frequent event in GC development in a number of studies. Our study validated the potential of microRNAs to serve as diagnostic and prognostic biomarkers in patients with GC from the Central European population. Materials and Methods: Using quantitative real-time polymerase chain reaction, expression levels of six microRNAs (miR-10b, -21, -93, -107, - 143, and -145) were examined in 67 tumor tissues and 67 paired adjacent gastric tissues, and correlated with clinicopathological features of GC patients. Results: Expression levels of miR-10b, miR-21, miR-93, and miR-107 were significantly higher in GC samples compared to non-tumor tissue. Furthermore, the expression levels of miR-10b, miR-143, and miR-145 positively correlated with advanced stages, and increased expression of miR-10b, miR-21 and miR-145 was significantly associated with worse prognosis of gastric cancer patients. Conclusion: Our results indicate that selected tissue microRNAs have the potential to serve as relevant diagnostic and prognostic biomarkers of GC in a central European population.

Biomarker analysis beyond angiogenesis: RAS/RAF mutation status, tumour sidedness, and second-line ramucirumab efficacy in patients with metastatic colorectal carcinoma from RAISE, a global phase 3 study

Abstract Background : Second-line treatment with ramucirumab+FOLFIRI improved overall survival (OS) versus placebo+FOLFIRI for patients with metastatic colorectal carcinoma (CRC) [hazard ratio (HR)=0.84, 95% CI 0.73–0.98, P = 0.022]. Post hoc analyses of RAISE patient data examined the association of RAS/RAF mutation status and the anatomical location of the primary CRC tumour (left versus right) with efficacy parameters. Patients and methods Patient tumour tissue was classified as BRAF mutant, KRAS/NRAS (RAS) mutant, or RAS/BRAF wild-type. Left-CRC was defined as the splenic flexure, descending and sigmoid colon, and rectum; right-CRC included transverse, ascending colon, and cecum. Results RAS/RAF mutation status was available for 85% of patients (912/1072) and primary tumour location was known for 94.4% of patients (1012/1072). A favourable and comparable ramucirumab treatment effect was observed for patients with RAS mutations (OS HR = 0.86, 95% CI 0.71–1.04) and patients with RAS/BRAF wild-type tumours (OS HR = 0.86, 95% CI 0.64–1.14). Among the 41 patients with BRAF-mutated tumours, the ramucirumab benefit was more notable (OS HR = 0.54, 95% CI 0.25–1.13), although, as with the other genetic sub-group analyses, differences were not statistically significant. Progression-free survival (PFS) data followed the same trend. Treatment-by-mutation status interaction tests (OS P = 0.523, PFS P = 0.655) indicated that the ramucirumab benefit was not statistically different among the mutation sub-groups, although the small sample size of the BRAF group limited the analysis. Addition of ramucirumab to FOLFIRI improved left-CRC median OS by 2.5 month over placebo (HR = 0.81, 95% CI 0.68–0.97); median OS for ramucirumab-treated patients with right-CRC was 1.1 month over placebo (HR = 0.97, 95% CI 0.75–1.26). The treatment-by-sub-group interaction was not statistically significant for tumour sidedness (P = 0.276). Conclusions In the RAISE study, the addition of ramucirumab to FOLFIRI improved patient outcomes, regardless of RAS/RAF mutation status, and tumour sidedness. Ramucirumab treatment provided a numerically substantial benefit in BRAF-mutated tumours, although the P-values were not statistically significant. ClinicalTrials.gov number NCT01183780.

Management of Metastatic Gastric Cancer

Metastatic gastric cancer is an incurable disease. Systemic chemotherapy prolongs survival, improves symptom control, and helps maintain a better quality of life of patients with metastatic gastric cancer. HER2 testing of the primary tumor and/or the metastases is warranted before initiation of first-line treatment. This review article outlines the indication and clinical data of medical treatment of advanced gastric cancer and highlights aspects of quality of life.