Georg-Martin Haag

Lapatinib versus lapatinib plus capecitabine as second-line treatment in human epidermal growth factor receptor 2-amplified metastatic gastro-oesophageal cancer: a randomised phase II trial of the Arbeitsgemeinschaft Internistische Onkologie.

INTRODUCTION Human epidermal growth factor receptor 2 (HER2) amplification is present in a subgroup of gastroo-esophageal cancers (GCs). HER2 inhibition with trastuzumab has shown to improve outcomes in advanced disease. Lapatinib ditosylate (LAP), a dual anti-epidermal growth factor receptor (EGFR) and anti-HER2 tyrosine kinase inhibitor with preclinical activity against GC, has been approved in HER2-positive breast cancer. We aimed to study the activity of LAP in HER2-amplified GC. MATERIALS AND METHODS Patients (pts) with HER2-positive (gene amplification or increased copy numbers based on predefined criteria) advanced GC were randomly allocated 1:1 to receive LAP 1250mg per day 1-21 plus capecitabine (CAP) 2000mg/m(2) on days 1-14 of a 21-day cycle or LAP 1500mg monotherapy day 1-21 after having failed on a platinum-based first-line therapy. HER2 status was assessed centrally. The primary end-point was the objective response rate (ORR) as assessed by the investigator using Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1). We aimed to include 38 pts per arm to show an interesting response rate of ⩾20% in either of the two arms. RESULTS 37 pts were enrolled (18 to LAP+CAP, 19 to LAP). Pts had received a median of three prior treatment lines. 12 pts in the LAP+CAP group (67%) and 12 pts in the LAP group (63%) had received prior trastuzumab. Only two pts (11.1%; 95% confidence interval (CI): 1.37-34.7), both in the LAP+CAP arm, achieved an objective response. The study was closed prematurely for futility. Median time to progression was 42 (95% CI: 38-61) days in the LAP group and 83 (95% CI: 42-86) days in the LAP+CAP group. Other secondary efficacy end-points (progression-free and overall survival) were comparable in the two treatment groups. Rates of diarrhoea were higher with LAP+CAP (61%; 95% CI: 35-83) compared to 26% (95% CI 9-51) with LAP mono, whereas other adverse events were mostly similar between the groups (18 [100%] versus 17 [90%]). DISCUSSION Lapatinib showed insufficient activity in HER2-amplified pretreated advanced GC. The safety profile of LAP or LAP+CAP was as expected with some more toxicity in the combination arm. (ClinicalTrials.gov Identifier, NCT01145404).

Treatment of long-term catheter-related bloodstream infections with a taurolidine block: a single cancer center experience

Purpose Catheter-related bloodstream infections (CRBSIs) are a common problem in cancer patients with long-term catheters. The effectiveness of taurolidine, a new antimicrobial solution, in the management of CRBSIs is still unknown. A retrospective analysis of patients with proven CRBSIs treated with a taurolidine block in combination with systemic antibiotic treatment was performed to define its role in the management of CRBSIs. Methods Twenty-four episodes of CRBSIs in 23 cancer patients with permanent use of the long-term catheter were treated with a taurolidine block for 3 consecutive days in combination with systemic antibiotic treatment. Results Treatment was successful in 16 of 24 events (67%). Explantation was performed in 8 cases (33%): in 3 patients due to a second positive blood culture, and in 1 patient due to recurrent fever after the conservative treatment. In 4 patients, the conservative approach was prematurely stopped due to persisting fever. Conclusion Taurolidine-based treatment may be a promising, noninvasive therapeutical approach in the management of long-term catheter-related bloodstream infections in cancer patients.

Immunotherapy of Colorectal Cancer

It is known that the immune response, reflected by high T cell infiltrates in primary tumors and metastases, influences the clinical course of colorectal cancer (CRC). Therefore, immunotherapy concepts have been adapted from other tumor entities, which typically rely on the activation of T cells in the tumor microenvironment (e.g. blockade of the immune checkpoint molecules PD-1 and CTLA-4). However, most of the strategies using the approved checkpoint inhibitors and/or combination strategies have more or less failed to produce impressive results in early phase trials in CRC. Therefore, a number of novel targets for checkpoint inhibition are currently in early phase clinical testing (TIM-3, Lag-3, OX40, GITR, 4-1BB, CD40, CD70). A simple activation of infiltrating T cells will not, however, lead to a meaningful anti-tumor response without modulating the environmental factors in CRC. Thus, it is absolutely necessary to improve our understanding of the complex regulation of the tumor microenvironment in CRC to design individual combination treatments leading to effective immune control.

Efficacy and safety of trastuzumab-based therapy in combination with different chemotherapeutic regimens in advanced esophagogastric cancer--a single cancer-center experience.

Background Trastuzumab-based therapy has significantly changed the management of Her-2 positive metastatic esophagogastric cancer. However, only limited experience exists for the management in patients who are not suitable for cisplatin-based therapy. Methods Patients treated with trastuzumab in combination with different chemotherapeutic regimens were analyzed. Response rates, progression-free survival, overall survival, patterns of cardiac toxicity and patterns of maintenance strategies were recorded. Results The response rates, progression-free survival and overall survival in patients with metastatic esophagogastric cancer treated with trastuzumab and different chemotherapeutic regimens compared well with the data published in the TOGA trial. No unexpected toxicity occurred. Different strategies were used for therapy de-escalation. Conclusion Trastuzumab-based therapy is effective in combination with several chemotherapeutic regimens with a safe toxicity pattern. The optimal maintenance strategy remains to be defined.

Randomized controlled trial of S-1 maintenance therapy in metastatic esophagogastric cancer – the multinational MATEO study

BackgroundThe optimal duration of firstline chemotherapy in metastatic esophagogastric cancer is unknown. In most clinical trials therapy was given until tumour progression or limiting toxicity. Maintenance concepts aiming to prolong the duration of response and maintain quality of life have been established in other tumour types but not in esophagogastric cancer. S-1 is an oral fluoropyrimidine with proven efficacy in metastatic esophagogastric cancer.MethodsThe Maintenance Teysuno® (S-1) in esophagogastric cancer (MATEO) trial is a multinational, randomized phase II study that explores the role of S-1 maintenance therapy in Her-2 negative, advanced esophagogastric adenocarcinoma. After a 12-week firstline platinum-fluoropyrimidine-based chemotherapy patients without tumour progression are randomized in a 2:1 allocation to receive S-1 alone or continue with the same regimen as during the primary period. The primary endpoint is overall survival. Secondary endpoints include safety and toxicity, progression-free survival and quality of life.Correlative biomarker analyses focus on the identification of a subgroup of patients with a prolonged benefit from S-1 based maintenance therapy.DiscussionMATEO will be the first trial to define the role of a S-1 based maintenance therapy in patients having received a platinum-based firstline chemotherapy.Trial registrationNCT02128243 (date of registration: 29–04-2014).

629PLAPATINIB VERSUS LAPATINIB PLUS CAPECITABINE AS SECOND-LINE TREATMENT IN HER2-OVEREXPRESSING METASTATIC GASTRO-ESOPHAGEAL CANCER (GC): A RANDOMIZED PHASE II TRIAL OF THE ARBEITSGEMEINSCHAFT INTERNISTISCHE ONKOLOGIE (AIO)

ABSTRACT Aim: Her2 amplification is present in a subgroup of gastroesophageal cancers (GCs). Her2 inhibition with Trastuzumab has shown to improve clinical outcomes in metastatic disease. Lapatinib ditosylate (LAP), a dual anti EGFR and anti Her2 tyrosine kinase inhibitor with preclinical activity against GC, has been approved in Her2 positive breast cancer. We aimed to study the activity of LAP in HER2 amplified GC. Methods: Patients (pts) with Her2 positive (FISH ratio ≥2.0 or IHC3+ if ratio was between 1.8 and 20% in either of the two arms. Results: 37 pts were enrolled (18 to LAP + CAP, 19 to LAP mono). Pts received a median of three treatment cycles. 10 pts in the LAP + CAP group (56%) and 7 pts in the LAP mono group (37%) had received prior Trastuzumab. Only two pts (11.1%; 95% CI: 1.37 – 34.7), both in the LAP + CAP arm, achieved an objective response. Therefore, the study was closed prematurely. Median time to progression was 42 (95% CI: 38 to 61) days in the LAP group and 83 (95% CI: 42 to 86) days in the LAP + CAP group (p = 0.07). The other secondary efficacy endpoints (progression-free [median 41 and 47 days] and overall survival [median values not yet mature]) were comparable in the two treatment groups. Rates of diarrhea (all grades) were higher with LAP + CAP (61%; 95% CI: 35 to 83) compared to 26% (95%CI 9 to 51) with LAP mono, while other adverse events were mostly similar between the groups (18[100%] vs. 17[90%]). Slightly more pts in the LAP-CAP group experienced serious adverse events (44 vs. 32%). Conclusions: Lapatinib showed insufficient activity, especially as monotherapy, in HER2 amplified pretreated advanced GC. This led to premature study termination. The safety profile of LAP or LAP + CAP was as expected with some more toxicity in the combination arm. Disclosure: P.C. Thuss-Patience: Research support by GSK; F. Lordick: GSK. All other authors have declared no conflicts of interest.