Entry Detail
| General information | |
| Database: | DB00448 |
| Objective: | Lapatinib, a dual EGFR and human epidermal growth factor receptor 2 inhibitor has shown disappointing results in clinical trials of metastatic oesophagogastric adenocarcinomas (OGAs), and in vitro studies suggest that MET, IGFR, and HER3 confer resistance. This trial applied Lapatinib in the curative neoadjuvant setting and investigated the feasibility and utility of additional endoscopy and biopsy for assessment of resistance mechanisms ex vivo and in vivo. |
| Authors: | De Silva N, et al |
| Title: | Molecular effects of Lapatinib in the treatment of human epidermal growth factor receptor 2 overexpressing oesophagogastric adenocarcinoma. |
| Journal: | Br J Cancer. |
| Year: | 2015 |
| PMID: | 26484410 |
| Trial Design | |
| Clinical Trial Id: | NA |
| Agent: | lapatinib |
| Target: | Epidermal growth factor receptor Receptor proteintyrosine kinase erbB2 |
| Cancer Type: | esophagusgastroesophageal junction cancer |
| Cancer Subtype: | esophagogastric adenocarcinoma |
| Therapy Type: | mono |
| Therapeutic Combination Type: | NA |
| Therapeutic Combination Content: | NA |
| Study Type: | retrospective analysis |
| Key Patients Feature: | Patients with human epidermal growth factor receptor 2 overexpressing oesophagogastric adenocarcinoma |
| Biomarker: | human epidermal growth factor receptor 2 overexpressing |
| Biomark Analysis: | The reduction in Phosphorylatedhuman epidermal growth factor receptor 2 (Phuman epidermal growth factor receptor 2) and PEGFR in the ex vivotreated biopsy demonstrated good correlation with the in vivo response at day 10. Proteomic analysis pre and postLapatinib demonstrated target inhibition (PERBB2, PEGFR, PPI3K, PAKT, and PERK) that persisted until surgery. There was also significant correlation between the activation of MET with the level of PErk (P=0.0005) and PPI3K : TPI3K (total PI3K) ratio (P=0.0037). There was no significant correlation between the activation status of IGFR and HER3 with downstream signalling molecules. |
| Control Group Info: | single arm |
| Treatment Info: | Endoscopic samples were taken for molecular analysis at: baseline including for ex vivo culture +/ Lapatinib to predict in vivo response, postLapatinib monotherapy and at surgery. Immunohistochemistry (IHC) and proteomic analysis was performed to assess cell kinetics and signalling activity. |
| Primary End Point: | biomarker analysis |
| Secondary End Point: | NA |
| Patients Number: | 10 |
| Trial Results | |
| DLT_MTD: | NA |
| Objective Response Rate: | There were no responses by PET at D10 in the maximal standard uptake value of for the maximal region of interest (1.5 cm2 circle). Fifty per cent of patients had a partial response on CT after neoadjuvant therapy, and the rest had stable disease. |
| Disease Control Rate: | NA |
| Median Time to Progression: | NA |
| Median PFS A vs. C: | 16.4 months |
| Median OS A vs. C: | 32.4 months |
| Adverse Event(agent arm): | The most common adverse effects noted were nausea and diarrhoea. These are in keeping with the known individual toxicities of the drugs, especially Capecitabine and Lapatinib. Three patients experienced grade 4 toxicity. This included two patients who experienced anastomotic leaks. One of these patients died after developing a chest infection. |
| Conclusions: | Additional endoscopy and biopsy sampling for multiple biomarker endpoints was feasible and confirmed in vitro data that MET is likely to be a significant mechanism of Lapatinib resistance in vivo. |