Retreatment with anti-EGFR monoclonal antibodies in metastatic colorectal cancer: Systematic review of different strategies.

BACKGROUND: Despite advances in precision oncology and immunotherapy of tumors, little progress has been made in metastatic colorectal cancer (mCRC) in recent years. Therefore, making the most of available therapies is a necessity. Several studies, based on the pulsatile behavior of RAS clones under EGFR blockade, investigated whether readministration of EGFR-targeted agents is effective beyond second line. METHODS: A systematic review of studies of retreatment with anti-EGFR monoclonal antibodies has been performed from January 2005 to December 2018 according to PRISMA criteria from PubMed, ESMO and ASCO meetings libraries and Clinicaltrial.gov. Efficacy has been evaluated as objective response rate and survival in available publications. In addition, type and incidence of side effects occurring during on anti-EGFR retreatment have been considered. RESULTS: 26 publications have been retrieved, of which 20 full-text articles and 6 abstracts and categorized as for the retreatment strategy into five groups: rechallenge (n = 10), reintroduction (n = 4), sequence (n = 5), dose escalation (n = 1) and mixed (n = 6). Data of efficacy displayed high heterogeneity across different strategies (objective response rate, ORR = 0.0-53.8%; disease control rate, DCR = 24.0-89.7%), with best results in the setting of rechallenge (ORR = 2.9-53.8%; DCR = 40.0-89.7%). CONCLUSIONS: Rechallenge with anti-EGFR provides clinical benefit in molecularly selected mCRC patients beyond second line. Further ctDNA-guided studies comparing this option of treatment with current approved advanced line treatments are warranted.

TRKA expression and NTRK1 gene copy number across solid tumours.

AIMS: Neurotrophic Tropomyosin Kinase Receptor 1 (NTRK1) gene encodes for the protein Tropomyosin-related kinase A (TRKA). Deregulated activity of TRKA has been shown to have oncogenic potential. We present here the results of an immunohistochemical (IHC) observational cohort study of TRKA expression together with gene copy number (GCN) assessment in various solid tumours. METHODS: Formalin-fixed, paraffin-embedded consecutive samples of different tumour types were tested for TRKA expression. Samples showing TRKA IHC staining in at least 10% of cells were analysed by fluorescence in situ hybridisation to assess NTRK1 gene rearrangements and/or individual GCN gain. All patients underwent this molecular assessment within the phase I ALKA-001 clinical trial. RESULTS: 1043 samples were tested and annotation for histology was available in 1023. Most of the samples were colorectal adenocarcinoma (CRC) (n=550, 52.7%) and lung adenocarcinoma (n=312, 29.9%). 24 samples (2.3%) were biliary tract carcinoma (BTC). Overall, 17 (1.6%) samples were characterised by TRKA IHC expression (four weak, eight moderate, five strong): 9/17 lung adenocarcinoma, 3/17 CRC, 3/17 BTC, 1/17 thyroid cancer and 1/17 cancer of unknown primary. Of these, 1/17 with strong TRKA IHC staining displayed NTRK1 gene rearrangement and 15/17 NTRK1 GCN gain by FISH. No correlation was found between intensity of TRKA IHC staining and number of copies of NTRK1. CONCLUSIONS: TRKA expression can be found in 1.6% of solid tumours and can be paralleled by NTRK1 gene rearrangements or mostly GCN gain. The prognostic and translational therapeutic impact of the latter remains to be established.