FOLFIRI plus panitumumab as second-line treatment in mutated RAS metastatic colorectal cancer patients who converted to wild type RAS after receiving first-line FOLFOX/CAPOX plus bevacizumab-based treatment: Phase II CONVERTIX trial

Introduction: Genomic studies of liquid biopsies in metastatic colorectal cancer (mCRC) have shown the evolutionary trajectory of wild type (WT) RAS colorectal tumours to mutant clones (mut). Recently, the disappearance of RAS mut has been reported supporting an unexpected negative selection of RAS mutations. Our objective is to evaluate the efficacy and safety of FOLFIRI plus panitumumab (P) as second-line treatment in mCRC patients who are RAS WT at treatment initiation (according to liquid biopsy) but were RAS mut at first-line initiation with FOLFOX/CAPOX plus bevacizumab-based treatment. Methods: CONVERTIX is a multicentric, single arm, phase II clinical trial (EudraCT number: 2017-003242-25). Eligible patients are those with unresectable mCRC who had RAS mut status in solid biopsies prior to receiving a first-line chemotherapy regimen based on FOLFOX/CAPOX plus bevacizumab and with WT RAS status in liquid biopsy prior to second-line initiation of FOLFIRI + P (every 14 days until disease progression, unacceptable toxicity, or patient/physician’s request to discontinue). The primary objective is progression-free survival (PFS) in second-line treatment. Other objectives include determining WT to mut RAS conversion rate, overall response rate (ORR), disease control rate (DCR), estimated proportion of subjects with early tumour shrinkage (ETS), depth and duration of response (DpR, DoR), time to response (TTR) and treatment failure (TTF), overall survival (OS), safety and tolerability, as well as biomarker analysis of the liquid biopsies. Tumour response will be evaluated every 8 weeks until disease progression. Patient follow-up will be at 36 months. Results: Sample size has been estimated according to clinical criteria: 40 total patients (36 events assuming a 10% censoring and a mean PFS of 6 months) will produce a two-sided 95% confidence interval with a width of 4 months for the estimation of the PFS. Due to the lack of information regarding RAS mut conversion to WT, the RAS mutational status will be evaluated in liquid biopsies in 20 patients. An early stop is planned if less than 2 of these mCRC patients have WT RAS in liquid biopsy analysis. The recruitment of patients from 8 centres began in July 2018. Conclusion: An interim analysis will take place once 10 patients have either had a PFS event or gone 6 months progression-free. If less than 5 have PFS > 6 months, the study will be stopped early. This work was supported by Amgen

Impact of HER2 status in resected gastric or gastroesophageal junction adenocarcinoma in a Western population

Background: HER2 status is a predictive biomarker of response to trastuzumab in advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma. However, there is relatively little known about the role of HER2 in resected gastric or GEJ adenocarcinoma in the Western population. Methods: Retrospective, observational, single centre study of patients with gastric or GEJ adenocarcinoma undergoing surgery with curative intent between January 2007 and June 2014 in the University Hospital Complex of Santiago de Compostela. The expression of HER2 was determined by immunohistochemistry (IHC) using DAKO-HercepTest and gene amplification with DuoCISH using a DAKO-DuoCISH kit. The study of HER2 expression and amplification was carried out in all the patients and it was correlated with classic clinicopathological parameters, survival and recurrence pattern. Results: 106 patients were included. HER2 expression was as follows: 71.7% HER2 negative, 21.7% HER2 equivocal and 6.6% HER2 positive, or with HER2 overexpression. 13.2% of patients (14/106) had HER2 amplification by DuoCISH. A significant association was seen between overexpression and amplification of HER2 (p < 0.001).HER2 positivity was associated with the intestinal subtype (p = 0.010) and a low grade of differentiation (p = 0.018). Likewise, HER2 was significantly associated with a worse prognosis: overall survival (OS) 32.3 months HER2 positive versus 93.9 months HER2 negative (HR 0.42; confidence interval 95% 0.18-0.93; p = 0.028); and the presence of distant metastasis without accompanying locoregional recurrence (p = 0.048). Conclusion: HER2 status defines a subgroup with differentiated clinicopathological characteristics, worse prognosis and distant dissemination, without accompanying locoregional recurrence, in patients with resected gastric or GEJ adenocarcinoma operated on in a Western population