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Panitumumab interaction with TAS-102 leads to combinational anticancer effects via blocking of EGFR-mediated tumor response to trifluridine.

ABSTRACT: Panitumumab is a monoclonal antibody developed against the human epidermal growth factor receptor (EGFR). TAS-102 is a novel chemotherapeutic agent containing trifluridine (FTD) as the active cytotoxic component. Both panitumumab and TAS-102 have been approved for the treatment of metastatic colorectal cancer. In this study, we revealed the mechanism underlying the anticancer effects of panitumumab/TAS-102 combination using preclinical models. Panitumumab/FTD cotreatment showed additive antiproliferative effects in LIM1215 and synergistic antiproliferative effects in SW48 colon cancer cells. Consistent with the in vitro effects, panitumumab/TAS-102 combination caused tumor regression in LIM1215 and COL-01-JCK colon cancer patient-derived xenograft models. In LIM1215 cells, FTD induced extracellular signal-regulated kinase (ERK)/protein kinase B (AKT)/signal transducer and activator of transcription 3 (STAT3) phosphorylation and subsequent serine/threonine phosphorylation of EGFR, while it had no effects on EGFR tyrosine phosphorylation. Panitumumab and the tyrosine kinase inhibitor erlotinib reduced the basal level of EGFR tyrosine phosphorylation and reversed FTD-induced ERK/AKT/STAT3 and EGFR serine/threonine phosphorylation. These results suggested that FTD in combination with the basal activity of EGFR tyrosine kinase induced downstream prosurvival signaling through ERK/AKT/STAT3 phosphorylation. Collectively, we propose that panitumumab interacts with FTD by targeting EGFR-mediated adaptive responses, thereby exerting anticancer effects when used in combination with TAS-102. These preclinical findings provide a compelling rationale for evaluating the combination of anti-EGFR antibodies with TAS-102 against metastatic colorectal cancer.

SUBMITTER: Baba Y

PROVIDER: S-EPMC5537908 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND:In the phase III RECOURSE trial, trifluridine/tipiracil (TAS-102) extended overall survival (OS) and progression-free survival (PFS) with an acceptable toxicity profile in patients with metastatic colorectal cancer refractory or intolerant to standard therapies. The present analysis investigated the efficacy and safety of trifluridine/tipiracil in RECOURSE subgroups. METHODS:Primary and key secondary end-points were evaluated using a Cox proportional hazards model in prespecified subgroups, including geographical subregion (United States of America [USA], European Union [EU], Japan), age (<65 years, ?65 years) and v-Ki-ras2 Kirsten rat sarcoma 2 viral oncogene homologue (KRAS) status (wild type, mutant). Safety and tolerability were reported with descriptive statistics. RESULTS:Eight-hundred patients were enrolled: USA, n = 99; EU, n = 403; Japan, n = 266. Patients aged ?65 years and those with mutant KRAS tumours comprised 44% and 51% of all patients in the subregions, respectively. Final OS analysis (including 89% of events, compared with 72% in the initial analysis) confirmed the survival benefit associated with trifluridine/tipiracil, with a hazard ratio (HR) of 0.69 (95% confidence interval [CI] 0.59-0.81; P = 0.0001). Median OS in the three regions was 6.5-7.8 months in the trifluridine/tipiracil arm and 4.3-6.7 months in the placebo arm (USA: HR 0.56; 95% CI 0.34-0.94; P = 0.0277; EU: HR 0.62; 95% CI 0.48-0.80; P = 0.0002; Japan: HR 0.75; 95% CI 0.57-1.00; P = 0.0470). Median PFS was 2.0-2.8 months for trifluridine/tipiracil and 1.7-1.8 months for placebo; HRs favoured trifluridine/tipiracil in all regions. Similar clinical benefits of trifluridine/tipiracil were observed in elderly patients and in those with mutant KRAS tumours. There were no marked differences among subregions in terms of safety and tolerability. CONCLUSIONS:Trifluridine/tipiracil was effective in all subgroups, regardless of age, geographical origin or KRAS status. This trial is registered with ClinicalTrials.gov: NCT01607957.

Project description:BackgroundTrifluridine/tipiracil (FTD/TPI) is an oral antimetabolite agent comprised of trifluridine, a thymidine-based nucleoside analogue that inhibits cell proliferation following its incorporation into DNA, and tipiracil that helps maintain the blood concentration of trifluridine by inhibiting the enzyme thymidine phosphorylase which inactivates trifluridine. It is approved as a third-line treatment option for patients with metastatic colorectal cancer (mCRC) and is administered at 35 mg/m2 two times daily from day 1 to 5 and from day 8 to 12 every 28 days. The aim of this investigator-initiated retrospective study (RETRO-TAS; NCT04965870) was to document real-world data on the clinical efficacy of FTD/TPI in patients with chemorefractory mCRC.MethodsThe clinical characteristics of patients with mCRC treated with FTD/TPI in 8 Cancer Centres were collected to assess physician's choice in the third or beyond line of treatment as well as the duration of treatment, dose modification, and toxicity. In addition, other important prognostic features related to mCRC such as molecular profile, performance status (PS), and primary site were analyzed. Statistical analysis for progression-free survival (PFS), overall survival (OS), 6-/8-month PFS rate and disease control rate (DCR) along with Cox regression model, Kaplan-Meier curves, and log-rank tests were carried out by using Stata/MP 16.0 for Windows.ResultsFrom October 2018 to October 2021, a total of 200 patients with mCRC and a median age of 67.0 (IQR 58.0, 75.0) years were treated with FTD/TPI. Τhe median follow-up time was 14 months (IQR 7, 23), 158 PDs and 106 deaths were reported at the time of this analysis. Of all the patients, 58% were males and 58% had mCRC at diagnosis. The molecular analysis identified mutations in KRAS (52%), NRAS (5%), HER2 (3.5%), BRAF (3.5%), and MSI (9%). Previous treatments included radical surgery in 51.5% and adjuvant chemotherapy in 39.5% of patients. FTD/TPI was administered in the third- (70.5%), fourth- (17.0%), or fifth-line (12.5%) treatment setting. Serious adverse events related to FTD/TPI included neutropenia (2%), anaemia (1%), thrombocytopenia (0.5%), diarrhoea (0.5%), nausea (0.5%), and fatigue (4%). A reduction of FTD/TPI dose, delay of next cycle initiation, and shorter duration were reported in 25%, 31%, and 14.5% of patients, respectively. Of all the patients 71.5% received FTD/TPI as monotherapy, 24.5% in combination with bevacizumab, and 4.0% with an anti-EGFR agent. The median FTD/TPI treatment duration was 119.5 days and 81% of patients discontinued treatment due to progressive disease. The DCR recorded by investigators' assessment was 45.5%. The median PFS was 4.8 and the median OS was 11.4 months. The 6- and the 8-month PFS rate was 41.4% and 31.5%, respectively. In the multivariate analysis, PS > 1 and presence of liver and lung metastasis were adversely associated with PFS and OS whereas mutational status and tumor sidedness were not.ConclusionsRETRO-TAS is a real-world observational study that confirms and adds on the findings of the pivotal RECOURSE Phase III study in relation to the efficacy of FTD/TPI in the third-line setting and in all subgroups of patients regardless of mutational status and sidedness.

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Panitumumab interaction with TAS-102 leads to combinational anticancer effects via blocking of EGFR-mediated tumor response to trifluridine.

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