Prediction of survival in patients with advanced, refractory colorectal cancer in treatment with trifluridine/tipiracil: real-world vs clinical trial data

Abstract

Trifluridine/tipiracil increases overall survival (OS) in patients with refractory, metastatic colorectal cancer (mCRC). A post hoc exploratory analysis of the RECOURSE randomized clinical trial (RCT) established two categories, a good prognosis corresponding to subjects having a low tumor burden and indolent disease. Other models in refractory mCRC are the FAS-CORRECT and Colon Life nomogram. The main objective was to externally validate the prognostic factors of the RECOURSE and FAS-CORRECT trials, and the Colon Life nomogram in a multicenter, real-world series of mCRC treated in 3rd and successive lines with trifluridine/tipiracil. The secondary aim was to develop an OS predictive model, TAS-RECOSMO. Between 2016 and 2019, 244 patients were recruited. Median OS was 8.15 vs 8.12 months for the poor (85% of the subjects) and good (15%) prognosis groups from the RESOURCE trial, respectively, log-rank p = 0.9. The most common grade 3–4 toxicities were neutropenia (17%), asthenia (6%), and anemia (5%). The AFT lognormal model TAS-RECOSMO included six variables: ECOG-PS, KRAS/NRAS/BRAF mutation status, time between diagnosis of metastasis and beginning of trifluridine/tipiracil, NLR, CEA, and alkaline phosphatase. The model’s bootstrapped bias-corrected c-index was 0.682 (95% CI, 0.636–0.722). The factors from the Colon Life model, FAS-CORRECT, and RECOURSE displayed a c-index of 0.690, 0.630, and 0.507, respectively. TAS-RECOSMO, FAS-CORRECT, and the Colon Life nomogram appear to predict OS in patients with refractory mCCR who begin trifluridine/tipiracil treatment in the real world. The prognostic groups of the RECOURCE RCT were unable to capture the situation of real-world subjects treated with trifluridine/tipiracil in this series.

Genomic landscape and survival analysis of ctDNA “neo-RAS wild-type” patients with originally RAS mutant metastatic colorectal cancer

“…Since its first description (14), the concept of "neo-RAS wt" in colorectal cancer has gained increasing attention, providing new insights for following targeted treatment selection. In fact, the absence of any clinically relevant mutation of RAS genes in blood has been recently used as a therapeutically exploitable window to change the clinically-based selection of patients to be treated with EGFR inhibitors (7)(8)(9)(10)(11). The rate of RAS mutation clearance in plasma is highly variable, ranging from 8% to 70% of cases according to studies (15).…”

“…This phenomenon, currently known as "neo-RAS wild-type (wt)", leads to the appearance of a frametime characterized by RAS wt disease in plasma, which has been described in course of treatment and at the time of disease progression, according to studies (4)(5)(6). This observation led to the hypothesis that RAS assessment in ctDNA at disease progression could change the clinically-based selection of patients to be treated with EGFR inhibitors (7)(8)(9)(10)(11). The genomic landscape of actionable alterations in "neo-RAS wt" patients has never been investigated to date.…”

The AGAMENON-SEOM model for prediction of survival in patients with advanced HER2-positive oesophagogastric adenocarcinoma receiving first-line trastuzumab-based therapy

“… 13 The contribution of NLR is known in AGA 29 and other advanced malignancies, reflecting the presence of a systemic proinflammatory state. 30 , 31 It should be noted that the effect on survival-based endpoints is non-linear, with a threshold between 6 and 8, beyond which successive increases are not associated with worse prognosis. The non-linear association with various endpoints has been described in oncology and non-oncology patients in various settings, 19 , 32 , 33 but does not occur in all studies.…”

Efficacy, safety and prognostic factors in patients with refractory metastatic colorectal cancer treated with trifluridine/tipiracil plus bevacizumab in a real-world setting

“…Patients with refractory mCRC often have poor prognosis 17 . In our real-world study, 22.9% of patients had an ECOG PS of 2 and therefore may be more representative of patients with refractory mCRC in routine clinical practice than the previous C-TASK FORCE and Danish clinical studies, which excluded patients with ECOG PS of 2 9 , 10 .…”

“…low tumour burden, less aggressive disease (≥ 18 months since diagnosis of metastatic disease) and liver metastases] 7 , high lymphocyte-to-monocyte ratio (≥ 3.18) 21 , and the TAS-RECOSMO predictive model [i.e. general status, neutrophil-to-lymphocyte ratio, KRAS , NRAS and BRAF mutation status, carcinoembryonic antigen (CEA) and alkaline phosphatase (ALP) levels, and time since metastatic disease diagnosis] 17 . However, our study did not identify liver metastases or the time since diagnosis of metastasis < 18 months (i.e.…”