Body weight loss (BWL) as a prognostic/predictive factor in previously treated patients (pts) with metastatic gastric or gastroesophageal junction cancer (mGC/GEJC): Post-hoc analyses of the phase III tags trial.
Authors: Ghidini Michele , Hochster Howard S. , Doi Toshihiko , Van Cutsem Eric , Makris Lukas , Benhadji Karim A. , Mansoor Wasat 
Published: January 2021

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Background: Nutritional status is closely linked to cancer mortality, and BWL has been shown to be prognostic for survival in curative, first-, and second-line settings in mGC/GEJC. In the phase III TAGS trial, trifluridine/tipiracil (FTD/TPI) showed clinical benefit versus placebo (PBO) and manageable safety in pts with mGC/GEJC who had received ≥2 prior chemotherapy regimens. The association of early BWL with survival outcomes in TAGS was examined in retrospective analyses. Methods: The TAGS intent-to-treat (ITT) population was categorized into pts who experienced <3% or ≥3% BWL from the start of treatment until day 1 of cycle 2 (each cycle: 28 days). Overall survival (OS), and progression-free survival (PFS) were compared between subgroups within each treatment arm due to significant imbalances of early BWL between treatment arms. The effect of early BWL on OS was assessed by a univariate Cox proportional hazards (PH) model as well as a multivariate Cox PH model that adjusted for baseline prognostic factors identified in the original ITT analysis. Results: Body weight data were available for 451 of 507 (89%) pts in the study (n=304, FTD/TPI; n=147, PBO). In the FTD/TPI and PBO arms, respectively, 74% (224/304 pts) and 65% (95/147) experienced <3% BWL, whereas 26% (80/304) and 35% (52/147) experienced ≥3% BWL at the end of cycle 1. Pts with <3% BWL had longer OS than those with ≥3% BWL in both FTD/TPI (median [m] OS: 6.5 vs 4.9 months [mo]; hazard ratio [HR], 0.75; 95% CI, 0.55–1.02) and PBO arms (mOS: 6.0 vs 2.5 mo; HR, 0.32; 95% CI, 0.21–0.49). The PFS HR for pts with <3% BWL vs ≥3% BWL was 0.95 (95% CI, 0.71–1.25; mPFS, 2.1 vs 1.9 mo) in the FTD/TPI group and 0.49 (95% CI, 0.34–0.72; mPFS, 1.9 vs 1.7 mo) in the PBO group. In the pooled ITT population, the unadjusted HR for the <3% vs ≥3% BWL group calculated using a univariate Cox model was 0.58 (95% CI, 0.46–0.73), indicating a strong prognostic effect of early BWL. Results of multivariate analyses were consistent with univariate analyses and suggested that early BWL was both a prognostic ( P<0.0001) and predictive (interaction P=0.0003) factor for OS in pts with mGC/GEJC. Grade ≥3 adverse events (AEs) of any cause were reported in 77% and 82% of FTD/TPI-treated pts in the <3% and ≥3% BWL subgroups, respectively, and in 45% and 67% of placebo-treated pts in the <3% and ≥3% BWL subgroups. Conclusions: To our knowledge, this is the first analysis to show that BWL is negatively associated with survival in pts with mGC/GEJC receiving third- or later-line treatment. In TAGS, early BWL (≥3% BWL at the end of cycle 1) was a strong negative prognostic factor for OS regardless of FTD/TPI or PBO treatment. Grade ≥3 AE frequencies were similar in FTD/TPI-treated pts with <3% or ≥3% BWL. The relationship of BWL to other prognostic factors will be explored further. Clinical trial information: NCT02500043.