Abstract
ABSTRACT Background NGR-hTNF (asn-gly-arg-human tumor necrosis factor) displays a biphasic dose-response curve with activity shown at very low or high doses. Treatment-induced shedding of circulating sTNF-R1 or -R2 may block drug effects. The impact of this counterregulatory mechanism on NGR-hTNF activity was assessed in two phase I trials. Methods Sixty patients (pts) with refractory solid tumors (median age, 60 years; M/F 44/16; PS 0/1-2 25/35; median prior treatment lines, 3) received NGR-hTNF every 3 weeks (q3w) given at low doses (0.2 to 1.6 µg/m2 n = 14) or high doses (60 to 325 µg/m2 n = 46). Tumor assessment by RECIST was done q6w until progressive disease (PD). We assessed the associations between baseline-normalized plasma levels of sTNF-R2 after 1st treatment cycle and clinical outcomes in terms of disease control rate (DCR, rate of pts without PD after 6 weeks) and progression-free survival (PFS) Results The levels of sTNF-R2 peaked significantly higher than sTNF-R1 (p 4.5 ng/mL n = 45). Mean number of cycles was 5.5 (range 1-29) and 2.5 (1-6) in pts with low or high levels, respectively. By univariate analyses, low sTNF-R2 levels were significantly associated with increased DCR (odds ratio, OR 3.8 p = 0.04) and improved PFS (hazard ratio, HR 0.29 p = .002). DCR was 58% (95% CI 32-81) and 26% (16-41) in pts with low or high levels, respectively. Six-month PFS rates were 29% in pts with low levels and 0% in pts with high levels (log-rank p = 0.0008). Median duration of disease control was 7.5 months in pts with low levels and 2.9 months in pts with high levels (log-rank p = .007). After adjusting for age, sex, PS, and prior lines, a low sTNF-R2 level remained independent predictor of higher DCR (OR 5.2 p = .03) and longer PFS (HR = 0.27 p = .002). The highest sTNF-R2 levels (75th percentile) were associated with the worst survival rates (HR 2.6 p = .01) Conclusions: Early treatment-induced changes in sTNF-R2 shedding may identify pts who have a greater likelihood of benefit from NGR-hTNF. Disclosure A. Lambiase: Employment - MolMed. C. Bordignon: Employment - MolMed. All other authors have declared no conflicts of interest.
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