488P - Impact of soluble tumor necrosis factor-receptors (STNF-RS) shedding on outcome in patients treated with NGR-HTNF

Date 01 October 2012
Event ESMO Congress 2012
Session Poster presentation III
Topics Drug Development
Presenter Paolo A. Zucali
Authors P.A. Zucali1, M. Simonelli1, F. De Vincenzo1, E. Lorenzi1, A. Santoro1, A. Lambiase2, C. Bordignon2
  • 1Department Of Oncology, Humanitas Cancer Center IRCCS, Rozzano/IT
  • 2Clinical Development, MolMed, 20132 - Milan/IT



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.


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)


The levels of sTNF-R2 peaked significantly higher than sTNF-R1 (p < .0001) and increased dose proportionally (p = .0003), with a median distribution value of 8.6 ng/mL (interquartile range 4.5-10.7). Using the 25th percentile as cut-off value, the sTNF-R2 levels were dichotomized in low (≤ 4.5 ng/mL n = 15) or high (> 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.


A. Lambiase: Employment - MolMed.

C. Bordignon: Employment - MolMed.

All other authors have declared no conflicts of interest.