Relationships of peripheral blood lymphocyte counts (PBLC) with antitumor activity of NGR-hTNF given in combination with chemotherapy (CT)

Transcription

1 ASCO 2013 Abstract #3038 Relationships of peripheral blood lymphocyte counts (PBLC) with antitumor activity of NGRhTNF given in combination with chemotherapy (CT) Alessandra Bulotta, 1 Vanesa Gregorc, 1 Gilda Rossoni 1, Gabriele Todisco, 1 Maria Grazia Viganò, 1 Cristina Ammannati, 2 Giulia Mazzola, 2 Antonio Lambiase, 2 Claudio Bordignon 2 1 Departement of Oncology, Istituto Scientifico San Raffaele, Milan; 2 MolMed, Milan, Italy Background and methods Baseline characteristics Baseline characteristics Progressionfree survival Overall survival Antitumor effects of NGRhTNF, a tumortargeted antivascular agent, are driven at low dose by an initial tumor blood vessel stabilization that increases both intratumoral CT uptake 1 and Tcell infiltration 2 Synergism with CT has been shown in immunocompetent mice, but not in nude mice lacking functional T cells 3 By means of an individual patient pooled analysis of 427 patients from 7 phase II trials in 6 tumor types, we assessed the effects of baseline PBLC on the antitumor activity of CT alone (n=104) or NGRhTNF given at low dose (0.8 μg/m 2 ) with CT (n=183) or without CT (n=140) Tumor types were ovarian cancer (OC), small cell lung cancer (SCLC), NSCLC, malignant pleural mesothelioma (MPM), colorectal cancer (CRC) and hepatocellular carcinoma (HCC) CT consisted of either doxorubicin or a platinumbased regimen In all trials, tumor response by RECIST was evaluated every 6 weeks Endpoints of interest were response rate (complete + partial response, CR/PR), duration of response, progression free survival (PFS) and overall survival PBLC data were dichotomized into high and low levels by the median cutpoint (1.5/mL; range, ; 95% CI, ; IQR, ) A MannWhitney test was used to assess differences in median values of baseline PBLC as a function of tumor response. Odds ratios (OR) and hazard ratios (HR) were derived by logistic and Cox proportionalhazards regression models, respectively Variables (all study treatments) NGRhTNF alone n=140 (%) CT alone n=104 (%) NGRhTNF plus CT n=183 (%) Patient age median (range) 66 (3486) 61 (3880) 61 (3976) Gender male female ECOG PS 0 12 Tumor type MPM CRC HCC OC SCLC NSCLC 87 (62) 53 (38) 89 (64) 51 (36) 55 (39) 45 (32) 40 (29) 36 (34) 70 (66) 126 (69) 57 (31) 49 (47) 55 (53) 55 (27) 128 (73) 76 (72) 30 (28) 95 (52) 28 (15) 60 (33) Variables (NGRhTNF plus CT) PBLC above median n=84 (%) PBLC below median n=99 (%) Patient age median (range) 61 (3576) 61 (3976) Gender male Female ECOG PS 0 1/2 Tumor type OC SCLC NSCLC Chemotherapy doxorubicin platinumbased 28 (33) 56 (67) 61 (73) 23 (27) 41 (49) 7 (8) 36 (43) 48 (57) 36 (43) 27 (27) 72 (73) 65 (66) 34 (34) 54 (54) 21 (21) 24 (24) 75 (76) 24 (24) (NGRhTNF plus CT) (NGRhTNF plus CT) Median baseline PBLC by tumor response (all study treatments) Response rate by baseline PBLC (all study treatments) Duration of response (NGRhTNF plus CT) Multivariate model for PFS (NGRhTNF plus CT) Variables Exp(B) 95% CI p Median age > 61 vs 61 years Gender female vs male PS 0 vs 1/ Tumor type OC vs SCLC vs NSCLC Conclusions In patients receiving NGRhTNF or CT alone, there was no statistically significant difference in tumor response according to baseline PBLC Conversely, in patients receiving NGRhTNF plus CT, high PBLC (vs low) were associated with improved treatment outcome (including increased response rate, duration of response, PFS and OS) in both univariate and multivariate models Consistently with preclinical data, these results highlight the role of baseline PBLC in predicting subsequent tumor response to NGRhTNF plus CT, which merits further clinical investigation Median PBLC > 1.5 vs 1.5/mL References 1. Curnis F. et al Nat Biotechnol 2000;18 (11): Johansson A et al PNAS 2012; 109 (20): Sacchi A et al Cancer Res 2004; 64: Acknowledgements (MolMed) Scialini Colombi, Gloria Rossoni, Floriana Fontana, Emma Redaelli, Veronica Savia, Simona Santucci, Antonella Troysi

2 Relationships of peripheral blood lymphocyte counts (PBLC) with antitumor activity of NGRhTNF given in combination with chemotherapy (CT) Alessandra Bulotta, 1 Vanesa Gregorc, 1 Gilda Rossoni, 1 Gabriele Todisco, 1 Maria Grazia Viganò, 1 Cristina Ammannati, 2 Giulia Mazzola, 2 Antonio Lambiase, 2 Claudio Bordignon 2 1 Departement of Oncology, Istituto Scientifico San Raffaele, Milan, Italy 2 MolMed, Milan, Italy ASCO 2013 Abstract # 3038 General Poster Session Mon, June 3 8:0011:45 AM S Hall A2

3 Background Antitumor effects of NGRhTNF, a tumortargeted antivascular agent, are driven at low dose by an initial tumor blood vessel stabilization that increases both intratumoral CT uptake 1 and Tcell infiltration 2 Synergism with CT has been shown in immunocompetent mice, but not in nude mice lacking functional T cells 3 2

4 Methods By means of an individual patient pooled analysis of 427 patients from 7 phase II trials in 6 tumor types, we assessed the effects of baseline PBLC on the antitumor activity of CT alone (n=104) or NGRhTNF given at low dose (0.8 μg/m 2 ) with CT (n=183) or without CT (n=140) Tumor types were ovarian cancer (OC), small cell lung cancer (SCLC) NSCLC, malignant pleural mesothelioma (MPM), colorectal cancer (CRC) and hepatocellular carcinoma (HCC) CT consisted of either doxorubicin or a platinumbased regimen In all trials, tumor response by RECIST was evaluated every 6 weeks Endpoints of interest were response rate (complete + partial response, CR/PR), duration of response, progression free survival (PFS) and survival PBLC data were dichotomized into high and low levels by the median cutpoint (1.5/mL; range, ; 95% CI, ; IQR, ) A MannWhitney test was used to assess differences in median values of baseline PBLC as a function of tumor response. Odds ratios (OR) and hazard ratios (HR) were derived by logistic and Cox proportionalhazards regression models, respectively 3

5 Baseline characteristics (all study treatments) Variables NGRhTNF alone n=140 (%) CT alone n=104 (%) NGRhTNF plus CT n=183 (%) Patient age median (range) 66 (3486) 61 (3880) 61 (3976) Gender male female 87 (62) 53 (38) 36 (34) 70 (66) 55 (27) 128 (73) Performance status (PS) (64) 51 (36) 126 (69) 57 (31) 76 (72) 30 (28) Tumor type MPM CRC HCC OC SCLC NSCLC 55 (39) 45 (32) 40 (29) 49 (47) 55 (53) 95 (52) 28 (15) 60 (33) 4

6 Median baseline PBLC by tumor response (all study treatments) 5

7 Response rate by baseline PBLC (all study treatments) 6

8 Baseline characteristics (NGRhTNF plus CT) Variables PBLC above median n=84 (%) PBLC below median n=99 (%) Patient age median (range) 61 (3576) 61 (3976) Gender male Female ECOG PS 0 1/2 Tumor type OC SCLC NSCLC Chemotherapy doxorubicin platinumbased 28 (33) 56 (67) 61 (73) 23 (27) 41 (49) 7 (8) 36 (43) 48 (57) 36 (43) 27 (27) 72 (73) 65 (66) 34 (34) 54 (54) 21 (21) 24 (24) 75 (76) 24 (24) 7

9 Duration of response (NGRhTNF plus CT) 8

10 Progressionfree survival (NGRhTNF plus CT) 9

11 Multivariate model for PFS (NGRhTNF plus CT) Variables Exp(B) 95% CI p Median age > 61 vs 61 years Gender female vs male PS 0 vs 1/ Tumor type OC vs SCLC vs NSCLC Median PBLC > 1.5 vs 1.5/mL

12 Overall survival (NGRhTNF plus CT) 11

13 Conclusions In patients receiving NGRhTNF or CT alone, there was no statistically significant difference in tumor response according to baseline PBLC Conversely, in patients receiving NGRhTNF plus CT, high PBLC (vs low) were associated with improved treatment outcome (including increased response rate, duration of response, PFS and OS) in both univariate and multivariate models Consistently with preclinical data, these results highlight the role of baseline PBLC in predicting subsequent tumor response to NGRhTNF plus CT, which merits further clinical investigation References 1. Curnis F. et al Nat Biotechnol 2000;18 (11): Johansson A et al PNAS 2012; 109 (20): Sacchi A et al Cancer Res 2004; 64: Acknowledgements (MolMed) Scialini Colombi, Gloria Rossoni, Floriana Fontana, Emma Redaelli, Veronica Savia, Simona Santucci, Antonella Troysi 12