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Purpose: NGR-hTNF exploits the tumor-homing peptide asparagine-glycine-arginine (NGR) for selectively targeting TNF-α to an aminopeptidase N overexpressed on cancer endothelial cells. Preclinical synergism with cisplatin was displayed even at low doses. This study primarily aimed to explore the safety of low-dose NGR-hTNF combined with cisplatin in resistant/refractory malignancies. Secondary aims included pharmacokinetics (PKs), pharmacodynamics, and activity. Experimental Design: NGR-hTNF was escalated using a doubling-dose scheme (0.2–0.4–0.8–1.6 μg/m2) in combination with fixed-dose of cisplatin (80 mg/m2), both given intravenously once every three weeks. PKs and circulating TNF-receptors (sTNF-Rs) were assessed over the first three cycles. Results: Globally, 22 patients (12 pretreated with platinum) received a range of one to ten cycles. Consistently with the low-dose range tested, maximum-tolerated dose was not reached. No dose-limiting toxicities (DLTs) were observed at 0.2 (n = 4) and 0.4 μg/m2 (n = 3). One DLT (grade 3 infusion-related reaction) was observed at 0.8 μg/m2. This dose cohort was expanded to six patients without further DLTs. No DLTs were noted also at 1.6 μg/m2 (n = 3). NGR-hTNF exposure increased dose-proportionally without apparent PK interactions with cisplatin. No shedding of sTNF-Rs was detected up to 0.8 μg/m2. At the dose level of 0.8 μg/m2, expanded to 12 patients for activity assessment, a platinum-pretreated lung cancer patient achieved a partial response lasting more than six months and five patients maintained stable disease for a median time of 5.9 months. Conclusions: The combination of NGR-hTNF 0.8 μg/m2 with cisplatin 80 mg/m2 showed favorable toxicity profile and promising antitumor activity. Clin Cancer Res; 17(7); 1964–72. ©2011 AACR.

Purpose NGR-hTNF consists of human tumor necrosis factor α (hTNF-α) fused to the tumor-homing peptide asparagine-glycine-arginine (NGR) able to selectively bind an aminopeptidase N isoform overexpressed on tumor blood vessels. Hypervascularity is a prominent and poor-prognosis feature of malignant pleural mesothelioma (MPM). Currently, there are no standard options for patients with MPM who are failing a front-line pemetrexed-based regimen. We explored safety and efficacy of NGR-hTNF in this setting. Patients and Methods Eligible patients had radiologically documented tumor progression and performance status ≤ 2. Primary study aim was progression-free survival (PFS). NGR-hTNF 0.8 μg/m2 was given intravenously every 3 weeks. A subsequent cohort of patients received 0.8 μg/m2 on a weekly basis. Results In the triweekly cohort (n = 43), only one grade 3 drug-related toxicity was noted, and the most common grades 1 to 2 were short-lived chills (71%). The median PFS was 2.8 months (95% CI, 2.3 to 3.3 months). Nineteen patients (44%) had disease control (one had partial response, and 18 had stable diseases) and experienced a median progression-free time of 4.4 months. In the weekly cohort (n = 14), there was no higher toxicity, and median PFS was 3.0 months (95% CI, 1.9 to 4.1 months). Seven patients (50%) had disease control (all stable diseases) and had a median progression-free interval of 9.1 months. In the overall study population (N = 57), median PFS was 2.8 months. Median progression-free time was 4.7 months in twenty-six patients (46%) who achieved disease control. Median survival was 12.1 months. Conclusion The tolerability and disease control of NGR-hTNF 0.8 μg/m2 weekly warrant additional evaluation in patients with advanced MPM.

Targeted delivery of TNF to tumour vessels has been achieved by coupling this protein with the CNGRC peptide, an aminopeptidase N (CD13) ligand that targets the tumour neovasculature.The so-called NGR-TNF enhances the penetration of chemotherapeutic drugs in tumours and improves their efficacy. Here we describe a case of hepatocarcinoma which showed response to NGR-hTNF in combination with doxorubicin, clinically proving this promising strategy.

A growing body of evidence suggests that the efficacy of cytokines in cancer therapy can be increased by targeting strategies based on conjugation with ligands that recognize receptors expressed by tumor cells or elements of the tumor microenvironment, including the tumor vasculature. The targeting approach is generally conceived to permit administration of low, yet pharmacologically active, doses of drugs, thereby avoiding toxic reactions. However, it is becoming clear that, in the case of cytokines, this strategy has another inherent advantage, i.e. the possibility of administering extremely low doses that do not activate systemic counter-regulatory mechanisms, which may limit their potential therapeutic effects. This review is focused on the use of tumor vasculature-homing peptides as vehicles for targeted delivery of cytokines to tumor blood vessel. In particular, we provide an overview of peptide-cytokine conjugates made with peptides containing the NGR, RGD, isoDGR or RGR sequences and describe, in more details, the biological and pharmacological properties of NGR-hTNF, a peptide-tumor necrosis factor-α conjugate that is currently being tested in phase II and III clinical studies. The results of preclinical and clinical studies performed with these products suggest that peptide-mediated vascular-targeting is indeed a viable strategy for delivering bioactive amounts of cytokines to tumor endothelial cells without causing the activation of counter-regulatory mechanisms and toxic reactions.

Background Although first-line therapy for patients affected by advanced mesothelioma is well established, there is a lack of data regarding the impact of second-line treatment. Methods We retrospectively collected data of patients affected by advanced mesothelioma, already treated with first-line therapy based on pemetrexed and platin, with a response (partial response or stable disease) lasting at least 6 months, and re-treated with a pemetrexed-based therapy at progression. The primary objective was to describe time to progression and overall survival after re-treatment. Results Overall across several Italian oncological Institutions we found 30 patients affected by advanced mesothelioma, in progression after a 6-month lasting clinical benefit following a first-line treatment with cisplatin and pemetrexed, and re-challenged with a pemetrexed-based therapy. In these patients we found a disease control rate of 66%, with reduction of pain in 43% of patients. Overall time to progression and survival were promising for a second-line setting of patients with advanced mesothelioma, being 5.1 and 13.6 months, respectively. Conclusions In our opinion, when a patient has a long-lasting benefit from previous treatment with pemetrexed combined with a platin compound, the same treatment should be offered at progression.

Background: NGR-hTNF consists of human tumour necrosis factor-alpha (hTNF-alpha) fused to the tumour-homing peptide NGR, a ligand of an aminopeptidase N/CD13 isoform, which is overexpressed on endothelial cells of newly formed tumour blood vessels. NGR-TNF showed a biphasic dose-response curve in preclinical models. This study exploring the low-dose range aimed to define safety and optimal biological dose of NGR-hTNF. Patients and methods: Pharmacokinetics, plasma biomarkers and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) were evaluated at baseline and after each cycle in 16 patients enrolled at four doubling-dose levels (0.2-0.4-0.8-1.6 mu g/m(2)). NGR-hTNF was given intravenously as 1-h infusion every 3 weeks (q3w). Tumour response was assessed q6w. Results: Eighty-three cycles (median, 2; range, 1-29) were administered. Most frequent treatment-related toxicity was grade 1-2 chills (69%), occurring during the first infusions. Only one patient treated at 1.6 mu g/m(2) had a grade 3 drug-related toxicity (chills and dyspnoea). Both C(max) and AUC increased proportionally with dose. No shedding of soluble TNF-alpha receptors was observed up to 0.8 mu g/m(2). Seventy-five percent of DCE-MRI assessed patients showed a decrease over time of K(trans), which was more pronounced at 0.8 mu g/m(2). Seven patients (44%) had stable disease for a median time of 5.9 months, including a colon cancer patient who experienced an 18-month progression-free time. Conclusion: Based on tolerability, soluble TNF-receptors kinetics, anti-vascular effect and disease control, NGR-hTNF 0.8 mu g/m(2) will be further developed either as single-agent or with standard chemotherapy. (C) 2009 Elsevier Ltd. All rights reserved.

7558 Background: NGR-hTNF, a tumor-targeted antivascular agent, promotes a vessel normalization that improves intratumor T-cell infiltration and chemotherapy uptake. The prognostic role of baseline...

7557 Background: Historically, the TFI (time from end of first-line to start of second-line therapy) has been reported as a prognostic factor and predictive marker of benefit of next treatment line...

2538 Background: NGR-hTNF, a selective antivascular agent, quickly and transiently modulates the release of systemic cytokines/chemokines. Intravenous infusion of NGR-hTNF is characterized by onset...

7584 Background: Both TFI (the time elapsing from end of first line to start of second line therapy) and DCR (the nonprogression rate at first tumor evaluation) have been found to predict overall s...

3038 Background: Antitumor effects of NGR-hTNF (N), a tumor-targeted antivascular agent, are driven at low dose by an early vessel stabilization that greatly enhances both intratumoral CT uptake and T-cell infiltration. Synergism with CT was shown in immunocompetent mice, but not in nude mice lacking functional T cells. Methods: By an individual patient pooled analysis of 396 patients (pts) from 7 ph II trials in 6 tumor types, we estimated the effects of baseline PBLC on the antitumor activity of N (with or without CT) and CT alone. Low dose N (0.8 μg/m2) was given in combination with CT in 171 pts. Control groups of 140 and 85 pts receiving N and CT alone, respectively, were also analyzed. CT was doxorubicin or a platinum-based regimen. In all trials, response to therapy was assessed every 6 weeks by RECIST. Endpoints of interest were response rate (RR, complete plus partial response), disease control rate (DCR, RR plus stable disease), duration of response (DOR) and progression-free survival (PFS). In logistic and Cox regression analyses, PBLC data were dichotomized in high or low levels by the median cutpoint (1.5/mL; 95% CI, 1.4-1.6). Multivariate models included age, sex, PS and tumor type as covariates. Results: In both N-alone and CT-alone groups, there was no statistically significant difference in treatment effect according to baseline PBLC. Conversely, high PBLC were related to better treatment outcome in the N plus CT group, compared to low PBLC. In this N plus CT group, high PBLC (vs low) were associated with higher RR (OR=2.8; 95% CI, 1.2-6.3; p=.01) and DCR (OR=2.6; 1.3-4.9; p=.004), and with longer DOR (HR=0.39; 0.16-0.96; p=.04) and PFS (HR=0.60; 0.43-0.85; p=.004). For high vs low PBLC, RR was 29% vs 14%, DCR 76% vs 57%, median DOR 8.2 vs 6.3 months, and median PFS 5.0 vs 3.0 months, respectively. On multivariate analyses, high PBLC remained an independent predictor of increased RR (OR=2.7; p=.01) and DCR (OR=2.6; p=.005), and improved DOR (HR=0.36; p=.04) and PFS (HR=0.60; p=.005). Conclusions: Consistently with preclinical data, these results highlight the potential value of PBLC in predicting tumor response to NGR-hTNF in combination with CT, which merits further clinical validation Clinical trial information: NCT00994097-NCT00484432-NCT00484276-NCT00484211-NCT00483509-NCT00483080-NCT01358071.

e13593 Background: NGR-hTNF, a selective antivascular agent, transiently modulates the systemic release of cytokines/chemokines. Intravenous infusion of NGR-hTNF is distinguished by an early on-target effect, IRR, which mostly consists of short-lived grade 1/2 chills. Methods: Incidence, predictors of development and relationships of IRR with treatment outcome were assessed in a pooled analysis of individual patient data from 5 phase II trials with NGR-hTNF. Global data set comprised 205 previously treated patients (pts) who had received NGR-hTNF 0.8 µg/m2 every 3 weeks (q3w) or weekly (q1w) alone in mesothelioma, colon and liver cancers or in combination with doxorubicin in small cell lung and ovarian cancers. In all trials, response to therapy (RECIST) was measured q6w until progression. Regression models estimated the effect size of IRR on response rate (RR; complete and partial response), disease control rate (DCR; RR plus stable disease) and progression free survival (PFS). Results: 137/205 pts (67%) experienced IRR on treatment, while 68 pts (33%) did not. In the IRR group, 63% of pts had grade 1 and 37% grade 2. By time to onset, 88% of pts developed IRR during first 6 weeks of therapy and 12% later. According to dosing schedule, IRR rates were higher with q1w than with q3w (85% vs 62%; p=.008). Baseline characteristics were (IRR vs non-IRR groups): median age: 66 vs 64; male: 50% vs 56%; PS ≥ 1: 34% vs 35%, range of prior lines: 1-4 vs 1-5. Among baseline characteristics, logistic regression analysis retained only a lower number of prior lines associated with higher IRR rates (OR=1.4; p=.02). Onset of IRR was related to better treatment outcome. RR was 12% in the IRR and 3% in the non-IRR group (OR=4.4; p=.05), while DCR was 50% in pts who had IRR and 34% in pts who did not (OR=2.0; p=.02). In pts with or without IRR, 6-month PFS was 21% vs 7% (HR=0.62; p=.001), respectively. Improvement in PFS time remained significant in a landmark analysis set at the 6-week time point (p=.004). On multivariate analyses adjusted for baseline variables, IRR independently predicted higher odds of tumor response (p=.05) and lower risk of progression or death (p=.009). Conclusions: Onset of IRR on NGR-hTNF treatment may predict subsequent clinical outcome. Clinical trial information: NCT00483080-NCT00483509-NCT00484211-NCT00484276-NCT00484432.

8035 Background: NGR-hTNF, a selective antivascular agent, induces at low dose an initial vascular normalization that greatly enhances the intratumoral chemotherapy uptake, with synergistic effects that were noted especially in combination with cisplatin and gemcitabine. Methods: Chemo-naive patients (pts) with advanced NSCLC were stratified by histology (nonsquamous or squamous) and PS (0 or 1) and randomly assigned to receive cisplatin 80 mg/m2/d1 plus either pemetrexed 500 mg/m2/d1 (nonsquamous) or gemcitabine 1,250 mg/m2/d1+8 (squamous) every 3 weeks (q3w) for 6 cycles, with (arm A) or without (arm B) NGR-hTNF given at 0.8 μg/m2/d1/q3w until progression. Progression-free survival (PFS) was primary aim (1-β=80%, 1-sided α=10%, n=102). Secondary aims comprised adverse events (AEs), response rate (RR), and overall survival (OS). Results: Baseline characteristics in arm A (n=62) vs B (n=59) were: median age: 62 vs 63 years; men: 37 vs 39; PS 1: 23 vs 23; squamous: 18 v 17; smokers: 41 vs 43. For the nonsquamous stratum, 299 cycles were given in arm A (mean 7.0; range 1-20) and 192 in arm B (4.8; 1-6), while for the squamous stratum, 113 in arm A (6.7; 1-31) and 52 in arm B (3.5; 1-6). Rates of grade 3/4 AEs were similar (arm A vs B): neutropenia 13% vs 18%, anaemia 7% vs 4% and fatigue 7% vs 11%. No grade 3/4 AEs related to NGR-hTNF or bleeding/pulmonary hemorrhage events were reported in the squamous subset. With median follow-up time of 24.2 months, median PFS (5.8 vs 5.6 months; HR=0.92), RR (25% vs 21%) and 1-year OS (53% vs 53%) were similar between the two treatment arms. However, by predefined analysis in the squamous stratum, median PFS was 5.6 months for arm A and 4.3 months for arm B (hazard ratio, HR=0.75) and median OS was 14.2 months for arm A and 9.7 months for arm B (HR=0.49; p=0.07). In pts with squamous histology, RR was 38% for arm A and 27% for arm B (odds ratio=1.6), while the median changes in tumor size on treatment from baseline to 2nd, 4th and 6th cycle for arm A vs B were -32% vs -20%, -41% vs -19%, and -42% vs -14%, respectively. Conclusions: Clinical tolerability and benefit were noted in squamous NSCLC with NGR-hTNF plus cisplatin and gemcitabine, which deserve further investigation. Clinical trial information: NCT00994097.

e18528 Background: Both TFI (the time elapsing from FLT completion to SLT initiation) and DCR (the rate of nonprogression at first tumor evaluation) have been found to predict OS in other tumor types. Methods: The impact on outcome of TFI after FLT and DCR on SLT was tested in an individual patient pooled analysis of 261 MPM patients (pts) who had radiologic progressive disease (PD) after a pemetrexed-based FLT before entering a ph 2 trial with single-agent NGR-hTNF (n=50) and a ph 3 trial with single-agent gemcitabine, vinorelbine or doxorubicin plus NGR-hTNF/placebo (n=211). In both trials, response to SLT was assessed every 6 weeks by MPM-modified RECIST. Progression-free survival (PFS) and OS were computed from SLT start. By ROC analysis, the cutpoint for estimating TFI in relation to OS was set at 6 months (AUC=0.59; p=.009). Results: After FLT, 60 pts (23%) had partial response (PR), 135 (52%) stable disease (SD), for a DCR of 75%, and 66 (25%) early PD. Median time to PD was 7.0 months (95% CI, 6.2-7.4) and median TFI was 4.4 months (3.8-5.0), with 97 pts (37%) having a TFI > 6 months. Among baseline factors (age, sex, PS and histology) used in logistic regression, only younger age was related to higher odds to attain a TFI > 6 months (OR=1.9; 95% CI, 1.2-3.3). A TFI > 6 months (vs ≤ 6) was weakly related to DCR (Spearman's r=0.16; p=.01) and strongly associated with longer PFS and OS, with HR of 0.48 (0.36-0.65) and 0.59 (0.42-0.83), respectively. After SLT, 9 pts (3%) had PR, 130 (50%) SD, for a DCR of 53%, and 122 (47%) early PD. Of 60 pts responding to FLT, 23 (38%) progressed early on SLT, while of 66 pts progressing early during FLT, 32 (48%) experienced disease control on SLT. Baseline factors did not relate with DCR at week 6. On landmark analysis set at the 6-week time point, DCR (vs PD) was associated with OS benefit (HR=0.46; 0.32-0.65), which persisted after adjusting for baseline factors (HR=0.40; 0.27-0.57). Conclusions: With a smaller HR, an early-look measure such as 6-week DCR on SLT shows some advantage over TFI after FLT in predicting subsequent OS. In relapsed MPM, TFI as stratification factor and DCR as surrogate endpoint may be considered. Clinical trial information: NCT00484276-NCT01098266.

Background NGR-hTNF (asn-gly-arg-human tumor necrosis factor) induces systemic release of cytokines and intratumoral infiltration of effector T cells. Intravenous infusion of NGR-hTNF is characterized by onset of IRR, mostly consisting of transient grade 1-2 chills. Incidence, predictors of development, and relationships with outcome of IRR were assessed across 5 phase 2 single-arm trials of NGR-hTNF. Methods 205 patients (pts) with solid tumors received NGR-hTNF 0.8 µg/m2 every 3 weeks (q3w) given either alone in colon cancer (n = 45), liver cancer (n = 40), and mesothelioma (n = 55), or with doxorubicin in small-cell lung cancer (n = 28) and ovarian cancer (n = 37). Tumor assessment by RECIST was done q6w until progressive disease (PD). Logistic and Cox proportional-hazards regression models were used to analyze associations between IRR and outcome, in terms of response rate (RR, complete and partial response), disease control rate (DCR, rate of pts without PD at 6 weeks), and progression-free survival (PFS). Results Overall, 137/205 pts (67%) experienced IRR on treatment, while 68 pts (33%) did not report IRR. In the IRR group, 63% of pts had grade 1 and 37% grade 2. By time of onset, 88% of pts developed IRRs within first 6 weeks and 12% later. Baseline characteristics in the IRR v non-IRR groups were: median age 66 v 64; male 50% v 56%; PS 1-2 34% v 35%, range of prior lines 1-4 v 1-5. Among baseline factors, only a low number of prior regimens predicted for IRR (odds ratio, OR 1.4 p = .02). The RR was 12% (95% CI 7-18) in the IRR group and 3% (1-10) in the non-IRR group (OR 4.4 p = .05), while DCR was 50% (42-59) in pts who had IRR and 34% (23-46) in pts who did not (OR 2.0 p = .02). On landmark analysis set at 6-week time point, PFS was significantly improved in pts with IRR (hazard ratio, HR 0.63 p = .007). Six-month PFS rates were 17% (11-23) for the IRR group and 6% (1-12) for the non-IRR group (log-rank p = .005). In multivariable analyses (adjusting for age, sex, PS, prior lines, and tumor types), the onset of IRR remained independent predictor of higher likelihood of response (OR 4.8 p = .05) and lower risk of progression or death (HR 0.62 p = .009). Conclusions Occurrence of IRR may identify pts who are more likely to gain benefit from NGR-hTNF treatment. Disclosure A. Lambiase: Employment- MolMed. C. Bordignon: Employment - MolMed. All other authors have declared no conflicts of interest.

Background NGR-hTNF (asn-gly-arg-human tumor necrosis factor) is a selective vascular targeting agent able to improve intratumoral chemotherapy uptake. Methods After stratification by histology (nonsquamous or squamous) and PS (0 or 1), previously untreated patients (pts) with advanced NSCLC were randomly assigned to receive cisplatin 80 mg/m2/d1 plus either pemetrexed 500 mg/m2/d1 (nonsquamous) or gemcitabine 1,250 mg/m2/d1 + 8 (squamous) q3w for 6 cycles with (arm A) or without (arm B) NGR-hTNF 0.8 µg/m2/d1 q3w given until progression. Progression-free survival (PFS) was primary endpoint of this phase 2 trial (β = 20%, α = 20%, n = 102). Secondary endpoints included adverse events (AEs), overall survival (OS), and response rate (RR). Results Baseline characteristics in arm A (n = 61) v B (n = 58): median age 62 v 63 years; male 36 v 38; PS of 1 22 v 22; squamous 17 v 16; nonsmokers 19 v 14; EGFR mutations 5 v 5. For the nonsquamous stratum, 295 cycles were given in A (mean 6.9; range 1-18) and 192 in B (4.8; 1-6), while for the squamous stratum, 95 in A (6.3; 1-24) and 49 in B (3.5; 1-6). The rates of grade 3 to 4 AEs were comparable in arm A v B: neutropenia 14% v 17% and fatigue 7% v 11%. Neither grade 3 to 4 AEs related to NGR-hTNF nor bleeding in pts with squamous histology were noted. With a median follow-up of 16.4 months for all pts, median PFS was 5.8 v 5.6 months, 1-year OS rate was 58% v 56%, and RR was 25% v 21% in arm A v B, respectively. For the nonsquamous stratum, trends toward higher 6-month PFS rates for arm A v B were noted in pts with PS 1 (65% v 33%), nonsmoking history (59% v 33%), younger age (64% v 30%), and EGFR mutations (75% v 25%). Similarly, in these pts the 1-year OS rates were: PS 1 (60% v 56%), nonsmoking history (77% v 65%), younger age (75% v 63%), and EGFR mutations (100% v 50%). For the squamous stratum, median PFS was 5.6 v 4.3 months (HR = 0.71) and median OS was 14.2 v 10.2 months (HR = 0.54) for arm A v B, respectively. In these pts, RR was 36% for arm A and 23% for arm B, while median changes from baseline in target tumor size after 2, 4, and 6 cycles were -27%, -39%, and -33%, respectively for arm A, and -18%, -22%, and -14%, respectively for arm B. Conclusion NGR-hTNF can be safely given with standard chemotherapy and may have therapeutic potential in squamous NSCLC Disclosure A. Lambiase: Employment - MolMed. C. Bordignon: Employment - MolMed. All other authors have declared no conflicts of interest.

7581 Background: NGR-hTNF (asparagine-glycine-arginine human tumor necrosis factor) is a selective vascular targeting agent able to improve intratumoral chemotherapy uptake. Methods: Chemo-naive, stage IIIb-IV NSCLC patients (pts), stratified by histology (nonsquamous or squamous) and PS (0 or 1), were randomized to cisplatin 80 mg/m2/day(d)1 plus either pemetrexed 500 mg/m2/d1 (nonsquamous) or gemcitabine 1,250 mg/m2/d1+8 (squamous) every 3 weeks (q3w) up to 6 cycles with (arm A) or without (arm B) NGR-hTNF 0.8 μg/m2/d1 q3w until progression. Progression free survival (PFS) was primary end point of this phase 2 trial (β=20%, α=20%, HR=0.62, and n=102). Secondary end points included adverse events (AEs), response rate (RR) and overall survival (OS). Results: 59 pts were assigned to arm A and 57 to arm B. Baseline characteristics in arm A/B were: median age 62/63; male 34/37; PS 1 21/21; squamous 15/15; nonsmokers 14/12; EGFR mutations 5/5. For the nonsquamous group, 281 cycles (mean 6.5; range 1-18) were given in arm A and 190 (mean 4.7; range 1-6) in arm B, while for the squamous group, 88 (mean 6.3; range 1-19) in arm A and 48 (mean 3.7; range 1-6) in arm B. Most common grade 3/4 AEs were neutropenia 14% vs 17% and fatigue 7% vs 11% in arm A and B, respectively. No grade 3/4 AEs related to NGR-hTNF or bleeding in pts with squamous histology were noted. Median follow-up was 12.4 months. In the whole study population, median (m)PFS was 5.8 vs 5.7 months (HR=0.95), RR was 23% vs 19%, and 1-year OS was 62% vs 62% in arm A and B, respectively. In the nonsquamous subset, a trend toward longer mPFS in arm A compared to arm B was noted in pts with a PS of 1 (6.7 vs 4.6 months, respectively), nonsmoking history (6.2 vs 3.4), younger age (6.5 vs 3.4), and EGFR mutations (7.2 vs 3.3). In the squamous subset, mPFS was 5.1 vs 3.9 months (HR=0.71) and mOS was 14.2 vs 10.8 months (HR=0.73) in arm A and B, respectively. In these pts, ORR was 36% in arm A and 23% in arm B, while median changes from baseline in target tumor size after 2, 4, and 6 cycles were -29%, -45%, and -41%, respectively in arm A, and -18%, -22%, and -14%, respectively in arm B. Conclusions: Regardless of histology, NGR-hTNF can be safely given with standard chemotherapy, showing tolerability and hint of activity in squamous NSCLC.

7076 Background: NGR-hTNF exploits the asparagine-glycine-arginine (NGR) peptide for selectively targeting tumor necrosis factor (TNF) to cancer endothelial cells. Tumor hypervascularity is an independent predictor of poor overall survival (OS) in MPM patients (pts). Methods: We report long-term results of a phase II trial that assessed NGR-hTNF in MPM pts with performance status (PS) ≤ 2 and radiologic progressive disease (PD) after a pemetrexed-based regimen. NGR-hTNF was given at 0.8 µg/m2 every 3 weeks (q3w) in 43 pts and weekly (q1w) in 14 pts. Primary endpoint was progression free survival (PFS), with restaging done q6w by MPM-modified RECIST criteria, while secondary aims included disease control (DC) rate and OS. We also tested the impact on outcome of neutrophil to lymphocyte ratio (NLR) at baseline (median 3; interquartile range 2-5). Median follow-up was 32.5 months (95% CI 27.5-37.5). Results: Baseline characteristics were (n=57): median age 57 years; M/F 35/22; PS 0/1-2 31/26; EORTC score good/poor 45/12. Median treatment free interval on prior therapy was 4.3 months. Only one drug-related grade ≥ 3 adverse events (AEs) was noted, common grade 1/2 AEs being transient chills (75%). No higher toxicity was reported using the q1w schedule. Median PFS was 2.8 months (95% CI 2.2-3.3). DC rate was 46% (95% CI 32-59; 26/57 pts; 1 partial response, 25 stable diseases) and was maintained for a median time of 4.7 months (95% CI 4.0-5.4). OS rates at 1 and 2 years were 47% and 16%, respectively. Median OS was longer in pts with DC than in those with early PD (16.2 and 8.3 months, respectively; p=.02). According to schedule, 6-month PFS rates were 11% and 36% and 2-year OS rates were 12% and 29% for q3w and q1w, respectively. In pts with DC, median PFS were 4.4 and 9.1 months and median OS were 13.3 and 24.8 months for q3w and q1w, respectively. By Cox analyses, a PS of 0 (p=.01) and a low baseline NLR (p=.004) were the only variables associated with improved OS. Median OS in pts stratified by NLR ≤ 2, 3 to 4, and ≥ 5 were 15.7, 10.5, and 4.2 months, respectively (p=.0002 for trend). Conclusions: NGR-hTNF showed promising PFS and OS in this study. A double-blind phase III trial is currently testing best investigator choice ± NGR-hTNF q1w in pemetrexed-pretreated MPM pts (NCT01098266).