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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.