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7544 Background: GA201, a humanized, engineered IgG1 anti-Epidermal Growth Factor Receptor (EGFR) mAb designed to enhance ADCC, has shown promising clinical activity in phase I and in the neoadjuvant treatment of head and neck cancer. This phase Ib study (NCT01185847) aimed to determine the safety, pharmacokinetics (PK), activity and recommended phase II dose (RP2D) of GA201 in combination with chemotherapy in non-squamous NSCLC. Methods: Successive cohorts received GA201 1000 mg or 1400 mg (IV d1, d8 then 2-weekly (q2W)) in combination with chemotherapy at standard doses. Data cut off was 7 months after enrolling the last patient. Results: 14 patients (4 female) with performance status 0-1 were enrolled. No maximum tolerated dose was reached. Most common adverse events (AEs – all grades) included rash (100%), hypomagnesaemia (71%), infusion-related reactions (64%), mucosal inflammation (57%) and anemia (50%). AEs of ≥ grade 3 included rash (71%), skin fissure (21%), dry skin (14%), paronychia (14%), and asthenia (14%). Median timeto improvement of rash grade 3 was 11 days. AEs led to dose reduction for 4 patients and discontinuation for 1 patient. There were 6 confirmed partial responses (43%, 5 in 1400 mg cohort) and 7 patients (50%) with stable disease >=9 weeks. Duration of response ranged between 5 and 42 weeks (3 patients still ongoing). Preliminary biomarker analysis shows a correlation between tumor-infiltrating CD16+ immune cells and target lesion shrinkage at first tumor assessment [R(spear)=-0.65 (p=0.02)]; no apparent correlation between EGFR H-score and response was found. PK data supports 1400 mg as the RP2D (d1, d8 then q2W). Conclusions: The RP2D of GA201 in combination with chemotherapy was established to be 1400 mg. The incidence of EGFR associated rash was high and guidelines to reduce its severity were implemented with a noted improvement in tolerability. Promising antitumor activity was observed. Biomarker data support the mode of action of GA201 via ADCC. A randomized phase II trial of this combination is ongoing and fully recruited.

7085 Background: By selectively damaging tumor vasculature, NGR-hTNF (asparagine-glycine-arginine human tumor necrosis factor) is able to improve intratumoral uptake of doxorubicin (D). A phase I trial selected NGR-hTNF 0.8 µg/m2/day(d)1 and D 75 mg/m2/d1 every 3 weeks (q3w) for phase II. Methods: SCLC pts failing one or more platinum-based regimen received NGR-hTNF until progressive disease (PD) and D up to 550 mg/m2. This phase II trial (n=27 pts) had progression-free survival (PFS) as primary end point, with tumor response assessed q6w by RECIST, while secondary end points included adverse events (AEs), disease control rate (DCR), and overall survival (OS). Results: Among 28 pts enrolled (median age 63 years; M/F 19/9; PS 0/1-2 13/15; prior lines 1/2-3 20/8), 16 pts had platinum-resistant (R) disease (PD≤3 months) and 12 pts platinum-sensitive (S) disease (PD>3 months). At baseline, median neutrophil to lymphocyte ratio (NLR) was 4 (range 1-20). A total of 114 cycles were given (range 1-10), with 13 pts (46%) having ≥ 4 cycles and 9 pts (32%) ≥ 6 cycles. No grade 3/4 AEs related to NGR-hTNF were noted, while grade 1/2 AEs were transient chills (61%). NGR-hTNF did not apparently increase D-related AEs. Median PFS was 3.2 months (95% CI 2.6-3.8) and 1-year OS rate was 34%. Overall, DCR was 55% (95% CI 35-74), comprising 6 partial responses (22%; median duration: 6.3 months) and 9 stable diseases (33%; median duration: 4.1 months). Mean changes from baseline in target tumor size after 2, 4, and 6 cycles were -9%, -29%, and -32%, respectively for R disease and -11%, -20%, and -43%, respectively for S disease. In pts pretreated with ≥ 2 lines, DCR was 75%, median PFS was 5.1 months, and 1-year OS rate was 44%. In pts with R or S disease, DCR were 50% and 58% (p=.72), median PFS were 2.7 and 4.1 months (p=.07), and 1-year OS rates were 27% and 42% (p=.65), respectively. At multivariate analyses, PFS was not related to baseline characteristics, while an improved OS was associated only with a low NLR. The 1-year OS rate was 48% in pts with NLR ≤ 4 and 10% in pts with NLR > 4 (p=.007), while in pts with NLR ≤ 4, 1-year OS rate was 46% in R disease and 50% in S disease. Conclusions: This combination is well tolerated and active in platinum resistant and sensitive SCLC and further development is of interest.

7077 Background: NGR-hTNF, a selective vascular targeting agent, improves the intratumoral doxorubicin penetration by normalizing tumor vasculature and decreasing tumor interstitial fluid pressure....

TPS214 Background: Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry analysis (MALDI ToF MS) of NSCLC patients’ pretreatment sera or plasma was shown to predict survival after EGFR TKIs therapy (Taguchi et al. JNCI 2007). The proteomic classifier (VeriStrat, Biodesix Inc), based on 8 distinct m/z peaks, separates patients (pts) into 2 groups (VeriStrat good and poor), significantly different in terms of time to progression and overall survival when treated with EGFR TKIs but not chemotherapy (CT). Aim of the current study is to prospectively evaluate the predictive value of the proteomic classifier on outcome in advanced NSCLC pts, treated with either EGFR-TKIs or standard CT in second-line setting. Methods: PROSE is a phase III, prospective, double-blinded trial where pts with advanced NSCLC are randomized in a 1:1 ratio to receive erlotinib 150 mg daily or standard second-line CT (pemetrexed 500 mg/m2 3w or docetaxel 75 mg/m2 3w). Pts are stratified according to ECOG Performan...

7089 Background: NGR-hTNF exploits the tumor-homing peptide NGR for selectively targeting tumor necrosis factor to tumor blood vessels. Methods: Here we report the long-term results of a phase II t...

7568 Background: NGR-hTNF is a highly selective vascular targeting agent, that binds CD13 overexpressed on tumor blood vessels, obtained by adding the NGR peptide to the human tumor necrosis factor...

e13612 Background: NGR-hTNF is a vascular targeting agent consisting of TNF fused with the peptide NGR, a ligand of a CD13 overexpressed on tumor blood vessels. Methods: Fifteen refractory patients (pts) received 83 cycles (range, 1-29) of NGR-hTNF (0.2-1.6 μg/m2) given every 3 weeks until progression. Median progression-free (PFS) and overall survival (OS) were 3.4 and 6.9 months, respectively. Ninety PBs were tested at baseline and 2-h after first cycle (post-dosing). Significant post-dosing changes in IL1/IL8/IL10/MCP1/MIP1b were noted. Based on their angiogenic role, an additional four PBs were selected: VEGF, matrix metalloproteinase-9 (MMP9), vascular-cell and inter-cellular adhesion molecule-1 (VCAM1 and ICAM1). The associations between these nine PBs and treatment duration (TD; ≤2 v >2 cycles), OS and maximal changes in tumour vascularity (assessed every cycle by DCE-MRI) were investigated. Results: TD was associated with OS (Spearman's r=0.55, p=.04), baseline DCE-MRI values (r=0.86, p=.004) and ...

e18043 Background: NGR-hTNF consists of tumour necrosis factor (TNF) fused to the tumour-homing peptide NGR, which selectively binds an aminopeptidase N overexpressed on tumour blood vessels. Both ...

Background: NGR-hTNF is a VTA consisting of TNF-α fused to the tumour-homing peptide NGR, which is able to selectively bind an aminopeptidase N overexpressed on tumour blood vessels. Methods: CRC pts failing standard therapies received low-dose NGR-hTNF given at 0.8 μg/m2 as 1-hour infusion every 3 weeks (q3w; triweekly cohort). Progression-free survival (PFS) was the primary study objective with restaging performed q6w. A 2-stage design was used, with 16 and 27 pts to be recruited. Ultimately, an additional 13 pts were treated with 0.8 μg/m2 on a weekly basis (weekly cohort). Results: In the triweekly cohort, 111 cycles (range, 1-10) were delivered to 33 pts with radiologically-documented progression after last therapy. Pts characteristics were: median age: 65 years (range, 5379); M/F 16/17; PS 0/1 26/7. Median number of prior lines was 3 (range, 2-5), whereas 8 pts (25%) had received ≥4 lines and 22 (67%) biologicals. No grade 3-4 drug-related toxicity was observed. Predominant grade 1-2 toxicities were short-lived, infusion-related chills (53%). The median PFS was 2.5 months (95% CI, 2.2-2.8) and the PFS rates at 3 and 4.5 months were 31% and 16%, respectively. The disease control rate was 39% (95% CI, 23-55), with one partial response (3%) and 12 stable diseases (36%). In pts with disease control, the median PFS time was 3.8 months and the 3and 4.5-month PFS rates were 67% and 42%, respectively. With a median follow-up of 18.4 months (95% CI, 18.318.5), the median OS time was 13.1 months (95% CI, 8.7-17.5). The proportions of pts alive at 18 and 24 months were 33% and 25%, respectively. Pts who achieved disease control had a median OS of 15.4 months, while those who did not had 9.3 months. Median OS in pts pretreated with

7582 Background: NGR-hTNF is a VTA exploiting a tumor-homing peptide (NGR) that selectively binds to an aminopeptidase N (CD13) overexpressed on tumor blood vessels. In preclinical models, NGR-hTNF has shown potent anti-vascular and antitumor activity, both at low and at high doses. Methods: Patients with advanced MPM were treated with a low-dose of NGR-hTNF given intravenously at 0.8 μg/m2 as 1-hour infusion every 3 weeks (q3w). This phase II trial had a 2-stage design with 16 and a total of 27 patients to be enrolled after first and second stage, respectively. Primary endpoint was progression-free survival (PFS) with restaging performed q6w according to MPM-modified RECIST criteria. Results: From May 2007 to January 2008, forty-three patients with radiologically-documented progressive disease after a pemetrexed-based regimen were evaluated over 167 cycles (range, 1 to 17). Patient characteristics were: median age 64 years (range, 54 to 80); male/female 27/16; epithelial/non-epithelial histology 34/9; PS 0/1/2 24/10/9; EORTC score good/poor 34/9. Main grade 1–2 toxicity was chills (71%), transiently occurring after the first infusions. Only one grade 3 treatment-related toxicity was observed. One patient (2%) had a partial response lasting 7.1+ months and 17 patients (40%) maintained stable disease for a median duration of 4.4 months (range, 1.3 to 12.4+ months). The median and 3-month PFS were 2.8 months and 43%, respectively, whereas the median and 1-year overall survival were 11.6 months and 48%, respectively. In an additional 14 patients treated at same dose with a weekly schedule, there was any suggestion of toxicity exacerbation. In this cohort, the PFS rate at 6 months was 36%, with 7 patients (50%) experiencing stable disease for a median duration of 6.9 months (range, 2.4 to 9.3+ months). Conclusions: NGR-hTNF 0.8 μg/m2 weekly is well tolerated, showing prolonged disease control in previously treated MPM patients, and will be further developed in this setting. [Table: see text]

e15500 Background: NGR-hTNF is a VTA exploiting a tumor-homing peptide (NGR) that selectively binds to aminopeptidase N (CD13) overexpressed on tumor blood vessels. In preclinical models, NGR-hTNF has shown potent anti-vascular and antitumor activity, both at low and at high doses. Methods: Patients with recurrent or metastatic HCC were treated with NGR-hTNF given intravenously at 0.8 μg/m2 as 1-hour infusion every 3 weeks (q3w). This phase II trial had a 2-stage design with 16 and a total of 27 patients to be enrolled after first and second stage, respectively. Progression-free survival (PFS) was the primary endpoint with reassessment performed q6w according to WHO criteria. Results: 27 patients with progressive disease following prior loco- regional treatment (59%), systemic therapy (56%), or both (33%) were evaluated over 86 cycles (range, 1 to 14). Patient characteristics were: median age 67 years (range, 53 to 79); M/F 21/6; PS 0/1 18/9; Child-Pugh class A/B: 21/6. No grade 3–4 treatment-related adverse events were observed. Main grade 1–2 toxicities were short-lasting infusion-related constitutional symptoms, including chills (55%). Median PFS was 2.3 months (95% CI, 1.7–2.9 months). One complete response (4%) lasting 9.0+ months was observed in a sorafenib-refractory patient and one partial response (4%) was reported in a Child-Pugh class B patient. Additionally, a 28% tumor shrinkage was detected in one out of six patients (22%) experiencing stable disease. The median PFS duration in stable or responder patients was 4.3 months (95% CI, 2.7–5.8 months). With a median follow-up of 7.6 months, the overall survival rates at 3 and 6 months were 82% and 60%, respectively. Conclusions: NGR-hTNF given at 0.8 μg/m2 every 3 weeks is well tolerated and appears to have promising antitumor activity in previously treated patients with advanced HCC. The drug will be further developed in this setting and, currently, an additional cohort of 12 patients has been enrolled and treated at same dose with a weekly schedule. [Table: see text]

4088 Background: NGR-hTNF is a VTA exploiting a tumor-homing peptide (NGR) that selectively binds to an aminopeptidase N/CD13 overexpressed by tumor blood vessels. In preclinical models, NGR-hTNF showed antitumor activity both at low and at high doses. Methods: Pts with CRC resistant/refractory to standard treatments, including biological agents, were treated with low-dose NGR-hTNF given intravenously at 0.8 μg/m2 as 1-hour infusion every 3 weeks (q3w). This phase II trial had a 2-stage design with 16 and 27 pts to be enrolled after first and second stage, respectively. Progression-free survival (PFS) was the primary end-point with reassessment performed q6w. Results: From January to May 2007, 33 pts with radiologically- documented progressive disease after last therapy were evaluated over 111 cycles (range, 1–10). Pts characteristics were: median age: 65 years (range, 53 to 79); M/F 16/17; PS 0/1 26/7. Median number of prior regimens was 3 (range, 2 to 5). Eight pts (25%) were pre-treated with ≥4 lines and 22 (67%) with biological agents. Neither grade 3–4 treatment-related adverse events nor toxicity-related deaths were observed. Main grade 1–2 toxicities per patient were infusion-related chills (47%) and transient blood pressure increase (9%). One partial response (3%) lasting 5 months and 12 stable diseases (36%) were reported. Median PFS was 2.5 months (95% CI, 2.2–2.8). In a post-hoc analysis, no differences in PFS were detected according to baseline characteristics. With a median follow-up time of 18.4 months (95% CI, 18.3–18.5), 11 pts (33%) were still alive. Median overall survival (OS) was 13.1 months and the 2-year OS rate was 22%. In the subset of stable or responder pts, the median PFS and OS were 3.8 months and 15.4 months, respectively. The 6-month PFS rate in the prior-biological and biological-naïve cohorts was 5% and 20%, respectively, whereas 1-year OS rate was 41% and 72%, respectively. Conclusions: Based on the favorable toxicity profile and disease control in heavily pre-treated CRC patients, NGR-hTNF will be further developed in combination with standard chemotherapy. [Table: see text]

3570 Background: NGR-hTNF is a VTA exploiting a tumor-homing-peptide (NGR) that selectively binds to an aminopeptidase N/CD13 overexpressed on tumor blood vessels. In preclinical models, significant synergy between low-dose NGR-hTNF and cisplatin was shown. Methods: Patients with resistant/refractory solid tumors were treated with NGR-hTNF given with a low-dose, doubling-dose scheme (0.2–0.4–0.8–1.6 μg/m2) as 1-hour intravenous infusion, in combination with cisplatin 80 mg/m2, both given every 3 weeks. A 3+3 escalation/de-escalation design was followed. PK sampling was performed after the first 3 cycles. DLT definition: any G3–4 toxicity related to NGR-hTNF. Results: 22 patients (median age: 60 years, range, 47–75; 14M/8F; ECOG PS 0/1 12/10) with different tumor types were evaluated over 77 cycles (range, 1–10). Median number of prior regimens was 3 (range, 1–6) and 12 patients (55%) were previously treated with platinum-based regimens. Both NGR-hTNF Cmax and AUC increased proportionally with dose. The combination was safe without PK interaction or exacerbation of platinum-associated toxicity profile. No shedding of soluble TNF receptors was observed up to 0.8 μg/m2. As expected for the low-dose range explored, MTD was not reached and no DLTs were registered at 0.2 μg/m2 (n = 4), 0.4 μg/m2 (n = 3) and 1.6 μg/m2 (n = 3). At 0.8 μg/m2, a patient had a G3 transient acute infusion reaction. This cohort was expanded up to 6 patients for safety reasons, with no DLTs registered, and up to 12 patients, for preliminary activity evaluation. At this dose level of 0.8 μg/m2, two lung cancer patients, both pre-treated with platinum, achieved a partial response (-79%) and a significant tumor shrinkage (-28%) lasting 7.2 and 6.7 months, respectively, and an additional 4 patients experienced stable disease for a median duration of 6.4 months. The median progression-free survival for all patients (n = 22), for patients enrolled at 0.8 μg/m2 (n = 12), and for patients pre-treated with platinum (n = 9) was 2.7, 4.7, and 4.3 months, respectively. Conclusions: The combination of NGR-hTNF 0.8 μg/m2 with cisplatin 80 mg/m2 shows a favourable toxicity profile and promising antitumor activity. [Table: see text]

4110 Background: NGR-hTNF is a VTA exploiting a tumor-homing peptide (NGR) that selectively binds to aminopeptidase N/CD13 highly expressed on tumour blood vessels. NGR-hTNF combines activity on tumour vascular permeability and direct anticancer activity. In preclinical models, NGR-hTNF showed antitumor activity at both low and high doses. Methods: Pts with CRC refractory to standard treatments, including biological agents, were enrolled to evaluate a low dose of NGR-hTNF given at 0.8 mcg/m2 as 1-hour intravenous infusion every 3 weeks (q3w). This phase II trial had a 2-stage design with 16 and 27 pts to be enrolled in stage 1 and 2, respectively. Progression-free survival (PFS) was the primary end point and reassessment was performed q6w. Results: 32 pts (16 M/16 F; PS 0/1 26/6; median age: 65 years, range 53–79) received 111 cycles (median 2, range 1–10) and 13 pts (41%) were treated with ≥4 doses. The median number of prior regimens was 3 (range: 2–5), with 8 pts (25%) pre-treated with ≥4 lines. In the...

8099 Background: NGR-hTNF is a VTA exploiting a tumor-homing peptide (NGR) that selectively binds to aminopeptidase N/CD13 highly expressed on tumour blood vessels. NGR-hTNF combines direct antican...

15544 Background: NGR-hTNF is a VTA exploiting a tumor-homing peptide (NGR) that selectively binds to aminopeptidase N/CD13 highly expressed on tumour blood vessels. NGR-hTNF combines activity on t...

14647 Background: NGR-hTNF is a VTA exploiting a tumor-homing peptide (NGR) that selectively binds to aminopeptidase N/CD13 highly expressed on tumour blood vessels. NGR-hTNF combines activity on tumour vascular permeability and direct anticancer activity. Consistently, preclinical data indicate significant synergy between low-dose NGR-hTNF and cisplatin. Methods: Pts with solid tumors refractory to standard treatments, were treated with extremely low doses (20–200 fold lower than MTD) of NGR-hTNF given with a doubling-dose scheme (0.2–0.4–0.8–1.6 μg/m2) as 1-hour (h) intravenous infusion, in combination with cisplatin 80 mg/m2, both given every 3 weeks. A standard 3+3 escalation/de-escalation design was followed. Blood samples for PK and soluble TNF receptors analysis were collected just prior to and 9 time points up to 6 h after the first 3 cycles. Definition of DLT: any severe (G3–4) toxicity clearly related to NGR-hTNF. Results: 13 pts (10M/3F; median age: 58 [range: 47–73]; ECOG PS 0/1: 40%/60%) were...

19034 Background: serum proteomics has been demonstrated to predict outcome in patients (pts) treated with EGFR-TKIs. VeriStrat is a classification test that separates pts into two groups: VeriStra...

3540 Background: NGRhTNF is a vascular targeting agent (VTA) exploiting a tumour homing peptide (CNGRCG) selectively binding angiogenic vessels in solid tumours where NGRhTNF specific binding relies on dynamic interactions with TNF-receptors and aminopeptidase N (CD13). NGRhTNF combines activity on tumour vascular permeability and direct anticancer activity. Consistently, mouse preclinical data indicate significant synergy between low dose NGRhTNF and cytotoxic agents. Methods: 4 dose levels of NGRhTNF (0.2 up to 1.6 mcg/sqm) have been administered q 3 w in 16 patients. Main end-points included safety, anticancer activity and pharmacokinetic.Measurement of circulating tumor and endothelial cells (CTC and CEC), sTNFRI and s TNFRII, along with plasma cyto-chemokine profile have been performed. Results: 16 patients were enrolled (6F/10M);median age 60,range 43–73). Toxicity was limited to constitutional symptoms, and chills were the most frequent event (40%). Over a median follow-up of 15 weeks, stable disease was achieved in 44% of patients, with long lasting disease control in 2 cases (27 and 75 weeks, with establishment of indication to radical surgery after 75 weeks, presently tumor free after removal of the residual tumor mass). In these 2 patients, VEGF, MMP-9, CA125, significantly decreased over time. DCE-MRI indicates that NGRhTNF increases vascular permeability after first drug exposure, particularly at the dose of 0.4 mcg/sqm, while following multiple infusions it exerts an antivascular effect, as demonstrated by the decrease of Ktrans values. Moreover NGRhTNF is able to elicit inflammatory and immune responses over time, as indicated by the modulation of expression of multiple cyto-chemokines. Finally, changes in CTC levels over time consistently matched the clinical outcome. Conclusions: Low dose NGRhTNF has an optimal safety profile along with anticancer activity acting on tumour vasculature and inducing relevant biological effects, thus rendering the agent suitable for a development both as monotherapy and in combination with chemotherapeutics. The phase II program is due to start in early 2007. [Table: see text]

14056 Background: NGRhTNF is a vascular targeting agent (VTA) exploiting a tumour homing peptide (CNGRCG) selectively binding angiogenic vessels in solid tumors, where NGRhTNF specific binding relies on dynamic interactions with TNF-receptors and aminopeptidase N (CD13). NGRhTNF combines activity on tumour vascular permeability and direct anticancer activity. At low dose, NGRhTNF increases tumour vascular permeability. Consistently, mouse preclinical data indicate significant synergy between low dose NGRhTNF and cytotoxic agents. Thus, we tested NGRhTNF in combination with doxorubicin. Methods: 4 doses of NGRhTNF (0.2, 0.4, 0.8 and 1.6 μg/m2) in combination with doxorubicin (75 mg/m2) have been administered every 3 weeks in 15 patients.Main end- points included safety, anticancer activity and pharmacokinetic. Measurement of circulating tumour (CTC) and endothelial cells, sTNF receptors, along with plasma chemokine profile are being performed. Results: All patients were enrolled (5F/10M). Toxicity was limited to constitutional symptoms, most frequently chills. After a median follow-up of 12 weeks (range 3–28), 5 episodes of chills (1 grade I and 4 grade II) were reported in 4/15 patients.One episode of grade I hypertension was reported. Of note, the toxicity profile commonly-associated to doxorubicin has not been exacerbated. Stabilization of disease occurred in 10/15 patients lasting 13 weeks (range 6–28 with 5 patients still ongoing at December 2006). In addition, partial response was achieved in 2 patients, lasting 23 and 14 (still ongoing) weeks, respectively. It is worth noting that anticancer activity was observed in 12/15 patients of whom 9 had previously received anthracycline-containing regimens and 5 were anthracycline-resistant suggesting a role of NGRhTNF in inducing tumour sensitivity to doxorubicin. Finally, changes in CTC levels over time consistently matched the clinical outcome. Conclusions: Coupling NGRhTNF with doxorubicin induced anticancer activity along with an optimal safety profile in pretreated patients providing support for the phase II combination studies addressing diseases suitable for anthracycline treatment such as sarcoma and ovarian cancer, and planned to start in early 2007. No significant financial relationships to disclose.

7004 Background: Assessment of epidermal growth factor receptor (EGFR) gene copy number, mutational status, and protein levels may predict response and possibly survival following treatment with EGFR tyrosine kinase inhibitors, but all these methods require tumor tissue, highlighting the need for a non-invasive predictive test. We evaluated the ability of MALDI-TOF MS profiling of serum to predict which patients (Pts) with NSCLC were likely to benefit from gefitinib treatment. Methods: Serum from Pts with NSCLC, collected prior to treatment with gefitinib, was subjected to MALDI-TOF MS using Voyager DE-STR or DE-PRO instruments. Replicate mass spectra obtained at two institutions were submitted to a third party for processing (background subtraction, noise estimation, normalization, spectral alignment and peak identification) and selection of discriminating mass/charge (m/z) values from a training cohort of 70 Caucasian Pts. The predictive capability of the profile was then assessed in independent cohorts of NSCLC Pts. Results: Intra- and inter- laboratory reproducibility of MALDI spectra were excellent. A set of 11 m/z values (mass range 5 - 12.5 kDa) predictive of clinical benefit were identified in the training cohort and confirmed by leave-one-out cross validation. Spectra from 19/70 Pts in the training cohort were unclassifiable. For the remaining 51 Pts the algorithm discriminated groups more or less likely to benefit with respect to time to progression (median 3.0 vs. 1.5 mo., p = 0.0325) and overall survival (median 14.6 vs. 2.3 mo., p = 0.0128). Validation was performed in an independent cohort consisting of serum from 69 Japanese Pts. Spectra from 13/69 Pts were unclassifiable. For the remaining 56 Pts it was possible to identify a group with superior time to progression (median 14.8 vs. 2.1 mo., p = 0.0012) and overall survival (median 19.1 vs. 7.9 mo., p = 0.0102). Conclusions: MALDI-TOF MS of pretreatment serum may aid with the identification of subsets of NSCLC Pts that will benefit from treatment with gefitinib. This algorithm is currently being evaluated in an expanded cohort of Pts receiving gefitinib treatment and in Pts treated with erlotinib. [Table: see text]

3022 Background: Gefitinib demonstrates substantial interindividual differences in response. Gefitinib interacts with its target EGFR and the efflux transporter ABCG2 (Ozvegy-Laczka, Mol Pharmacol ...

7156 Background: Because elderly patients (pts) may tolerate combination chemotherapy poorly, single-agent chemotherapy is often the preferred treatment. This study evaluated the efficacy (primary ...

3004 Background: At the present time there is no reliable and identifiable marker that would help to identify those patients who are more likely to respond to gefitinib therapy. In some of the patients with NSCLC, EGFR may be the critical pathway signalling tumor growth. It is possible that responding patients are those in whom cell survival is maintained by activated EGFR-dependent pathways and in whom these pathways are suppressed by gefitinib. We investigated whether the evaluation of the Ras/raf/MAPK and the PI3K-AKT pathways before starting gefitinib therapy could help in identifying responding patients. This trial has been designed in order to possibly correlate Phospho-AKT/Phospho-MAPK status and gefitinib activity in terms of Response Rate (RR) and Time to Progression (TTP). Methods: Consecutive patients with NSCLC progressing or relapsing with standard therapy received gefitinib at a daily dose of 250 mg given until disease progression, unacceptable toxicity or refusal. Tumor tissue specimens obt...

IntroductionOur previous study showed that pretreatment serum or plasma Matrix-Assisted Laser Desorption/Ionization Time-of-Flight Mass Spectrometry may predict clinical outcome of non-small cell lung cancer (NSCLC) patients treated with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). In this study, plasma proteomic profiles of NSCLC patients were evaluated in the course of EGFR TKIs therapy.Materials and MethodsPlasma samples were collected at baseline, in the course of gefitinib therapy and at treatment withdrawal. Samples were analyzed by Matrix-Assisted Laser Desorption/Ionization Time-of-Flight Mass Spectrometry. Acquired spectra were classified by the VeriStrat test into “good” and “poor” profiles. The association between VeriStrat classification and progression-free survival (PFS) and overall survival (OS), and types of clinical progression, was analyzed.ResultsPlasma samples from 111 NSCLC patients treated with gefitinib were processed. VeriStrat “good” classification at baseline correlated with longer PFS (hazard ratio [HR], 0.54; 95% confidence interval, 0.35–0.83; p = 0.005) and OS (HR, 0.40; 95% confidence interval, 0.26–0.61; p < 0.0001), when compared with VeriStrat “poor.” Multivariate analysis confirmed longer PFS (HR, 0.52; p = 0.025) and OS (HR, 0.44; p = 0.001) in patients classified as VeriStrat “good”, when VeriStrat was considered as a time-dependent variable. About one-third of baseline “good” classifications had changed to “poor” at the time of treatment withdrawal; progression in these patients was associated with the development of new lesions.ConclusionsOur findings support the role of VeriStrat in the assistance in treatment selection of NSCLC patients for EGFR TKI therapy and its potential utility in treatment monitoring.

IntroductionThis prospective study examined association between circulating plasma DNA, microsatellite alterations (MA), p53 mutations with time to relapse and survival in surgically treated non-small cell lung cancer (NSCLC) patients (pts).MethodsPlasma samples, adjacent lung tissue, and lung tumor tissue specimens were collected from consecutive patients with stage I–III NSCLC. Blood samples of 66 matched healthy donors with positive smoking history were collected as controls. The plasma DNA amount was determined by real-time PCR. The analysis of MA at loci D3S1300, D3S1289, D3S1266, and D3S2338 on chromosome 3p was performed by radiolabeled PCR. p53 Mutations (exons 5, 6, 7, and 8) were detected by PCR-single-strand conformational polymorphism assay.ResultsThere were 76 patients, 65 men; median age was 68 years (range, 42–86), 20 had stage I, 40 stage II, and 16 stage III, the majority of pts (48.7%) had squamous-cell histology. Sixty-nine (91%) were smokers and most had good Eastern Cooperative Oncology Group performance status (0/1:72/4). Mean circulating DNA of all pts was 60 ng/ml versus 5 ng/ml in smoker-matched controls (p < 0.0001). In pts without recurrence, mean circulating DNA was 48.5 ng/ml at baseline, 32.8 ng/ml at 3rd month, and 20.6 ng/ml at 12th month after surgery. In pts with recurrence, mean circulating DNA at baseline was 97.1 ng/ml. At 3rd month after surgery, mean DNA concentration was significantly lower in disease-free pts than in patients with recurrent disease (32.8 versus 292.7 ng/ml; p = 0.0016). MA in at least one locus was found in 39.5% of NSCLC tumors. p53 Genomic mutations were observed in 54.0% of tumor samples. Statistically significant associations were observed between MA and squamous-cell histotype (p = 0.007) and between p53 mutations and lymph node involvement (p = 0.012). MA and p53 mutations were found to be significantly associated with recurrence of disease (p = 0.033 and 0.026, respectively).ConclusionOur results suggest that MA and p53 mutations in tumor DNA have a potential prognostic role for disease recurrence in NSCLC patients, and elevated levels of plasma circulating DNA identify patients with possible systemic disease at diagnosis. This might be proposed as an early detection test of disease recurrence.

e18096 Background: Matrix Assisted Laser Desorption Ionization Time of Flight Mass Spectrometry (MALDI TOF MS) was used to create and validate a plasma proteomic algorithm VeriStrat (VS), based on 8 m/z peaks, and able to select advanced NSCLC pts who may benefit from EGFR TKIs. The algorithm was associated with PFS and OS of patients treated with EGFR TKIs and not with chemotherapy. Standardized Uptake Value (SUV) is of prognostic value for survival in non-small cell lung cancer. Aim of the current study was to analyze the OS and TTP in advanced NSCLC pts treated with erlotinib (E) according to baseline VeriStrat classification and baseline SUVs of FDG-PET. Methods: Plasma samples were collected before the beginning of E from metastatic NSCLC patients. Acquired spectra were classified according to the VeriStrat algorithm. The FDG-PET was performed the day before the beginning of E. Results: Thirty eight NSCLC pts on E therapy with the following characteristics were analyzed: median age 62 years old, 63% were males, 53% had adenocarcinoma histology, response rate was 26%, median OS 10 mos and (TTP) 3.4 mos. Twenty-six (68%) were classified as VS Good, 12 (32%) as Poor. TTP and OS for VS Good and Poor were 4.1 vs 2.1 mos (HR 0.86, log-rank p=0.6) and 11.1 vs 4.1 mos (HR 0.45,log-rank p=0.02), respectively. Baseline SUV levels were associated with TTP (Wilcoxon test p=0.001) but not with OS (all pts progressed, 5 still alive). All Poor classified pts had SUV ≥ 7 and had the worst TTP and OS; VS Good classified patients had worse TTP and OS if their baseline SUV level was > 7 than those who were VS Good and had SUV

Aims and Background The aim of this study was to evaluate the relationship between a panel of biological markers (p53, Bcl-2, HER-2, Ki67, DNA ploidy and S-phase fraction) and clinical-pathological parameters and its impact on outcome in non-small cell lung cancer (NSCLC). Methods and Study Design Tumor tissue specimens obtained after surgical resection were collected from consecutive patients with NSCLC. We used an immunocytochemical technique for p53, Bcl-2, HER-2 and Ki67 analysis in fine-needle aspirates obtained from surgical samples that were also evaluated by flow cytometric DNA analysis using a FACScan flow cytometer. Results From April 2000 to December 2005, 136 patients with radically resected NSCLC were recruited. Median age was 66 years (range, 31–84 years), male/female ratio 117/19, ECOG performance status 0/1 127/4, stage I/II/III 76/25/35, squamous/adenocarcinoma/large-cell/mixed histology 62/49/17/8, smokers yes/no 121/11. Positivity of p53, Bcl-2, HER-2 and Ki67 was detected in 51.4%, 27.9%, 25.0% and 55.8% of the samples, respectively; 82.9% of the cases revealed aneuploid DNA histograms and 56.7% presented an S-phase fraction of more than 12%. Statistically significant associations between high Ki67 and poorly differentiated tumors (P = 0.016) and a smoking history (P = 0.053); p53 positivity and high Ki67 (P = 0.002); HER-2 positivity and adenocarcinoma subtype (P = 0.015) and presence of lymph node involvement (P = 0.006); and Bcl-2 positivity and squamous cell carcinoma subtype (P = 0.058) were observed. At univariate analysis, high Ki67 proved to be the only marker associated with disease-free survival (P = 0.047). After adjusting for stage, none of the examined immunocytochemical markers emerged as an independent factor for disease-free and overall survival; only pathological stage was identified as an independent prognostic factor for disease-free survival (P = 0.0001) and overall survival (P = 0.0001). In the group of 76 patients classified as TNM stage I, high Ki67 was the only marker associated with recurrence of disease (P = 0.05). Conclusions Our data do not support a relevant prognostic role of immunocytochemical markers in NSCLC, even if the Ki67 index might have particular relevance to identify patients with more aggressive tumors who are at high risk for disease relapse.