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Background The capacity of inducing tumor shrinkage in advanced soft tissue sarcomas (STS) is an unmet need beyond the first-line of systemic therapy. Pivotal studies of approved drugs reported RECIST response rates below 10%. Thus, it is challenging to relieve symptoms related to tumor volume in patients progressing to anthracycline-based schemes. Besides that, the overall response rate (ORR) is an appropriate surrogate for overall survival. This phase II trial explores the combination of trabectedin (T) and concurrent radiotherapy (RT) in the metastatic setting and is supported by preclinical experiments and previous phase I trial. Methods Patients received T 1.5 mg/m2 in 24-h infusion and started RT (30 Gy, 3 Gy/day) from the end of the first T perfusion. Most relevant inclusion criteria were metastatic progressing STS, a maximum of two previous systemic lines for advanced disease with at least one previous anthracycline-based line. Neither all the lesions nor all the sites were required to be irradiated. The main endpoint was ORR by RECIST 1.1. A Simon 2-stage was used to estimate 35% ORR of interest for further investigation (α = 0.1, power 90%; P0 = 0.10). Central pathology and radiological review were mandatory. Results From 10/2017 to 11/2018, 27 patients were enrolled. Histologies were: leiomyosarcoma 7 (26%), synovial sarcoma 6 (22%), liposarcoma 4 (15%) and other 10 (37%). The median of previous lines was 2, and ECOG distribution was 0: 19 (70%) and 1: 8 (30%). With a median follow-up of 6 months (1-12), there were 9 events of progression and 3 events of death. The 6-month PFSR was 75% and the 6-month OSR was 86%. From 26 evaluable patients by RECIST, there were 15 PR (57.7%), 7 SD (26.9%) and 4 PD (15.4%). One G3 and 3 G1 pneumonitis were observed. One toxic death occurred (sepsis) being G3-4 neutropenia observed of 7 (26%) while febrile neutropenia was reported in 2 (7.4%) cases. Conclusions T concurrent with RT showed a relevant activity in progressing metastatic setting in a wide range of STS types, giving options for tumor shrinkage beyond the first-line of advanced STS. The RECIST ORR of 57.7% and 6-m PFSR of 75% confirm the synergy of T+RT. Clinical trial identification NCT02275286. Legal entity responsible for the study GEIS (Spanish Group for Research on Sarcoma). Funding GEIS, ISG (Italian Sarcoma Group), FSG (French Sarcoma Group); PharmaMar. Disclosure J. Martin Broto: Research grant / Funding (institution): EISAI; Research grant / Funding (institution): Novartis; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: PharmaMar; Advisory / Consultancy: Lilly. A. Italiano: Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Roche; Honoraria (self), Advisory / Consultancy: Daiichi Sankyo; Advisory / Consultancy: Inmune Design; Honoraria (self), Advisory / Consultancy: Epizyme; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Bayer; Honoraria (self), Advisory / Consultancy: Lilly; Honoraria (self): Novartis; Research grant / Funding (self): Merck Serono; Research grant / Funding (self): AstraZeneca/MedImmune; Research grant / Funding (self): MSD Oncology. R.M. Alvarez Alvarez: Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Travel / Accommodation / Expenses: PharmaMar; Advisory / Consultancy: Lilly; Honoraria (self), Advisory / Consultancy: Boehringer Ingelheim; Research grant / Funding (self), Travel / Accommodation / Expenses: Roche; Honoraria (self): Pierre Fabre; Honoraria (self): Pfizer; Honoraria (self), Research grant / Funding (institution): Novartis; Honoraria (self): Bayer; Honoraria (self): Bristol-Myers Squibb; Research grant / Funding (self): Roche; Research grant / Funding (self): AstraZeneca; Research grant / Funding (self): Peregrine Pharmaceuticals; Research grant / Funding (self): AbbVie; Research grant / Funding (self): Merrimack; Research grant / Funding (institution): Janssen. A. Lopez Pousa: Travel / Accommodation / Expenses: PharmaMar. A. Redondo: Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche; Advisory / Consultancy, Travel / Accommodation / Expenses: AstraZeneca; Advisory / Consultancy: Tesaro; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: PharmaMar; Advisory / Consultancy: Clovis Oncology; Research grant / Funding (institution): Eisai. J. Blay: Honoraria (self), Research grant / Funding (self): PharmaMar. A. Gronchi: Honoraria (self), Advisory / Consultancy: Novartis; Advisory / Consultancy: Bayer; Honoraria (self), Advisory / Consultancy: Lilly; Advisory / Consultancy, Travel / Accommodation / Expenses: Nanobiotix; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: PharmaMar; Honoraria (self): Pfizer. N. Hindi: Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: PharmaMar; Research grant / Funding (institution): Eisai; Research grant / Funding (institution): Novartis. All other authors have declared no conflicts of interest.

Background Patients (pts) not candidates to platinum-based therapies have limited therapeutic options. The addition of P to PTX followed by RT + P may be an alternative to platinum-based therapy. This study aimed to evaluate the activity of P + PTX as induction treatment (Tx) in pts with LAHNC. Methods Phase II, single arm, multicenter study, in pts≥18 years with CT/RT-naive stage III-IVb LAHNC not candidates to aggressive Tx. All pts received PTX (80 mg/m2/week [w]) + P (6 mg/kg every 2w) during 9w as induction Tx followed by P and RT (70 Gy/35 fractions/7w).The primary endpoint was RR after induction Tx. With a Simon’s two stage design, p1 at the end of the study was defined as > 36 of 61 patients achieving complete (CR) or partial response (PR) to induction Tx. Results The study included 51 pts: median 70 years (range 45-84), 98% men. Reasons for cisplatin ineligibility: > 70 years old in 3 pts, mild or moderate adult comorbidity [ACE-27 comorbidity index] in 46 pts, severe adult comorbidity in 1 pt and ECOG: 2 in 1 pt. RR after induction was 66.7% (95% confidence interval [CI]: 53.7-79.6): 8 (15.7%) CR and 26 (51.0%) PR. Median progression-free survival was 12.2 months (m) (95% CI: 7.6 - 35.0] and median overall survival was 31.5 m (95%: 14.3 - not reached) with a median duration of follow-up of 31.9 m (range, 1-61). Incidence of grade 3/4 P and/or PTX-related Adverse Events (AEs) was 72.5%. Most frequent grade 3/4 P and/or PTX- related AEs (>5% of pts) were: 5.9% dermatitis, 5.9% neutropenia, 5.9% dry mouth, 5.9% stomatitis, 7.8% asthenia, 15.7% eruption, 15.7% skin toxicity and 27.5% mucosal inflammation. Five (9.8%) pts had fatal AEs, 2 (3.9%) of them related to P and/or PTX. Conclusions Despite the study ended prematurely, the RR observed is higher than the pre-specified boundary to consider the treatment active to justify further studies. PTX combined with P as induction Tx provide a clinically significant benefit with an acceptable safety profile. Clinical trial identification 2012-003038-17. Editorial acknowledgement Marta Munoz-Tuduri (TFS, S.L.). Legal entity responsible for the study Study carried out by Grupo Espanol de Tratamiento de Tumores de Cabeza y Cuello (TTCC). Funding Amgen S.A. Disclosure J. Martinez Trufero: Advisory / Consultancy: PharmaMar, Merck, Lilly, Eisai, Bristol-Myers; Honoraria (self), Medical meetings sponsor: PharmaMar, Merck, Lilly, Eisai. R. Mesia Nin: Advisory / Consultancy: Merck, BMS, MSD, AZ, Roche, Nanobiotix; Speaker Bureau / Expert testimony: Merck, BMS, MSD. M. Taberna Sanz: Non-remunerated activity/ies: Merck; Non-remunerated activity/ies: AstraZeneca; Honoraria (self): Merck; Honoraria (self): Nanobiotics; Honoraria (self): MSD; Honoraria (self): Bristol Myers. J. Lambea Sorrosal: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Merck-Serono, MSD, Bristol. All other authors have declared no conflicts of interest. L. Iglesias: Honoraria (self), Advisory / Consultancy: Merck Serono, MSD, BMS, Bayer, Sanofi; Honoraria (self), medical education with honoraria: Merck Serono, MSD, AstraZeneca y BMS; Research grant / Funding (institution): Merck Serono, MSD, AstraZeneca, BMS, Novartis, Kura Oncology, Sanofi y Kura Oncology. P. Perez Segura: Speaker Bureau / Expert testimony: BMS, Merck. J.J. Cruz-Hernandez: Honoraria (self): Amgen, AstraZeneca, Bristol-Myers Squibb, Novartis, Pfizer, Roche; Advisory / Consultancy, Advisory Board: Bristol-Myers Squibb, Merck, MSD, Roche, Pfizer, Janssen Cilag; Advisory / Consultancy, Consulting: Roche.

J. M. Buesa, J. Fra, A. Anton, A. Lopez-Pousa, J. Martin, J. Garcia del Muro, P. Escudero, A. Casado & A. Poveda 'Hospital Central de Asturias, Oviedo; Hospital Miguel Serve!, Zaragoza; Hospital San Pau. Barcelona; Hospital Son Dureta, Palmade Mallorca; lnstitut Catala d'Oncologia, Barcelona; Hospital Clinico. Zaragoza; ^Hospital Clinico San Carlos, Madrid; Instituto Valenciano de Oncologia, Valencia, Spain

Aim: We analyzed retrospectively data about treatment outcome with existing treatments in DTF. Methods: Descriptive analysis of data related to diagnosis and treatment from all DTF was collected in patients (p) between Sept. 1999 and Nov. 2013 in 26 hospitals of GEIS . Ethics committee approval was obtained. Results: 185 patients. Age: median 37 years (6-85) .63.2% female .Median time lapse from first symptom to diagnosis: 4 months(m). Location : trunk wall 81p (43.8%), extremities 50p (27%), retroperitoneum 10p (5.4%), Gastro-intestinal 16p (8.6%), Head/neck 6p( 3.2%), others 6p(3.2%), 2p (1.1%) missing . 20p (11%) presented a second neoplasia (throughout the whole process). Median tumor size: 8 cm(range 1-96). 3 p (1.6%) presented distant peritoneal disease. First treatment : No treatment 6p (2.7%), Surgery (S) alone 144 p ( 77.8%, 3p >1), S+radiotherapy (RT) 7p (3.7%), S+ chemotherapy (CT) 2 p (1.08%), S+hormonetherapy (HT) 3p (1.62%), S +HT+ Non steroidal antiinflammatory drug (NSAID)+Tirosin-kinasa inhibitor(TKI) 1p (0.54%), CT 5p (2.7%), RT 3p ( 1.6%),NSAID 5p (2.6%), HT 2p (1.08%), TKI 1p(0.54%), HT+NSAID 6p (2.7%). 128p (69.2%) became free of disease, in 49p (26.5%) residual disease remained . 61p (33%) progressed. Median Progression free survival (PFS) :109 m (95%CI 44.6-175.1).Multivariate analysis for PFS: extended/radical surgery(p=0.000) and tumor size Response to CT /other treatments CT treatment Other treatments (TKI, HT, NSAID) p % p % PR 12 30.7 4 7.4 SD 15 38.4 31 55.3 PD 3 7.6 10 17.8 NE 4 10.2 6 10.7 NA 5 12.8 5 8.9 Total 39 100 56 100 PR: partial response; SD: stable disease; PD: progressive disease; NE: non evaluable; NA: non available data. Conclusions: Surgical quality and tumor size seems to play a relevant role in predicting PFS in DFT. Other sistemic treatments showed meaningful activity in progressive disease. Disclosure: All authors have declared no conflicts of interest.

Aim: SFT are soft tissue sarcomas with low incidence and intermediate biological potential behavior. The main aim of this observational study is to get new insights in clinical presentation, biological behavior and therapeutic approaches of SFT in our country. Methods: A web-based registry was built to collect diagnostic and therapeutic processes in patients (p) with SFT diagnosed in 22 centers (centers of reference and secondary centers) involved in this program. Median progression-free survival (PFS) and overall survival (OS), were estimated by Kaplan-Meier method. Ethics committee approval was obtained. Results: Between September 1999 and November 2013, 163 p (median age 52 years, 52.8% females, 88% had Karnofsky≥80%) were diagnosed. 12 p lacked some relevant data after diagnosis. 7 hospitals included 70% of cases. Primary tumor location was: 24% extremities and trunk-wall, 15% lungs, 13% pleural, 13% head and neck, 14% retroperitoneum and 2.5% meningeal sites. Excisional biopsy and core-biopsy were the method of diagnosis in 65% and 22% of p respectively. Median size was 8.6 cm (range 1-29). 11 p were metastatic at diagnosis. Initial treatment was surgery in 89% of 151 p, followed by adjuvant treatment in 23: 2 chemotherapy (CT), 15 radiotherapy (RT), 5 CT and RT, and 1 radiosurgery. The remaining p received: 1 CT, 2 RT, 1 sunitinib and 2 palliative care. 36 p progressed: 19 p could be resected. Antiangiogenic therapy was used in advanced disease:13 p received sunitinib (5 first line, 3 second line and 5 further lines), 5 p temozolamide-bevacizumab (3 first line and 2 further lines) and 2 p pazopanib (1 first line) . Sunitinib showed clinical benefit (CB) in 8 cases (35, 36, 30, 22, 8, 5, 4 and 2 months of duration), 4 progressions (PR) and 1 unknown. 2 p stopped for toxicity grade III-IV. Temozolamide-bevacizumab experienced CB in 3 cases (30,12, and 6 months of duration), 1 PR and 1 p stopped for toxicity grade III. 1p progressed with pazopanib and 1 was not evaluated for response. Median PFS was 5 years and median OS was not reached. OS and PFS at 10 years were 70% and 50% respectively. Conclusions: SFT are tumors that appear in different localizations, where radical surgery is the treatment of choice. In advanced disease, antiangiogenic therapy could provide longer CB in 60% of progressing cases. Studies with these drugs in advanced SFT are guaranteed. Disclosure: All authors have declared no conflicts of interest.

Aim: Sunitinib is approved for advanced GIST resistant/refractory to IM; however, disease control rate (DCR) at 12 wk was only ≈ 40%. Thus, novel therapeutic second-line strategies are needed to improve outcomes. Dovitinib inhibits several tyrosine kinases (eg, FGFR, VEGFR, PDGFRb, KIT). DOVIGIST (NCT01478373) is a multicenter, single-arm study to evaluate the efficacy and safety of second-line dovitinib in GIST. Methods: Eligible pts (≥ 18 y) had histologically confirmed GIST; pts had advanced/metastatic GIST refractory/intolerant to IM ≥ 400 mg/day or recurrent GIST after adjuvant IM. All pts had ≥ 1 measurable lesion at baseline. Prior tyrosine kinase inhibitors other than IM were not allowed. Pts received dovitinib 500 mg/day (5 days on/2 days off) until progressive disease (PD), unacceptable toxicity, death, or discontinuation. The primary endpoint was DCR (per RECIST 1.1) at 12 wk. Based on prior trials, DCR ≥45% was deemed clinically meaningful. Key secondary endpoints were progression-free survival (PFS), overall response rate (ORR), and safety. Results: Of 39 pts who received ≥1 dose of dovitinib, 1 had unconfirmed GIST histology; thus, the efficacy analysis included 38 pts (median age, 60 y). The median time from diagnosis to first dose of dovitinib was 46.3 mo; 81.6% had PD on IM, 13.2% discontinued IM due to intolerance, and 5.2% had intolerance and PD. The most common grade 3/4 dovitinib-related adverse events (AEs) were fatigue (12.8%), diarrhea, vomiting, and hypertriglyceridemia (7.7% each); 21.1% discontinued due to AEs. One pt died of a heart attack (suspected drug related). The median PFS was 20.1 wk (90% CI, 12.3-32.1). DCR at 12 wk was 52.6% (Table). Conclusions: DOVIGIST met its primary endpoint. The DCR of 52.6% compares favorably with that of other second-line treatments. Dovitinib had promising efficacy and a manageable safety profile, warranting further studies in GIST. Best Response at 12 Wk, n = 38 n % 90% CI Partial response (PR) 1 2.6 Stable disease (SD) 19 50.0 PD 5 13.2 Unknowna 13 34.2 ORR (≥ PR) 1 2.6 0.1-11.9 DCR (≥ SD) 20 52.6 38.2-66.7 a Not all baseline lesions evaluated during follow-up; no PD detected ≤12 wk on dovitinib. Disclosure: H. Joensuu: The Clinical Research Institute of Helsinki University Hospital has received financial support from Novartis and Bayer AG because HJ participated in advisory group meetings or speaking events; J-Y. Blay: Received research support and honoraria from Novartis, GSK, Roche, Pharmamar, Bayer, MSD, JNJ; E. Fumagalli: Founds for studies and research activities: Amgen Dompe, Bayer, Glaxo SK, Merck SD, Novartis, Pfizer, PharmaMar, Sanofi-Aventis, ImClone, Infinity, Janssen Cilag, Lilly, Molmed, Merck SD, Schering Plough Travel for medical meetings: Novartis; G.E. Grignani: Received travel reimbursement from PharmaMar. Expert opinion for Bayer and Glaxo-Welcome; O. Bouche: Received research support and honoraria from Novartis; S. Bauer: received honoraria by Novartis, Pfizer, Bayer and have received a research grant by Novartis (for a clinical trial). Advisory board for Pfizer; C. Barone: Received honoraria as a speaker and chairman; C. Weiss, S. Crippa, M. Camozzi and R. Castellana: Novartis employee; A. Le Cesne: Received honoraria from GSK, Novartis, Pharmamar and Pfizer for advisory board. All other authors have declared no conflicts of interest.

Aim: Most GISTs have mutations in KIT or PDGFRA. Patients with advanced GIST with KIT exon 9, with PDGFRA mutation or WT for KIT and PDGFRA have a worse progression-free survival (PFS) compared to patients with KIT exon 11 mutated tumors. We evaluated expression of p-IGF-1R (Y1316) and MMP3 as predictors of PFS or overall survival (OS) Methods: Ninety-six advanced GIST patients included in GEIS-16 study with KIT and PDGFRA mutational information were examined for p-IGF-1R (Y1316) and MMP3 expression in a tissue micro-array. To study activation of the IGF-1R system, we have used an antibody (anti-pY1316) that specifically recognizes the phosphorylated (active) form of the IGF-1R. DNA was extracted from paraffin-embedded tissues and intronic PCR primers were used to amplify exons 9,11,13 and 17 of KIT, 12 and 18 of PDGFRA. Bidirecctional sequencing with specific primers was performed on a ABI3100 sequencer using the Big Dye Terminator v3.1 kit. Multivariate model was built using a stepwise automated variable selection approach with criterion to enter the variable in the model of p Results: MMP3 was overexpressed in 10% of cases and p-IGF-1R in only 2% of cases. 68% of patients had KIT mutations, 4% had PDGFRA mutations and 28% were WT for KIT and PDGFRA. At univariate analysis KIT exon 11/13 vs rest (WT/WT, KIT exon 9 mutations and PDGFRA mutations) had better PFS (p = 0.038; HR: 0.58; 95%CI (0.35-0.96). Less than 24 months disease free-interval (HR 24.2, 95% CI 10.5-55.8), poor performance status (PS) (HR 6.3, 95% CI 2.5-15.9), extension of disease; > 1 organ (HR 1.89; 95% CI 1.03-3.4) and positive expression of p-IGF-1R or MMP3 (HR 2.1; 95% CI 1.01-4,2) but not mutational analysis (HR 1.02; 95%CI 0.53-1.96) were the strongest prognostic factors for PFS in the multivariate analysis. For OS only PS, disease free-interval and number of metastatic sites remain significant. Conclusions: Our findings suggest that p-IGF-1R (Y1316) and MMP3 expression have major prognostic significance for PFS in advanced GIST treated with imatinib therapy. Disclosure: All authors have declared no conflicts of interest.

Background Advanced STS are rare diseases that need development of efficacious new treatments, as exemplified by doxorubicin still being the reference standard after 30 years of existence. Trabectedin is a new antineoplastic with a novel mechanism of action that obtained in 2007 the Marketing Authorization in Europe for the treatment of STS after anthracycline and ifosfamide failure, or in pts unsuited to receive these drugs. The academic GEIS-20 study arises from the need to bring to the first-line of treatment of advanced STS agents that have shown activity in second-line. The combination Doxo and trabectedin, drugs with different mechanisms of action and potential synergy, may be a clear advantage to obtain better results. The toxicity profiles of both study drugs are different; worsening or cumulative adverse effects are not expected. Methods The GEIS-20 is an ongoing phase II, randomized, open label and multicentre (27 centres) study in the first-line setting conducted in Spain and Portugal. This trial, lead by the Spanish Sarcoma Group, has started pts enrolment in Arm A (control): Doxo 75 mg/m2 20 min i.v. infusion; and Arm B (experimental): Trabectedin 1.1 mg/m2 3-h i.v. infusion + Doxo 60 mg/m2 20 min i.v. infusion + i.v. dexamethasone pre-treatment. Both treatments are given every 3 weeks for a maximum of 6 cycles. Sample size: 182 pts. The primary endpoint is to compare the radiological progression-free survival between arms. Secondary endpoints include the evaluation of response (RECIST v.1.1), tumor control rate, overall survival, activity per Choi criteria, toxicity and pharmacogenomics. Key eligibility criteria: Chemo-naive pts with advanced, non operable and/or metastatic STS, aged 18-70 years, with performance status ≤1, normal cardiac, renal, haematological functions and liver function tests. Pts are stratified by metastatic disease free interval ≤12 months vs. >12 months. A central pathology and radiology review will be performed. Disclosure A.M. Poveda: I was compensated as consultant from PharmaMar. All other authors have declared no conflicts of interest.

Background Patients (Pts) with GIST harboring mutations in KIT exon 9 or wild type tumors showed better responses to sunitinib along with longer median progression-free survival (PFS) rates compared with exon 11 mutant tumors pts. We have hypothesized that the combination of S plus I in unresectable GIST would be synergistic and associated to a tolerable side effect profile. Methods This is a phase I, dose-escalation study to determine the maximum-tolerated dose (MTD), safety and antitumor activity measured by response rate of S plus I in naive patients with metastatic or unresectable GIST. Pts with adequate organ function, performance status (ECOG) 0-1, age >18 years, were eligible. Treatment consisted on oral S 25mg/day d1-28 combined with oral I 300mg/day d1-28 (level I) or oral I 400mg/day d1-28 (level II). Results 3 pts were enrolled on Level I. No DLTs were observed. At level II 7 pts were enrolled and 1 DLT was observed (posterior reversible encephalopathy syndrome on day19). Although 1DLT was observed in 7 pts, decision was not to increase the S dose to 37.5 mg due to toxicity. Other non-DLTs adverse events were G4 hyperbilirubinemia in cycle 2 and G4 intratumoral haemorrhage in cycle 3. The MTD was determined as I 400mg/day and S 25mg/day. Other toxicities were neutropenia, diarrhoea, vomiting, asthenia, musculoskeletal pain, anaemia and bacteraemia. Median time on treatment with the combination was 16 weeks (range 12-152) on level I and 20 weeks (range 3-88) on level II. 66% of patients completed 20 weeks of treatment. Serious Adverse Events were reported in 4 pts; 3 deaths were reported, one due to disease progression, another due to reversible encephalopathy syndrome and the last one due to septic shock. A partial response was achieved in 6 (60%) pts; complete response in 2 (1 wild-type) (20%) and stable disease in 1 (10%). Conclusions Sunitinib 25mg/day plus Imatinib 400mg/day is the MTD and a safe and well tolerated combination in pts with metastatic or unresectable GIST. Response rates seems to be higher than those expected and previously observed with S or I monotherapy. This study was supported by an Independent Investigator Research grant from Pfizer, Inc Disclosure All authors have declared no conflicts of interest.

Background The identification of predictors of efficacy of chemotherapy in NSCLC could help in the selection of patients who are more likely to benefit from a particular scheme and the avoidance of undue toxicity in poor responders. We examined the role of several polymorphisms in DNA repair and DNA synthesis genes as pharmacogenetic markers in the outcome of NSCLC patients. Methods A blood sample was collected from 117 patients with NSCLC and genomic DNA was isolated from the peripheral blood nucleated cells. Polymorphisms were analyzed by polymerase chain reaction amplification and automated sequencing techniques or using a 48.48 dynamic array on the BioMark system. The germline polymorphisms studied were excision repair cross-complementing-1 (ERCC1 Asn118Asn), xeroderma pigmentosum group D (XPD Lys751Gln), thymidylate synthase (TS) (VNTR/5′UTR, 2R G > C SNP, 3R G > C SNP) and methylenetetrahydrofolate reductase (MTHFR) (C677T, A1298C). Progression-free survival (PFS) and overall survival (OS) were evaluated according to each genotype. Results 103 patients with stage III-IV NSCLC (47% adenocarcinoma, 41% squamous cell carcinoma, 12% NOS) receiving platinum-based chemotherapy were eligible (14 patients with stage I-II were excluded). The median PFS was significantly longer in patients with C/T or T/T genotypes in codon 118 in ERCC1: 13 months (m) and 10 m, respectively, as compared to 6 m for the C/C patients (p = 0.034). Patients with ERCC1 C/T or T/T genotypes had a trend to longer median OS (20 m) than those C/C (10.5 m; p = 0.1). Subgroup analysis revealed that ERCC1 C/T or T/T genotypes were associated with increased PFS in male (p = 0.005), smokers (p = 0.036) and age Conclusions ERCC1 C/T or T/T genotype in codon 118 might be useful for predicting the outcome of NSCLC patients treated with platinum-based chemotherapy specially in male, smokers and age Disclosure All authors have declared no conflicts of interest.

Background TH-302 is a hypoxia targeted prodrug with a hypoxia-triggered 2-nitroimidazole component designed to release the DNA alkylator, bromo-isophosphoramide mustard (Br-IPM), when reduced in severe hypoxia. A randomized Phase 2B study (NCT01144455) was conducted to assess the benefit of G + T to standard dose G as first-line therapy of PAC. Materials and methods An open-label multi-center study of two dose levels of TH-302 (240 mg/m2 or 340 mg/m2) in combination with G versus G alone (randomized 1:1:1). G (1000 mg/m2) and T were administered IV over 30-60 minutes on Days 1, 8 and 15 of a 28-day cycle. Patients on the G could crossover after progression and be randomized to a G + T arm. The primary efficacy endpoint was a comparison of progression-free survival (PFS) between the combination arms and G alone (80% power to detect 50% improvement in PFS with one-sided alpha of 10%). Summary PFS outcome has previously been reported; more detailed PFS as well as the initial overall survival (OS) data are presented. Results 214 pts were treated; 164 (77%) Stage IV and 50 (23%) Stage IIIB. Median age 65 (range 29-86); 126 M/88 F; 40% ECOG 0/60% ECOG 1. Receiving 6 or more cycles: 32% G; 45% G + T240; 55% G + T340. Median PFS was 3.6 mo in G vs 5.5 mo in G + T240 (p = 0.031) and 6.0 mo in G + T340 (p = 0.008). Poorer prognostic factors (older age, poorer performance status, reduced albumin) were associated with larger treatment effect. Median OS was 7.0 mo in G vs 9.0 in G + T240 and 9.5 mo in G + T340. RECIST best response was 12% in G vs 17% in G + T240 and 27% in G + T340. CA19-9 decreases were significantly greater G + T340. A >50% CA19-9 decrease was 52% with G vs 50% with G + T240 and 70% with G + T340. AEs leading to discontinuation were: 16% G, 15% G + T240 and 11% G + T340. Rash (45% in G + T340) and stomatitis (36% in G + T340) were greater in combination, 4 pts Grade 3 rash. Grd 3/4 thrombocytopenia were 11% G, 39% G + T240 and 59% G + T340 and Grd 3/4 neutropenia were 28% G, 56% G + T240 and 59% G + T340. Conclusions The combination of G plus TH-302 improved the efficacy of G. A TH-302 dose of 340 mg2 was identified for future studies. Skin and mucosal toxicity and myelosuppression were the most common TH-302 related AEs with no increase in treatment discontinuation. Disclosure All authors have declared no conflicts of interest.