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Programmed cell death 1 (PD-1) inhibitors have limited effect in pancreatic ductal adenocarcinoma (PDAC), underscoring the need to co-target alternative pathways. CXC chemokine receptor 4 (CXCR4) blockade promotes T cell tumor infiltration and is synergistic with anti-PD-1 therapy in PDAC mouse models. We conducted a phase IIa, open-label, two-cohort study to assess the safety, efficacy and immunobiological effects of the CXCR4 antagonist BL-8040 (motixafortide) with pembrolizumab and chemotherapy in metastatic PDAC (NCT02826486). The primary outcome was objective response rate (ORR). Secondary outcomes were overall survival (OS), disease control rate (DCR) and safety. In cohort 1, 37 patients with chemotherapy-resistant disease received BL-8040 and pembrolizumab. The DCR was 34.5% in the evaluable population (modified intention to treat, mITT; N = 29), including nine patients (31%) with stable disease and one patient (3.4%) with partial response. Median OS (mOS) was 3.3 months in the ITT population. Notably, in patients receiving study drugs as second-line therapy, the mOS was 7.5 months. BL-8040 increased CD8+ effector T cell tumor infiltration, decreased myeloid-derived suppressor cells (MDSCs) and further decreased circulating regulatory T cells. In cohort 2, 22 patients received BL-8040 and pembrolizumab with chemotherapy, with an ORR, DCR and median duration of response of 32%, 77% and 7.8 months, respectively. These data suggest that combined CXCR4 and PD-1 blockade may expand the benefit of chemotherapy in PDAC and warrants confirmation in subsequent randomized trials. Results from the phase IIa COMBAT trial combining CXCR4 and PD-1 inhibition in patients with metastatic cancer show encouraging clinical responses in association with enhanced antitumor immune activation.

Purpose: Pancreatic ductal adenocarcinoma (PDAC) is largely unresponsive to checkpoint inhibitors. Blockade of the CXCR4/CXCL12 axis increases intratumoral trafficking of activated T cells while restraining immunosuppressive elements. This study evaluates dual blockade of CXCR4 and PD1 with chemotherapy in PDAC. Patients and Methods: Multicenter, single-arm, phase II study to evaluate the safety and efficacy of motixafortide and pembrolizumab combined with chemotherapy in patients with de novo metastatic PDAC and disease progression on front-line gemcitabine-based therapy (NCT02826486). Subjects received a priming phase of motixafortide daily on days 1–5, followed by repeated cycles of motixafortide twice a week; pembrolizumab every 3 weeks; and nanoliposomal irinotecan, fluorouracil, and leucovorin every 2 weeks (NAPOLI-1 regimen). The primary objective was objective response rate (ORR). Secondary objectives included overall survival (OS), progression-free survival (PFS), disease control rate (DCR), safety, and tolerability. Results: A total of 43 patients were enrolled. The ORR according to RECISTv1.1 was 21.1% with confirmed ORR of 13.2%. The DCR was 63.2% with median duration of clinical benefit of 5.7 months. In the intention-to-treat population, median PFS was 3.8 months and median OS was 6.6 months. The triple combination was safe and well tolerated, with toxicity comparable with the NAPOLI-1 regimen. Notably, the incidence of grade 3 or higher neutropenia and infection was 7%, lower than expected for this chemotherapy regimen. Conclusions: Triple combination of motixafortide, pembrolizumab, and chemotherapy was safe and well tolerated, and showed signs of efficacy in a population with poor prognosis and aggressive disease.

Protocol tittle: Study of BO-112 with pembrolizumab for colorectal or gastric/GEJ cancer with liver metastasis.Background: Gastric (GC), oesophagogastric junction (EGJC) and colorectal tumors (CRC) with microsatellite stability (MSS) are poorly responders to PD(L)-1 inhibition, due to low CD8+ T cell infiltration and PD-L1 expression. Therefore, modulation of the tumor microenvironment (TME) could increase disease control. In these tumors the presence of liver lesions is difficult to control because of the hepatic immune tolerance. Control of the hepatic disease could increase survival.BO-112 is a non-coding dsRNA agonist of TLR3, MDA5 and RIG-I which activates the innate and adaptative immune response, inducing apoptosis and immunogenic cell death, with a local and a systemic effect. A prior Phase I trial showed that the combination of pembrolizumab and intratumoral (IT) BO-112 has a good safety profile and encouraging activity. Study design: This is a single arm phase IIa trial to assess the efficacy of intrahepatic IT BO-112 and iv pembrolizumab in 3W cycles in patients with MSS CRC, GC or EGJ tumors. Up to 69 patients with at least one liver lesion and 2 prior lines for CRC and 1 for GC/EGJC will be enrolled. Primary endpoints: ORR and related TEAEs ≥ grade 3. Secondary endpoints: ORR (iRECIST), PFS, 6-months OS and safety. Exploratory endpoint: Changes in TME (PD-L1 expression and CD8+ T cell infiltration) from baseline to C2D1.Results: A total of 11 CRC and 7 GC/EGJC patients were enrolled since July 2020. This abstract focuses on the CRC patients´ biomarker expression. These patients had low PD-L1 CPS (combined positive score) expression and CD8+ T cell infiltration with a median value of 5 and 4%, respectively, in the TME at baseline. Following two IT BO-112 injections, an important increase in PD-L1 expression and CD8+ T cell infiltration was observed in 5 and 7 patients, respectively. PD-L1 CPS median value increased to 37.9 while CD8+ T cell infiltration median values raised to 12.9%.Conclusions: A meaningful increase in PD-L1 expression and CD8+ T cell infiltration was achieved in MSS CRC patients after one cycle of BO-112-pembrolizumab. Table 1.Baseline characteristics and TME changesBaseline characteristicsCRC N=11Demographics-Sex-Male-Female-Age (mean, range)7 (63.6%)4 (36.4%)55 (38-74)Location of primary tumor-Right colon-Left colon2 (36.4%)7 (63.6%)Presence of extrahepatic disease-No-YesLocation of the extrahepatic disease-Lungs-Lymph nodes-Ohers (bone, adrenal gland, peritoneum, pancreas)2 (18.2%)9 (81.8%)6 (54.5%)5 (45.5%)1 (9.1%)Molecular characteristics:-MMR status-MSS-KRAS-Wild type-Mutant -PD-L1-CPS Citation Format: Mariano Ponz-Sarvisé, Elena Élez, Andrés Muñoz, Marc Van den Eynde, Antonio Gaetano Rampoldi, Alain Hendlisz, Hans Prenen, Mercedes Rodríguez, María Teresa Cano, Marya Chaney, Helena Escuin, Vanesa Pons, Marisol Quintero, Andrés Cervantes. Phase IIa open-label clinical study of intratumoural administration of BO-112 in combination with pembrolizumab in subjects with liver metastasis from colorectal cancer or gastric/gastro-oesophageal junction cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT192.

Background: Gastric or gastroesophageal junction cancer (GC) represents a worldwide problem;radical surgery remaining the gold standard of curative treatment. In the West, even with peri-operative chemotherapy, 5-year survival rate is approximately 40%. GC is a heterogeneous disease, well-characterized by different molecular classifications, all having in common the role of the immune system and a T-cell inflamed phenotype across all subtypes. The anti-PD-L1 avelumab (Av) antibody has demonstrated efficacy in GC with response rates of around 10% in the refractory setting. The addition of other immune checkpoint inhibitors to chemotherapy has demonstrated efficacy in the metastatic setting. The combination of Av to perioperative chemotherapy may increase pathological responses by a synergistic effect, and then improving the survival (OS). Trial design: MONEO is an open-label, non-randomized, multicentric, phase II study that explores the combination of Av plus peri-operative FLOT (docetaxel, oxaliplatin, fluorouracil/leucovorin) in resectable GC pts. EudraCT 2019-000782-21;ClinicalTrials NCT03979131. Main inclusion criteria require pts with histologically proven GC, stage Ib (T1N1 only) - IIIC (7th AJCC Ed), available paraffin block from diagnosis and surgery, evaluable disease (RECIST 1.1) amenable to radical surgery. Significant comorbidities and active autoimmune diseases are excluded. Treatment consists of surgery with 4 peri-operatory cycles of FLOT + Av, followed by Av up to one year. The primary objective is the pathological complete response (pCR) rate, compared to historical data. Secondary objectives include OS, disease-free survival, R0 resection rate, tolerability and biomarker analysis. Key point is the comprehensive biomarker analysis from tissue and blood samples (pathological immune response, TCR clonality, immune contexture characterization, immunodynamic monitoring). Statistics for an estimated 33% pCR (historical 16%), 82% power, 0.1 one-side type I error. 37 pts will be recruited from 10 Spanish centers. The sponsor is Vall d'Hebron Institute of Oncology (VHIO), principal investigators Dr. Melero and Dr. Alsina. In compliance with the Helsinki Declaration. At a data cut-off day of 20th of March 2021, 40 patients have been enrolled, 28 of them have had surgery. Despite the difficulties during the COVID19 pandemic, only two patients had been withdrawn from the study. Clinical trial identification: EudraCT 2019-000782-21 ClinicalTrials NCT03979131. Legal entity responsible for the study: VHIO Vall d'Hebron Institute of Oncology. Funding: Merck. Disclosure: A. Vivancos: Advisory / Consultancy: Bayer, Merck, Novartis, Roche (Advisory Board), Bristol Myers Squibb, Guardant Health (Advisory Board), Sysmex (Consultant), Ferrer (Technology Transfer DX Field);Research grant / Funding (institution): Bristol Myers Squibb, Cellestia Biotech, Chittern, Debbio, Novartis, Roche, Sysmex. J. Tabernero: Honoraria (self): educational collaboration with Imedex, Medscape Education, MJH Life Sciences, PeerView Institute for Medical Education and Physicians Education Resource (PER);Advisory / Consultancy: Array Biopharma, AstraZeneca, Avvinity, Bayer, Boehringer Ingelheim, Chugai, Daiichi Sankyo, F. Hoffmann-La Roche Ltd, Genentech Inc, HalioDX SAS, Hutchison MediPharma International, Ikena Oncology, IQVIA, Lilly, Menarini, Merck Serono, Merus, MSD, Mirati, Neophore, Novartis, Orion Biotechnology, Peptomyc, Pfizer, Pierre Fabre, Samsung Bioepis, Sanofi, Seattle Genetics, Servier, Taiho, Tessa Therapeutics and TheraMyc. G. Villacampa: Honoraria (Institution): MSD;Advisory / Consultancy: AstraZeneca. I. Melero: Advisory / Consultancy: BMS;Phamamar;F-STAR, Alligator;AstraZeneca;Roche-Genentech;Numab, EMD;Gossamer;Genmab;Research grant / Funding (self): BMS;Roche, AstraZeneca, Genmab;Alligator. All other authors have declared no conflicts of interest.

Background Combination immunotherapy has the potential to achieve additive or synergistic effects. Combined local injections of dsRNA analogues (mimicking viral RNA) and repeated vaccinations with tumor-lysate loaded dendritic cells shows efficacy against colon cancer mouse models. In the context of immunotherapy, radiotherapy can exert beneficial abscopal effects. Patients and methods In this two-cohort pilot phase I study, 15 advanced cancer patients received two 4-week cycles of four intradermal daily doses of monocyte-derived dendritic cells preloaded with autologous tumor lysate and matured for 24h with poly-ICLC (Hiltonol), TNF-α and IFN-α. On days+8 and+10 of each cycle, patients received intratumoral image-guided 0.25mg injections of the dsRNA-analogue Hiltonol. Cyclophosphamide 600mg/m2 was administered 1 week before. Six patients received stereotactic ablative radiotherapy (SABR) on selected tumor lesions, including those injected with Hiltonol. Expression of 25 immune-relevant genes was sequentially monitored by RT-PCR on circulating peripheral blood mononuclear cell (PBMCs) and serum concentrations of a cytokine panel were sequentially determined before and during treatment. Pre- and post-treatment PBMC from patients achieving durable stable disease (SD) were studied by IFNγ ELISPOT-assays responding to tumor-lysate loaded DC and by TCRβ sequencing. Results Combined treatment was, safe and well tolerated. One heavily pretreated castration-resistant prostate cancer patient experienced a remarkable mixed abscopal response to SABR+ immunotherapy. No objective responses were observed, while nine patients presented SD (five of them in the six-patient radiotherapy cohort). Intratumoral Hiltonol increased IFN-β and IFN-α mRNA in circulating PBMC. DC vaccination increased serum IL-12 and IL-1β concentrations, especially in patients presenting SD. IFNγ-ELISPOT reactivity to tumor lysates was observed in two patients experiencing durable SD. Conclusions This radio-immunotherapy combination strategy, aimed at resembling viral infection in tumor tissue in combination with a dendritic-cell vaccine and SABR, is safe and shows immune-associated activity and signs of preliminary clinical efficacy.

PURPOSE: Limited options exist for patients with advanced pancreatic cancer progressing after 1 or more lines of therapy. A phase II study in patients with previously treated metastatic pancreatic cancer showed that combining GVAX pancreas (granulocyte-macrophage colony-stimulating factor-secreting allogeneic pancreatic tumor cells) with cyclophosphamide (Cy) and CRS-207 (live, attenuated Listeria monocytogenes expressing mesothelin) resulted in median overall survival (OS) of 6.1 months, which compares favorably with historical OS achieved with chemotherapy. In the current study, we compared Cy/GVAX + CRS-207, CRS-207 alone, and standard chemotherapy in a three-arm, randomized, controlled phase IIb trial. PATIENTS AND METHODS: Patients with previously treated metastatic pancreatic adenocarcinoma were randomized 1:1:1 to receive Cy/GVAX + CRS-207 (arm A), CRS-207 (arm B), or physician’s choice of single-agent chemotherapy (arm C). The primary cohort included patients who had failed ≥2 prior lines of therapy, including gemcitabine. The primary objective compared OS between arms A and C in the primary cohort. The second-line cohort included patients who had received 1 prior line of therapy. Additional objectives included OS between all treatment arms, safety, and tumor responses. RESULTS: The study did not meet its primary efficacy endpoint. At the final study analysis, median OS [95% confidence interval (CI)] in the primary cohort (N = 213) was 3.7 (2.9–5.3), 5.4 (4.2–6.4), and 4.6 (4.2–5.7) months in arms A, B, and C, respectively, showing no significant difference between arm A and arm C [P = not significant (NS), HR 1.17; 95% CI, 0.84–1.64]. The most frequently reported adverse events in all treatment groups were chills, pyrexia, fatigue, and nausea. No treatment-related deaths occurred. CONCLUSIONS: The combination of Cy/GVAX + CRS-207 did not improve survival over chemotherapy. (ClinicalTrials.gov ID: NCT02004262)

Background: Improving outcomes of PDAC with checkpoint inhibitors (CPIs) have been ineffective, underscoring the need to co-target alternative pathways. Preclinical data showed that CXCR4-SDF1 axis modulates the tumor microenvironment (TME) in PDAC and that CXCR4 inhibition enhances T cell access to the TME, increasing tumor sensitivity to CPIs. This was confirmed in the COMBAT Cohort 1 (CC1) study showing that the dual combination M+P increases activated CD8+ T cells and decreases myeloid derived suppressor cells (MDSCs) within the TME. Moreover, our pre-clinical studies showed that adding C to M+P resulted in improved efficacy vs C alone. The COMBAT Cohort 2 (CC2) aims to test the safety and efficacy of the triple combination of M+P+C in 2L mPDAC. Methods: Single arm phase 2a study in mPDAC. In cohort 2, patients with stage IV PDAC at diagnose who had progressed to 1L gemcitabine-based C received 5 days M priming, followed by M BIW + P Q3W plus C [Irinotecan liposomal injection/5-FU/LV (OFL)] Q2W. The primary endpoint was RR. Results: A total of 43 patients with stage 4 PDAC, 98% of whom were diagnosed with stage 4 disease, were enrolled. Median age was 68 (40-85) and 74.4% had liver disease. The safety profile was consistent with the individual profiles of each treatment alone. Of note, the incidence of ≥G3 neutropenia (G3Neu) was 7% and ≥G3 infection was 7%, which is lower than expected for C (OFL) alone (20% and 17%, respectively). The levels of T-cells increased during M priming and returned to normal values, which remained stable across the study despite the OFL treatment. For the evaluable patients (N=38) the ORR was 21.1% with a 13.2% confirmed ORR (defined as two consecutive assessments showing PR) and a 63.2% DCR (PR+SD). Median duration of clinical benefit was 5.6 months. Median OS and PFS were 6.5 months and 4.0 months, respectively (6.6 months and 3.8 months, respectively, for the ITT population). Conclusions: The triple combination of M+P+C is tolerable and shows encouraging results with cORR 13.2%, mPFS 4.0 months and mOS 6.5 months (compared to 7.7%, ~3 months and 4.7 months, respectively, on a historical basis for OFL alone in the stage 4 diagnosis subpopulation). SD of 42.1% and DCR of 63.2% were also higher than historical data on SoC chemotherapy used in 2L patients. The incidence of severe neutropenia and infections is lower than the historical data on C. The results from the CC2 suggest that M+P may expand the efficacy and safety benefit of OFL in PDAC, and warrants further investigation in a randomized study. Citation Format: Manuel Hidalgo, Teresa Macarulla, Valerya Semenisty, Erkut Borazanci, Jaime Feliu, Mariano Ponz-Sarvise, David Gutierrez Abad, Paul Oberstein, Angela Alistar, Andres Muñoz, Ravit Geva, Carmen Guillén-Ponce, Mercedes Salgado Fernandez, Amnon Peled, Marya Chaney, Irit Glicko-Kabir, Liron Shemesh-Darvish, Debby Ickowicz, Ella Sorani, Shaul E. Kadosh, Abi Vainstein-Haras, Bruno Bockorny. A multi-center phase 2a trial of the CXCR4 inhibitor motixafortide (BL-8040) (M) in combination with pembrolizumab (P) and chemotherapy (C), in patients with metastatic pancreatic adenocarcinoma (mPDAC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT177.

TPS4155 Background: GC represents a worldwide problem; radical surgery remaining the gold standard of curative treatment. In the West, even with peri-operative chemotherapy, 5-year survival rate is approximately 40%. GC is a heterogeneous disease, well characterized by different molecular classifications, all having in common the role of the immune system and a T-cell inflamed phenotype across all subtypes. The anti-PD-L1 Av antibody has demonstrated efficacy in GC with response rates of around 10% in the refractory setting. The addition of other immune checkpoint inhibitors to chemotherapy have demonstrated efficacy in the metastatic setting. The combination of Av to perioperative chemotherapy may increase pathological responses by a synergistic effect, and then improving the survival (OS). Methods: The MONEO is an open-label, non-randomized, multicentric, phase II study that explores the combination of Av plus peri-operative FLOT (docetaxel, oxaliplatin, fluorouracil/leucovorin) in resectable GC pts. EudraCT 2019-000782-21; ClinicalTrials NCT03979131. Main inclusion criteria require pts with histologically proven GC, stage Ib (T1N1 only) - IIIC (7th AJCC Ed), available paraffin block from diagnosis and surgery, evaluable disease (RECIST 1.1) amenable to radical surgery. Significant comorbidities and active autoimmune diseases are excluded. Treatment consists of surgery with 4 peri-operatory cycles of FLOT + Av, followed by Av up to one year. The primary objective is the pathological complete response (pCR) rate, compared to historical data. Secondary objectives include OS, disease-free survival, R0 resection rate, tolerability and biomarker analysis. Key point is the comprehensive biomarker analysis from tissue and blood samples (pathological immune response, TCR clonality, immune contexture characterization, immunodynamic monitoring). Statistics for an estimated 33% pCR (historical 16%), 82% power, 0.1 one-side type I error. 37 pts will be recruited from 10 Spanish centers. The sponsor is Vall d'Hebron Institute of Oncology (VHIO), principal investigators Dr. Melero and Dr. Alsina. In compliance with the Helsinki Declaration. At a data cut-off day of 5th of February 2021, 38 patients have been enrolled, 27 of them have had the surgery. Although the difficulties during the COVID19 pandemia, only two patients had been withdrawn from the study. Clinical trial information: NCT03979131.

Although molecular subtype–based stratification and genomic signatures of increasing complexity are becoming a new strategy to guide therapeutic decisions in stage II/III colon cancer, several prognostic factors that can be easily obtained from formalin-fixed paraffin-embedded (FFPE) specimens should be considered to create combined models that better define individual patients' needs. Clin Cancer Res; 24(16); 3787–9. ©2018 AACR. See related article by Kandimalla et al., p. 3867

Background: The degree of histopathological response after neoadjuvant therapy in locally advanced gastric cancer (GC) is a key determinant of patients' long-term outcome. We aimed to assess the pattern of histopathological regression after two neoadjuvant approaches and its impact on survival times. Methods: Regression grade of the primary tumour (Becker criteria) and the degree of nodal response by a 4-point scale (grades A–D) were assessed. Grade A—true negative lymph nodes (LNs); grade B and C—infiltrated LNs with any or little evidence of nodal response; and grade D—complete pathological response in a previously infiltrated LN. A favourable pathological response was defined as Becker Ia–b and grade D. Results: From 2004 to 2014, 80 patients with GC (cT3–4/N+ by CT-scan/EUS) were treated with either preoperative chemotherapy (ChT, n=34) or chemoradiation (CRT, n=46). Patients in the CRT group had a higher likelihood of achieving a Becker Ia–b response (58 vs 32%, P=0.001), a grade D nodal regression (30 vs 6%, P=0.009) and a favourable pathological response (23 vs 3% P=0.019). Patients with a grade D nodal response had a longer 5-year PFS and OS compared with those with a grade B or C response. Patients with a baseline negative LN status had similar outcomes irrespective of the preoperative therapy received (5-year OS; ChT vs CRT, 58 vs 51%, P=0.92). Conclusions: Preoperative chemoradiation increases the likelihood of achieving favourable histopathological features that correlate with a 5-year OS>70% in GC patients.

4104 Background: Preliminary results from ongoing randomised trials suggest that neoadjuvant chemotherapy (NAC) may be an alternative approach to conventional adjuvant therapy. We assessed the feasibility and activity of incorporating a pharmacokinetically (PK) guided dose adjustment of 5-FU within preoperative Folfox. Methods: Radiologically staged LACC pts, T4 or T3 with extramural depth >5mm beyond the muscularis propia, were planned to receive 4-6 biweekly cycles of Oxalipatin (85mg/m²), Leucovorin (400 mg/m²), bolus 5-FU (400 mg/m2) and infusional 5-FU (initial dose of 2400mg/m² in 46h and subsequent cycles tailored according to PK monitoring in order to reach a target 5-FU area under the curve (AUC) between 20-30 mg∙h∙L-1). Dihidrouracil deshidrogenase was determined before the first cycle in order to detect pts with 5-Fu intolerance. Three serum samples were obtained during the 5-Fu infusion in the first two cycles. Pathological tumor regression was graded according to the MSKCC classification and toxicity to the NCI-CTCAE 4.0. Results: From June 2012 to August 2017, 45 pts (M/F: 35/10; median age 63) with LACC (T3: 66.7%; T4: 31.1%; T2: 2.2%; N+:66.6%) were evaluated. Median dose of 5-FU was 4500 mg. 48.9% of the pts required a 5-FU dose increase to reach the target AUC. Side effects profile included G3 neutropenia (3 pts), G2 diarrhea (2 pts) and G2 asthenia (9 pts). NAC was discontinued in 3 pts due to small bowell obstruction requiring surgery (no progressive disease during NAC). R0 resection rate was 100% (93.3% laparoscopy-assited). MSKCC score included grades 4, 3+ and 3 in 11.1%, 26.7% and 28.9% of pts, respectively. A complete pathological response was found in 5 pts (11.1%). Median number of harvested nodes was 16 (7-51), 80% ypN0. Those pts with AUC 25-30 had a 3-fold higher likelihood of achieving a MSKCC 3, 3+ and 4 responses. Median time to hospital discharge was 7 days (range 4-22). After a median follow-up of 60 months (44-66), 5-year actuarial PFS is 88.8%. Conclusions: Preoperative PK-adjusted FOLFOX in LACC pts is safe and well tolerated, achieving remarkable rates of major pathological responses and R0 resections.

e14094 Background: Selection of patients for enrolment in phase I trials is critical. Initial scores (RMS or MDAS) were designed to select patients with higher probability to obtain benefit in a clinical trial, followed by others such as GRIM score and the LIPI score. In this study, we have performed a comparison of the four scores in order to detect the most optimal one to select patients for immunotherapy phase I trials. Methods: We retrospectively studied 248 patients who participated in immunotherapy phase I trials in our institution from 2012-2019. We calculated high or low risk for each patient according to punctuation in RMS (number of metastasis,LDH, albumin), GRIM score (LDH, Albumin, NLR > 6), MDAS (RMS, ECOG > = 1, gastrointestinal tumors) and LIPI score (LDH, NLR > 3) at the time of screening. Overall survival (OS) was defined as the time between first dose and date of death or lost to follow up. Cox regression model was performed for predicting OS. C-Harrell index and its confidence interval were calculated for each score for measuring the power of prediction. Differences between c-Harrell indexes were calculated. All calculations were performed with STATA v16.0. Results: In terms of predicting overall survival we found that a higher punctuation in RMS (high vs low HR = 2.14 95% CI 1.47-3.10), Grim score (high vs low HR = 2.14; 95% CI1.51-3.02), MDAS (HR = 1.17 95% CI 1.04-1.31) and LIPI score (high vs low HR = 1.83; 95% CI 1.42-2.37) were all statistically significant. In terms of power of prediction, we found that LIPI score presented a c-Harrel index slightly higher (0.63; 95% CI 0.59-0.68) than GRIM score (0.62; 95% CI 0.57-0.66), MDACC score (0.55 95% CI 0.50-0.62) and RMS (0.62; 95% CI 0.59-0.66). Differences between c-index of each score were not statistically significant. In terms of predicting survival at 90 days, differences between ROC areas for LIPI score (0.64 95% CI 0.56-0.72), Grim Score (0.69 95% CI 0.61-0.76), MDAS (0.57 95% CI 0.48-0.66), and RMS (0.68 95% CI 0.62-0.73) were not statistically significant. Conclusions: Although in this study we have seen a slightly higher predictive power for LIPI score in comparison to GRIM score, MDAS or RMS, differences were not statistically significant. Nevertheless, and assuming the most parsimonious model, LIPI score seemed to be an easy and accurate model for predicting survival. These results might suggest that further prospective analysis are needed to avoid excluding patients based on these scores and who may benefit from phase I trials.

First line therapies usually induce the longest progression free survival (PFS) in metastatic gastrointestinal cancers (GIC) as compared to subsequent lines of treatment. However, immunotherapy (IT) due to its mechanisms of action could influence sensitivity to conventional cancer therapy (CCT) after progression to IT and thereby, influence both tumor growth rate (TGR) and PFS. We have studied TGR and PFS before and after participation in phase I IT trials.

Surgically resectable synchronic and metachronic liver metastases of colon cancer have high risk of relapse in spite of standard-of-care neoadjuvant and adjuvant chemotherapy regimens. Dendritic cell vaccines loaded with autologous tumor lysates were tested for their potential to avoid or delay disease relapses (NCT01348256). Patients with surgically amenable liver metastasis of colon adenocarcinoma (n = 19) were included and underwent neoadjuvant chemotherapy, surgery and adjuvant chemotherapy. Fifteen patients with disease-free resection margins were randomized 1:1 to receive two courses of four daily doses of dendritic cell intradermal vaccinations versus observation. The trial had been originally designed to include 56 patients but was curtailed due to budgetary restrictions. Follow-up of the patients indicates a clear tendency to fewer and later relapses in the vaccine arm (median disease free survival –DFS-) 25.26 months, 95% CI 8.74-n.r) versus observation arm (median DFS 9.53 months, 95% CI 5.32–18.88). Electronic supplementary material The online version of this article (10.1186/s40425-018-0405-z) contains supplementary material, which is available to authorized users.

Background In the prostate-specific antigen era, potentially indolent prostate tumors are radically treated, causing overtreatment. Molecular prognostic factors might differentiate indolent from aggressive tumors, allowing avoidance of unnecessary treatment. Patients and Methods Fifty-two prostate cancer patients (20 organ-confined and 32 metastatic) were selected. All formalin-fixed and paraffin-embedded primary biopsies and matched metastases of 15 of them were evaluated for tumor and endothelial cell Id1 protein expression. Seventy-nine additional patients with organ-confined prostate cancer were selected for Id1 mRNA in silico analysis. Results Among metastatic cancer subjects, 48% of primary tumors and 38% of metastases showed Id1 tumor cell expression, and 79% of primary tumors and 81% of metastases showed endothelial immunoreactivity. In the organ-confined group none of them showed Id1 protein tumor cell expression and 50% displayed endothelial expression. In the metastatic patients group, lower levels of Id1 protein predicted a nonsignificant longer overall survival (13 months vs. 7 months; P = .79). In the in silico analysis, however, lower levels of Id1 mRNA predicted a longer disease-free survival (61 months vs. not-reached; P = .018) and the hazard ratio for progression was 0.451 ( P = .022) in favor of patients showing lower levels. Conclusion In our cohort, it seems to be a differential epithelial expression of Id1 protein according to the prognostic features (metastatic/poor prognosis vs. organ-confined/good prognosis). In localized tumors treated with radical prostatectomy, higher Id1 mRNA expression levels might predict a higher hazard ratio for progression and a shorter disease-free survival. Further validation of these results in larger prospective series is warranted.

Background To investigate whether single nucleotide polymorphisms (SNPs) in gemcitabine (GMB) metabolism genes were associated with clinical outcome in pre-treated metastatic colorectal cancer (mCRC) patients. Patients and methods SNPs of hCNT1, hENT1, CDA, dCTD and RRM1 genes were evaluated in 95 mCRC patients and detected using TaqMan genotyping assays. Association of genotypes with overall response rate (ORR), time to progression (TTP) and overall survival (OS) was tested by univariate and multivariate analysis. RRM1 –37A>C polymorphism was correlated with GMB IC50 value and with the RRM1 gene expression level in CRC cell lines. Results The ORR was 38.9%. The median TTP and OS were 4 and 14.3 months, respectively. By multivariate analysis, patients carrying the RRM1 –37CC genotype or the CDA A-76 C-containing allele had a significantly higher likelihood of achieving a tumour response. RRM1 –37A>C polymorphism remained associated with clinical efficacy (TTP). In vitro experiments, in CRC cell lines, showed that the RRM1 A-37C genotype was associated with the levels of RRM1 expression and with GMB IC50 values. Finally, the down-regulation of RRM1 with a specific siRNA strongly influenced GMB sensitivity. Conclusion RRM1 –37A>C polymorphism may represent a useful biomarker to select mCRC patients most likely to benefit from GMB-based salvage therapy.

Colorectal cancer remains a major public health concern in Europe and North America. It is responsible for one million new cases and half a million deaths per year worldwide. During the past few years new effective treatments have evolved improving the outcome of patients with this disease. Several alternatives are currently available for advanced colorectal cancer patients including different chemotherapeutic regimens (fluoropyrimidines, irinotecan and oxaliplatin) and targeted therapies such as bevacizumab and cetuximab. Different combinations achieve a median survival of over 2 years. Intense efforts focus on identifying agents targeting growth factor receptors, signal transduction pathways or angiogenesis mediators. One of the last available drugs for the management of advanced colorectal cancer is panitumumab, a well-tolerated and effective anti-EGFR monoclonal antibody approved as a single agent in chemotherapy refractory patients. We discuss the current evidence supporting panitumumab for metastatic colorectal cancer treatment, potential predictive biomarkers and ongoing clinical trials with different combinations including panitumumab.

A dose-finding study was performed to evaluate the dose-limiting toxicity (DLT), maximum-tolerated dose (MTD) and the recommended dose (RD) of escalating the doses of capecitabine and fixed doses of irinotecan and oxaliplatin on a biweekly schedule for metastatic colorectal cancer patients (mCRC). A pharmacogenomic analysis was performed to investigate the association between SNPs and treatment outcome. METHODS: Eighty-seven chemotherapy-naive mCRC patients were recruited through a two-step study design; 27 were included in the dose-finding study and 60 in the pharmacogenomic analysis. Oxaliplatin (85 mg m(-2)) and CPT-11 (150 mg m(-2)), both on day 1, and capecitabine doses ranging from 850 to 1500 mg m(-2) bid on days 1-7 were explored. Peripheral blood samples were used to genotype 13 SNPs in 10 genes related to drug metabolism or efficacy. Univariate and multivariate Cox analysis was performed to examine associations between SNPs, ORR and PFS. RESULTS: The capecitabine RD was 1000 mg m(-2) bid. Diarrhoea and neutropenia were the DLTs. After a median follow-up of 52.5 months, the median PFS and OS were 12 (95% CI; 10.6-13.4) and 27 months (95% CI; 17.2-36.8), respectively.The GSTP1-G genotype, the Kohne low-risk category and use of a consolidation approach strongly correlated with decreased risk of progression. Patients with all favourable variables showed a median PFS of 42 months vs 3.4 months in the group with all adverse factors. A superior clinical response was obtained in patients with one GSTP1-G allele as compared with GSTP1-AA carriers (P=0.004). CONCLUSION: First-line therapy with oxaliplatin, irinotecan and capecitabine is efficient and well-tolerated. The GSTP1 polymorphism A>G status was significantly associated with ORR and PFS in mCRC treated with this triplet therapy.

TPS530 Background: CIT has demonstrated significant survival benefits across multiple cancers. Despite remarkable success, only subsets of pts derive clinical benefit from CIT monotherapy. Thus, CIT combinations may be needed to address the mechanisms that allow cancers to escape antitumor immunity. However, a large number of potential combinations would have to be tested to identify an effective CIT combination regimen. The MORPHEUS platform consists of multiple, global, open-label, randomized Phase Ib/II trials designed to assess the impact of CIT combination therapies in pts with different tumor types. The randomized trial designs allow comparison of a single control arm vs multiple CIT combination arms. The trials will aid development of CIT combinations by identifying early signals and have the flexibility to open arms with new CIT combinations and close arms that show minimal clinical activity or unacceptable toxicity. Various CIT combinations that simultaneously enhance immune cell priming and activation, tumor infiltration and/or recognition of tumor cells for elimination will be evaluated. Here, we will describe Phase Ib/II trials in pts with gastric or gastroesophageal junction cancer (GC) and metastatic pancreatic ductal adenocarcinoma (mPDAC), both of which represent populations with high unmet medical need. Methods: MORPHEUS-GC (NCT03281369) will enroll 2 cohorts including pts with advanced unresectable or metastatic GC who have not received prior chemotherapy (chemo) or have progressed on platinum- or fluoropyrimidine-based chemo. MORPHEUS-PDAC (NCT03193190) will enroll pts with mPDAC who have progressed on prior chemo. Further eligibility criteria details will be provided. Pts will be randomized to one of the CIT combination arms or a control arm (up to 8 arms across 2 cohorts in GC; 4 arms in PDAC). Pts experiencing loss of clinical benefit or unacceptable toxicity may be eligible to continue on a different CIT combination arm. Primary endpoints are investigator-assessed ORR per RECIST v1.1 and safety. Secondary endpoints include PFS, OS, DCR and DOR. Multiple exploratory biomarkers will also be examined. Clinical trial information: NCT03281369, NCT03193190.

e20553 Background: NSCLC therapeutic paradigm has changed with immune checkpoint blockers. Biomarkers predicting clinical benefit are still lacking. As previously shown in melanoma, changes in absolute lymphocytes and neutrophils count (ALC and ANC) during IT (PD-1/PD-L1 inhibitors) may be related to response in NSCLC (Nakamuta et al, Oncotarget 2016). TTF1 expression has been associated with PD-L1 expression (Vieira et al, Lung Cancer 2016). We aimed to investigate TTF1 expression and changes in ALC and ANC after 2 cycles and their potential association with clinical outcomes to IT. Methods: We retrospectively analyzed 26 consecutive patients with stage IV NSCLC treated with IT at Clínica Universidad de Navarra (Spain) during 2016. Radiological response was evaluated according to RECIST v1.1. The potential correlation between ALC and ANC changes during the first two cycles and response to treatment [disease control rate (DCR) vs progression] was evaluated using Student’s T-test. Fisher’s exact test was used to study the association between changes in ALC ( < 1,000 vs > 1,000) and ANC ( < 4,000 vs > 4,000) after 2 cycles and response to IT. TTF-1 expression was correlated with treatment response. Overall survival (OS) was assessed with Kaplan-Meier analysis and Log-rank test according to ALC and ANC. Results: An ALC increase after 2 cycles was significantly associated with DCR compared to progression (192 vs -155; p = 0.043). ALC > 1,000 after 2 cycles was more frequent among patients experiencing DCR compared to progression (87% vs 50%; p = 0.07). ALC > 1,000 after 2 cycles was more frequently observed among patients with TTF1+ tumors (93% vs 55%; p = 0.03). Patients with ANC < 4,000 showed a longer median OS (NR vs 19.25 months; p = 0.03). TTF1 expression in adenocarcinoma (n = 18) was associated with response to IT (83% vs 16%, p = 0.01). Conclusions: Despite this retrospective small series’ limitations, our results show that ALC and ANC changes during IT and TTF1 expression may act as early predictors of clinical benefit in stage IV NSCLC patients treated with PD1/PD-L1 blockers. Our results warrant further investigation in larger prospective series.

Purpose: High inhibitor of differentiation-1 (Id1) levels have been found in some tumor types. We aimed to study Id1 levels and their prognostic impact in a large series of stages I to IV non-small cell lung cancer (NSCLC) patients. Experiments in cell lines and cells derived from malignant pleural effusions (MPE) were also carried out. Experimental Design: A total of 346 NSCLC samples (three different cohorts), including 65 matched nonmalignant tissues, were evaluated for Id1 expression by using immunohistochemistry. Additional data from a fourth cohort including 111 patients were obtained for Id1 mRNA expression analysis by using publicly available microarrays. In vitro proliferation assays were conducted to characterize the impact of Id1 on growth and treatment sensitivity. Results: Significantly higher Id1 protein levels were found in tumors compared with normal tissues (P < 0.001) and in squamous carcinomas compared with adenocarcinomas (P < 0.001). In radically treated stages I to III patients and stage IV patients treated with chemotherapy, higher Id1 levels were associated with a shorter disease-free survival and overall survival in adenocarcinoma patients in a log-rank test. A Cox model confirmed the independent prognostic value of Id1 levels for both stages I to III and stage IV patients. In silico analysis confirmed a correlation between higher Id1 mRNA levels and poor prognosis for adenocarcinoma subjects. In vitro Id1 silencing in radio/chemotherapy-resistant adenocarcinoma cells from MPEs restored sensitivity to both therapies. Conclusions: In our series, Id1 levels showed an independent prognostic value in patients with adenocarcinoma, regardless of the stage. Id1 silencing may sensitize adenocarcinoma cells to radiotherapy and chemotherapy. Clin Cancer Res; 17(12); 4155–66. ©2011 AACR.

Colorectal cancer constitutes one of the most common malignancies and the second leading cause of death from cancer in the western world representing one million new cases and half a million deaths annually worldwide. The treatment of patients with metastatic colon cancer comprises different regimens of chemotherapeutic compounds (fluoropyrimidines, irinotecan and oxaliplatin) and new targeted therapies. Interestingly, most recent trials that attempt to expose patients to all five-drug classes (fluoropyrimidines, irinotecan, oxaliplatin, bevacizumab and cetuximab) achieve an overall survival well over 2 years. In this review we will focus on the main epidermal growth factor receptor inhibitors demonstrating clinical benefit for colorectal cancer mainly cetuximab, panitumumab, erlotinib and gefitinib. We will also describe briefly the molecular steps that lie beneath them and the different clinical or molecular mechanisms that are reported for resistance and response.

Aim: We previously reported the prognostic impact of Id1 in all NSCLC stages and of the combined Id1/Id3 expression in stage III-N2 patients undergoing radical chemo-radiotherapy. Further, we found that Id1 expression in the tumor microenvironment is crucial for the development of liver metastasis from lung cancer in an in-vivo model. In other neoplasms, Id genes are considered to be regulators of EMT-facilitated metastasis. Here we study Id1 and Id3 combined expression in a large NSCLC cohort and its correlation with EMTrp and overall survival (OS). Methods: Three tissue microarrays of 538 NSCLCs including 284 squamous-cell carcinomas (SCC) and 254 adenocarcinomas (AC) were stained by immunohistochemistry using the following antibodies: Sox10, Beta-catenin, E-cadherin, Vimentin, Slug, Podoplanin, S6, ERCC1, Id1 and Id3. Immunoreactivity was H-scored for intensity (range 0 to 3) multiplied by percentage of positive cells and computed by Spearman's Rho correlation test. Results: Among SCC histology a significant positive correlation was observed between the combined expression of Id1 and Id3 and the expression of Sox10, Beta-catenin, E-Cadherin, Slug, Podoplanin and ERCC1. In the AC subset, significant positive correlations were found between Id1/Id3 and Beta-catenin, E-Cadherin, Vimentin, pS6, and ERCC1. As expected, Id1/Id3 expression showed a negative correlation with OS (r= -0.157; p=0.013). Protein SCC AC (n.s; not significant) r p value r p value Sox10 0.146 0.018 n.s. n.s. Beta-Catenin 0.218 0.001 0.161 0.01 E-cadherin 0.128 0.038 0.150 0.017 Vimentin n.s. n.s. 0.147 0.019 Slug 0.187 0.002 n.s. n.s. Podoplanin 0.127 0.039 n.s. n.s. S6 n.s. n.s. 0.150 0.014 ERCC1 0.265 0.001 0.185 0.003 Conclusions: In NSCLC, the combined expression of Id1 and Id3 negatively correlated with OS and positively with several key EMTrp, suggesting a possible key regulation of the EMT process favoring vessel infiltration and distant organ metastasis, respectively. Disclosure: All authors have declared no conflicts of interest.

High Id1 levels have been found in some tumor types, particularly in advance stages. We aimed to study Id1 levels and their prognostic value in a large series of different histologies of stage I-IV NSCLC patients and to test Id1 function in cell lines and cells derived from malignant pleural effusions (MPE) from patients (pts). Id1 expression was analyzed in NSCLC samples from 311 pts and 65 normal lung tissues by immunohistochemistry. Id1 mRNA expression was also studied in 111 pts using publicly available microarrays. Significantly higher Id1 protein expression levels were found in tumors compared to normal tissue (p Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2219. doi:10.1158/1538-7445.AM2011-2219

e13579 Background: Gemcitabine (GMB) exerts its antitumor activity through inhibition of ribonucleotide reductase (RRM1) and DNA synthesis. Although GMB monotherapy has minimal activity in mCRC, salvage therapy with gemcitabine- based combinations has proved to be clinically active and manageable in this setting. We aimed to investigate whether single nucleotide polymorphisms (SNPs) in gemcitabine metabolism genes were associated with clinical outcome in mCRC pts treated with GMB-based salvage regimens. Methods: We retrospectively evaluated SNPs of hCNT1, CDA, DCTD and RRM1 genes in 90 mCRC patients treated from January 2005 to October 2009 through a compassionate use program. Polymorphisms were detected using the TaqMan genotyping assays (Applied Biosystems, CA). The association of genotypes with objective response (OR), disease control rate (DCR: PR, CR and SD>6 months), progression-free survival (PFS) and overall survival (OS) were tested by univariate and multivariate analysis (Cox regression). Result...

e13523 Background: Cetuximab has shown a clinically significant antitumor activity against metastatic colorectal cancer (mCRC) both in first and subsequent lines of therapy. Biweekly schedules have...

10611 Background: Id1, a basic helix-loop-helix family member is involved in cell differentiation, proliferation, angiogenesis and metastasis in different preclinical models. Although high Id1 leve...

e16119 Background: Id1, involved in cell differentiation, proliferation, tumor angiogenesis and metastasis, has recently showed to mediate lung MTS from breast cancer (PNAS 2007). The expression of Id1 in human cancer has been related to poor prognosis breast, prostate (Gil-Bazo, Amer Soc Clin Oncol GU. 2009) and other non-adenocarcinoma tumors. To date one study showed remarkable Id1 expression (exp.) in 28% of unselected human BCa using a new MoAb (195–14) for immunohistochemistry (IHC) analysis. Our aim is to study Id1 exp. in a group of PP BCa and their matched MTS using this MoAb (195–14). Methods: We selected 22 patients (pts) treated in our institution. Formalin-fixed and paraffin- embedded bladder biopsy samples of each patient and matched MTS samples of 9 of them were stained and scored for tumor and endothelial Id1 exp. Anti-human Id1 rabbit MoAb 195–14 (1:500), (Biocheck), was used for IHC. Results: 90% of pts were males; median age was 61. Most pts had PP advanced (22,7 % stage III; 68,2% stage IV) BCa. Primary tumor samples and additional 9 matched MTS biopsy samples were analyzed. In contrast with the previous data 80% of primary invasive BCa and more than 75% of MTS showed tumor cell Id1 exp. As previously reported Id1 exp. in tumor samples endothelial cells reached 70%. We also observed Id1 exp. in tumor in situ areas near the invasive carcinoma in 16 out of 20 pts expressing Id1 in the primary tumor. Conclusions: For the first time using a MoAb against Id1 and in accord with our previous observations in prostate cancer the selection of PP pts increases tumor cell Id1 exp. from 28 up to 80%. Interestingly we show BCa MTS to express Id1 with a similar exp. pattern than primary tumors. Id1 exp. profile in PP and metastatic initiation of BCa needs further research. Id1 exp. in tumor in situ areas suggests Id1 as an initial factor in the BCa carcinogenic process and in the case of being confirmed Id1 could represent a target in BCa prophylaxis. No significant financial relationships to disclose.

e16128 Background: In the PSA era a significant proportion of PCa patients (pts) at onset have potential indolent tumors that will not impact their life expectancy or quality of life. Most of them will be radically treated and suffer its consequences. Thus, PCa overtreatment is a great concern among clinicians. Pre-treatment molecular factors may help differentiate indolent from aggressive PCa. Id1, involved in cell differentiation and angiogenesis, has recently showed to mediate lung metastasis (mts) from breast cancer. Its role in PCa endothelial (end) cells is well established but its exp and role in PCa cells is controversial. Using a new monoclonal antibody (MoAb) (195–14) for immunohistochemistry (IHC), Id1 exp is limited to some PP breast and bladder tumors. Whether Id1 exp is relevant in PCa prognosis is unknown. We tested 195–14 in PP and GP PCa samples and matched mts where available. Methods: 52 PCa pts were studied, 20 GP + 32 PP. All formalin-fixed and paraffin-embedded primary biopsies and matched mts of 16 of them were stained for tumor and end cell Id1 exp. 195–14 (1:500), (Biocheck), was used for IHC. Results: GP group: median age 65, all pts T2N0M0, median Gleason score 6 (6–9), median PSA at onset 5,5 ng/ml. After a median follow-up of 38 months (ms) 1 pt showed radiological and PSA progression (P); other PSA P. All but one remain alive. PP group: median age was 70, T3-T4 (70%), Gleason 8–10 (61%), median PSA at onset 58 ng/ml, 2 or more mts locations (79%), 94% showed P to docetaxel, median time-to- progression and overall survival after chemotherapy were 18 weeks and 7 ms. Among PP, 39% of primary PCa and 38% of mts showed Id1 tumor cell exp and 79% of primary tumors and 81% of mts showed end Id1 exp. In the GP group 0% showed Id1 tumor cell exp, and 50% showed end Id1 exp. The unexpected Id1 exp difference in tumor cells in PP compared to GP pts predicted clinical outcome. Consistently with other reports end Id1 exp is high in both groups. PP showed higher levels. Conclusions: Id1 exp discriminated GP from PP in our PCa cohort. These novel results highlight Id1 as a prognostic marker in PCa. Whether Id1 exp in the diagnostic biopsy can impact PCa therapeutic decision-making needs further investigation. No significant financial relationships to disclose.

15657 Background: To determine the toxicity profile and dose limiting toxicity (DLT) of a neoadjuvant schedule including escalating doses of docetaxel with oxaliplatin, capecitabine and concurrent ...

15020 Background: The combination of oxaliplatin, irinotecan and 5-fluorouracile has shown encouraging results in metastasic CRC patients. The aim of this study was to determine the maximum-tolerat...

15666 Background: Different schedules of HAI-oxaliplatin have demonstrated preliminary evidence of activity in g.i. tumours. The aim of this study is to establish the maximun tolerated dose (MTD) a...

4636 Background: Neoadjuvant therapy is an increasingly used approach in patients with resectable pancreatic cancer (PC). A positive link between chemotherapy dose intensity and patients’ outcome has been suggested in PC. The aim of this study was to rule out whether 5-FU pharmacokinetic (PK) parameters correlate with outcome in resectable PC patients treated with preoperative FOLFOXIRI. Methods: Patients with resectable and borderline resectable PC treated with Oxaliplatin (85mg/m2), Leucovorin (400mg/m2), Irinotecan (150 mg/m2) and 5-FU (initial dose of 3200 mg/m2 in 46h infusion and subsequent doses based on PK-guided dose adjustements targeting an AUC of 25-30 mcg*h/ml) were included. 5-FU PK analysis was performed taking two plasma samples during 5-FU infusion in at least two cycles. Drug concentrations were analysed by High-Perfomanced Liquid Chromatography. After induction polychemotherapy (IPCT), patients with no progressive disease received chemoradiation (CRT) (50.4 Gy with concurrent Capecitabine and Oxaliplatin) followed by surgical resection 4 to 6 weeks after the completion of CRT. Subsequent follow-up until disease progression was remained. An exploratory analysis with Log-Rank test was performed to assess progression free survival (PFS) based on 5-FU AUC values. Results: From November 2012 to October 2018, 29 patients were retrospectively assessed: median age 63 (46-75); M/F rate 20/9; R0 resection rate of 90% in the intention-to-treat analysis. The pathological response according to CAP classification was 0, 1, 2 and 3 in 14, 58, 19.5 and 8.5%, respectively; and median number of resected lymph nodes was 11 (2-22), with lymph node infiltration (ypN1) in 14% of patients. Grade 3-4 IPCT related toxicities and grade 3 CRT related toxicities were reported in 40 and 30% of patients, respectively. Median PFS was 723 days (24 months) and median 5-FU AUC 28.5 mcg*h/ml (23-53). Median PFS for patients with 5-FU AUC ≥27 mcg*h/ml was 29 months versus 15 months in patients with 5-FU AUC < 27 mcg*h/ml (adjusted hazard ratio for disease progression 0.223; 95% CI = 0.059-0.848; p = 0.028; in a model controlled by age, sex and irinotecan dose intensity). Conclusions: 5-FU pharmacokinetic parameters achieving a target of AUC ≥ 27 mcg*h/ml seem to correlate with longer PFS in this subset of patients.