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Background Radiotherapy association with immunotherapy has a strong rationale. This study evaluates this combination before surgery in locally advanced rectal cancer (RC). Methods R-IMMUNE (NCT03127007), a multicentric phase Ib/II prospective trial includes patients with stage II/III RC treated with a preoperative combination of radio-chemotherapy (45-50 Gy/25 fractions, 5FU 225 mg/m2/d, 5d/w from week 1-5) + atezolizumab 1200 mg/infusion (ATZ). The phase Ib had a 3+3 design with a safety period up to surgery and evaluated a single infusion of ATZ at week 3. The phase II, in progress, evaluates 4 infusions of ATZ at weeks 3, 6, 9 and 12. Surgery is planned at week 15. Primary objectives are safety and efficacy based on pathological complete response rate (pCR). Based on a 2-stage Simon design, 36 patients are needed in the phase II to detect a pCR rate increase from 15% to 35% (α = 0.1 and β = 0.1). At least 4 pCRs must be observed among 19 patients treated in the 1st stage to move the 2nd stage. Results This analysis concerns 26 patients treated with the study treatment (median age 66 y-old, 48% male, 88% stage III). Safety was evaluated in 6 patients from phase Ib and 20 from phase II. Overall, 151 AEs were reported and 20 (13%) were grade 3-4 on 9/26 patients, including 2/20 (10%) anastomotic leakage/infections, 4/20 (20%) urinary infections, 1/20 (5%) renal function impairment and 1/20 (5%) immune thrombocytopenia. Three grade 2 immune endocrine disorders were observed. Efficacy was evaluable on 25/26 patients after 1 exclusion for inclusion criteria deviation. Four among 19 patients included in the 1st stage of phase II had a pCR. Overall, 6/25 (24%) pCRs were observed. Conclusions R-IMMUNE interim analysis reveals an acceptable safety profile. Observed pCR rate until now supports the pursuit of the trial. Clinical trial identification NCT03127007.

T. Seufferlein1, J. L. Van Laethem2, E. Van Cutsem3*, J. D. Berlin4, M. Buchler5, A. Cervantes6, K. Haustermans3, M. Hidalgo7, E. M. O’Reilly8, C. Verslype3, W. Schmiegel9 & P. Rougier10 Department of Internal Medicine I, University of Ulm, Ulm, Germany; Department of Gastroenterology, Hopitaux Universitaires Bordet-Erasme, Brussels; Digestive Oncology and Radiation Oncology, University Hospitals and KU Leuven, Leuven, Belgium; Department of Medicine, Vanderbilt University, Nashville, USA; Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany; Department of Hematology and Medical Oncology, INCLIVA, University of Valencia, Valencia; Gastrointestinal Cancer Clinical Research Unit, Spanish National Cancer Research Centre, Madrid, Spain; Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, USA; Department of Internal Medicine, Knappschaftskrankenhaus, Ruhr-University Bochum, Bochum, Germany; Department of Digestive Oncology, European Hospital Georges Pompidou, Paris, France

BACKGROUND: To assess the safety and preliminary efficacy of concurrent radiotherapy, capecitabine, and cetuximab in the preoperative treatment of patients with rectal cancer. PATIENTS AND METHODS: Forty patients with rectal cancer (T3-T4, and/or N+, endorectal ultrasound) received preoperative radiotherapy (1.8 Gy, 5 days/week for 5 weeks, total dose 45 Gy, three-dimensional conformal technique) in combination with cetuximab [initial dose 400 mg/m(2) intravenous given 1 week before the beginning of radiation followed by 250 mg/m(2)/week for 5 weeks] and capecitabine for the duration of radiotherapy (650 mg/m(2) orally twice daily, first dose level; 825 mg/m(2) twice daily, second dose level). RESULTS: Four and six patients were treated at the first and second dose level of capecitabine, respectively. No dose-limiting toxicity occurred. Thirty additional patients were treated with capecitabine at 825 mg/m(2) twice daily. The most frequent grade 1/2 side-effects were acneiform rash (87%), diarrhea (65%), and fatigue (57%). Grade 3 diarrhea was found in 15%. Three grade 4 toxic effects were recorded: one myocardial infarction, one pulmonary embolism, and one pulmonary infection with sepsis. Two patients (5%) had a pathological complete response. CONCLUSIONS: Preoperative radiotherapy in combination with capecitabine and cetuximab is feasible with some patients achieving pathological downstaging.

Pancreatic adenocarcinoma is one of the most lethal cancers in the Western world with a median survival of approximately 3 months. Patient survival depends on the extent of disease and performance status at diagnosis. The extent of disease is best categorised as resectable, locally advanced or metastatic. Surgery is the only curative treatment. It is, however, an option in only 10-20% of patients. Long-term survival after surgical resection of pancreatic cancer is less than 20%. Local recurrence occurs in up to 85% of patients who undergo surgery alone. Local-regional tumour control is maximised with combined modality therapy in the form of chemoradiation and surgery. With improved therapy for local-regional disease, liver metastases become the predominant form of tumour recurrence and occur in 50 to 70% of patients following potential curative combined modality treatment. At the time of diagnosis, 40% of patients have locally advanced disease and more than 40% have visceral metastases, most frequently in the liver. Therefore, with new surgical and radiotherapeutic techniques improving locoregional control, we will face distant metastases being responsible for therapy failure more often and effective systemic treatment will become even more important for prolonging survival. Unfortunately results obtained with chemotherapy failed to have an important impact on the final outcome and have been the reason for scepticism among clinicians and oncologists for many years. However, a totally fatalistic approach is not justified, because a significant proportion of patients do achieve benefit from chemotherapy. Several new and innovative therapeutic modalities are in development and offer hope for an improved outcome for patients with pancreatic cancer in the future.

International audience; Knowledge of the biology and management of rectal cancer continues to improve. A multidisciplinary approach to a patient with rectal cancer by an experienced expert team is mandatory, to assure optimal diagnosis and staging, surgery, selection of the appropriate neo-adjuvant and adjuvant strategy and chemotherapeutic management. Moreover, optimal symptom management also requires a dedicated team of health care professionals. The introduction of total mesorectal excision has been associated with a decrease in the rate of local failure after surgery. High quality surgery and the achievement of pathological measures of quality are a prerequisite to adequate locoregional control. There are now randomized data in favour of chemoradiotherapy or short course radiotherapy in the preoperative setting. Preoperative chemoradiotherapy is more beneficial and has less toxicity for patients with resectable rectal cancer than postoperative chemoradiotherapy. Furthermore chemoradiotherapy leads also to downsizing of locally advanced rectal cancer. New strategies that decrease the likelihood of distant metastases after initial treatment need be developed with high priority. Those involved in the care for patients with rectal cancer should be encouraged to participate in well-designed clinical trials, to increase the evidence-based knowledge and to make further progress. Health care workers involved in the care of rectal cancer patients should be encouraged to adopt quality control processes leading to increased expertise.

Aim: To assess the activity and safety of bevacizumab (A) with capecitabine (X) and radiotherapy (RT) with or without oxaliplatin (E) in the preoperative treatment (thx) of locally advanced rectal cancer (LARC). To identify biomarkers for early response prediction. Methods: Patients (pts) with LARC were randomized to RT (1.8Gy/day) with the triplet A (5mg/kg), X (1650mg/m2/day) and E (50mg/m2) in Arm A or the doublet A + X without E in Arm B. Chemoradiotherapy (CRT) started at 2 weeks after 1st infusion of A and continued for 5 weeks. Total mesorectal excision (TME) was planned at 6-8 weeks post CRT. Pathological complete response (pCR) rate in Arm A was the primary endpoint. Safety profile and identification of biomarkers for early response prediction were secondary endpoints. Immunohistochemical staining for the functionality of blood vessels, proliferation and hypoxia as well as Luminex analyses to assess changes in circulating VEGF ligands are performed on tissues and blood samples from consenting pts. Results: Eighty-four pts with median age 61 completed thx, 81 including surgery, with a relative dose intensity of 98% for A and X and 93% for E. During CRT, serious adverse events (SAEs) were more frequent in Arm A vs Arm B: fever (4 vs 0), diarrhea (3 vs 0), infection (4 vs 1). Postoperative SAEs (wound infections, leaks) occurred in 17 pts, 10 in Arm A and 7 in Arm B. Five pts deceased post-study, 3 due to distant disease progression, 2 to postoperative complications. Post-surgery data are available for 81 pts. pCR was seen in 18 pts, 33% (14/43) in Arm A and 10% (4/41) in Arm B in an intent-to-treat analysis (ITT). The rate of good responders (Dworak TRG 3, 4) was higher in Arm A 29/43 vs Arm B 16/41 in ITT. Changes of the pericyte coverage of the blood vessels were observed. The decrease of plasma concentration of PDGF-AA and PDGF-BB correlated with pCR (p = 0.04 and 0.03 respectively). Conclusions: Both triplet and doublet combination showed acceptable safety profiles. The addition of E to X and A with RT seemed beneficial in terms of pCR rates in this patient population, with a slight increase of toxicity. The main endpoint has been reached with 14/43 pCRs in Arm A. PDGF may be a predictor of response in this setting. Final data after a blind central review of the main endpoint and translational research data will be available at the conference. Support from Roche and Sanofi Aventis. Disclosure: K. Haustermans: The author declares an educational grant from Roche for this study. No further conflict of interest; E. Van Cutsem: The author received research funding from Roche and Sanofi, paid to the university. All other authors have declared no conflicts of interest.

Aim: The PETACC-6 trial investigates the role of oxaliplatin in addition to preoperative chemoradiation (CRT) and adjuvant chemotherapy (CT) with capecitabine to improve disease-free survival (DFS) in locally advanced rectal cancer. Methods: Patients with rectal adenocarcinoma within 12 cm from the anal verge, T3/4 and/or node-positive, without evidence of metastatic disease, considered either resectable at the time of entry or expected to become resectable, were randomized to 5 weeks of preoperative CRT with capecitabine, followed by surgery and 6 cycles of adjuvant CT with capecitabine (standard control arm 1) or capecitabine + oxaliplatin before and after surgery (arm 2). 440 DFS events were required to have 80% power to detect an improvement in 3-year DFS from 65% to 72% (HR = 0.763), with two-sided alpha of 5% and allowing for an interim analysis for early efficacy at 200 events. Results: 1094 patients were randomized (547 in each arm). From 1081 eligible patients, 543 in arm 1 and 528 in arm 2 started preoperative treatment (3/528 patients without oxaliplatin in arm 2), and of these 77.3% and 72.6%) patients started postoperative chemotherapy within protocol. In arm 2, 11.8% patients did not receive the planned postoperative oxaliplatin. Major reasons for protocol discontinuation were progressive disease (3.9% in arm 1 vs. 3.8% in arm 2), toxicity (7.7% vs. 16.5%), surgery complication (8.7% vs. 9.1%), patient's refusal (5.9% vs. 10.8%). At planned interim analysis, the independent data monitoring committee recommended the early release of the results. At a median follow-up of 31months, 124 and 121 DFS events were observed in arm 1 and 2 (adjusted HR = 1.036, 95% CI: 0.81 -1.33, P = 0.78). 3-year DFS was 74.5% (95% CI: 70.1% - 78.3%) in arm 1 (which is higher than anticipated) vs. 73.9% (95% CI: 69.5% - 77.8%) in arm 2; conditional power under HR = 0.763 is only 7%. Less locoregional and distant failures were recorded in the experimental arm with oxaliplatin (95 in arm 2 vs. 109 in arm 1) but a higher rate of deaths without progression (26 in arm 2 vs. 15 in arm 1). Conclusions: Interim results at a median follow up of 2.6 y currently indicate no DFS-benefit for the addition of oxaliplatin to capecitabine-based CRT and adjuvant CT. However, with actually only 245 out of the required 440 events, final evaluation cannot be done before at least 2 further years follow-up. Disclosure: H.J. Schmoll: has a consultant or advisory relationship to disclose with Roche, Sanofi and Bayer; has honoraria to disclose from Roche; has research funding to disclose from Merck and Roche; K. Haustermans: has research funding to disclose from Roche; T.J. Price: has a consultant or advisory relationship to disclose with Roche; R. Hofheinz: has a consultant or advisory relationship to disclose with Roche; has honoraria and research funding to disclose from Roche; B. Brenner: has a consultant or advisory relationship to disclose with Sanofi-Aventis; has research funding to disclose from Sanofi-Aventis; J. Zalcberg: has a consultant or advisory relationship to disclose with Sanofi-Aventis and Roche; has honoraria, research funding and other remuneration to disclose from Sanofi-Aventis and Roche. M.P. Lutz: has a consultant or advisory relationship to disclose with Roche; E. Van Cutsem: has research funding to disclose from Roche and Sanofi.All other authors have declared no conflicts of interest.

In an academic multicentric phase II study, patients (pts) with locally advanced rectal cancer are randomized to receive bevacizumab (5mg/kg), capecitabine (1650mg/m2/day) and radiotherapy (1.8Gy/day) with (Arm A) or without (Arm B) oxaliplatin (50mg/m2). Chemoradiotherapy (CRT) starts at 2 weeks after 1st infusion of bevacizumab and continues for 5 weeks. Total mesorectal excision is planned at 6-8 weeks post CRT. Immunohistochemical staining to study the functionality of blood vessels and Luminex analyses to assess the changes in circulating VEGF ligands are performed on tissues and blood samples from consenting pts. Pathological complete response (pCR) rate, safety profile and identification of biomarkers for early response prediction are the main endpoints. Results Sixty five pts with median age 60 have been enrolled to date. Fifty seven pts completed the full protocol scheme, with a relative dose intensity of 97% for bevacizumab, 95% for capecitabine and 93% for oxaliplatin. Preliminary safety data from 60 evaluable pts show that the regimen is generally well tolerated. Most severe adverse events were post-operative (wound infections, leaks) in 9 pts, equally distributed between arms. During CRT, grade 3 toxicities were more frequent in Arm A: fatigue (1), diarrhea (2), infection (2), febrile neutropenia (1), sensory neuropathy (1). Two pts deceased due to disease progression and one due to lung embolism post-surgery. Fifty two pts are evaluable for response. pCR was seen in 11 pts, 30% (8/26) in Arm A and 12% (3/26) in Arm B (p = 0.08). The rate of good responders (Dworak TRG 3,4) was higher in Arm A 18/26 versus Arm B 10/26 (p = 0.05). Changes in the pericyt coverage of the blood vessels, proliferation of the tumour cells and plasma concentrations of PDGF-AA, PDGF-BB and VEGF were observed and will be further assessed. Conclusions Chemoradiotherapy in combination with bevacizumab showed an acceptable safety profile in this patient population. Adding oxaliplatin determined a slight increase of toxicity but might enhance the percentage of responders. PDGF may be a predictor of response in this setting. Further analyses are ongoing. Conducted with support from Roche and Sanofi Aventis. Disclosure K. Haustermans: The author has received research funding from Roche. E. Van Cutsem: The author has received research funding by Roche and Sanofi Aventis. All other authors have declared no conflicts of interest.