449P Randomized phase II study comparing pathological responses of resected colorectal cancer metastases (CRCM) after bevacizumab (BEV) with FOLFOX or FOLFIRI (BEV-ONCO trial)

Background Pathological response (PR) of resected CRCM after preop treatment is a recognized prognostic factor. Retrospective studies reported that BEV + oxaliplatin-based chemotherapy increased PR compared to irinotecan-based chemotherapy. In this trial, we aim to demonstrate that preop BEV + FOLFOX would increase PR. Methods BEV-ONCO (NCT01858649) is a multicenter prospective randomized (1/1) phase II trial evaluating PR on resected CRCM after 3 to max 6 cycles of mFOLFOX (ARM A) or FOLFIRI (ARM B) + BEV (5mg/kg/2 weeks). Primary endpoint is the major pathological response rate (MPRR) defined as the % of patients presenting CRCMs with a mean tumor regression grade (TRG) <3. Secondary endpoints include DFS, OS, safety, complete PR, R0 resection rate and liver toxicity comprising sinusoidal obstruction syndrome (SOS) and nodular regenerative hyperplasia (NRH). 54 pts (27 per arm) are needed to detect a difference (alpha=0.05; beta=0.2) of MPRR proportion of 0.40 between treatment arms (two-sided Fisher's Exact test). Results Among 65 pts included between 06/2013 and 09/2018, 57 pts (28 ARM A / 29 ARM B) have had CRCM resection. Clinical and treatment characteristics were similar in both treatment arms (median age 60 y-old, 51% male, 33% RAS wt, 98% liver CRCM, 75% synchronous, median 2 CRCM/pt, median of 4 chemo cycles and 3 BEV cycles). 11/28 pts presented 1-month postop surgical complications in ARM A (39%, grade 3-4: 17.9%) and 9/29 pts in ARM B (31%, grade 3-4: 6.9%, p=0.58). MPRR was 32% in ARM A and 21% in ARM B (p=0.38). 4 pts presented complete PR (ARM A/B: 14%/0%, p=0.05). No difference between treatment arms was observed for R0 resection (ARM A/B: 89%/93%, p=0.80), SOS (ARM A/B: 54%/38%, p=0.50), NRH (ARM A/B: 21%/17%, p=0.75), DFS (ARM A/B: HR=1.14, 95%CI:0.58-2.21, p=0.71) and OS (ARM A/B: HR=1.38, 95%CI:0.48-4.00, p=0.55). Pts with PR among all CRCM (Max TRG≤3; 44% of pts) had a lower risk of relapse/death (DFS: HR=0.41, 95%CI=0.20-0.82, p=0.01) and death (OS: HR=0.34, 95%CI=0.10-1.11, p=0.07). Conclusions This trial fails to demonstrate any significant difference of PR between BEV with FOLFOX or FOLFIRI but confirms PR as a prognostic factor

397P R-IMMUNE interim analysis: A phase Ib/II study to evaluate safety and efficacy of atezolizumab combined with radio-chemotherapy in a preoperative setting for patients with localized rectal cancer

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