595P The DUREC trial: Durvalumab plus total neoadjuvant therapy in locally advanced rectal cancer - a multicenter, single-arm, phase II study (GEMCAD-1703)

Total neoadjuvant therapy (TNT) is a new standard of care for locally advanced rectal cancer (LARC). However, the activity of immunotherapy in combination with chemoradiotherapy (CRT) in microsatellite-stable (MSS) rectal cancer has been limited. We explored the efficacy and safety of TNT in combination with the anti-PD-L1 durvalumab (D) in LARC pts with MSS rectal adenocarcinoma. The DUREC study is a multicenter, single-arm, phase II trial that recruited pts with stage II and III MSS rectal adenocarcinoma with MRI-defined high-risk T3 (extramural vascular invasion (EMVI), >5mm of perirectal fat infiltration, mesorectal fascia involvement), T4, N2, or distal third tumors (T3/4). Pts received 6 cycles of FOLFOX with D at 1500 mg q4W, followed by CRT with capecitabine and D, continuing D until surgery. The first 6 pts underwent a safety run-in phase. Primary endpoint was pathological complete response (pCR) rate. Assuming a minimum efficacy for pCR of 16% and an optimum of 30%, with an α error of 0.1 and a β error of 0.1 (90% power), the study aimed to recruit 58 pts. 61 pts were enrolled (median age, 61.3 years; 70% male). Clinical staging was T3/T4 tumors (78/22%), N2 (53%), and 60% had EMVI positivity. Mean number of administered cycles of mFOLFOX6 and durvalumab were 5.8 and 6.2, respectively, with 41 patients (67.2%) receiving 7 cycles of durvalumab before surgery. Among the 56 (92%) pts who underwent surgery, 22 (39%) achieved a pCR and 18 (32%) achieved a major response (71% of major pathological responses). pCR rate for the intention-to-treat population was 36% (95% CI 24.2%-49.4%). Reasons for not performing surgery were metastatic disease progression during therapy (n=3), toxicity (n=1) and major protocol deviation (n=1). Eight pts (13%) had treatment-related serious adverse events, with diarrhea being the most common (3.3%). The DUREC trial is the first prospective clinical study evaluating the combination of immunotherapy throughout the TNT process for treating MSS LARC. The study met its primary endpoint, demonstrating promising activity and safety, and deserving further development in a phase III study.