Phase II study of durvalumab plus total neoadjuvant therapy (TNT) in locally advanced rectal cancer: The GEMCAD-1703 DUREC trial.

Abstract

TPS4122 Background: In clinical stages II and III (cT3-4 and/or N+), preoperative chemoradiotherapy (CRT) or short-course radiation followed by total mesorectal escision (TME) have been the standard of care for the last 15 years. Induction chemotherapy (CT) before CRT (strategy known as TNT) results in fewer toxic effects and improved compliance. TNT may release tumor-neoantigens with platinum-based induction CT, and radiotherapy has the potential ability to induce an immunogenic cell death and counteract an immune-suppressive tumor microenvironment that provides the rationale for combining with immunotherapies. In addition, the presence of tumor infiltrating lymphocytes has been demonstrated in patients with rectal cancer treated with neoadjuvant CRT, reinforcing the rational for immune check-point inhibitors in this setting. We hypothesize that combining TNT with durvalumab (an optimized monoclonal antibody directed against programmed cell death-1 ligand 1) would improve outcome. Methods: DUREC is a multicenter, single-arm, open-label, phase Ib/II study for patients with magnetic resonance (mr) image middle or distal third, mrT3c-d/T4/N2 rectal adenocarcinoma. Treatment: Patients will receive 6 cycles of modified FOLFOX6 prior to CRT (capecitabine with 50.4 Gy in 28 fractions) and TME, combined with durvalumab 1500 mg every 4 weeks during induction CT, CRT and waiting period until surgery. To assess the tolerability and toxicity profile we plan to perform a run-in treatment phase including the first 6 patients in the study, holding recruitment until all of them will be operated and 30-days post-surgery period completed. If ≤ 2 durvalumab-related dose-limiting toxicities (DLTs) are observed, recruitment will continue. The primary objective is pathological complete response (pCR) rate. Secondary endpoints include toxicity, tumor regression grade, R0 resections, clear circumferential margins, surgical complications, NAR score, disease-free survival and a biomarker program on tumor tissue, blood samples and stool microbiota. Statistical design: 58 evaluable patients (assuming a P0 of 16% and a P1 of 30%, with 0.1 alpha and 0.1 beta); Study started recruitment on December 2019. Clinical trial information: 2018-004835-56 .

Total Neoadjuvant Therapy vs Standard Therapy in Locally Advanced Rectal Cancer

“…In addition, immune checkpoint inhibitors such as durvalumab, avelumab, and nivolumab and other novel agents such as peposertib, a DNA protein kinase inhibitor, and aflibercept, an angiogenesis inhibitor, are being investigated in a TNT setting. 32 , 33 , 34 , 35 , 36 A list of recent and ongoing TNT trials that are yet to be published is included in eTable 2 in the Supplement . 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 …”

“…[32][33][34][35][36] A list of recent and ongoing TNT trials that are yet to be published is included in eTable 2 in the Supplement. [30][31][32][33][34][35][36][37][38] Identifying predictive biomarkers for patients who are more likely to benefit from TNT is a current need. A National Cancer Database study 39 looked at more than 5000 patients and reported a significantly reduced rate of PCR after neoadjuvant CRT in patients with microsatellite instability (stability vs instability, 8.9% vs 5.9%; OR, 0.65).…”

Neoadjuvant immunotherapy for colorectal cancer: Right regimens, right patients, right directions?

“…The AVACROSS study reported an increase in the pCR rate to 36% at the cost of more serious surgery-associated complications when bevacizumab was added to induction chemotherapy (32). Poly ADP-ribose polymerase inhibitors (e.g., veliparib) and DNA protein kinase inhibitors (e.g., peposertib) are being evaluated in combination with NACRT or chemotherapy before surgery during TNT (22,(33)(34)(35). However, these studies are at an exploratory stage, and relative sequence studies deserve consideration.…”

Understanding the Philosophy, Anatomy, and Surgery of the Extra-TME Plane of Locally Advanced and Locally Recurrent Rectal Cancer; Single Institution Experience with International Benchmarking

“…Optimal TNT strategies have not been established yet; type of chemotherapy agents vary between studies as well as the order in which chemotherapy and radiotherapy are being administered. Recently, there is a growing interest in the use of immunotherapy in the treatment of colorectal cancer and there are various ongoing TNT trials for patients with LARC who have added immunotherapy agents (durvalumab, nivolumab), DNA-dependent protein kinase inhibitors (peposertib), and poly ADP ribose polymerase inhibitors (Veliparib) to the TNT regimens [ 38 , 39 , 40 , 41 , 42 , 43 , 44 ].…”