Radiotherapy, atezolizumab, and bevacizumab in rectal cancers with the aim of organ preservation: The TARZAN study.

158 Background: Rectal cancer is traditionally treated with total mesorectal excision (TME), with/without neoadjuvant radiotherapy (RT) and chemotherapy. This approach often leads to temporary or permanent colostomies and other long-term morbidity such as urinary and sexual dysfunction in over 60% of patients. Organ preservation is increasingly being pursued in patients with a clinical complete response (cCR) following neoadjuvant treatment, thereby aiming to avoid TME-surgery. Based on preclinical data suggesting immunomodulatory effects of RT, and the synergy of combined PD-L1/VEGF blockade in several tumor types, the TARZAN study (NCT04017455) combines these treatments aiming to increase chances of organ preservation in patients with mainly MMR proficient (pMMR) rectal cancer without the need for chemotherapy. Methods: Patients with clinical stage ≤T3ab N0-1 distal-mid rectal tumors without mesorectal fascia involvement underwent 5x5 Gy RT followed by 3 cycles of atezolizumab and bevacizumab. Response was evaluated by MRI and endoscopy. The primary endpoint was clinical complete and near-complete response (CR) rate at 12 weeks after RT. Secondary endpoints included safety, organ preservation, pathologic (near) CR in case of surgery, and relapse free survival. According to a Simon’s 2-stage design, ≥3 responders were needed in stage I (18 patients) to continue accrual into stage II. Here we report data from stage I. Results: Eighteen patients (14 male, median age 63), all with pMMR tumors, were treated. Six tumors were cN1 on MRI, 10/18 tumors were ≥4cm and for 10/18 patients abdominoperineal resection (APR) appeared necessary due to distal tumor location. At the time of response evaluation, (near-)CR was achieved in 10/18 (56%) patients according to the primary endpoint. With a median follow-up of 20 months, 9/18 (50%) patients remain without TME surgery. Of these 9 patients, 5 underwent local excision to achieve organ preservation and in 5 patients no additional intervention was needed (cCR). The remaining 9 patients underwent TME surgery (4 APR), and pathologic assessment revealed near-CR in two patients, and a pCR in one patient. Three patients developed distant recurrences, one in the organ-sparing group. Neoadjuvant treatment was well-tolerated with grade 3 study drug-related adverse events (AEs) in 1 (5%) patient. Grade 3 surgery-related AEs occurred in 5/9 (55%) patients, including 4 anastomotic leaks and 1 abscess. Conclusions: Neoadjuvant RT followed by atezolizumab and bevacizumab resulted in a promising rate of clinical (near-)CRs in 56% of patients without the need for chemotherapy, reaching the primary endpoint. Accrual is ongoing in stage II, in which an additional 20 patients will be treated. Clinical trial information: NCT04017455 .