Phase 1b trial of NG-350A, a CD40 agonist antibody expressing adenoviral vector, in combination with chemoradiotherapy (CRT), in patients with mismatch repair-proficient (pMMR) locally advanced rectal cancer (LARC): Initial results from the FORTRESS study

Background: The CEDAR study (NCT03916510) showed that combining our first-generation oncolytic immunotherapy with CRT in LARC significantly improved the response rate (RR) by magnetic resonance imaging (MRI) compared to standard CRT alone, warranting further study. The ongoing FORTRESS study (NCT06459869) aims to demonstrate improved RR for our next-generation oncolytic immunotherapy NG-350A, in combination with CRT in pMMR LARC, compared to contemporary CRT outcomes. Methods: Stage II/III LARC patients (pts) with risk factors for recurrence (cT3a-d, N0-2, MRF+ or EMVI+) received NG-350A at 1x e12 on Day (D) 1 and 3x e12 virus particles on D3 & 5 in week (W)1, 5 & 9. All pts received pelvic long-course CRT (capecitabine 825mg/m2 orally twice a day) to 50Gy (option for 4Gy boost) during W2 to 6. The active study period was 12 Ws; the study allowed for total neoadjuvant therapy. Efficacy was assessed in week 12 using MRI Tumor Regression Grade, endoscopy and digital rectal examination. Circulating tumor DNA (ctDNA) was measured throughout the active study period and follow up using the NeXT Personal™ Dx assay (Personalis, City, CA). The primary objective is the proportion of pts achieving a response [(near) complete clinical response or (n)cCR] to NG-350A in combination with CRT. Key secondary objectives include safety and tolerability of NG-350A in combination with CRT and the effect of study treatment on ctDNA as a molecular marker of tumor burden and response. Results: Ten pts have been enrolled to date, and enrollment is ongoing. Treatments have been well-tolerated, and no serious adverse events (SAEs) or new safety signals related to NG-350A have been detected. Related AE are limited to the effects of systemic viremia; to date, no AEs attributable to the CD40 agonist transgene encoded by NG-350A have been observed. Transient aPTT prolongation has been observed in 4 pts. Four (all stage IIIB) out of 5 evaluable pts (80%) to date achieved a ncCR at W12 and all pts continued to consolidation chemotherapy immediately after the active study period. ctDNA clearance (incl. 1 transient) was observed at or before W12 in all pts. Results will be updated with W12 response data from all pts. Conclusions: In this small pt cohort, NG-350A plus long-course CRT thus far has achieved a high RR. Early efficacy and safety data suggest the combination may reach/exceed the RR level seen in CEDAR (not screened for MMR status). Preliminary ctDNA kinetics data assessed by the ultrasensitive tumor-educated whole genome sequencing assay are consistent with the encouraging RR and may enable non-operative management after CRT, as implemented in CEDAR, with the potential for patients to avoid additional chemotherapy or surgical interventions.