Outcomes and Immune Responses from INNATE: A Randomized Phase II Trial of Sotigalimab Immunotherapy during Neoadjuvant Therapy of Rectal Cancer

Purpose/Objective(s)

Immunotherapy benefit has yet to show benefit in unselected colorectal cancer. The addition of a CD40 agonist, sotigalimab (Sotiga), to short course radiotherapy (SCRT) and FOLFOX chemotherapy (CT) is hypothesized to improve pathologic complete response (pCR) in locally advanced rectal cancer (LARC).

Materials/Methods

INNATE (NCT04130854) is a multi-institutional Phase II randomized trial for patients with Stage III or high-risk Stage II LARD. Patients were randomized 3:2 to receive daily SCRT (5 Gy x 5) and 6 cycles of FOLFOX ± 6 infusions of Sotiga, followed by total mesorectal excision stratified by stage. Tumor tissue was collected including pre- and post-SCRT for single cell RNA sequencing and multiplex immunofluorescence. Target accrual was 58 patients with the primary pCR endpoint powered for a 22% difference.

Results

From 7/30/20 to 6/23/22, 30 patients were enrolled by 4 centers (19 randomized to Sotiga), after which accrual was held. Patients had unfavorable disease: all were T3/4, 20 (67%) had N2 disease and 21 (70%) had tumor involving or threatening the mesorectal fascia. Of 26 patients that underwent TME, pCR was achieved in 4/18 (22.2%) in the study arm and 1/7 (14.3%) in the control arm. Major response of pCR, near CR, or sustained 12-month clinical CR occurred in 7/19 (36.8%) in the study arm and 6/10 (60%) control arm patients. Average radiology contoured tumor volumes pre- and post-treatment were respectively: 52.2 cc (SD = 34.39) and 11.05 cc (-78.82%) in the study arm, and 36.46 cc (SD = 29.34) 16.77 cc (-54.00 %) in control arm. Grade 3-4 toxicities occurred in 5 (26%) study arm patients and 5 (45%) control arm patients. The most common toxicities were Grade 3 GI related (n=7), infection (n=5), and thromboembolism (n=2). Other toxicities included abdominal pain, rectal fistula, radiation proctitis, and perforation (n=1ea). The study arm had 1 Grade 4 (unrelated) postoperative stercoral perforation, and the control arm had a Grade 5 sepsis and cardiac arrest after perforation during CT. Comparisons pre-post SCRT revealed significant increases in infiltration of antigen-presenting cells in both arms (FDR < 0.05). Higher anti-tumor M1 macrophage signature after SCRT (p = 0.01) was more pronounced with SCRT+Sotiga (p = 5.74e-08). Type 1 dendritic cell activation and antigen presentation pathways and CD40 signaling were significantly increased after SCRT and SCRT+Sotiga. Anti-tumor effects extended to T cells, with increased cytotoxic activity in CD8 T cells (IL-2, GZMB, GZMK, NKG7) and NK cells (PRF1, GZMB). Expression of immune checkpoints shifted in each arm suggesting additional targets for combination therapy with SCRT or Sotiga.

Conclusion

Adding Sotiga to SCRT and CT in LARC appears to be safe and shows robust responses to unfavorable disease, with evidence of increased antitumor adaptive immune responses compared to SCRT alone. Disease control outcomes are pending.