Subgroup Analysis of the Benefit of Avasopasem Manganese on the Incidence, Severity, Duration and Onset of Severe Oral Mucositis in ROMAN Phase 3 Trial

Purpose/Objective(s) IMRT plus cisplatin is established treatment for LAHNC, but ∼70% of patients develop severe oral mucositis (SOM; WHO grade 3 or 4), limiting their ability to eat solids (gr 3) or liquids (gr 4), and often requiring feeding tube nutrition. Radiotherapy (RT)-induced bursts of superoxide initiate SOM (Sonis 2004). Avasopasem (AVA) is an investigational small molecule selective dismutase mimetic converting superoxide to hydrogen peroxide, which may protect normal cells from, and potentially sensitize cancer cells to, RT (Anderson 2019, Sishc 2021). Randomized, blinded, placebo (PBO)-controlled phase 3 was conducted and showed AVA significantly reduced SOM incidence and duration in ITT population, as well as reducing cisplatin kidney damage. The present analysis looks at reductions in SOM incidence, duration & severity, and delay in onset in key LAHNC subsets. Materials/Methods Patients with oral cavity (OC) or oropharynx (OP) LAHNC receiving 60-72 Gy of IMRT (≥50 Gy to ≥2 OM sites) plus cisplatin (weekly or q3 weeks) randomized 3:2 to IV AVA 90 mg vs PBO before each RT fraction. WHO scale OM was assessed by trained evaluators biweekly during RT & weekly for 2 weeks thereafter. Endpoints: SOM & gr 4 OM incidences through IMRT end; SOM duration through 2 weeks post-IMRT; time to SOM onset. Key subpopulations: Definitive vs Post-op; OC vs OP; HPV- vs HPV+; QW vs Q3W cisplatin. Results 80.8% (329/407) of patients were treated on study with definitive chemoradiation therapy between October 2018 and August 2021. In this group, SOM incidence was 51.2% in AVA arm vs. 66.5% in PBO arm (RR 0.77, p-value 0.0071), while gr 4 OM incidence was 23.0% for AVA vs. 35.2% for PBO (RR 0.65, p-value 0.0102, and median SOM duration was reduced by 12 days (8 days AVA vs. 20.5 days PBO; least square means 13.5 days AVA vs. 19.5 days PBO, p-value 0.0012). Median time of SOM onset was delayed by 14 days (Day 51 AVA vs. Day 37 PBO). Patients treated with postoperative chemoradiation therapy (19.2%) had no improvement in SOM incidence, severity, duration, or time to onset with AVA. Improvements in SOM incidence, severity, duration and onset with AVA did not vary significantly based on cisplatin schedule, HPV status or primary tumor type and were similar to ITT. Conclusion In this phase 3 randomized placebo-controlled trial, AVA markedly reduced SOM incidence, severity and duration, and delayed its onset, in patients treated definitively, but not postoperatively. Cisplatin schedule, HPV status and primary tumor type did not influence AVA benefit. Future trials of novel mucosal radioprotectant agents should consider that postoperative patients may experience SOM differently than definitive chemoradiation patients.