KEY TAKEAWAYS
- The ROMAN phase 3 trial aimed to examine reductions in SOM incidence, duration, and severity, and delays in onset, among key subsets of LAHNC.
- The endpoints were SOM & grade 4 OM incidences until IMRT completion, SOM duration post-IMRT, and time to SOM onset.
- The results showed that AVA significantly reduced SOM incidence, severity, duration, and delayed onset in definitive treatment, with consistent benefits.
IMRT combined with cisplatin is a standard treatment for locally advanced head and neck cancer (LAHNC), but around 70% of patients experience severe oral mucositis (SOM), categorized as WHO grade 3 or 4. This severity often impedes solid food intake (grade 3) or even liquids (grade 4), frequently necessitating feeding tube support. Radiotherapy (RT) triggers bursts of superoxide, initiating SOM according to Sonis (2004).
Avasopasem (AVA) is an investigational small molecule acting as a selective dismutase mimetic, converting superoxide to hydrogen peroxide. This conversion potentially shields normal cells from RT damage and might sensitize cancer cells to RT, as indicated by Anderson (2019) and Sishc (2021).
A randomized, blinded, placebo-controlled phase 3 trial demonstrated that AVA significantly reduced SOM incidence and duration in the intention-to-treat (ITT) population, while also mitigating cisplatin-induced kidney damage.
Christopher M. Lee and the team conducted a study that aimed to examine reductions in SOM occurrence, duration, and severity, and onset delay in specific LAHNC groups.
The LAHNC patients affecting the oral cavity (OC) or oropharynx (OP), receiving 60-72 Gy of IMRT (≥50 Gy to ≥2 OM sites) alongside cisplatin (weekly or every 3 weeks), were randomized in a 3:2 ratio to receive either intravenous AVA 90 mg or placebo (PBO) before each radiotherapy (RT) fraction. Trained evaluators assessed WHO scale oral mucositis (OM) biweekly during RT and weekly for 2 weeks post-IMRT.
Endpoints included SOM and grade 4 OM incidences until the end of IMRT, SOM duration up to 2 weeks post-IMRT, and time to SOM onset. Key subpopulations evaluated were definitive versus post-operative treatment, OC versus OP tumors, HPV-negative versus HPV-positive status, and weekly (QW) versus every 3 weeks (Q3W) cisplatin administration.
Of the patients enrolled, 80.8% (329/407) underwent definitive chemoradiation therapy from October 2018 to August 2021. In this cohort, the incidence of SOM was 51.2% in the AVA arm compared to 66.5% in the PBO arm (RR 0.77, P-value 0.0071). Grade 4 OM incidence was 23.0% for AVA versus 35.2% for PBO (RR 0.65, P-value 0.0102). The median SOM duration was reduced by 12 days (AVA: 8 days vs. PBO: 20.5 days; least square means 13.5 days vs. 19.5 days, P-value 0.0012). The median time of SOM onset was delayed by 14 days (Day 51 for AVA vs. Day 37 for PBO).
Patients receiving postoperative chemoradiation therapy (19.2%) did not experience improvements in SOM incidence, severity, duration, or time to onset with AVA. The enhancements in SOM metrics with AVA did not significantly differ based on cisplatin schedule, HPV status, or primary tumor type, and were consistent with the intention-to-treat (ITT) analysis.
The analysis showed that the AVA significantly decreased SOM incidence, severity, and duration, delaying its onset in definitively treated patients, but not in those treated postoperatively. The efficacy of AVA was not influenced by cisplatin schedule, HPV status, or primary tumor type.
Future studies on mucosal radioprotectant agents should account for differing SOM experiences between postoperative and definitive chemoradiation patients.
The trial was sponsored by Galera Therapeutics, Inc.
Source: https://astro.confex.com/astro/hncs2024/meetingapp.cgi/Paper/59731
Clinical Trial: https://clinicaltrials.gov/study/NCT03689712
Lee CM, Kelley JR, Dunlap NE, et al. (2024) “Subgroup analysis of the benefit of avasopasem manganese on the incidence, severity, duration and onset of severe oral mucositis in ROMAN Phase 3 Trial.” Presented at MHNCS 2024 (166).
