Avasopasem manganese treatment for severe oral mucositis from chemoradiotherapy for locally advanced head and neck cancer: phase 3 randomized controlled trial (ROMAN)
Giving avasopasem before each radiotherapy session lowered the share of head and neck cancer patients who got severe mouth ulcers from 64 to 54 percent and cut how long the ulcers lasted from 18 days to 8, but the gain was smaller than hoped and the FDA wanted another trial.
Overview
Primary publication of ROMAN (NCT03689712). Patients receiving 60 to 72 Gy of intensity-modulated radiotherapy (more than 50 Gy to at least two oral mucosal sites) plus cisplatin for locally advanced head and neck cancer were randomised 3:2 to avasopasem manganese 90 mg or placebo before each radiotherapy fraction. Severe oral mucositis (WHO grade 3 or 4) was assessed twice weekly during radiotherapy and weekly for two weeks after. The primary endpoint was the incidence of severe oral mucositis through the end of radiotherapy; secondary endpoints included its duration and onset, grade 4 incidence and duration, tumour outcomes and renal function.
455 patients were randomised and 407 (241 avasopasem, 166 placebo) entered the primary analysis. Severe oral mucositis incidence was 54 percent versus 64 percent (relative risk 0.84; 95 percent CI 0.71 to 1.00; p = 0.045) and median duration 8 versus 18 days (p = 0.002); onset was nominally delayed (median 49 versus 38 days). Grade 4 incidence (27 percent, p = 0.052) and days (24 percent, p = 0.143) were not significantly reduced. Adverse-event frequencies were comparable; tumour outcomes were maintained at one year, and two-year overall survival was 89 percent (84 to 93) with avasopasem versus 93 percent (88 to 96) with placebo. The authors write that the incidence benefit was smaller than the phase 2b had predicted, that avasopasem's contribution to adverse events could not be excluded, and that ROMAN did not provide a sufficiently favourable benefit-risk determination for FDA approval; a confirmatory phase 3 trial was requested.
- Severe oral mucositis incidence 54 percent with avasopasem vs 64 percent with placebo (relative risk 0.84; 95 percent CI 0.71 to 1.00; p = 0.045).
- Median duration of severe oral mucositis 8 vs 18 days (p = 0.002); onset delayed to a median of 49 vs 38 days.
- Grade 4 mucositis not significantly reduced; two-year overall survival 89 percent vs 93 percent.
Severe mouth ulcers are the most disabling acute effect of head and neck chemoradiation and there is still no approved drug to prevent them. ROMAN shows that a radioprotector can reduce them, but by less than the phase 2b suggested, and the upper confidence limit of 1.00 plus the numerically lower two-year survival left the FDA unconvinced. The product stays investigational until a confirmatory trial reports.
- The confidence interval for the primary relative risk reaches 1.00, and the p value is 0.045.
- Two-year overall survival was numerically lower on avasopasem (89 percent vs 93 percent); the confidence intervals overlap, but the authors say a contribution to adverse events could not be excluded.
- The primary analysis population (407) is smaller than the randomised population (455).
- Funded by Galera Therapeutics; published two years after the FDA complete response letter.
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