Benefit of Avasopasem Manganese on Severe Oral Mucositis in Head and Neck Cancer in the ROMAN Trial: Unplanned Secondary Analysis

Abstract

IntroductionOral mucositis is a debilitating side effect of cisplatin and intensity-modulated radiation therapy (IMRT) in patients with head and neck cancer. The phase 3 ROMAN trial showed avasopasem manganese (AVA) significantly decreased individual endpoints of incidence and duration of severe oral mucositis (SOM, World Health Organization [WHO] grade 3-4), with nominal decrease in severity (WHO grade 4) and significant increase in the delay in onset of SOM. We sought to determine the Net Treatment Benefit (NTB) of AVA versus placebo (PBO) using the generalized pairwise comparisons (GPC) method. MethodsGPC is a statistical method that permits simultaneous analysis of several prioritized outcomes, comparing all possible pairs of a patient in the active (i.e., AVA) group and a patient from the control (i.e., PBO) group. NTB is the net benefit across all the outcomes for AVA compared to PBO. Key clinically relevant outcomes from ROMAN were prioritized: 1) WHO grade 4 OM incidence, 2) SOM incidence, 3) days of SOM, 4) days to SOM onset, with 7 days difference defined as the clinical relevance threshold for SOM days and SOM onset. ResultsGPC analysis of 407 patients (AVA = 241, Placebo = 166) stratified by cisplatin schedule and treatment setting resulted in 13,969 pairwise comparisons. AVA showed statistically significant net benefit on all four key outcomes with a 53.9% probability that AVA would benefit patients versus a 35.0% probability that PBO would; the difference between these probabilities was a NTB of 18.9% (p=0.0012), translating to an AVA number needed to treat of 5.3 patients. All outcomes contributed to NTB, reflecting improvements in SOM incidence, onset and duration, and in Grade 4 OM incidence seen in the original ROMAN analysis. ConclusionsThis GPC analysis shows compelling evidence from the ROMAN trial of AVA's clinical benefit across key parameters of SOM burden.