Findings from the phase 3 ROMAN trial showed a significant reduction in severe oral mucositis with receipt of avasopasem manganese during chemoradiotherapy for patients with locally advanced, nonmetastatic head and neck cancer.
Avasopasem manganese helped to significantly reduce severe oral mucositis for those receiving chemoradiotherapy for locally advanced, nonmetastatic head and neck cancer, according to the phase 3 ROMAN trial (NCT03689712) presented at the 2022 American Society of Clinical Oncology Annual Meeting.1
Through the course of intensity-modulated radiation therapy (IMRT), treatment with the incidence rate of severe oral mucositis was 54% among those who received avasopasem (n = 241) compared with 64% among those who received placebo (n = 126; relative risk [RR], 0.84; P = .045) meeting the trial’s primary end point. In addition to overall treatment course, findings showed that avasopasem significantly reduced incidence of severe oral mucositis across all IMRT landmarks.
Additionally, treatment with avasopasem administered prior to IMRT resulted in a 56% reduction in median days of severe oral mucositis (18 vs 8 days, respectively; P =.002), a 27% reduction in grade 4 incidence (33% vs 24%, respectively; P = .052), and a 24% reduction in the mean number of days of grade 4 incidence (7.2 vs 5.5 days, respectively; P = .143).
“IMRT and cisplatin [are] concurrently the standards of care for locally advanced head and neck cancer,” Carryn M. Anderson, MD, clinical associate professor of radiation oncology, and Residency Program Director in the Department of Radiation Oncology at The University of Iowa Hospitals and Clinics, said in a presentation of the data. “[However,] the majority of these patients are going to experience severe oral mucositis during their treatment course [with these treatments]. We all struggle to treat this [adverse] effect [AE] for our patients. [Our patients] struggle with a lot of pain, they are often on narcotics, [and] sometimes they end up needing a feeding tube.”
Approximately 70% of oral mucositis incidences will be grade 3 or 4 and the typical onset is in conjunction with radiation dose of 40 Gy. Unfortunately, there are no FDA-approved agents to mitigate severe oral mucositis for patients with head and neck cancer, Anderson noted. However, findings with avasopasem may hold the potential to change the treatment landscape.
Avasopasem manganese is a selective small molecule dismutase mimetic, which protects normal cells, but not cancer cells from radiation by converting radiation therapy induced superoxide to hydrogen peroxide. This is crucial because superoxide is what initiates the tissue damage and inflammatory cascade that ultimately leads to oral mucositis, Anderson explained.
Data from a phase 2b trial (NCT02508389) showed that 90 mg of avasopasem elicited clinically meaningful reductions in duration (P = .024) and incidence (P = .045) of severe oral mucositis with a comparable AE profile to placebo. Of note, tumor outcomes were maintained at 1- and 2- year follow-up, in both the experimental and control arms.2
ROMAN sought to confirm those findings. This randomized, multicenter, phase 3, clinical trial treated 407 patients with locally advanced, nonmetastatic head and neck cancer from 69 different sites across the United States and Canada.
Eligible participants needed to be 18 years of older, have a diagnosis of squamous cell carcinoma of the head and neck, and have a plan to receive IMRT as single daily fractions of 2.0 to 2.2 Gy with a cumulative radiation dose of 60 to 72 Gy plus standard cisplatin therapy. In addition, eligible participants must have an ECOG performance status of 2 or higher, adequate hematologic, renal and liver function, negative serum pregnancy test, and use of effective contraception.
Exclusion for enrollment included tumor of the lips, larynx, hypopharynx, nasopharynx, sinuses, or salivary glands, metastatic disease, Prior radiotherapy to the region of the study cancer or adjacent anatomical, prior induction therapy, concurrent participant in another investigational clinical study or any other concurrent approved or investigational anticancer agent.
Furthermore, patients who could not eat soft foods at baseline, were pregnant or breastfeeding, had another malignant tumor within the past 5 years, had oral mucositis or another infections disease at baseline, or had known allergies or intolerance to cisplatin were not able to participate.
Patients were randomized 3:2 to receive either 90-mg avasopasem or placebo via a 60-minute infusion, Monday to Friday, prior to undergoing radiation. Prophylaxis with avasopasem or placebo concluded within less than 60 minutes of radiotherapy initiation.
This treatment cycle lasted for 7 weeks. Stratification factors included surgery status (pre vs post operation) and cisplatin schedules (once every 3 weeks vs weekly). The trial’s primary end point was the cumulative incidence of severe oral mucositis from the first IMRT fraction until the end of the study treatment periods. On average, this time was estimated to be approximately 7 weeks.
Key secondary end points included the duration of severe oral mucositis (total number of days), as well as the incidence and total number of days that grade 4 severe oral mucositis endured. Safety and tolerability, as well as tumor outcomes at 1 to 2 years of follow-up, represented additional end points. Tumor follow-up is still in progress.
The investigative and control arms were well-balanced with most patients having oropharyngeal histology (80% and 85%, respectively), HPV-positive status (80% and 81%), and were receiving definitive treatment (81% and 81%).
Treatment with avasopasem demonstrated improvements across key parameters including all IMRT landmarks: at 30 Gy, the incidence among the experimental and placebo arm was 9% vs 16% , respectively (RR, 0.86; P = .030); at 40 Gy, the incidence was 17% v 32% (RR, 0.5; P = .001); at 50 Gy, the incidence was 28% vs 45% (RR, 0.6; P < .001); at 60 Gy, the incidence was 42% vs 58% (RR, 0.7; P = .002), and post IMRT, the incidence was 58% vs 71%, (RR, 0.82; P = .012).
Anderson noted that those who received full courses of avasopasem (≥ 25 infusions) had better incidence reduction with only 51% of patients developing severe oral mucositis.
Across all grades, the most frequent AEs were lymphopenia, followed by all-grade nausea, fatigue, oropharyngeal pain, and constipation, and grade 3 or greater leukopenia, neutropenia, dysphagia, and oropharyngeal pain. Notably, higher rates of AEs were reported among patients receiving placebo than those receiving avasopasem.
“In conclusion, [avasopasem] at 90 milligrams is the first drug to show a statistically significant and clinically meaningful reduction and severe oral mucositis incidence and duration,” Anderson said. “There [were] also meaningful improvements in severity and delay in onset of severe oral mucositis, [and] the safety profile [were] compared comparable to placebo.”
“The results we present today are consistent with our published phase 2 results,” Anderson concluded, noting that the supporting company plans to move forward with an FDA submission.