Avasopasem for Radiotherapy-Induced Oral Mucositis in Head & Neck Cancer

cancer patient: cancer patientEvery year in the U.S., roughly 42,000 patients with head and neck cancer (HNC) undergo standard-of-care radiotherapy. Unfortunately, 70 percent of patients who receive radiotherapy for locally advanced HNC (LAHNC) develop severe oral mucositis (SOM). SOM is defined by the inability to eat solids (WHO Grade 3) or drink liquids (WHO Grade 4). Currently, there are no FDA-approved agents to mitigate SOM for these patients. Now, findings with avasopasem manganese (avasopasem or GC4419) may potentially change the treatment landscape. It is a selective small molecule dismutase mimetic in development for the reduction of radiotherapy-induced SOM in patients with LAHNC who are undergoing standard treatment. In December 2022, a new drug application (NDA) was submitted to the FDA seeking approval of avasopasem manganese. Positive findings from a total of 678 patients enrolled in the Phase IIb GT-201 trial (NCT02508389) and the Phase III ROMAN trial (NCT03689712) supported the NDA submission. Phase IIb GT-201 Trial The randomized, double-blind, placebo-controlled GT-201 trial (GTI-4419-201) enrolled 223 patients. The study evaluated the capability of avasopasem to decrease radiation-induced SOM in patients with LAHNC, receiving 7 weeks of standard-of-care radiotherapy plus cisplatin (J Clin Oncol 2019; doi: 10.1200/JCO.19.01507). Trial participants were randomized into three treatment groups (1:1:1) to receive either 30 mg or 90 mg of avasopasem or placebo by infusion on the days they receive their radiation treatment. The findings revealed that avasopasem 90 mg elicited significant reduction in SOM duration versus placebo, at a median of 1.5 days versus 19 days (P=.024). In addition, it also brought about clinically meaningful reductions in the incidence (P=.045), severity (Grade 4 incidence), and onset of SOM compared to placebo. The adverse effects (AEs) profile was also comparable to placebo. Furthermore, tumor outcomes were maintained at 1-year and 2-year follow-up in both the experimental and control arms. The researchers sought to confirm these data in the Phase III ROMAN trial. Phase III ROMAN Trial The Phase III ROMAN trial (GTI-4419-301) was a randomized, double-blind, placebo-controlled trial that further evaluated the ability of avasopasem to reduce radiation-induced SOM in 407 patients with LAHNC from 69 different sites across the U.S. and Canada (J Clin Oncol 2022; doi: 10.1200/JCO.2022.40.16_suppl.6005). Study participants were randomized to one of the two treatment groups (3:2) to receive 90 mg of avasopasem (N=241) or placebo by 60-minute IV infusion (N=166) on the days they receive their radiation treatment. Stratification factors included surgery status (postoperative vs. definitive) and cisplatin schedule (every 3 weeks vs. weekly). The primary endpoint of the trial was incidence of SOM (WHO Grade 3 or 4) from the first intensity-modulated radiation therapy (IMRT) fraction through to the end of the study's treatment periods. Key secondary endpoints included SOM duration through 2 weeks post-IMRT and Grade 4 OM incidence through the end of IMRT. Additional endpoints included safety and tolerability, in addition to tumor outcomes at 1-2 years of follow-up. The avasopasem and placebo arms were balanced and most patients had oropharyngeal histology (80% and 85%, respectively), disease in the oral cavity (16% and 13%, respectively), and HPV-positive status (80% and 81%, respectively). In addition, they were receiving definitive treatment (81% and 81%, respectively). Avasopasem demonstrated meaningful improvements, including all IMRT landmarks: at 30 Gy, the incidence among the experimental and placebo arm was 9 percent versus 16 percent , respectively (relative risk [RR]: 0.86; P=.030); at 40 Gy, the incidence was 17 percent versus 32 percent (RR: 0.5; P=.001); at 50 Gy, the incidence was 28 percent versus 45 percent (RR: 0.6; P<.001); at 60 Gy, the incidence was 42 percent versus 58 percent (RR: 0.7; P=.002); and post IMRT, the incidence was 58 percent versus 71 percent, (RR: 0.82; P=.012). Specifically, with IMRT, the incidence rate of SOM was 54 percent in those who received avasopasem compared with 64 percent with placebo (RR: 0.84; P=.045) meeting the primary endpoint of the trial. With avasopasem given prior to IMRT, patients had a 56 percent relative reduction in SOM duration (median, 8 days vs. 18 days; respectively; P=.002), a 27 percent reduction in Grade 4 incidence of SOM (33% vs. 24%, respectively; P=.052), and a 24 percent reduction in the mean number of days of Grade 4 incidence (7.2 days vs 5.5 days, respectively; P=.143). Improvement was observed in several secondary and exploratory endpoints. Regarding safety, AE frequencies (all-grade, Grade 3+, serious) were similar between treatment groups without clear avasopasem-specific toxicity or increase in cisplatin-attributable toxicity. Across all grades, common AEs were lymphopenia, all-grade nausea, fatigue, oropharyngeal pain, and constipation. The most frequent Grade 3 or higher AEs were lymphopenia, leukopenia, and neutropenia. Oncology Times connected with Carryn M. Anderson, MD, to discuss the recent results of the ROMAN trial and how avasopasem can potentially change the treatment landscape for patients with locally advanced head and neck cancer who experience severe oral mucositis. She is Clinical Associate Professor of Radiation Oncology and Residency Program Director in the Department of Radiation Oncology at The University of Iowa Hospitals and Clinics. Oncology Times: What are some of the treatment challenges for patients with LAHNC who experience SOM? Anderson: “SOM is a very difficult side effect to manage. The pain from the ulcers is exacerbated by talking, eating, and drinking, and prescription pain medications including narcotics may not sufficiently manage the pain to allow a patient to meet their nutritional needs by mouth. “As a result, many patients with SOM will require feeding tube placement and utilization for several weeks and sometimes months. Oral mucositis can be an entry point for infection and in patients who are neutropenic from chemotherapy, sepsis can be a life-threatening condition requiring hospitalization and IV antibiotics. The duration of SOM can be several weeks and sometimes longer, causing a major impact on patient quality of life.” Oncology Times: How can the findings of the ROMAN Phase III trial with avasopasem potentially change the treatment landscape for these patients? Anderson: “To date, there are no FDA-approved drugs that decrease the incidence, severity, or duration of SOM in patients with LAHNC receiving concurrent chemoradiation. The results of the ROMAN Phase III trial showed a statistically significant and clinically meaningful reduction in SOM incidence and duration with a trend towards decreased Grade 4 incidence with avasopasem compared to placebo. The incidence of SOM was significantly reduced throughout IMRT and in the 2 weeks post-IMRT completion. Patients who received avasopasem utilized fewer narcotics and were less dependent on feeding tubes. “As reported at the 2022 ASTRO Annual Meeting in San Antonio, avasopasem also decreased the incidence of acute and chronic kidney injury from cisplatin, cutting the incidence of chronic kidney disease at 1 year in half (20% vs. 10%, P=0.0043). Avasopasem has the potential to dramatically decrease patient suffering from both acute (oral mucositis and kidney injury) and late (chronic kidney disease) treatment side effects.” Oncology Times: What are the molecular mechanisms in which avasopasem manganese exerts its effects? Anderson: “Avasopasem manganese is a small molecule superoxide dismutase mimetic that rapidly converts superoxide to hydrogen peroxide. Normal cells have ample secondary enzymes like catalase and peroxidases that convert the hydrogen peroxide to oxygen and water, thereby sparing normal tissues from the damaging effects of radiation-induced and cisplatin-induced superoxide. “Multiple lab experiments have shown that malignant cells are deficient in the secondary enzyme processes, leading to accumulation of damaging hydrogen peroxide and increased likelihood of cell death. Both the Phase IIb and Phase III ROMAN trials have shown that tumor outcomes are preserved with avasopasem manganese compared to placebo, reassuring us that avasopasem's mechanisms are not sparing cancer cells from the damaging effects of cisplatin and radiation.” Oncology Times: Are you exploring any other endpoints for this drug? Anderson: “Avasopasem manganese is also being evaluated in a Phase IIa trial to determine efficacy in lowering the incidence of esophagitis among lung cancer patients (NCT04225026).” Dibash Kumar Das is a contributing writer.

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