Dr. Stuart J. Wong
Dr. Carryn M. Anderson
Although IMRT minimizes radiation dose to normal tissue, approximately 70% of patients receiving IMRT and cisplatin will develop severe (grade 3 or 4) OM. Patients with these adverse events develop ulcers and require a liquid diet (grade 3) or intravenous/tube feeding (grade 4), based on the World Health Organization OM grading system.
GC4419, which is a manganese superoxide dismutase mimetic, “provides a clinically meaningful reduction in severe OM duration, incidence, and severity,” Carryn M. Anderson, MD, of University of Iowa Hospitals and Clinics, said.
In the trial, 223 patients with locally advanced squamous cell cancer of the oral cavity or oropharynx were randomly assigned to receive GC4419 or placebo (74 participants) at 44 sites in the United States and Canada. The study stratified patients by tumor HPV status and cisplatin dosing.
Intravenous GC4419 was given at doses of either 30 mg (73 participants) or 90 mg (76 participants) over 60-minute infusions ending 60 minutes before IMRT delivery, based on safety data from a phase I trial of GC4419. Patients received IMRT daily Monday to Friday at 2.0-2.2 Gy intervals up to about 70 Gy.
“Importantly, almost 95% of the patients had three or more [oral] sites receiving 50 Gy or more, and nearly 40% of patients had five or more visible oral sites receiving 50 Gy or more, so we were expecting OM to develop in this heavily treated population,” Dr. Anderson said.
The median duration of severe OM, which was the trial’s primary endpoint, was 19 days among patients in the placebo arm and 1.5 days among patients who received 90 mg GC4419, representing a 92% decrease (p = 0.024). The median duration among patients who received 30 mg was 8 days and not statistically different from placebo.
Among the patients who received up to 60 Gy of radiation, the incidence of severe OM—a secondary endpoint—was 58% in the placebo group and 37% among patients who received 90 mg GC4419, representing a 36% relative reduction (p = 0.010). The reduction among patients receiving 30 mg GC4419 was not statistically different from placebo.
Toxicity was comparable between the three arms, and GC4419 did not appear to increase cisplatin-related toxicities, Dr. Anderson said. The known GC4419-related side effects such as grade 1/2 hypertension and grade 1 facial paresthesia resolved within about an hour of the infusions, she noted.
Based on the findings of this trial, the U.S. Food and Drug Administration (FDA) granted GC4419 Fast Track designation, Dr. Anderson said.
This study led to a “dramatic” reduction in severe OM duration, Discussant Stuart J. Wong, MD, of the Medical College of Wisconsin, said. Additionally, the relative reduction in incidence may eventually result in FDA approval, based on the endpoints in two trials that led to palifermin approval for cancer treatment–related OM, Dr. Wong noted.
“It is safe to say that we are making progress in OM,” Dr. Wong said. “But opioid analgesia still remains the cornerstone of the management of OM.”
–Carina Storrs, PhD