The FDA has granted a breakthrough therapy designation to Debio 1143, an inhibitor of apoptosis protein antagonist, for the treatment of patients with previously untreated, unresectable, locally advanced squamous cell carcinoma of the head and neck in combination with standard cisplatin-based concomitant fractionation chemoradiation therapy
The FDA has granted a breakthrough therapy designation to Debio 1143, an inhibitor of apoptosis protein (IAP) antagonist, for the treatment of patients with previously untreated, unresectable, locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN) in combination with standard cisplatin-based concomitant fractionation chemoradiation therapy (CRT).1
The designation is based on results from a phase I/II trial (NCT02022098), in which Debio 1143 plus CRT demonstrated a 20.8% improvement in investigator-assessed 18-month locoregional control rate (LCR) compared with CRT/placebo (odds ratio [OR], 2.69; 95% CI, 1.13-6.42; P = .026).2 After a 2-year follow-up period, progression-free survival (PFS) also favored the Debio 1143 arm (HR, 0.37; P = .007).
Debio 1143 was also found to have a predictable and manageable safety profile and did not compromise the full delivery of standard CRT, Debiopharm, the developer of the agent, stated in a press release.
"Despite today's current standard of care, high-risk locally-advanced head and neck cancer remains an area of unmet medical need,” Angela Zubel, chief development officer, Debiopharm, stated in the press release. “This breakthrough therapy designation will allow us to maximize the potential of Debio 1143 to become an innovative radio-chemo enhancing treatment for LA-SCCHN patients.”
More than half of patients with LA-SCCH experience relapse, and resistant to radiation is a significant cause of poor survival rates in this disease. IAPs are found to negatively regulate apoptosis and modulate immune responses, and are overexpressed in several tumor types, including SCCHN.
Debio 1143 is a potential first-in-class oral antagonist of IAPs that sensitizes tumor cells to chemoradiation by promoting programmed cell death and fostering antitumor immunity.
In the 2-part phase I/II trial, investigators evaluated the optimal combination dose and efficacy and safety of Debio 1143 in combination with CRT in patients with previously untreated LA-SCCHN.
Those who were eligible for enrollment had stage III, IVa, or IVb disease; a smoking history of >10 pack-years; negative HIV/hepatitis B/hepatitis C status; and an ECOG performance status of 0 or 1. Tumor sites could include oral cavity, hypopharynx, larynx, and oropharynx that was HPV/p16-positive or -negative.
Patients without compensated liver cirrhosis, were >75 years old, and were ineligible for cisplatin were excluded from enrollment.
The phase I portion was a dose-escalation phase to determine the maximum-tolerated dose (MTD) of Debio 1143 when given in combination with CRT. Once the MTD was identified, which was 200 mg daily, the phase II portion of the trial then randomized 94 patients to receive Debio 1143 or placebo, both of which were given with concomitant CRT.
Debio 1143 was administered orally or via feeding tube daily for 14 days every 3 weeks. Chemotherapy comprised of 3 cycles of cisplatin as a 1-hour infusion on days 2, 23, and 44, and was given 30 minutes following Debio 1143. Radiation was standard fraction radiotherapy to the primary tumor and was delivered daily for 5 days per week over 7 weeks.
Patients were stratified by N0/N1 and N2/N3 stage and primary tumor site, and baseline characteristics were well balanced between the 2 arms. More than 80% of patients whose disease originated from the oropharynx were HPV/p16-negative, all patients were heavy smokers and had high-risk disease, and more than 80% of patients had stage IV disease. All patients also had high alcohol consumption.
In the phase II portion, the primary endpoint was LCR at 18 months from the end of CRT. Key secondary endpoints included complete response rate, overall response rate (ORR), 6-month LCR, PFS, distant relapse rate, disease-specific survival rate at 1 and 2 years, overall survival (OS), and safety.
Results showed that the investigator-assessed 18-month LCR rate was 54.2% (95% CI, 39.2-68.6) and 33.3% (95% CI, 20.4-48.4) in the Debio 1143 and control arms, respectively. Also by investigator assessment, LCR (HR, 0.53; P = .165) and OS (HR, 0.65; P = .243) favored the Debio 1143 arms.
At 3 and 6 months, Debio 1143 elicited a 62.5% and 66.7% ORRs compared with 66.7% and 47.9% in the placebo/CRT arms, leading to an odds ratio of 18.8% (P = .06). However, investigators noted that there was a delayed effect at 6 months following Debio 1143/CRT treatment.
Regarding safety, the rates of adverse events were similar between arms. However, in the Debio 1143 arm, there was a higher rate of grade 3 dysphagia (50.0%), mucositis (31.3%), and anemia (35.4%) compared with the control arm at 21.3%, 21.3%, and 23.4%, respectively, but this was found to be consistent with the radio-sensitizing effect of Debio 1143.
Debio 1143 is also being investigated in combination with PD-1/PD-L1 inhibitors in various solid tumors, the company stated in the press release. Currently, more than 200 patients have been treated with Debio 1143 in various indications and lines of treatment, showing an adequate and consistent safety profile across trials.