The phase 2 CP-MGA271-06 trial closed early following an internal review of safety data of enoblituzumab plus retifanlimab or tebotelimab as a first-line treatment for patients with recurrent or metastatic head and neck squamous cell carcinoma.
The phase 2 CP-MGA271-06 trial (NCT04634825) closed early following an internal review of safety data of enoblituzumab (MGA271) plus retifanlimab (INCMGA 00012) or tebotelimab (MGD013) as a first-line treatment for patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC), according to an announcement from MacroGenics.1
Safety data from the study included seven fatalities potentially linked to hemorrhagic events in the 2 arms of the trial. Six of the deaths were assessed by investigators as secondary to disease progression and/or unrelated to study treatment, and the other death was deemed possibly related to study treatment. MacroGenics informed the FDA of the decision to end the trial, and no additional patients were to enroll or receive treatment after July 7, 2022.
“Our top concern in conducting clinical trials is the safety of study participants,” Scott Koenig, MD, PhD, president and chief executive officer of MacroGenics, stated in a press release. “We were surprised by the emergence of these events in first-line HNSCC patients, as we had not observed any such events in an earlier, smaller study in patients with later-line HNSCC disease who were treated with enoblituzumab in combination with an anti–PD-1 antibody. Similar safety events have not been reported in patients treated with MGC018, our B7-H3–targeted [antibody-drug conjugate] molecule, and the decision to close the CP-MGA271-06 study does not impact our ongoing MGC018 study activities. We’d like to thank all patients, their families and caregivers who participated in the CP-MGA271-06 study.”
Although fatal tumor-related hemorrhages and airway obstruction are known risks for patients with HNSCC, a higher rate of incidents occurred in the CP-MGA271-06 trial vs past rates for this patient population. Data reported in December 2019 from a phase 3 trial (NCT00588770) evaluating chemotherapy with or without bevacizumab (Avastin) in patients with recurrent or metastatic HNSCC showed rates of grade 5 bleeding adverse effects (AEs) of 1% and 3.6% in the chemotherapy alone and bevacizumab arms, respectively.2
MacroGenics will continue to monitor and study the hemorrhagic AEs. Notably, the company said no hemorrhagic events or coagulopathies were observed in nonclinical toxicology studies of enoblituzumab. In more than 340 patients with a broad range of tumor types treated with enoblituzumab in prior trials, the rate of fatal hemorrhages was less than 1%.
The nonrandomized, open-label CP-MGA271-06 trial investigated enoblituzumab, an anti–B7-H3 monoclonal antibody, in combination with the anti–PD-1 monoclonal antibody retifanlimab or the bispecific DART molecule tebotelimab as a first-line treatment for patients with histologically proven recurrent or metastatic HNSCC that was not curable by local therapy. Patients were not permitted to have prior systemic therapy for HNSCC in the recurrent or metastatic setting, unless the therapy was completed more than 6 months prior to the trial as a part of a multimodal treatment for locally advanced disease.3
Other eligibility criteria included a primary tumor location of the oropharynx, oral cavity, hypopharynx, or larynx; an ECOG performance status of 0 or 1; a life expectancy of at least 6 months; adequate end organ function; and at least 1 radiographically measurable lesion.
Patients were excluded from the trial if they had a primary tumor site of the upper esophagus, salivary gland, or nasopharynx. Other exclusion criteria included progressive disease within 6 months of completion of curatively intended systemic therapy for locoregionally advanced HNSCC; radiation or other non-systemic therapy within 2 weeks of the first dose of study treatment; or prior therapy with an anti–B7-H3, anti–PD-1, anti–PD-L1, or anti–LAG-3 agent.
Patients who had a PD-L1 combined positive score (CPS) of at least 1 were placed in the retifanlimab cohort, and those with a PD-L1 CPS below 1 went into the tebotelimab cohort. All enrolled patients received 15 mg/kg of enoblituzumab every 3 weeks. Those in the retifanlimab arm received the agent at a dose of 375 mg every 3 weeks, and patients in the tebotelimab arm were administered the drug at a dose of 600 mg every 3 weeks.
The primary end points of the trial comprised the objective response rates of enoblituzumab/retifanlimab and enoblituzumab/tebotelimab, plus the safety of enoblituzumab/tebotelimab. Secondary end points included progression-free survival, disease control rate, duration of response, overall survival, safety of enoblituzumab/retifanlimab, pharmacokinetics, and immunogenicity.