Nivolumab plus ipilimumab did not significantly improve overall survival over the EXTREME regimen in the frontline treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck, missing the primary end points of the phase 3 CheckMate-651 trial.
The combination of nivolumab (Opdivo) plus ipilimumab (Yervoy) did not significantly improve overall survival (OS) over the EXTREME regimen comprised of cetuximab (Erbitux), cisplatin/carboplatin, and fluorouracil in the frontline treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck, missing the primary end points of the phase 3 CheckMate-651 trial (NCT02741570).1
However, the dual immunotherapy combination did demonstrate a clear, positive trend toward OS in the subset of patients whose tumors had PD-L1 expression of a combined positive score (CPS) of 20 or higher.
Moreover, data regarding the toxicity profile of nivolumab and ipilimumab in the trial proved to align with what had been reported in prior studies examining the agents in patients with solid tumors.
“Numerous studies have shown long-term survival improvements with the [nivolumab] plus [ipilimumab] combination across various tumor types, bringing benefit to patients around the world,” Abderrahim Oukessou, MD, vice president of thoracic cancers and development lead at Bristol Myers Squibb, stated in a press release. “In the CheckMate-651 trial, [nivolumab] plus [ipilimumab] showed a positive OS trend relative to EXTREME in patients with squamous cell carcinoma of the head and neck whose tumors express PD-L1, despite the control arm performing better than expected based on historical data.”
The multicenter, phase 3 trial enrolled patients with histologically confirmed metastatic or recurrent squamous cell carcinoma of the head and neck that is not amenable to curative therapy.2 Patients had to have measurable disease detected by CT or MRI and tumor tissue available for PD-L1 expressing testing. Patients could not have previously received systemic treatment for recurrent or metastatic disease.
If patients had metastatic or recurrent carcinoma of the nasopharynx, squamous cell carcinoma of unknown primary, squamous cell carcinoma originating from the skin and salivary glands or non-squamous histologies, they were excluded. Patients with unacceptable hematologic, renal, or hepatic function, or those with active autoimmune disease, type I diabetes, hypothyroidism requiring hormone replacement, active infection, or psychiatric disorder were also not eligible.
Study participants received nivolumab at 3 mg/kg every 2 weeks in combination with ipilimumab at 1 mg/kg every 6 weeks vs the EXTREME regimen in the first-line setting.
The primary end points of the trial included OS in the intent-to-treat population of the trial and OS in those with tumors that expressed PD-L1 with a CPS of 20 or higher. Important secondary end points included OS in patients with PD-L1–expressing tumors at different cut-off values, objective response rate, duration of response, and progression-free survival in all patients and in the subset of those with PD-L1–expressing tumors.
“We are disappointed that these results did not reach statistical significance, and we remain committed to advancing research and supporting patients with this difficult-to-treat cancer,” Oukessou added.
Previously, in 2016, the FDA approved nivolumab for the treatment of patients with metastatic or recurrent squamous cell carcinoma of the head and neck following progression on platinum-based chemotherapy.3
The regulatory decision was based on findings from the phase 3 CheckMate-141 trial (NCT02105636), which demonstrated that nivolumab resulted in a median OS of 7.5 months (95% CI, 5.5-9.1) vs 5.1 months (95% CI, 4.0-6.0) with standard, single-agent systemic therapy in the form of methotrexate, docetaxel, or cetuximab (HR, 0.70; 95% CI, 0.51-0.96; P = .01).4 Moreover, the median progression-free survival in the investigative and control arms was 2.0 months (95% CI, 1.9-2.1) and 2.3 months (95% CI, 1.9-3.1), respectively (HR, 0.89; 95% CI, 0.70-1.13; P = .32).