FDA Grants Nivolumab Priority Review for Head and Neck Cancer

Jean Viallet, MD

The FDA has granted a priority review designation to nivolumab (Opdivo) as a treatment for patients with previously treated metastatic or recurrent squamous cell carcinoma of the head and neck (SCCHN), based on findings from the CheckMate-141 study. The agency is scheduled to make a decision on the application for the PD-1 inhibitor by November 11, 2016, as part of the Prescription Drug User Fee Act (PDUFA).

In the phase III study, which was presented at the 2016 ASCO Annual Meeting, the median overall survival (OS) with nivolumab was 7.5 months compared with 5.1 months with investigator's choice (HR, 0.70; 95% CI, 0.51-0.96; P = .0101). The objective response rate (ORR) was 13.3% with nivolumab and 5.8% for investigator's choice.

“Squamous cell carcinoma of the head and neck that progresses after platinum therapy is a devastating disease with a poor prognosis and has had very few treatment advancements in nearly a decade," Jean Viallet, MD, Global Clinical Research Lead, Oncology, Bristol-Myers Squibb, said in a statement. "Based on findings from CheckMate -141, Opdivo is the first and only PD-1 inhibitor to show an overall survival benefit in a phase III trial in these patients."

In the trial, 361 patients with cancer of the oral cavity, pharynx, or larynx were randomized in a 2:1 ratio to receive nivolumab (n = 240) or investigator's choice of cetuximab (12.4%), methotrexate (44.6%), or docetaxel (43%; N = 121). Nivolumab was administered intravenously at 3 mg/kg every 2 weeks. Cetuximab was administered at 400 mg/m² for the first dose followed by 250 mg/m² weekly. Methotrexate was administered at 40 mg/m² weekly. Docetaxel was administered at 30 mg/m² weekly.

The 1-year OS rates were 36% with nivolumab (95% CI, 28.5-43.4) compared with 16.6% for investigator’s choice (95% CI, 8.6-26.8). Similar improvements in survival were seen across demographic subgroups. The ORR in the nivolumab arm consisted of 6 complete responses (2.5%) and the stable disease (SD) rate was 22.9%. In the investigator's choice arm, 1 patient had a complete response and the SD rate was 35.5%.

The median progression-free survival (PFS) was 2.0 months with nivolumab versus 2.3 months with investigator's choice (HR, 0.89; 95% CI, 0.70-1.10; P = .3236). The 6-year PFS rates were 19.7% for nivolumab and 9.9% for investigator's choice of therapy.

Further analyses revealed distinct populations of patients who responded better to nivolumab monotherapy versus investigator's choice, specifically those with PD-L1-positive and HPV-positive SCCHN. Those with PD-L1 expression on ≥1% of cells experienced a median OS of 8.7 months with nivolumab compared with 4.6 months in the control arm (HR, 0.55; 95% CI, 0.36-0.83). In the HPV-positive group, the median OS was 9.1 months with nivolumab compared with 4.4 months with investigator's choice (HR, 0.56; 95% CI, 0.32-0.99).

Those who tested negative for PD-L1 had a median OS of 5.7 months with nivolumab versus 5.8 months in the control arm (HR, 0.89; 95% CI, 0.54-1.45). In the HPV-negative arm, the median OS with nivolumab was 7.5 versus 5.8 months (HR, 0.73; 95% CI, 0.42-1.25).

AEs were significantly less with nivolumab versus investigator's choice. There were 2 treatment-related deaths in the nivolumab arm related to pneumonitis and hypercalcemia. In the investigator's choice arm, there was 1 death related to lung infection.

Overall, grade 3/4 events were experienced by 13.1% of patients treated with nivolumab versus 35.1% for investigator’s choice. All-grade AEs were experienced by 58.9% of patients treated with nivolumab compared with 77.5% with investigator's choice. The most common grade 3/4 AEs with nivolumab were fatigue (2.1%), anemia (1.3%), and asthenia (0.4%). For investigator's choice, the most common grade 3/4 AEs were anemia (4.5%), alopecia (2.7%), fatigue (2.7%), diarrhea (1.8%), asthenia (1.8%), and mucosal inflammation (1.8%).

"Nivolumab is a new standard-of-care option for patients with recurrent or metastatic head and neck squamous cell carcinoma after platinum-based therapy," said lead investigator Robert L. Ferris, MD, PhD, from the University of Pittsburgh Medical Center Cancer Center, when he presented the findings at ASCO. "Nivolumab is the first agent to demonstrate a significant improvement in survival in patients with head and neck squamous cell carcinoma who progress after platinum-based therapy in a global, phase III comparative trial."

In addition to the FDA priority review, the application was also validated by the European Medicines Agency for patients with previously treated metastatic or recurrent SCCHN. Validation of the application begins the European approval process, with the first step of the process beginning with the Committee for Medicinal Products for Human Use.

"These milestones are important steps in the regulatory processes, and we look forward to working with authorities in the US and Europe to offer Opdivo to this patient population,” Viallet noted.

In April 2016, nivolumab was granted a breakthrough therapy designation as a treatment for patients with SCCHN. This designation was also based on findings from the CheckMate-141 study, which was stopped early in January 2016 after showing an improvement in OS.

Since its initial approval for patients with melanoma in 2014, nivolumab has received numerous additional indications. The agent is approved for patients with non—small cell lung cancer, renal cell carcinoma, classical Hodgkin lymphoma, and for patients with melanoma as a single-agent and with the CTLA-4 inhibitor ipilimumab (Yervoy).

Ferris RL, Blumenschein GR, Fayette J, et al. Further evaluations of nivolumab (nivo) versus investigator’s choice (IC) chemotherapy for recurrent or metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN): CheckMate 141. J Clin Oncol. 2016;34 (suppl; abstr 6009).

The median age of patients in the trial was 60 years, and 31.3% were ≥65 years of age. The majority of patients were male (83%), Caucasian (83%), and had an ECOG PS of 1 (78.4%). Most patients received ≥2 prior systemic therapies (54.8%), and over 90% had received prior radiation therapy. HPV status was known for 49.3% of patients, using p16 status, and PD-L1 expression was available for 72% of enrolled patients.