The FDA has approved the PD-1 inhibitor nivolumab as a treatment for patients with metastatic or recurrent squamous cell carcinoma of the head and neck following progression on platinum-based therapy.
Robert L. Ferris, MD, PhD
The FDA has approved the PD-1 inhibitor nivolumab (Opdivo) as a treatment for patients with metastatic or recurrent squamous cell carcinoma of the head and neck (SCCHN) following progression on platinum-based therapy, based on an improvement in overall survival (OS) in the phase III CheckMate-141 study.
In the pivotal study, median OS with nivolumab was 7.5 months compared with 5.1 months with investigator's choice (HR, 0.70; 95% CI, 0.52-0.92;P= .0101). The objective response rate (ORR) was 13.3% with nivolumab and 5.8% for investigator's choice.
"The FDA approval of nivolumab in the setting of patients with cisplatin-refractory is important because cisplatin is the most effective systemic agent in head and neck cancer and has been for decades, so this is transformative, especially to have level 1 evidence, which is the highest level of evidence that we have," said lead investigator Robert Ferris, MD, PhD, vice chair for Clinical Operations, associate director for Translational Research, and coleader of the Cancer Immunology Program at the University of Pittsburgh Cancer Institute. "This holds out great hope that these patients now have an agent that is effective."
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/m2for the first dose followed by 250 mg/m2weekly. Methotrexate was administered at 40 mg/m2weekly. Docetaxel was administered at 30 mg/m2weekly.
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 (54.8%) received ≥2 prior systemic therapies, 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.
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 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-L1positive 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).
Adverse events (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%).
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 nonsmall cell lung cancer, renal cell carcinoma, and classical Hodgkin lymphoma, as well as 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