Nivolumab Improves OS, ORR in Phase III Head and Neck Cancer Study

Robert Ferris, MD, PhD

Treatment with single-agent nivolumab (Opdivo) improved overall survival (OS) and objective response rates (ORR) compared with investigator's choice of therapy for patients with recurrent or metastatic head and neck squamous cell carcinoma (SCCHN), according data from the phase III CheckMate-141 study presented at the 2016 ASCO Annual Meeting.

Across the full study, the median OS 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 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 objective response rate (ORR) was 13.3% with nivolumab and 5.8% for investigator's choice.

Further analyses revealed distinct populations of patients who responded better to nivolumab monotherapy, specifically those with PD-L1-positive and HPV-positive SCCHN. In these groups, the reduction in the risk of death with nivolumab was near 50% versus investigator's choice of therapy.

"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. "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 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 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.

The primary endpoint was OS, with secondary outcome measures focused on response rates and progression-free survival (PFS). The study was initiated in May 2014 and was not scheduled to complete until October 2016; however, it was stopped early after an independent monitoring panel determined the primary endpoint was met with the anti—PD-1 agent versus the investigator's choice of therapy.

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 6-year PFS rates were 19.7% for nivolumab and 9.9% for investigator's choice of therapy.

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%.

"Nivolumab doubled the 1-year survival rate, from 36% with nivolumab to 17% for investigator's choice of therapy," said Ferris. "Nivolumab demonstrated a survival benefit in the overall study population, regardless of PD-L1 expression or p16 status."

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). 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 those with PD-L1 expression on ≥5% cells, the median OS was 8.8 versus 4.6 months for nivolumab and investigator's choice, respectively (HR, 0.50; 95% CI, 0.30-0.83). For those with ≥10% expression, median OS was and 8.7 versus 5.2 months, for nivolumab and the control, respectively (HR, 0.56; 95% CI, 0.31-0.99).

"Magnitude of OS benefit of nivolumab versus investigator's choice was greater in patients expressing PD-L1, and increasing PD-L1 expression did not result in further benefit," said Ferris.

For those with ≥1% PD-L1 expression, the median PFS was 2.1 months with nivolumab versus 2.0 months for investigator's choice (HR, 0.64; 95% CI, 0.44-0.93). For the ≥5% expression group, the median PFS with nivolumab was 3.2 months compared with 2.0 months in the comparator arm (HR, 0.53; 95% CI, 0.33-0.84). In the ≥10% expression group, median PFS was 2.1 versus 2.1 months (HR 0.53; 0.31—0.88), for nivolumab and the control, respectively.

In patients with tumors that expressed PD-L1 on ≥1% of cells, the ORR was 17% with nivolumab compared with 1.6% with investigator's choice. In those with ≥5% and ≥10% expression, the ORRs were 22.2% versus 2.3% and 27.9% versus 2.9%, for nivolumab and the control arm, respectively. In the PD-L1-negative group, the ORR was 12.3% with nivolumab and 10.5% with investigator's choice of therapy.

HPV status also played a role in the responses experienced by patients treated with nivolumab. 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). 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).

Those with PD-L1 expression ≥1% and HPV-positive SCCHN had a median OS of 8.8 months with nivolumab and 3.9 months in the control arm (HR, 0.50; 95% CI, 0.21-1.19). In those with ≥1% PD-L1 expression and HPV-negative disease, the median OS was 8.8 versus 5.6 months, for nivolumab and control, respectively (HR, 0.44; 95% CI, 0.18-1.10).

For those with PD-L1-negative and HPV-positive disease, the median OS was 10.0 versus 6.4 months (HR, 0.55; 95% CI, 0.22-1.39). In those with PD-L1-negative/HPV-negative SCCHN, the median OS was 7.1 months with nivolumab and 7.4 months with investigator's choice of therapy (HR, 0.82; 95% CI, 0.31-2.19).

AEs were significantly less with nivolumab versus investigator's choice. 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%).

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.

"There were fewer treatment-related adverse events with nivolumab versus investigator's choice of therapy," said Ferris. "Nivolumab stabilized patient-reported outcomes while investigator's choice led to meaningful declines in function and worsening of symptoms."

A phase III study is planned, to assess the frontline combination of nivolumab and ipilimumab (Yervoy) compared with standard of care for patients with recurrent or metastatic SCCHN. This trial plans to enroll 460 patients with dual primary endpoints of OS and PFS (NCT02741570).

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).

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