Treatment with single-agent nivolumab reduced the risk of death by 30% and double 1-year overall survival rates compared investigator's choice of therapy for patients with recurrent or metastatic head and neck squamous cell carcinoma.
Maura Gillison, MD, PhD
Treatment with single-agent nivolumab (Opdivo) reduced the risk of death by 30% and doubled 1-year overall survival (OS) rates compared investigator's choice of therapy for patients with recurrent or metastatic head and neck squamous cell carcinoma (SCCHN), according to findings from the phase III CheckMate-141 study presented at the 2016 AACR Annual Meeting.
Median OS with nivolumab was 7.5 months compared with 5.1 months with investigator's choice of therapy (HR, 0.70; 95% CI, 0.51-0.96; P = .0101). Additionally, the 1-year OS rates were 36% with nivolumab compared with 16.6% for investigator’s choice. Adverse events (AEs) were significantly less with nivolumab versus investigator's choice, specifically for grade 3/4 events (13.1% vs 35.1%).
“What we think is most important about this trial is the number of patients who survive for a year, which is doubled with nivolumab in comparison with investigator’s choice. There was a 20% absolute improvement, which is something that has never been seen in this patient population before,” said lead investigator Maura Gillison, MD, PhD, Jeg Coughlin Chair of Cancer Research, The Ohio State University Wexner Medical Center. “Nivolumab represents a new standard of care option for patients with relapsed/metastatic head and neck cancer after platinum-based chemotherapy.”
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, methotrexate, or docetaxel (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 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 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. Patients were stratified based on prior cetuximab therapy, and HPV status was known for 49.3% of patients.
Findings were not presented at the conference for objective response rates and PFS. The only efficacy endpoint released during the session was OS, which was the primary focus of the interim analysis that led to the halting of the study.
“Nivolumab is the first agent to demonstrate a significant improvement in survival in patients with head and neck cancer that has progressed after platinum-based chemotherapy that was demonstrated in this randomized, phase III comparative trial,” said Gillison. “This fulfills an incredible unmet need in the clinic.”
Improvements in OS with nivolumab varied, based on HPV status. 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).
PD-L1 expression, which was available for 72% of enrolled patients, was associated with response to nivolumab. 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 those with PD-L1 expression of <1%, the median OS was 5.7 versus 5.8 months, for nivolumab and the control arm, respectively (HR, 0.89; 95% CI, 0.54-1.45).
“Nivolumab provided survival benefits in all of these subgroups; however, the magnitude of the reduction in the risk of death was greater for patients whose tumors expressed PD-L1 in greater than 1% of cells or were HPV-positive,” said Gillison. “In those two groups, the risk of death was reduced by approximately half.”
All-grade AEs were experience 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.
“No anticancer agent has been shown to improve survival for this patient population and no new treatments have been approved in over a decade,” said Gillison. “These data provide a new therapeutic opportunity for this patient population. Head and neck cancer was not previously considered a reasonable disease target for immunotherapy. The nivolumab data is already serving as a platform for combination therapy, adding other immunotherapies with nivolumab.”
Bristol-Myers Squibb, the developer of the PD-1 inhibitor, is currently discussing the phase III results with the FDA. Additionally, a second 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).
In conclusion, Gillison noted that a number of studies were planned to further explore nivolumab in head and neck cancer. “We are about to launch a couple studies incorporating these agents into initial therapy," she said. "It is moving quite rapidly, and it is very exciting.”
Gillison ML, Blumenschein G, Fayette J, et al. Nivolumab Versus Investigator’s Choice (IC) for Recurrent or Metastatic (R/M) Head and Neck Squamous Cell Carcinoma (SCCHN): CheckMate-141. Presented at: AACR 2016 Annual Meeting, New Orleans; April 16-20, 2016. Abstract CT099.