FDA Grants Nivolumab Breakthrough Designation for Head and Neck Cancer

Jean Viallet, MD

The FDA has granted a breakthrough therapy designation to nivolumab (Opdivo) as a treatment for patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) following a platinum-based therapy, according to the developer of the PD-1 inhibitor Bristol-Myers Squibb

The designation was based on findings from the open-label phase III CheckMate-141 study, which demonstrated an improvement in overall survival (OS) with nivolumab versus investigator's choice of therapy. 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). The 1-year OS rates were 36% with nivolumab compared with 16.6% for investigator’s choice.

“The breakthrough therapy designation for Opdivo in advanced squamous cell carcinoma of the head and neck underscores the immediate need for new treatment approaches for this devastating disease, and reflects our commitment to advancing Immuno-Oncology research with the goal of addressing hard-to-treat cancers and changing survival expectations for patients,” Jean Viallet, MD, Global Clinical Research Lead, Oncology, Bristol-Myers Squibb, said in a statement.

The CheckMate-141 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 primary endpoint was OS, with secondary outcome measures focused on response rates and progression-free survival (PFS), although these findings have not yet been presented.

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 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.

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).

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.

“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, when she presented the data at the 2016 AACR Annual Meeting. “Nivolumab represents a new standard of care option for patients with relapsed/metastatic head and neck cancer after platinum-based chemotherapy.”

The breakthrough designation is meant to expedite the development of therapies that offer substantial benefits over existing option. Under the program, a rolling submission of data is allowed along with more communication with the FDA. Bristol-Myers Squibb initiated discussions with the FDA regarding potential approval for nivolumab in head and neck cancer when the study was stopped in late January.

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).

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.