Nivolumab, Alectinib Gain Approvals in Japan

Sandra Horning, MD

The PD-1 inhibitor nivolumab and the second-generation ALK inhibitor alectinib have each gained their first approvals as treatments for patients in Japan. This action makes nivolumab the first PD-1 inhibitor to gain regulatory approval.

Nivolumab will be indicated for the treatment of patients with unresectable melanoma while alectinib is intended for the treatment of patients with ALK-positive non-small cell lung cancer (NSCLC). In Japan, nivolumab will be marketed as Opdivo and alectinib as Alecensa. Each of the regulatory decisions was based on findings from early-phase clinical trials.

The standard of care for unresectable melanoma in Japan is currently dacarbazine, which generally elicits an overall response rate (ORR) of 13% and a median overall survival (OS) ranging from 5.6 to 11 months. Early studies of nivolumab in unresectable melanoma have demonstrated 3-year OS rates of 41% with an ORR of 32%.

Ono Pharmaceuticals, the company developing nivolumab in Japan, Korea, and Taiwan, noted that post-marketing surveys would be required for all patients treated with the drug, in order to accumulate further safety and efficacy data. In June 2014, nivolumab demonstrated superiority to dacarbazine in a randomized phase III study. However, this study was not conducted in an Asian population. Full results from this analysis will be presented and published later on.

"We are delighted to obtain a manufacturing and marketing approval as a drug targeting PD-1, which receives a lot of attention in tumor immunity, for the first time in the world," Gyo Sagara, the President and Representative Director of Ono Pharmaceuticals, said in a press release. "Ono would like to obtain approvals for additional indications on ongoing development for other cancers to bring many patients Opdivo as soon as possible."

The Japanese approval for alectinib was based on results from the single-arm phase I/II AF-001JP study. Twenty-four patients were enrolled in the phase I dose findings portion of the study, which revealed a 300 mg twice-daily dose without uncovering any dose limiting toxicities.

In the phase II portion of the study, 46 patients with ALK-positive NSCLC received continuous alectinib at 300 mg twice daily. Patients in the study were ALK inhibitor naive, with 62% having received ≥2 prior chemotherapy regimens. The primary endpoint of the study was ORR.

In the phase II study, 2 patients experienced a complete response and 41 had a partial response for an ORR of 93.5% (95% CI, 82.1-98.6%). At 12 months, 83% of patients remained progression free (95% CI, 68-92%). Patients with CNS metastases (n = 14) experienced responses, with 64% remaining progression-free after 12 months.

Grade 4 or higher adverse events were not observed in the clinical trial. Neutrophil count decrease occurred in 7% of patients and was the only major grade 3 adverse event. The most common all-grade adverse events were dysgeusia (36%), rash (33%), AST increased (33%), blood bilirubin increased (33%), constipation (29%), and blood creatinine increased (29%).

“The approval of alectinib, a treatment specifically targeted to ALK-positive lung cancer, in Japan is great news for people living with this difficult to treat disease,” Sandra Horning, MD, Chief Medical Officer and Head of Global Product Development at Roche, the company developing the drug, said in a statement. “Another interesting aspect of alectinib is that based on early studies it may also work in people living with tumors that have spread to the brain, a difficult area to reach with current medicines. Our research will continue in this area."

Nivolumab is currently being explored as a monotherapy and in combination across a variety of tumor types. More than 7,000 patients are receiving treatment with nivolumab in clinical trials, according to Bristol-Myers Squibb (BMS) the company that markets the drug outside of Japan, Korea, and Taiwan. In April 2014, BMS announced plans to initiate a rolling submission to the FDA for nivolumab as a third-line treatment for patients with squamous cell NSCLC. This submission is expected to be complete by the end of the year.

Alectinib received a breakthrough therapy designation from the FDA in June 2013 as a treatment for patients with ALK-positive NSCLC following progression on crizotinib. In addition to this indication, a phase III study is planned to compare alectinib to crizotinib as a frontline therapy (NCT02075840).