FDA Grants Nivolumab Priority Review in Nonsquamous NSCLC

Michael Giordano, MD

Nivolumab (Opdivo) has received an FDA priority review designation for patients with previously treated nonsquamous non­—small cell lung cancer (NSCLC), according to the developer of the PD-1 inhibitor, Bristol-Myers Squibb (BMS). Under the expedited process, the FDA’s decision deadline is January 2, 2016.

The FDA simultaneously granted nivolumab a breakthrough therapy designation in this setting. The priority and breakthrough designations are based on data from the phase III CheckMate-057 trial, in which second-line nivolumab reduced the risk of death by 27% versus docetaxel in patients with nonsquamous NSCLC, including a 60% risk reduction among patients with the highest levels of PD-L1 expression.

Nivolumab was previously approved in March 2015 for patients with squamous cell NSCLC who have progressed on or after platinum-based chemotherapy.

“We are pleased with this important step forward in the FDA’s consideration to expand the use of Opdivo to include nonsquamous non—small cell lung cancer patients, as well as the breakthrough therapy designation...We look forward to working with the FDA to make this treatment option available to more patients," Michael Giordano, MD, senior vice president, head of Development, Oncology, BMS, said in a statement.

Results from the phase III open-label CheckMate-057 trial were presented at the 2015 ASCO Annual Meeting. The study randomized 582 patients with advanced nonsquamous NSCLC after the failure of platinum-based doublet chemotherapy to nivolumab at 3 mg/kg IV every 2 weeks (n = 292) or docetaxel at 75 mg/m² intravenously every 3 weeks (n = 290). The treatments were administered until disease progression or unacceptable toxicity.

Patients received a median of 6 and 4 doses in the nivolumab and docetaxel arms, respectively. Patients had an ECOG performance status of 0 or 1. The median patient age was 61 years in the nivolumab arm and 64 years in the docetaxel cohort. Prior maintenance with bevacizumab, pemetrexed, or erlotinib was allowed, as was TKI therapy for known EGFR mutations or ALK translocation. Forty-percent and 38% of patients in the nivolumab and docetaxel arms, respectively, had received prior maintenance therapy. In the nivolumab arm, 15% of patients were EGFR-positive and 4% were ALK-positive, with comparable rates of 13% and 3%, respectively, in the docetaxel group.

Overall survival (OS) was the primary endpoint, with secondary objectives focused on progression-free survival (PFS), objective response rate (ORR) per RECIST v1.1, efficacy by PD-L1 expression, and safety.

The study was stopped early after an independent monitoring panel determined the primary endpoint of improved OS had been reached. Eligible patients were allowed to continue treatment or cross over to the nivolumab arm in an open-label extension of the study.

The median OS was 12.2 months with nivolumab versus 9.4 months with docetaxel (HR, 0.73; 96% CI, 0.59-0.89; P = .00155), with a 1-year OS of 50.5% versus 39.0%, respectively.

“Nivolumab is the first PD-1 inhibitor to significantly improve OS as compared to docetaxel in [NSCLC] patients with prior treatment and nonsquamous histology,” lead author Luis Paz-Ares, MD, Hospital Universitario Doce de Octubre, Madrid, Spain, said when presenting the data in a press conference at the ASCO meeting.

ORR was 19% with the PD-1 inhibitor compared with 12% with chemotherapy (Odds Ratio = 1.72; 95% CI, 1.1-2.6; P = .0246). Complete and partial response rates were 1% and 18% in the nivolumab arm and <1% and 12% in the docetaxel group, respectively. The stable disease rate was 25% and 42% with PD-1 inhibition and chemotherapy, respectively.

Median time to response was 2.1 months with nivolumab versus 2.6 months with docetaxel. Median duration of response was 17.2 months versus 5.6 months in the nivolumab and control arms, respectively. Fifty-two percent of the nivolumab responses are still ongoing compared with 14% of the docetaxel responses.

Median PFS was comparable between the cohorts at 2.3 months in the nivolumab arm compared with 4.2 months in the docetaxel group (HR, 0.92; 95% CI, 0.77-1.11; P = .393). One-year PFS favored nivolumab at 18.5% versus 8.1% for the control arm.

The researchers measured PD-L1 levels in pretreatment tumor biopsies with the Dako automated IHC assay. Higher PD-L1 expression was associated with improved survival outcomes among the 78% of patients for whom PD-L1 status was detectable. “PD-L1 emerged as a clear predictive factor for the benefit from nivolumab treatment,” said Paz-Ares.

In PD-L1—positive patients (PD-L1 expression on ≥1% of tumor cells), median OS was improved by 41% among 123 individuals treated with nivolumab versus 123 patients who received docetaxel (median OS = 17.2 months vs 9.0 months; HR , 0.59).

The OS benefit continued to rise as PD-L1 levels increased. The reduction in the risk of death was 57% (median OS = 18.2 months) and 60% (median OS = 19.4 months) for patients expressing PD-L1 on ≥5% and ≥10% of their tumor cells, respectively.

The researchers did not observe a similar OS benefit among patients with low or undetectable PD-L1 levels. Median OS was 10.4, 9.7, and 9.9 months among patients with PD-L1 expression levels <1%, <5%, and <10%, respectively.

Nivolumab was well tolerated and had a better safety profile than docetaxel. Among patients evaluable for safety, all-grade adverse event (AE) rates were 69% versus 88% in the nivolumab versus docetaxel arms, respectively. The most common all-grade AEs with nivolumab versus docetaxel were fatigue (16% vs 29%), nausea (12% vs 26%), decreased appetite (11 vs 16%), asthenia (10 vs 18), and diarrhea (8% vs 23%).

Grade 3-5 adverse events were reported in 10.5% of the nivolumab arm compared with 53.7% of the docetaxel cohort. The most common grade 3/4 AEs with nivolumab were fatigue, nausea, and diarrhea, at 1% each. Twenty-seven percent of patients in the docetaxel arm had grade 3/4 neutropenia versus 0 in the nivolumab arm.

Toxicity-related discontinuations occurred in 4.9% of patients receiving nivolumab compared with 14.9% of those treated with chemotherapy. Systemic therapy was administered to 42.1% and 49.7% of patients who discontinued nivolumab and docetaxel, respectively. No treatment-related deaths occurred in the nivolumab group compared with 1 in the docetaxel arm.

The FDA is also currently reviewing an application for the PD-1 inhibitor pembrolizumab (Keytruda) as a treatment for patients with advanced NSCLC across all histologies whose disease has progressed on or after platinum-containing chemotherapy, as well as a targeted agent in EGFR- or ALK-positive patients. A final approval decision on pembrolizumab is scheduled by October 2, 2015.

Beyond squamous NSCLC, nivolumab is approved for patients with unresectable or metastatic melanoma following treatment with ipilimumab (Yervoy) and/or a BRAF inhibitor. The FDA is scheduled to make an approval decision by November 27, 2015, on a supplemental application for nivolumab in the frontline advanced melanoma setting.