Nivolumab Obtains Expanded FDA Approval in NSCLC

Three months ahead of schedule, nivolumab (Opdivo) has obtained FDA approval for patients with nonsquamous non—small cell lung cancer (NSCLC) who progressed on or following platinum-based chemotherapy.

“There is still a lot to learn about the PD-1/PD-L1 pathway and its effects in lung cancer, as well as other tumor types,” said Richard Pazdur, MD, director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “While Opdivo showed an overall survival benefit in certain non—small cell lung cancer patients, it appears that higher expression of PD-L1 in a patient’s tumor predicts those most likely to benefit.”

The nivolumab approval is 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. A diagnostic for PD-L1, the IHC 28-8 pharmDx test, was approved along with nivolumab, to help guide treatment decisions for patients with both histologies of NSCLC.

The phase III open-label CheckMate-057 trial included 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/m²intravenously 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 permitted, as was TKI therapy for known EGFRmutations or ALKtranslocation. 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 wereEGFRpositive and 4% wereALKpositive, 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.

Data from an interim analysis presented at the 2015 ASCO Annual Meeting showed a median OS of 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.

Updated long-term OS data were for CheckMate-057 were recently presented at the 2015 European Cancer Congress and simultaneously published in&nbsp;The New England Journal of Medicine. At a minimum follow-up of 17.2 months, the OS rate with nivolumab was 39% compared with 23% for docetaxel. There remained a 2.8-month OS benefit with nivolumab versus docetaxel (HR, 0.72; 95% CI, 0.60-0.88;&nbsp;P<.001).

ORR was 19% with the PD-1 inhibitor compared with 12% with chemotherapy (OR = 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.

In PD-L1—positive patients (PD-L1 expression on &ge;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 &ge;5% and &ge;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.

&ldquo;Non—small cell lung cancer is a difficult-to-treat disease with high mortality, and patients with squamous and nonsquamous NSCLC often respond differently to treatment,&rdquo; said Roy Herbst, MD, PhD, chief of Medical Oncology, Yale Cancer Center and Smilow Cancer Hospital at Yale-New Haven, in a statment. &ldquo;Opdivo is becoming an important treatment option for more patients with previously treated metastatic NSCLC, and is a welcome addition to our therapy of this disease.&rdquo;

Roy Herbst, MD, PhD

Roy Herbst, MD, PhD

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 to 5 AEs 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.

With the approval, nivolumab joins pembrolizumab as the second PD-1 inhibitor approved for second-line NSCLC across all histologies. Pembrolizumab was recently approved for patients with NSCLC who progressed on or after platinum-containing chemotherapy or EGFR-or&nbsp;ALK-targeted agents in patients harboring those mutations. However, unlike nivolumab, pembrolizumab is only approved for patients with PD-L1—positive tumors, as determined by the PD-L1 IHC 22C3 pharmDx companion diagnostic that was simultaneously approved with the drug.&nbsp;