FDA Expands Opdivo Approval in Lung Cancer


The approval is based on data from the phase 3 CheckMate-057 trial, in which second-line Opdivo reduced the risk of death by 28 percent versus docetaxel in patients with nonsquamous NSCLC.

Acting three months ahead of schedule, the FDA approved Opdivo (nivolumab) for patients with nonsquamous non—small cell lung cancer (NSCLC) who progressed on or following platinum-based chemotherapy.

The approval is based on data from the phase 3 CheckMate-057 trial, in which second-line Opdivo reduced the risk of death by 27 percent versus docetaxel in patients with nonsquamous NSCLC, including a 60 percent risk reduction among patients with the highest levels of PD-L1 expression.

Jennifer Temel from @MassGeneralNews on today's approval of Opdivo (nivolumab) for lung cancer #lcsm pic.twitter.com/x5d7oGG2Zv

— CURE Magazine (@cure_magazine) October 9, 2015

Opdivo 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 Opdivo, to help guide treatment decisions for patients with both histologies of NSCLC. The test is a "complementary," not a "companion," diagnostic, meaning its use is not mandated prior to administering nivolumab, according to Bristol-Myers Squibb, the developer of the drug.

The phase 3 open-label CheckMate-057 trial 582 patients with advanced nonsquamous NSCLC after the failure of platinum-based doublet chemotherapy to Opdivo at 3 mg/kg IV every two weeks (292 patients) or docetaxel at 75 mg/m2 intravenously every three weeks (290 patients). The treatments were administered until disease progression or unacceptable toxicity.

Patients received a median of six and four doses in the Opdivo and docetaxel arms, respectively. Patients had an ECOG performance status of 0 or 1. The median patient age was 61 years in the Opdivo 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 percent of patients in the Opdivo and docetaxel arms, respectively, had received prior maintenance therapy. In the Opdivo arm, 15 percent of patients were EGFR-positive and 4 percent were ALK-positive, with comparable rates of 13 percent and 3 percent, 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 Opdivo 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 Opdivo versus 9.4 months with docetaxel, with a one-year OS of 50.5 percent versus 39.0 percent, respectively.1

Updated long-term OS data for CheckMate-057 were recently presented at the 2015 European Cancer Congress2 and simultaneously published in The New England Journal of Medicine. At a minimum follow-up of 17.2 months, the overall survival (OS) rate with Opdivo was 39 percent compared with 23 percent for docetaxel. There remained a 2.8-month OS benefit with nivolumab versus docetaxel.

The median OS with Opdivo was 12.2 versus 9.4 months with docetaxel. The one-year progression-free survival (PFS) rates were 19 percent and 8 percent.

ORR was 19 percent with the PD-1 inhibitor compared with 12 percent with chemotherapy. Complete and partial response rates were 1 percent and 18 percent in the Opdivo arm and less than 1 percent and 12 percent in the docetaxel group, respectively. The stable disease rate was 25 percent and 42 percent with PD-1 inhibition and chemotherapy, respectively.

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

Median PFS was comparable between the cohorts at 2.3 months in the Opdivo arm compared with 4.2 months in the docetaxel group. One-year PFS favored Opdivo at 18.5 percent versus 8.1 percent 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 percent of patients for whom PD-L1 status was detectable.

In PD-L1—positive patients (PD-L1 expression on at least 1 percent of tumor cells), median OS was improved by 41 percent among 123 individuals treated with Opdivo versus 123 patients who received docetaxel (median OS was 17.2 months vs 9.0 months).

The OS benefit continued to rise as PD-L1 levels increased. The reduction in the risk of death was 57 percent (median OS = 18.2 months) and 60 percent (median OS = 19.4 months) for patients expressing PD-L1 on at least 5 percent and at least 10 percent 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 less than 1 percent, less than 5 percent and less than 10 percent, respectively.

“Non-small cell lung cancer is a difficult to treat disease with high mortality, and patients with squamous and non-squamous NSCLC often respond differently to treatment,” Roy Herbst, chief, Medical Oncology, Yale Cancer Center and Smilow Cancer Hospital at Yale-New Haven, said in a statment. “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.”

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

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

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


  1. Paz-Ares LG, Horn L, Borghaei H, et al. Phase III, randomized trial (CheckMate 057) of nivolumab (NIVO) versus docetaxel (DOC) in advanced non-squamous cell (non-SQ) non-small cell lung cancer (NSCLC). J Clin Oncol. 2015;33 (suppl; abstr LBA109).
  2. Horn L, Brahmer J, Reck M, et al. Phase 3, randomized trial (CheckMate 057) of nivolumab (NIVO) vs docetaxel (DOC) in advanced non-squamous (non-SQ) non-small cell lung cancer (NSCLC): Subgroup analyses and patient reported outcomes (PROs). Presented at: 2015 European Cancer Congress; September 25-29; Vienna, Austria. Abstract 3010.
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