Europe Expands Nivolumab Lung Cancer Approval

The European Commission has approved nivolumab (Opdivo) for the treatment of patients with nonsquamous non–small cell lung cancer, regardless of PD-L1 levels.

Luis Paz-Ares, MD

The European Commission has approved nivolumab (Opdivo) for the treatment of patients with nonsquamous non—small cell lung cancer (NSCLC), regardless of PD-L1 levels, according to Bristol-Myers Squibb (BMS), the developer of the PD-1 inhibitor.

The 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 Europe for the second-line treatment of NCSLC patients with squamous cell carcinoma.

“Today’s approval expands the availability of Opdivo as a treatment option for a broader range of lung cancer patients—previously treated metastatic squamous and now nonsquamous non—small cell lung cancer—which represents the majority of diagnosed lung cancer cases,” Luis Paz-Ares, MD, Hospital Universitario Doce de Octubre, in Madrid, Spain, said in statement.

“As the only approved PD-1 inhibitor proven to have demonstrated a survival benefit versus a standard of care, regardless of PD-L1 expression, healthcare providers can offer treatment with Opdivo to appropriate patients who have received prior chemotherapy without the need to first conduct biomarker testing to determine PD-L1 expression. This approval is meaningful news for patients and their families who are in need of new treatment options.”

The phase III open-label CheckMate-057 trial 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 IV 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. The median patient age was 61 years in the nivolumab arm and 64 years in the docetaxel cohort, and all patients had an ECOG performance status of 0 or 1.

Prior maintenance with bevacizumab (Avastin), pemetrexed (Alimta), or erlotinib (Tarceva) 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.

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 = .0015), with a 1-year OS of 50.5% versus 39.0%, 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 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; P <.001).

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 PD-L1 IHC 28-8 PharmDx test, which is now Conformité Européene (CE) marked in Europe and can be used by physicians to obtain additional clinical information.

Higher PD-L1 expression in patients enrolled in CheckMate-057 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 ≥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 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.

BMS reported that the safety profile for nivolumab in CheckMate-057 was similar to outcomes observed in previous studies. The most frequently reported adverse events (AEs) among patients received nivolumab were fatigue (49%), musculoskeletal pain (36%), cough (30%), decreased appetite (29%), and constipation (23%).

Serious AEs were reported in 47% of patients receiving nivolumab. Serious AEs occurring in ≥2% of nivolumab-treated patients included pneumonia, pulmonary embolism, dyspnea, pleural effusions, and respiratory failure. AEs led to treatment delays in 29% of patients receiving nivolumab, with 13% discontinuing due to toxicities.

Commenting on the approval, Emmanuel Blin, senior vice president, head of Commercialization, Policy and Operations at BMS, said, “Today’s approval is indicative of our commitment to bringing our immuno-oncology science and the potential for long-term survival to a broader range of lung cancer patients in Europe. Opdivo is the only PD-1 inhibitor approved in Europe to have demonstrated, in two separate phase III trials, a significant survival advantage in this patient population, offering a much-needed new treatment option to patients fighting this disease.”


  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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