Bristol-Myers Squibb Company (BMY) announced that the European Commission has approved Opdivo (nivolumab) monotherapy for locally advanced or metastatic non-small cell lung cancer (NSCLC) after prior chemotherapy in adults. Opdivo is the only approved PD-1 inhibitor to demonstrate superior overall survival (OS) in two separate phase 3 trials in previously treated metastatic NSCLC; one trial in squamous NSCLC (CheckMate -017) and the other in non-squamous NSCLC (CheckMate -057), the basis of this approval. Together, these trials confirm the benefit of Opdivo for patients with previously treated metastatic NSCLC, regardless of PD-L1 expression. The approval allows for the expanded marketing of Opdivo in previously treated metastatic NSCLC in all 28 Member States of the European Union.


Emmanuel Blin, senior vice president, Head of Commercialization, Policy and Operations, Bristol-Myers Squibb, commented, “At Bristol-Myers Squibb, our goal is to help improve survival outcomes for patients with hard-to-treat cancers, such as advanced non-small cell lung cancer. 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 3 trials, a significant survival advantage in this patient population, offering a much-needed new treatment option to patients fighting this disease.”

The approval is based on the results of Phase 3 trial, CheckMate -057, which were published in The New England Journal of Medicine. In CheckMate -057, Opdivo was evaluated in patients with metastatic non-squamous NSCLC compared to docetaxel, and included patients regardless of PD-L1 expression. Opdivo demonstrated superior OS compared to docetaxel, with a 27% reduction in the risk of death (HR=0.73 [95% CI: 0.59-0.89; p=0.0015]) with a one-year survival rate of 51% for Opdivo (95% CI: 44.6-56.1) versus 39% for docetaxel (95% CI: 33.3-44.6). Biomarker testing for PD-L1 expression is not required with Opdivo. The Summary of Product Characteristics (SmPC) notes that physicians should consider the delayed onset of Opdivo effect before initiating treatment in patients with poorer prognostic features and/or aggressive disease. In non-squamous NSCLC, a higher number of deaths within the first 3 months was observed with Opdivo compared to docetaxel. Factors associated with early deaths were poorer prognostic factors and/or more aggressive disease combined with low or no tumor PD-L1 expression.

Luis Paz-Ares, M.D., Hospital Universitario Doce de Octubre, Madrid, Spain, commented, “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 non-squamous non-small cell lung cancer – which represents the majority of diagnosed lung cancer cases. 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.”

CheckMate -057 is an open-label, randomized phase 3 study, which evaluated Opdivo versus docetaxel in patients with metastatic non-squamous non-small cell lung cancer (NSCLC), with overall survival (OS) as the primary endpoint. Objective response rate (ORR) and progression-free survival (PFS) were evaluated as secondary endpoints. This study included patients regardless of PD-L1 expression level. In the study, patients were randomized to receive Opdivo (3 mg/kg administered intravenously every two weeks) versus docetaxel (75 mg/m2 administered intravenously every three weeks). The prespecified interim analysis was conducted when 413 events were observed (93% of the planned number of events for final analysis).

Opdivo demonstrated superior OS in previously treated metastatic non-squamous NSCLC compared to docetaxel, with a 27% reduction in the risk of death (HR=0.73 [95% CI: 0.59-0.89; p=0.0015]) with a one-year survival rate of 51% for Opdivo (95% CI: 44.6-56.1) compared to 39% for docetaxel (95% CI: 33.3-44.6). The median OS was 12.2 months in patients receiving Opdivo (95% CI: 9.66-14.98) and 9.4 months with docetaxel (95% CI: 8.0-10.68). The ORR in the Opdivo arm was 19% (56/292; 4 complete responses, 52 partial responses; 95% CI: 15-24) and 12% with docetaxel (36/290; 1 complete response, 35 partial responses; 95% CI: 9-17, p=0.0246). For patients administered Opdivo, median duration of response was 17.2 months and 5.6 months for docetaxel. Median PFS was 2.3 months for Opdivo versus 4.2 months for docetaxel (HR=0.92 [95% CI: 0.77-1.11, p=0.3932]).


Results of a post-hoc, exploratory multivariate analysis conducted in support of the SmPC development, indicated that Opdivo-treated patients with poorer prognostic features and/or aggressive disease when combined with low or no tumor PD-L1 expression may be at higher risk of death within the first 3 months (Opdivo arm [59/292, 20.2%] as compared to the docetaxel arm [44/290, 15.2%]). There were no early deaths due to study drug toxicity in either arm.

The safety profile of Opdivo in CheckMate -057 was consistent with prior studies. Serious adverse reactions occurred in 47% of patients receiving Opdivo. In the overall patient population, the most frequent serious adverse reactions in at least 2% of patients receiving Opdivo were pneumonia, pulmonary embolism, dyspnea, pleural effusions and respiratory failure. Opdivo was discontinued in 13% of patients and was delayed in 29% of patients for an adverse reaction. The most common adverse reactions in patients treated with Opdivo (reported in >20% of patients) were fatigue (49%), musculoskeletal pain (36%), cough (30%), decreased appetite (29%) and constipation (23%).


The PD-L1 IHC 28-8 PharmDx, a test which was used to assess PD-L1 expression in the CheckMate -057 trial, is now Conformité Européene (CE) marked in Europe, and can be used to provide additional information for physicians. PD-L1 testing is not required to initiate Opdivo treatment for locally advanced or metastatic NSCLC patients.

CheckMate -017 is a landmark, phase 3, open-label, randomized clinical trial that evaluated Opdivo 3mg/kg intravenously over 60 minutes every two weeks versus standard of care, docetaxel 75 mg/m2 intravenously administered every three weeks in patients with advanced squamous NSCLC who had progressed during or after one prior platinum doublet-based chemotherapy regimen. The study’s primary endpoint was OS and secondary endpoints included PFS and ORR. The trial included patients regardless of their PD-L1 expression status.

Results from CheckMate -017 showed a 41% reduction in the risk of death with a one-year survival rate of 42% for Opdivo (42.1% [95% CI: 33.7, 50.3]) versus 24% (23.7% [95% CI: 16.9, 31.1]) for docetaxel (HR=0.59 [96.8% CI: 0.43, 0.81; p=0.0002]). Median OS was 9.2 months versus 6 months for Opdivo and docetaxel, respectively. Opdivo also demonstrated consistent, statistically significant and clinically meaningful improvements across secondary endpoints, ORR and PFS, versus docetaxel in patients with previously treated advanced squamous NSCLC. Survival benefit was observed regardless of PD-L1 expression across all pre-specified expression levels (1%, 5% and 10%). The safety profile of Opdivo in CheckMate -017 was consistent with prior studies. Findings from CheckMate -017 were published in The New England Journal of Medicine and presented at the 2015 American Society of Clinical Oncology Annual Meeting.