Immune Checkpoint Inhibitor Nivolumab Promising in Lung Cancer

Treatment with the immune checkpoint antibody, nivolumab (Opdivo), resulted in a 14.5% overall response rate, including one complete response in a phase II trial of heavily pretreated squamous non-small cell lung patients (NSCLC). The median duration of response has not yet been reached, and currently, 13 of the 17 responses (77%) are ongoing as of the last trial assessment.

The results from the CheckMate 063 clinical trial with the antiprogrammed cell death-1 (anti-PD-1) immunotherapy antibody are published  in The Lancet Oncology. The initial results were previously presented at the 2014 Multidisciplinary Symposium in Thoracic Oncology.

An additional 30 patients on the trial (26%) had stable disease with a median duration of 6.0 months. The median time to response was 3.3 months.

Of the 17 responders, eight (47%) had progressive disease in response to their previous treatment.

“Nivolumab has clinically meaningful activity and a manageable safety profile in previously treated patients with advanced, refractory, squamous non-small cell lung cancer. These data support the assessment of nivolumab in randomized, controlled, phase III studies of first-line and second-line treatment,” concluded the study authors.

The single-arm trial enrolled 117 patients in the United States and Europe who had failed two or more therapies for their advanced disease. Sixty-five percent of the patients had failed at least three prior therapies. The median patient age on trial was 65. Thirty-three percent of patients had received a prior anti-EGFR tyrosine kinase inhibitor and all patients had received a platinum-based chemotherapy.

Patients received 3 mg/kg of nivolumab as an intravenous infusion every 2 weeks until disease progression or unacceptable adverse events. Patients received a median of 6 nivolumab doses.

Patients with refractory squamous NSCLC have no therapeutic options after failing two systemic treatments and a short overall survival of less than 6 months. The two-year survival rate is only 3%.

The median progression-free survival (PFS) was 1.9 months, and the PFS rate at 6 months and 1 year was 25.9% and 20.0%, respectively. Median overall survival was 8.2 months with an overall survival rate at 1 year of 40.8%.

Both patients with tumors expressing PD-L1, the ligand for PD-L, and those whose tumors lacked PD-L1 expression responded to treatment. Of the 25 PD-L1 positive patients, six (24%) had a partial response while seven of the 51 (14%) of the PD-L1-negative patients had a partial response.

Treatment related grade 3-4 adverse events included fatigue (4%), pneumonitis (3%), and diarrhea (3%). There were two treatment-associated deaths; one from pneumonitis and another from an ischemic stroke in two patients who had multiple comorbities and progressive disease. Discontinuation due to an adverse event occurred in 12% of patients.

In a commentary accompanying this study publication, Ramon Andrade de Mello, MD, and Inés Pousa, PhD, of the University ofAlgarve, Faro, Portugal, and Deolinda Pereira, MD  of the Portuguese Oncology Institute, Porto, Portugal, highlight two concerns with the study: the use of Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 to evaluate responses rather than the newer immune-related response criteria better suited for the types of responses seen to immunotherapies, and the role of nivolumab in targeting brain metastases, which was not well-addressed in the study.

Nivolumab is currently approved by the US Food and Drug Administration (FDA) for treatment of metastatic melanoma. In January of 2015, a phase III trial comparing nivolumab to docetaxel in previously treated metastatic squamous NSCLC was stopped early because the study demonstrated a superior overall survival of patients in the nivolumab therapy arm.

Bristol-Myers Squibb, the manufacturer of nivolumab, has submitted a marketing authorization application to the European Medicines Agency for use of nivolumab in NSCLC. The company also has a rolling submission with the FDA of nivolumab as a third-line therapy for squamous NSCLC.