Phase II Study Shows Promising Efficacy for Nivolumab in Advanced NSCLC

Suresh S. Ramalingam, MD

The PD-1 immune checkpoint inhibitor nivolumab (Opdivo) achieved an objective response rate (ORR) of 15% (95% CI, 8.7- 22.2) with a median duration of response that was not yet reached at an 11-month follow-up for patients with advanced, refractory non-small cell lung cancer (NSCLC).

The data were presented at the 2014 Multidisciplinary Symposium in Thoracic Oncology, where lead author Suresh S. Ramalingam, MD, professor and director of medical oncology, Winship Cancer Institute of Emory University, called the study findings encouraging.

"There are currently no effective treatment options for patients with refractory squamous cell lung cancer after their disease has progressed through 2 prior therapies," he said at the symposium. "Historically, these patients have had ORRs of 2%-8% and median overall survival (OS) of about 5 months so, even though we have not yet reached the median duration of response [in this study], the signs are very promising."

ORR was the primary endpoint of this study, known as Checkmate-063. The study was designed for patients who had failed 2 or more systemic treatments (n = 117). Notably, 65% of patients (n = 76) had previously failed 3 or more treatments. Seventy-six percent of patients were within 3 months of completion of their most recent therapy.

Patients in the study were treated with nivolumab as a single agent at 3 mg/kg by intravenous infusion every 2 weeks until disease progression or treatment discontinuation. Responders were further characterized by duration of response. Secondary endpoints included investigator-assessed ORR, and exploratory endpoints were overall survival (OS), progression free survival (PFS), and efficacy by PD-L1 expression status.

With approximately 11 months of minimum follow up, the ORR was 15% (95% CI, 8.7, 22.2) as assessed by an independent review committee (IRC) using RECIST 1.1 criteria. The median duration of response was not reached. The estimated 1-year survival rate was 41% (95% CI, 31.6-49.7) and the median OS was 8.2 months (95% CI, 6.05-0.91). This compares favorably with the previously demonstrated 1-year survival rate of 5.5% to 18% for patients with third-line squamous cell NSCLC, noted Ramalingam.

An additional 26% of patients had stable disease for a median duration of 6 months (95% CI, 4.73-10.91), demonstrating a disease control rate (defined as ORR + stable disease) of 41%. For patients with quantifiable PD-L1 expression, responses were observed independent of PD-L1 status.

Adverse events (AEs) of all types and grades occurred in 74% of patients; however, 85% of patients were able to receive at least 90% of their planned dose intensity. Grade 3-4 drug-related AEs were reported in 17% of patients. The most common (greater than or equal to 2%) Grade 3-4 AEs were fatigue (4.3%), pneumonitis (3.4%), and diarrhea (2.6%). Discontinuations due to drug-related AEs of any grade occurred in 12% of patients. Two drug-related deaths (1 hypoxic pneumonia, 1 ischemic stroke) occurred in patients with multiple comorbidities and progressive disease.

Among the 15% of patients who responded to nivolumab, the response was durable and remained ongoing in 76% of patients. Additionally, the authors noted that nivolumab was well tolerated with a manageable safety profile, and showed clinical activity in patients who were both PD-L1-positive and PD-L1-negative.

In recognition of the urgent need for therapies for squamous NSCLC, the study authors pointed out a phase III trial is currently under way comparing the OS of nivolumab to docetaxel for squamous NSCLC. At this point, 4 phase III trials are evaluating nivolumab as monotherapy in patients with NSCLC: 3 in previously treated patients and 1 in the frontline setting.

The study has already garnered attention within the oncology community, with the thoracic symposium accepting results from the phase II Checkmate-063 study as a late-breaking abstract, to highlight its rapidly developing data.

In an interview with OncLive, immunotherapy discussant Vassiliki Papadimitrakopoulou, MD, a professor at MD Anderson Cancer Center, described results from the Checkmate-063 study as the most promising of 5 immunotherapy studies presented at the symposium.

"The study looking at nivolumab monotherapy for squamous NSCLC is quite unprecedented," Papadimitrakopoulou said. "It shows promise for a group of patients who are not able to be served by any existing therapies. And it gives us a signal where to focus our further studies in this important area."

S.S. Ramalingam, J. Mazieres, D. Planchard et al. Phase II study of nivolumab (Anti-PD-1, BMS-936558, ONO-4538) in patients with advanced, refractory squamous non-small cell lung cancer. Presented at: 2014 Multidisciplinary Symposium in Thoracic Oncology; October 30-November 1, 2014; Chicago, IL. Abstract Number: LB2.

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