Nivolumab Survival Benefit Extended in Updated NSCLC Results

David Spigel, MD

The PD-1 blocking antibody nivolumab continues to demonstrate sustained clinical activity in previously treated patients with advanced non-small cell lung cancer (NSCLC), according to updated long-term survival data from a phase I trial.

Survival rates at one year with nivolumab were 42% and reached 24% at two years, according to the median 20.3-month follow up. Additionally, the objective response rate (ORR) with nivolumab, defined as complete or partial responses by standard RECIST criteria, was 17% for patients with NSCLC. Results from the updated analysis will be presented during the 2013 World Conference on Lung Cancer on October 29.

“Lung cancer is very difficult to treat and there continues to be a high unmet medical need for these patients, especially those who have received multiple treatments,” David R. Spigel, MD, the program director of Lung Cancer Research at the Sarah Cannon Research Institute and one of the authors of the updated analysis, said in a statement.

“With nivolumab, we are investigating an approach to treating lung cancer that is designed to work with the body’s own immune system, and these are encouraging phase I results that support further investigation in larger scale trials.”

In the phase I trial, 306 patients received intravenous nivolumab at 0.1—10 mg/kg every-other-week for ≤12 cycles (4 doses/8 week cycle). In all, the trial enrolled patients with NSCLC, melanoma, renal cell carcinoma, colorectal cancer, and prostate cancer.

The long-term follow up focused specifically on the 129 patients with NSCLC. In this subgroup, patients treated with nivolumab showed encouraging clinical activity. The participants had a median age of 65 years and good performance status scores, and more than half had received three or more prior therapies. Across all doses of nivolumab, the median overall survival was 9.9 months, based on Kaplan-Meier estimates.

In a previous update of the full trial results presented at the 2013 ASCO Annual Meeting, drug-related adverse events of all grades occurred in 72% of patients and grade 3/4 events occurred in 15%. Grade 3/4 pneumonitis related to treatment with nivolumab emerged early in the trial, resulting in 3 deaths. As a result, a treatment algorithm for early detection and management was developed to prevent this serious side effect.

Nivolumab is a fully human monoclonal antibody that blocks the PD-1 receptor from binding to both of its known ligands, PD-L1 and PD-L2. This mechanism, along with early data, suggested an associated between PD-L1 expression and response to treatment.

In separate analysis presented at the 2013 World Conference on Lung Cancer, the association of tumor PD-L1 expression and clinical activity in patients with NSCLC treated with nivolumab was further explored. Of the 129 patients with NSCLC treated with nivolumab in the phase I trial, 63 with NSCLC were tested for PD-L1 expression by immunohistochemistry (29 squamous; 34 non-squamous).

In total, 31 of the 63 patients tested positive for PD-L1 expression, without an apparent association between the marker and histology (52% squamous; 47% non-squamous). For patients with all histology, a clear advantage was seen in patients who tested positive for PD-L1, though PD-L1-negative patients still experienced responses to treatment with nivolumab.

In the entire subpopulation that were tested, PD-L1-positive patients experienced an ORR of 16.1% (5/31) compared with 12.5% (4/32) in those testing negative. In the squamous population, ORR was 21.4% (3/14) in patients who tested negative for PD-L1 compared with 13.3% (2/15) in patients who tested positive. In patients with non-squamous histology, ORR was 18.8% (3/16) in the positive group compared with 5.6% (1/18) in the negative group.

“Our goal with immuno-oncology is to change survival expectations and the way patients live with cancer,” Michael Giordano, senior vice president, Head of Development, Oncology & Immunology, Bristol-Myers Squibb, said. “These are encouraging phase I results from the expanded cohort of patients with lung cancer, the leading cause of cancer deaths globally, and we are seeking to confirm these early data in ongoing phase III trials.”

There are currently over 25 studies examining treatment with nivolumab, including 3 phase III trials in NSCLC, melanoma, and renal cell carcinoma. At this point, the treatment remains investigational.