Madrid, Spain—Durvalumab (Imfinzi), a PD-L1 inhibitor, improved progression-free survival (PFS) by 11.2 months compared with placebo in patients with locally advanced, unresectable stage III non–small-cell lung cancer (NSCLC) that did not progress after standard treatment with chemoradiotherapy. These results—presented at the 2017 European Society for Medical Oncology (ESMO) Congress—come from PACIFIC, the first phase 3 clinical trial of a PD-L1 inhibitor in patients with locally advanced NSCLC outside of the metastatic setting.
“We saw a clear improvement in outcome versus placebo. Progression-free survival improved with durvalumab across all prespecified end points. Durvalumab is a promising new therapeutic option for patients with stage III locally advanced NSCLC,” said Luis Paz-Ares, MD, PhD, Chair, Medical Oncology Department, Hospital Universitario 12 de Octubre, Madrid, Spain, who presented the results. The results were simultaneously published in the New England Journal of Medicine (Antonia SJ, et al. N Engl J Med. 2017 Sep 8. Epub ahead of print).
Most patients who present with stage III NSCLC at diagnosis have unresectable disease. Despite standard treatment with platinum-based chemotherapy and concurrent radiation therapy, the disease will relapse in the majority of patients, and the 5-year survival is only 15%.
Dr Paz-Ares suggested that the checkpoint inhibitor durvalumab extends the duration of disease control, improving PFS by more than 11 months.
“We haven’t analyzed survival data yet, but we hope we can increase the percentage of patients alive at 5 years with this therapy,” he said.
In July 2017, durvalumab received a breakthrough therapy designation from the FDA as a potential treatment for locally advanced, unresectable NSCLC that has not progressed after chemoradiation. In May 2017, it was approved by the FDA for bladder cancer.
PACIFIC Trial Results
The PACIFIC clinical trial is conducted at 235 centers in 26 countries and has enrolled 713 patients with locally advanced, unresectable stage III NSCLC that had not progressed after platinum-based chemotherapy and concurrent radiation therapy for up to 42 days.
Patients were randomized in a 2:1 ratio to durvalumab 10 mg/kg every 2 weeks or to placebo for up to 12 months.
At baseline, response rates to chemotherapy were similar between the 2 arms—50.6% for durvalumab and 49.8% for placebo.
At a preplanned interim analysis at 14.5 months, the median PFS was 16.8 months in the durvalumab arm versus 5.6 months with placebo, a 48% reduction in the likelihood of disease progression with durvalumab (hazard ratio, 0.52; P <.0001). At 18 months, PFS rates were 44.2% for durvalumab and 22% for placebo. Overall survival data are not mature yet.
The study includes unselected patients for PD-L1 expression. All patient subgroups benefited from durvalumab, including those with PD-L1–positive and PD-L1–negative disease.
The overall response rate was 28.4% with durvalumab versus 16% with placebo. The complete response rate was 1.4% for durvalumab versus 0.5% for placebo. The median duration of response has not yet been reached in the durvalumab arm versus 13.8 months with placebo.
Adverse events of all grades were reported in 96.8% of patients in the durvalumab group and 94.9% in the placebo group. Grade 3 or 4 adverse events occurred in 29.9% versus 26.1% of patients, respectively. Treatment-related adverse events occurred in 67.5% and 53.4%, respectively; serious adverse events were reported in 28.6% and 22.6%, respectively.
Experts Comments on the PACIFIC Trial
The formal discussant of this trial, Johan F. Vansteenkiste, MD, PhD, Head of Clinic, Respiratory Oncology Unit, Department of Pulmonology, University Hospital KU Leuven, Belgium, said, “We had an earthquake of immunotherapy in lung cancer last year at ESMO. After an earthquake, there is a tsunami of risk versus benefit. I think the results of PACIFIC represent a tsunami of benefit.”
“This is the first strong interim analysis of progression-free survival in a phase 3 trial for systemic therapy for stage III NSCLC in decades,” he emphasized. “Overall survival results will have more weight. For sure, we need to follow these data for survival in the curative setting. Three overall survival analyses are planned for PACIFIC.”
Pilar Garrido, MD, PhD, Head of the Thoracic Tumour Section, Medical Oncology Department, Ramón y Cajal University Hospital, Madrid, Spain, also commented on the study. “PACIFIC is one of the largest clinical trials recruiting patients with unresectable stage III NSCLC. Giving durvalumab after finishing chemoradiation improved progression-free survival by three-fold compared to placebo, which is a clinically relevant benefit. The results for 12 and 18-month progression-free survival were also highly encouraging,” she said. “It is important to highlight the acceptable toxicity profile of durvalumab in this setting, with severe adverse events rates very similar between both arms.”