Several lung cancer trials have shown prolonged progression-free survival with checkpoint inhibitor therapy. For the first time, the phase III PACIFIC trial has found an overall survival benefit for the selective programmed cell death ligand 1 (PD-L1) checkpoint inhibitor durvalumab (Imfinzi) vs placebo in patients with unresectable stage III non–small cell lung cancer (NSCLC).1 These findings suggest that durvalumab may become a new standard of care.
Durvalumab improved survival by 32% vs placebo in patients whose disease had not progressed on concurrent chemoradiotherapy. These results were published in The New England Journal of Medicine2 to coincide with the presentation of the survival data at the International Association for the Study of Lung Cancer (IASLC) 19th World Conference on Lung Cancer in Toronto.
This is the first study in many years to support a survival advantage for unresectable stage III NSCLC with no disease progression following chemoradiotherapy.— Scott J. Antonia, MD
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“The survival analysis showed a statistically significant and clinically meaningful difference in overall survival for durvalumab vs placebo in patients with unresectable stage III NSCLC,” said lead author Scott J. Antonia, MD, of Moffitt Cancer Center and Research Institute, Tampa, Florida. “We saw improvements in progression-free survival, time to distant metastases, and emergence of new lesions with durvalumab, and the drug was well tolerated. This is the first study in many years to support a survival advantage for unresectable stage III NSCLC with no disease progression following chemoradiotherapy.”
Patients with locally advanced unresectable stage III NSCLC traditionally are treated with conventional chemotherapy and radiotherapy with curative intent, but only 15% to 30% are cured. “We’ve been stuck with those numbers for decades. This past year, we saw an 11.2-month improvement in progression-free survival with durvalumab in the PACIFIC trial. Today, we see improved overall survival,” he told listeners.
The rationale for combining chemotherapy and radiation with immunotherapy is based on preclinical evidence suggesting that chemoradiotherapy upregulates PD-L1 expression in tumor cells. It is hypothesized that PD-L1 blockade can “jump-start” the immune response after chemoradiotherapy, he explained.
A randomized, placebo-controlled, phase III trial, PACIFIC was conducted at 235 investigative sites in 26 countries. The study included 713 patients whose disease did not progress after chemoradiotherapy for unresectable stage III NSCLC. Patients were randomly assigned 2:1 to receive durvalumab or placebo 1 to 42 days after radiation and were treated every 2 weeks, for up to 12 months or disease progression.
“We took all-comers regardless of PD-L1 expression,” Dr. -Antonia told the audience.
Baseline characteristics were well balanced between the two treatment arms. The 12-month overall survival rate was 83.1% for durvalumab vs 75.3% for placebo. The 24-month overall survival rate was 66.3% vs 55.6%, respectively. The median overall survival was not reached in the durvalumab group and was 28.7 months in the placebo group, representing a 32% improvement in survival for the PD-L1 inhibitor (P = .0025).
An updated analysis of progression-free survival showed no difference from the first interim analysis of PACIFIC.3 The median progression-free survival was 16.8 months with durvalu-mab vs 5.6 months with placebo (P < .001), an 11.2-month -improvement.
Dr. Antonia said that the previously reported advantage in various subsets has held up in the overall survival analysis. “Nonsmokers did benefit, and we usually don’t expect an impact of immunotherapy in this group. Our results in the conventional arm suggest that cisplatin is the better drug,” he added.
PD-L1 testing was obtained prior to chemoradiotherapy. More than one-third of patients had an unknown PD-L1 status. The only patients who did not derive benefit were those with PD-L1 expression < 1%, he said. The time to death or distant metastasis was longer in the durvalumab group than in the placebo group: median of 28.3 months vs 16.2 months.
Safety profiles were consistent with those previously reported, Dr. Antonia told the audience. Grade 3 or 4 adverse events of any cause were reported in 30.5% of the durvalumab group and 26.1% of the placebo group. Treatment discontinuations due to adverse events were reported in 15.4% and 9.8%, respectively. The most frequent event leading to treatment discontinuation was pneumonitis (4.8% in the durvalumab group and 2.6% in the placebo group). Serious adverse events were reported in 29.1% of the durvalumab group and 23.1% of the placebo group. Death due to adverse events occurred in 4.4% and 6.4%, respectively.
“There was no difference in grades 3 and 4 pneumonitis-related deaths,” Dr. Antonia stated. ■
DISCLOSURE: Dr. Antonia reported no conflicts of interest.
1. Antonia S, Villegas A, Daniel D, et al: Overall survival with durvalumab versus placebo after chemoradiotherapy in stage III NSCLC: Updated results from PACIFIC. 2018 World Conference on Lung Cancer. Abstract PL02.01. Presented September 25, 2018.
3. Antonia SJ, Villegas A, Daniel D, et al: Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer. N Engl J Med 377:1919-1929, 2017.
Everett Vokes, MD
“PACIFIC is a positive trial, with a 32% improvement in survival, and maintenance durvalumab is a new standard of care,” stated formal discussant Everett Vokes, MD, Chair of the Department of Medicine at the University of Chicago and a pioneer in the concurrent use of...!-->!-->