Sean Bohen, MD, PhD
Durvalumab (Imfinzi) significantly improved overall survival (OS) versus placebo when used as a sequential treatment in patients with locally-advanced, unresectable non–small cell lung cancer (NSCLC) who had not progressed following standard chemoradiotherapy, according to updated findings from the phase III PACIFIC trial.
The statistically significant OS benefit was determined by an independent data monitoring panel at an interim analysis, AstraZeneca, the manufacturer of the PD-L1 inhibitor, reported in a press release. There were no new safety signals, according to the company, which plans to share the data from the study at an upcoming medical conference.
“The readout of positive overall survival data at the interim analysis of the PACIFIC trial provides additional compelling evidence of the clinical benefit that Imfinzi can offer patients in this earlier stage of lung cancer. We look forward to sharing these results with health authorities to support ongoing regulatory interactions and to update the Imfinzi label with these important data,” Sean Bohen, executive vice president of global medicines development and chief medical officer at AstraZeneca, said in a statement.
In February 2018, the FDA approved durvalumab for the treatment of patients with locally advanced, unresectable stage III NSCLC who have not progressed following chemoradiotherapy, based on progression-free survival (PFS) data from the PACIFIC trial. Durvalumab improved the median PFS by 11.2 months compared with placebo (16.8 vs 5.6; HR, 0.52; 95% CI, 0.42-0.65; P
<.0001). The 12-month PFS rate was 55.9% versus 35.3%, and the 18-month PFS rate was 44.2% versus 27.0%, again favoring the durvalumab arm.
“After concurrent therapy, this is the first major advance in stage III NSCLC. Improved survival firms up the role of durvalumab in this setting,” Suresh S. Ramalingam, MD, deputy director of Winship Cancer Institute of Emory University, noted on Twitter following AstraZeneca’s report of the OS benefit in the PACIFIC trial.
Also commenting on Twitter, H. Jack West, MD, thoracic oncologist, Swedish Cancer Institute of Swedish Medical Center, wrote, “Durvalumab (Imfinzi) consolidation in unresectable stage III NSCLC after chemo/radiation on PACIFIC trial confers significant OS benefit. Important (though I would argue expected) result that cements role for durvalumab here.”
In the PACIFIC trial, which took place at 235 centers in 26 countries, 473 patients were randomized to durvalumab and 236 were randomized to placebo. PFS was the primary endpoint, along with OS.
The median age of patients in the study was 64 years, and most were current or former smokers (91%). The majority were men (70.1%), and most had squamous histology (45.7%). Chemotherapy use was similar between groups, with 25.8% and 28.7% receiving induction chemotherapy before definitive chemoradiotherapy, in the durvalumab and placebo groups, respectively. Response to chemoradiotherapy was similar between the two arms, with objective response rates (ORR) of 50.6% and 49.8%, for the PD-L1 and placebo groups, respectively.
The PFS benefit associated with durvalumab was consistent across all prespecified subgroups, as defined according to patient demographic characteristics, baseline clinicopathologic features, and response to previous treatment. The PFS benefit held irrespective of PD-L1 expression before chemoradiotherapy. The HR was 0.59 (95% CI, 0.43-0.82) for patients with a PD-L1 expression level of <25%, and the HR was 0.41 (95% CI, 0.26-0.65) for patients with a PD-L1 expression level of ≥25%.
Objective response rate, as assessed by blinded independent central review, was also significantly higher with durvalumab (28.4% vs 16.0%; P
<.001). Of the patients who had a response to durvalumab, 72.8% had an ongoing response at both 12 and 18 months as compared with 56.1% and 46.8%, respectively, in the placebo arm.
Just 16.5% of patients in the durvalumab group experienced disease progression compared with 27.7% of the placebo group (P
Nearly all patients in both groups, 96.8% for durvalumab and 94.9% for placebo, experienced adverse events (AEs) of any cause and grade. Grade 3/4 AEs were slightly more common with durvalumab (29.9% vs 26.1%). Pneumonia was the most common grade 3/4 AE, and was observed in 4.4% of patients in the durvalumab group and 3.8% of patients in the placebo group.
AEs caused discontinuations in 15.4% of patients in the durvalumab group and 9.8% of patients in the placebo group. About 29% of patients in the durvalumab group experienced serious AEs compared with 22.6% of the placebo arm.
The most frequent AEs leading to discontinuation were pneumonitis or radiation pneumonitis and pneumonia in both groups. One-third of patients assigned to durvalumab experienced any-grade pneumonitis or radiation pneumonitis compared with 24.8% in the placebo group. Grade 3/4 pneumonitis or radiation pneumonitis occurred in 3.4% of the durvalumab group and 2.6% of the placebo group. Deaths due to AEs occurred in 4.4% of patients in the durvalumab group and 5.6% of patients in the placebo group.
Antonia SJ, Villegas A, Daniel D, et al. Durvalumab after chemoradiotherapy in stage III non–small-cell lung cancer. N Engl J Med. 2017;377(20):1919-1929 doi: 10.1056/NEJMoa1709937.