Sean Bohen, MD, PhD
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended approval of durvalumab (Imfinzi) for the treatment of patients with locally advanced, unresectable stage III non–small cell lung cancer (NSCLC) who have not progressed following chemoradiotherapy and whose tumors express PD-L1 on ≥1% of tumor cells.
The CHMP recommendation is based on the phase III PACIFIC trial, in which the PD-L1 inhibitor improved median progression-free survival (PFS) by 11.2 months compared with placebo (16.8 vs 5.6 months; 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.
AstraZeneca, the manufacturer of durvalumab, announced in May 2018 that the PD-L1 inhibitor also significantly improved overall survival (OS) versus placebo in the PACIFIC trial. The company plans to share the OS data from the study at an upcoming medical conference.
The European Commission will now review the application for its final decision. If approved, the combination would be available for use in the 28-member EU, along with Norway, Liechtenstein, and Iceland.
“The CHMP positive opinion brings European patients closer to having a treatment following chemoradiation therapy. There have been no new treatments in this setting for decades. With approximately a third of European non–small cell lung cancer patients presenting with this stage of disease, we are excited by this potential new standard of care in this curative-intent setting,” Sean Bohen, MD, PhD, executive vice president, Global Medicines Development and chief medical officer at AstraZeneca, said in a statement.
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.