FDA Approves Durvalumab for Locally Advanced NSCLC

The FDA has approved 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.

The approval is based on the phase III PACIFIC trial, in which the PD-L1 inhibitor durvalumab 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.

“This is the first treatment approved for stage III unresectable non-small cell lung cancer to reduce the risk of the cancer progressing, when the cancer has not worsened after chemoradiation,” Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, said in a statement.

“For patients with stage III lung cancer that cannot be removed surgically, the current approach to prevent progression is chemoradiation. Although a small number of patients may be cured with the chemoradiation, the cancer may eventually progress. Patients now have an approved therapy that has been shown to keep the cancer from progressing for a longer time after chemoradiation,” added Pazdur.

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 overall survival (OS). OS data are still immature and were not included in this analysis.

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 <.001).

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.