Objective. To evaluate the efficacy of the PD-L1 antibody durvalumab in the treatment of patients with unresectable stage III non-small-cell lung cancer (NSCLC) following completion of standard chemoradiotherapy.
Design. Interim analysis of the phase III PACIFIC study, a randomized, double-blind, international study.
Setting and participants. A total of 709 patients underwent randomization between May 2014 and April 2016. Eligible patients had histologically proven stage III, locally advanced and unresectable NSCLC with no evidence of disease progression following chemoradiotherapy. The enrolled patients had received at least 2 cycles of platinum-based chemotherapy concurrently with definitive radiation therapy (54 Gy to 66 Gy). Initially, patients were randomized within 2 weeks of completing radiation; however, the protocol was amended to allow randomization up to 42 days following completion of therapy. Patients were not eligible if they had previous exposure to anti-PD-1 or PD-L1 antibodies or active or prior autoimmune disease in the last 2 years. All patients were required to have an WHO performance status of 0 or 1. The patients were stratified at randomization by age (< 65 or > 65 years), sex and smoking status. Enrollment was not restricted to level of PD-L1 expression.
Intervention. Patients were randomized in a 2:1 ratio to receive consolidation durvalumab 10 mg/kg or placebo every 2 weeks for up to 12 months. The intervention was discontinued if there was evidence of confirmed disease progression, treatment with an alternative anticancer therapy, toxicity or patient preference. The response to treatment was assessed every 8 weeks for the first year and then every 12 weeks thereafter.
Main outcome measures. The primary endpoints of the study were progression-free survival (PFS) by blinded independent review and overall survival (OS). Secondary endpoints were the percentage of patients alive without disease progression at 12 and 18 months, objective response rate, duration of response, safety, and time to death or metastasis. Patients were given the option to provide archived tumor specimens for PD-L1 testing.
Results. The baseline characteristics were balanced. The median age at enrollment was 64 years and 91% of the patients were current or former smokers. The vast majority of patients (> 99% in both groups) received concurrent chemoradiotherapy. The response to initial concurrent therapy was similar in both groups with complete response rates of 1.9% and 3% in the durvalumab and placebo groups, respectively, and partial response rates of 48.7% and 46.8%. Archived tumor samples showed ≥ 25% PD-L1 expression in 22.3% of patients (24% in durvalumab group versus 18.6% in placebo group) and < 25% in 41% of patients (39.3%% in durvalumab group versus 44.3% in placebo group). PD-L1 status was unknown in 36.7% of the enrolled patients. Of note, 6% of patients enrolled had EGFR mutations.
After a median follow-up of 14.5 months, the median PFS was 16.8 months with durvalumab versus 5.6 months with placebo (P < 0.001; hazard ratio [HR] 0.52, 95% confidence interval [CI] 0.42–0.65). The 12-month PFS rate was 55.9% and 35.3% in the durvalumab and placebo group, respectively. The 18-month PFS rate was 44.2% and 27% in the durvalumab and placebo group, respectively. The PFS results were consistent across all subgroups. The PFS benefit was observed regardless of PD-L1 expression. The median time to death or metastasis was 23.2 months in the durvalumab group versus 14.6 months with placebo (HR 0.52; 95% CI 0.39–0.69). The objective response rate was significantly higher in the durvalumab group (28.4% vs. 16%, P < 0.001). The median duration of response was longer with durvalumab. Of the patients who responded to durvalumab, 73% had ongoing response at 18 months compared with 47% in the placebo group. OS was not assessed at this interm analysis.
Adverse events (AE) of any grade occurred in over approximately 95% in both groups. Grade 3 or 4 AE occurred in 29.9% in the durvalumab group and 26.1% in the placebo group. The most common grade 3 or 4 AE was pneumonia, occurring in about 4% of patients in each group. More patients in the durvalumab group discontinued treatment (15.4% vs 9.8%). Death due to an AE occurred in 4.4% of the durvalumab group and 5.6% of the placebo group. The most frequent AE leading to discontinuation was pneumonitis or radiation pneumonitis and pneumonia. Pneumonitis or radiation pneumonitis occurred in 33.9% (3.4% grade 3 or 4) and 24.8% (2.6% grade 3 or 4) of the durvalumab and placebo groups, respectively. Immune-mediated AE of any grade were more common in the duvalumab group occurring in 24% of patients (vs. 8% in placebo). Of these, 14% of patients in the durvalumab group required glucocorticoids compared with 4.3% in the placebo group. The most AE of interest was diarrhea, which occurred in 18% of the patients in both groups.