Durvalumab Improves PFS in Unresectable NSCLC After Chemoradiotherapy
核心洞察
The PACIFIC-5 study demonstrated that durvalumab consolidation therapy significantly improved progression-free survival (PFS) in patients with unresectable NSCLC (搜索).
A 25% reduction in the risk of disease progression or death was observed with durvalumab compared to placebo (HR, 0.75; 95% CI, 0.58-0.99; P = .038).
The median PFS was 14.0 months in the durvalumab arm versus 6.5 months in the placebo arm, showing a clinically meaningful benefit.
Durvalumab (Imfinzi) has shown a statistically significant improvement in progression-free survival (PFS) compared to placebo in patients with locally advanced, unresectable non-small cell lung cancer (搜索) (NSCLC (搜索)) who had not progressed following concurrent or sequential platinum-based chemoradiotherapy (CRT). These findings come from the phase 3 PACIFIC-5 study (NCT03706690), which were presented at the 2024 ESMO Asia Congress.
The PACIFIC-5 study met its primary endpoint by demonstrating improved PFS with durvalumab consolidation therapy after CRT in patients with unresectable stage III NSCLC (搜索).
With a median follow-up of 35.7 months in the durvalumab arm (n = 252) and 30.5 months in the placebo arm (n = 129), the median PFS was 14.0 months (95% CI, 10.9-18.0) in the durvalumab arm compared to 6.5 months (95% CI, 5.4-13.8) in the placebo arm, as assessed by blinded independent central review (BICR). This translated to a 25% reduction in the risk of disease progression or death (HR, 0.75; 95% CI, 0.58-0.99; P = .038).
Subgroup analyses indicated a consistent PFS benefit with durvalumab, regardless of whether patients received concurrent or sequential CRT. For those who underwent concurrent CRT, the median PFS with durvalumab (n = 168) was 16.5 months (95% CI, 11.0-26.9) versus 9.5 months (95% CI, 5.6-16.6) with placebo (n = 90; HR, 0.76; 95% CI, 0.55-1.06; P = .103). In patients who received sequential CRT, the median PFS was 11.0 months (95% CI, 5.6-16.4) in the durvalumab arm (n = 84) and 5.4 months (95% CI, 3.6-7.9) in the placebo arm (n = 39; HR, 0.75; 95% CI, 0.49-1.18; P = .213).
A trend towards improved overall survival (OS) was observed with durvalumab compared to placebo, with a median OS of 38.3 months (95% CI, 28.9-42.8) and 32.5 months (95% CI, 20.6-40.4), respectively (HR, 0.87; 95% CI, 0.66-1.17; P = .346).
Expert Commentary
Yi-Long Wu, MD, from Guangdong Lung Cancer (搜索) Institute, emphasized the significance of the findings: “PACIFIC-5 supports the use of consolidation immunotherapy after either concurrent or sequential CRT, consistent with the PACIFIC trial and real-world evidence.”
Study Design and Patient Population
The double-blind, placebo-controlled, multicenter, phase 3 PACIFIC-5 study included patients with unresectable, stage III NSCLC (搜索) who had not experienced disease progression after concurrent or sequential CRT. Enrolled patients had an ECOG performance status of 0 or 1 and available data on PD-L1 expression, as well as EGFR (搜索) and ALK (搜索) mutational status. The intention-to-treat (ITT) population comprised 407 patients, while the modified ITT (mITT) population included 381 patients, excluding those with sensitizing EGFR mutations or ALK rearrangements.
Patients were randomized in a 2:1 ratio to receive either durvalumab at 1500 mg or placebo every 4 weeks until disease progression. Stratification factors included the type of CRT (concurrent vs. sequential) and PD-L1 tumor cell (TC) expression (≥1% vs. <1%). The primary endpoint was PFS by BICR and RECIST 1.1 criteria in the mITT population, with OS as a key secondary endpoint.
Baseline Characteristics
In the mITT population, the median age was 63.0 years (range, 33-80) in both arms. The majority of patients were male (92.1% durvalumab vs. 88.4% placebo), Asian (71.4% vs. 72.9%), current or former smokers (84.9% vs. 88.4%), and had an ECOG performance status of 1 (68.3% vs. 55.0%) with squamous histology (69.8% vs. 65.1%). A higher proportion of patients in the durvalumab arm had stage IIIC disease at study entry (23.4% vs. 14.7%). PD-L1 TC expression was <1% in 40.1% of the durvalumab arm and 39.5% of the placebo arm, while ≥1% expression was observed in 59.9% and 60.5%, respectively.
Treatment Exposure and Discontinuation
In the durvalumab arm, 99.6% of patients received the drug, with 19.1% continuing treatment at the data cutoff date of June 23, 2024. The most common reason for treatment discontinuation was disease progression (53.4%). In the placebo arm, 99.2% received placebo, and 17.2% were still receiving it at the data cutoff, with disease progression being the primary reason for discontinuation (66.4%).
Additional Efficacy Outcomes
The 12-month PFS rates were 53.6% in the durvalumab arm and 42.7% in the placebo arm, while the 24-month PFS rates were 39.9% and 30.2%, respectively. Among patients who received concurrent CRT, the 12-month PFS rates were 56.5% (durvalumab) and 49.2% (placebo), and the 24-month rates were 43.4% and 34.9%. For those who received sequential CRT, the 12-month PFS rates were 47.9% (durvalumab) and 28.3% (placebo), and the 24-month rates were 33.1% and 19.8%.
The 12-month OS rates in the mITT population were 80.9% in the durvalumab arm and 75.8% in the placebo arm, with 24-month rates of 60.7% and 54.4%, respectively.
Safety Profile
The adverse event (AE) profile was consistent with previous observations for single-agent durvalumab following CRT. Any AE was reported in 94.8% of patients in the durvalumab arm and 83.6% in the placebo arm, with 63.5% and 39.6% being causally related to the study treatment. Grade 3 or 4 AEs occurred in 26.9% and 23.9% of patients in the durvalumab and placebo arms, respectively. Immune-mediated AEs were reported in 27.7% and 14.9% of patients, respectively.
Treatment discontinuation due to AEs occurred in 14.4% of the durvalumab arm and 8.2% of the placebo arm. Serious AEs were reported in 38.4% and 33.6% of patients, respectively. Fatal AEs occurred in 9.2% of the durvalumab arm and 1.5% of the placebo arm, with 4 in the durvalumab arm being causally related to treatment.
The most common AEs (≥10%) in the durvalumab and placebo arms included pneumonitis or radiation pneumonitis (39.5% vs. 40.3%), pneumonia (18.8% vs. 11.2%), hypothyroidism (18.8% vs. 7.5%), anemia (15.1% vs. 14.9%), COVID-19 (搜索) (12.9% vs. 11.2%), cough (11.8% vs. 11.9%), upper respiratory tract infection (11.4% vs. 11.9%), hyperthyroidism (12.2% vs. 6.0%), and increased alanine aminotransferase level (10.0% vs. 4.5%).