Durvalumab Consolidation After Chemoradiotherapy Improves Progression-Free Survival in Stage III Non–Small Cell Lung Cancer


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Scott J. Antonia, MD, PhD

Scott J. Antonia, MD, PhD

As reported by Scott J. Antonia, MD, PhD, of the H. Lee Moffitt Cancer Center and Research Institute, and colleagues in The New England Journal of Medicine, an interim analysis of the phase III -PACIFIC trial showed improved progression-free survival with the programmed cell death protein 1 (PD-1) inhibitor durvalumab (Imfinzi) vs placebo as consolidation in patients with unresectable stage III non–small cell lung cancer (NSCLC) without progression after at least two cycles of definitive platinum-based chemoradiation therapy.1

Study Details

In the international double-blind trial, 709 patients were randomized 2:1 between May 2014 and April 2016 to receive durvalumab at 10 mg/kg intravenously (n = 473) or placebo intravenously every 2 weeks (n = 236) for up to 12 months. Patients had received at least two cycles (defined by local practice) of platinum-based chemotherapy containing etoposide, vinblastine, vinorelbine, a taxane (paclitaxel or docetaxel), or pemetrexed (Alimta) concurrently with definitive radiation therapy (54–66 Gy), in which the mean dose to the lung was less than 20 Gy, the volume of lung parenchyma that received ≥ 20 Gy was less than 35%, or both. Randomization was stratified by age, sex, and smoking history. The study drug was administered 1 to 42 days after receipt of chemoradiotherapy. The coprimary endpoints are progression-free survival on blinded independent central review and overall survival (with analysis of overall survival not planned at the time of the current interim analysis). 

These positive findings in an unselected patient population, irrespective of baseline expression of PD-L1 on tumor cells, suggest that durvalumab may be an effective adjuvant therapy in patients with stage III [NSCLC] after standard treatment.
— Scott J. Antonia, MD, PhD

Among all patients: median age was 64 years; 70% were male; 69% were white and 27% were Asian; disease stage was IIIA in 53% and IIIB in 45%; the World Health Organization (WHO) performance status was 0 in 49% and 1 in 51%; histology was squamous in 46% and nonsquamous in 54%; smoking status was current, former, and never for 16%, 75%, and 9%; 92% had received radiotherapy at ≥ 54 to ≤ 66 Gy and 7% at > 66 to ≤ 74 Gy; and best response to chemoradiotherapy was complete in 2%, partial in 48%, and stable disease in 47%. 

Progression-Free Survival

As of data cutoff in February 2017, median follow-up was 14.5 months. Median progression-free survival was 16.8 months in the durvalumab group vs 5.6 months in the placebo group (hazard ratio [HR] = 0.52, P < .001). Progression-free survival rates were 55.9% vs 35.3% at 12 months and 44.2% vs 27.0% at 18 months in the durvalumab and placebo groups, respectively. A progression-free survival benefit of durvalumab was consistently observed across all prespecified subgroups, including among 159 patients with programmed cell death ligand 1 (PD-L1) expression ≥ 25% (HR = 0.41, 95% confidence interval [CI] = 0.26–0.65), 292 with PD-L1 expression < 25% (HR = 0.59, 95% CI = 0.43–0.82), 262 with unknown PD-L1 status (HR = 0.59, 95% CI = 0.42–0.83), and never smokers (HR = 0.29, 95% CI = 0.15–0.57). 

Objective response was observed in 28.4% vs 16.0% (< .001), with 72.8% vs 46.8% of responders having an ongoing response at 18 months. Median distant metastasis–free survival was 23.2 vs 14.6 months (< .001). New lesions were observed in 20.4% vs 32.1%, and new brain metastases occurred in 5.5% vs 11.0%. 

Adverse Events

Grade 3 or 4 adverse events occurred in 29.9% of the durvalumab group vs 26.1% of the placebo group, with the most common event being pneumonia (4.4% vs 3.8%). Adverse events led to discontinuation of study drug in 15.4% vs 9.8% of patients, with the most common causes being pneumonitis or radiation pneumonitis (6.3% vs 4.3%) and pneumonia (1.1% vs 1.3%). Pneumonitis or radiation pneumonitis of any grade occurred in 33.9% vs 24.8%, and grade 3 or 4 pneumonitis or radiation pneumonitis occurred in 3.4% and 2.6%; pneumonia of any grade occurred in 13.1% vs 7.7%, and grade 3 or 4 pneumonia occurred in 4.4% vs 3.8%. Serious adverse events occurred in 28.6% vs 22.6% of patients, and adverse events led to death in 4.4% vs 5.6%. 

DURVALUMAB IN NSCLC

  • Durvalumab consolidation significantly prolonged progression-free survival.
  • Durvalumab significantly prolonged distant metastasis-free survival.

Potentially immune-related adverse events of any grade occurred in 66.1% vs 48.7%, with grade ≥ 3 events occurring in < 10% of patients in both groups. The most common events of any grade were diarrhea (18.3% vs 18.8%), pneumonitis (12.6% vs 7.7%), rash (12.2% vs 7.3%), and pruritus (12.2% vs 4.7%).

The investigators concluded: “Progression-free survival was significantly longer with durvalumab than with placebo. The secondary endpoints also favored durvalumab, and safety was similar between the groups…. These positive findings in an unselected patient population, irrespective of baseline expression of PD-L1 on tumor cells, suggest that durvalumab may be an effective adjuvant therapy in patients with stage III disease after standard treatment. Uncertainty about the potential mechanisms driving the interaction between immunotherapy and chemoradiotherapy warrants further investigation.” ■

DISCLOSURE: The study was funded by AstraZeneca. For full disclosures of the study authors, visit www.nejm.org.

REFERENCE

1. Antonia SJ, Villegas A, Daniel D, et al: Durvalumab after chemoradiotherapy in stage III non–small-cell lung cancer. N Engl J Med 377:1919-1929, 2017.


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