Clinical Pearls & Morning Reports
Antonia et al. recently reported the results from an interim analysis of the randomized, double-blind, international, phase 3 PACIFIC study comparing durvalumab as consolidation therapy with placebo in patients with stage III, locally advanced, unresectable non–small-cell lung cancer (NSCLC) that had not progressed after platinum-based chemoradiotherapy. Read the latest NEJM Original Article.
Q: How does the monoclonal antibody durvalumab exert its effects?
A: Durvalumab is a selective, high-affinity, human IgG1 monoclonal antibody that blocks programmed death ligand 1 (PD-L1) binding to programmed death 1 (PD-1) and CD80, allowing T cells to recognize and kill tumor cells. An early-phase clinical study involving multiple advanced solid tumors, including stage IIIB or IV NSCLC, showed that durvalumab had encouraging antitumor activity, and this agent was recently approved in the United States for patients with locally advanced or metastatic urothelial carcinoma who had received platinum-based chemotherapy.
Q: What is the general prognosis for patients with locally advanced, unresectable NSCLC after they receive chemoradiotherapy?
A: Approximately one third of patients with NSCLC have stage III, locally advanced disease at diagnosis. The standard of care for patients with a good performance status and unresectable stage III NSCLC is platinum-based doublet chemotherapy concurrent with radiotherapy (chemoradiotherapy). However, the median progression-free survival among patients who have received chemoradiotherapy is poor (approximately 8 months), and only 15% of patients are alive at 5 years. No major advances in the treatment for patients in this context have been made in many years.
A: In the trial by Antonia et al., among patients with locally advanced, unresectable NSCLC, progression-free survival was 11 months longer among patients who received durvalumab than among those who received placebo (hazard ratio for disease progression or death, 0.52; P<0.001). Median progression-free survival from randomization, as assessed by means of blinded independent central review, was 16.8 months (95% confidence interval [CI], 13.0 to 18.1) with durvalumab versus 5.6 months (95% CI, 4.6 to 7.8) with placebo (stratified hazard ratio for disease progression or death, 0.52; 95% CI, 0.42 to 0.65; two-sided P<0.001). Notably, the progression-free survival benefit with durvalumab was observed irrespective of PD-L1 expression before chemoradiotherapy. In addition, the frequency of new lesions, as assessed by means of blinded independent central review, was 20.4% with durvalumab and 32.1% with placebo, with a lower incidence of new brain metastases with durvalumab (5.5% vs. 11.0%). An analysis of overall survival was not planned at the time of this interim analysis of progression-free survival.
A: The safety profile of durvalumab in this population was consistent with that of other immunotherapies and with its known safety profile as monotherapy in patients with more advanced disease (stage IIIB or IV NSCLC). Pneumonitis or radiation pneumonitis in patients who received durvalumab was mostly low grade, and the incidence of clinically important grade 3 or 4 events was well balanced between the groups (3.4% in the durvalumab group and 2.6% in the placebo group). The most common grade 3 or 4 adverse event was pneumonia (in 4.4% of patients in the durvalumab group and 3.8% of patients in the placebo group).