Recent data from trials of programmed death receptor-1 (PD-1) and PD-L1 inhibitors have changed the standard of care for patients with metastatic non-small cell lung cancer (NSCLC) in both the first-line and second-line settings. The standard of care therapy for patients with stage III, locally advanced, unresectable NSCLC is platinum-based doublet chemotherapy, concurrent with radiotherapy (CRT). However, the median progression-free survival (PFS) after CRT is only about 8-10 months and the prognosis of these patients remains poor.
At the 2017 European Society for Medical Oncology (ESMO) meeting, Luis Paz-Ares, MD, PhD (Hospital Universitario, Madrid, Spain), presented results from an interim analysis of the randomized, double-blind, international, phase III PACIFIC study (N = 713), which compared consolidation therapy with the anti-PD-L1 antibody durvalumab (10 mg/kg every two weeks up to 12 months) to placebo in patients with stage III, locally advanced NSCLC that had not progressed after CRT. These results were simultaneously published in the New England Journal of Medicine. At a median follow-up of 14.5 months, consolidation therapy with durvalumab significantly improved median PFS, from 5.6 months with placebo to 16.8 months with durvalumab (HR 0.52, P<.0001). The PFS benefit of durvalumab was consistent across all prespecified subgroups and was observed regardless of PD-L1 expression. Overall survival (OS), the co-primary endpoint of the study, was not analyzed due to immaturity and study remains blinded for this endpoint. However, durvalumab consolidation compared to placebo yielded a higher response rate (28.4% vs 16.0%; P<.001), with 6 complete responses (CR) in the durvalumab group, compared to 1 in the placebo group. At 18 months, 72.8% of responses in the durvalumab group were ongoing, compared to 46.8% in the placebo group. In addition, time to distant metastasis or death was 23.2 months in patients treated with durvalumab, compared to 14.6 months in patients treated with placebo (HR 0.52, P<.0001). Furthermore, patients receiving durvalumab had lower frequency of new metastases, including lower incidence of new brain metastases.
The safety profile of durvalumab was consistent with that of other immunotherapies and its known safety profile as monotherapy in patients with more advanced NSCLC. Grade 3/4 adverse events (AEs) occurred in 29.9% of patients receiving durvalumab and 26.1% of patients receiving placebo. Discontinuation of therapy due to AEs occurred in 15.4% of patients in the durvalumab group and 9.8% of patients in the placebo group. The most frequent AEs of any grade associated with durvalumab were cough (35.4% vs 25.2%), pneumonitis/radiation pneumonitis (33.9% vs 24.8%), pyrexia (14.7% vs 9.0%), pneumonia (13.1% vs 7.7%), rash (12.2% vs 7.3%), and hypothyroidism (11.6% vs 1.7%). The incidence of grade 3/4 pneumonitis was similar among the treatment groups (3.4% with durvalumab and 2.6% with placebo).
Doctor Paz-Ares concluded that results from the PACIFIC trial support durvalumab as a therapeutic option in patients with stage III, locally advanced, unresectable NSCLC following chemoradiation. In his discussion, Johan Vansteenkiste, MD, PhD (University Hospital Leuven, Leuven, Belgium), said that ‘’these are the first strong interim-PFS positive phase III trial results on systemic therapy for stage III NSCLC in decades.’’ However, he highlighted that this is a curative setting, and it will be important to see if the impressive PFS benefit will translate to a survival benefit.