SUMMARY: Lung cancer is the second most common cancer in both men and women and accounts for about 14% of all new cancers and 27% of all cancer deaths. The American Cancer Society estimates that for 2018 about 234,030 new cases of lung cancer will be diagnosed and over 154,050 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Non Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers. Of the three main subtypes of Non Small Cell Lung Cancer (NSCLC), approximately 30% are Squamous Cell Carcinomas (SCC), 40% are Adenocarcinomas, and 10% are Large cell carcinomas.
Approximately one third of all patients with NSCLC have stage III, locally advanced disease at the time of initial presentation. Worldwide, about 500,000 patients are diagnosed with unresectable, stage III NSCLC, each year. These patients include those with locally advanced primary tumors with tumor invading the vital mediastinal organs, as well as those with involvement of locoregional mediastinal lymph nodes. These patients are often treated with platinum-based doublet chemotherapy with concurrent radiation and have a median Progression Free Survival (PFS) of approximately 8 months and 5 year survival of only 15%. There is hence a significant unmet need for this patient group, with no major treatment advances thus far.
Preclinical evidence had suggested that chemotherapy and radiotherapy may upregulate PD-L1 expression in tumor cells. IMFINZI® (Durvalumab) is a selective, high-affinity, human IgG1 monoclonal antibody, that blocks the binding of Programmed Death Ligand 1 (PD-L1) to Programmed Death 1 (PD-1) receptor and CD80, thereby unleashing the T cells to recognize and kill tumor cells. IMFINZI® showed encouraging antitumor activity in an early phase clinical study involving multiple advanced solid tumors, including stage IIIB or IV NSCLC.
PACIFIC trial is a randomized, double-blind, international, phase III study in which IMFINZI® as consolidation therapy was compared with placebo, in patients with stage III, locally advanced, unresectable NSCLC, that had not progressed following platinum-based chemoradiotherapy. Eligible patients received two or more cycles of platinum-based doublet chemotherapy concurrently with definitive radiation therapy (54-66 Gy). Following completion of concurrent chemoradiation treatment, 713 patients were randomized, of whom 709 patients in a 2:1 ratio received consolidation treatment, within 6 weeks after completion of chemoradiation, with IMFINZI® 10 mg/kg every 2 weeks (N=473) or placebo (N=236), for up to 12 months. The median age was 64 years, and the majority of patients were men (70%) and 46% had a squamous histology. The co-Primary end points were Progression Free Survival (PFS) and Overall Survival (OS). Secondary end points included 12-month and 18-month PFS rates, Objective Response Rate (ORR), Duration of Response, time to death or distant metastasis, and safety.
The authors had previously reported the results of the first preplanned interim analysis, after a median follow up of 14.5 months. The median PFS from randomization to consolidation treatment was 16.8 months with IMFINZI® versus 5.6 months with placebo (HR=0.52; P<0.001). This meant a 11.2-month improvement in PFS with IMFINZI® versus placebo, and a 48% decrease in the probability of disease progression with IMFINZI®. This improvement was consistent across all patient subgroups that were analyzed.
The authors in this publication report the results for the second Primary end point of Overall Survival. At a median follow up of 25.2 months, the 24-month Overall Survival rate was 66.3% in the IMFINZI® group and 55.6% in the placebo group, suggesting a significantly prolonged Overall Survival with IMFINZI® when compared with placebo and a 32% reduction in the risk of death (HR for death=0.68; P=0.0025). The Overall Survival benefit with IMFINZI®, was observed across all the prespecified subgroups. In this updated analysis, the PFS was similar to those previously reported, with a median duration of 17.2 months in the IMFINZI® group and 5.6 months in the placebo group (HR=0.51). The median time to death or distant metastasis was 28.3 months in the IMFINZI® group and 16.2 months in the placebo group (HR=0.53). Approximately 30% of the patients in the IMFINZI® group and 26% of those in the placebo group had grade 3 or 4 adverse events of any cause, and 15% and 10% of the patients respectively, discontinued the trial regimen because of adverse events.
The authors concluded that in this updated analysis of the PACIFIC trial, the Primary end point of Overall Survival was significantly longer with IMFINZI® than with placebo, among patients with unresectable stage III NSCLC, in all the prespecified subgroups. The updated results for Secondary end points, including the time to death or distant metastasis, the incidence of new lesions, and the Objective Response Rate, were similar to those that were previously reported. The authors commented that PACIFIC trial is the first study to demonstrate a survival advantage for unresectable Stage III NSCLC, supporting this regimen as the standard of care. Overall Survival with Durvalumab after Chemoradiotherapy in Stage III NSCLC. Antonia SJ, Villegas A, Daniel D, et al. [published online ahead of print September 25, 2018]. N Eng J Med. doi: 10.1056/NEJMoa1809697.