Delayed disease progression with the PD-L1 inhibitor durvalumab in patients with locally advanced, unresectable stage III lung cancer
PACIFIC is the first phase III trial to test an immune checkpoint inhibitor as sequential treatment in patients with stage III NSCLC who had not progressed following platinum-based chemotherapy concurrent with radiation therapy. Data of this trial were presented during the presidential session at ESMO 2017 and demonstrated that durvalumab significantly improves the progression-free survival (PFS) in these patients. The results of this trial were simultaneously published in the New England Journal of Medicine.
About one-third of patients with non-small-cell lung cancer (NSCLC) have a stage III presentation. Standard treatment with platinum-based chemotherapy concurrent with radiation therapy gives a PFS of about 8 months and only 15% of patients are alive at 5 years. Evidence of synergy between radiotherapy and immunotherapy, such as programmed death-ligand 1 (PD-L1) inhibitors formed the basis for the PACIFIC trial which explored the impact of PD-L1 inhibition with durvalumab after standard chemoradiation treatment in this setting. In the PACIFIC trial, patients with a WHO performance status 0/1 (any PD-L1 status) who received ≥2 cycles of platinum-based concurrent chemoradiation therapy (cCRT) without progression were randomized (2:1) 1–42 days post-cCRT to receive durvalumab (10 mg/kg IV Q2W) or placebo for up to 12 months, stratified by age, sex, and smoking history. The co-primary endpoints of the study were PFS by blinded independent central review and overall survival (OS), while secondary objectives included 12- and 18-month PFS rates, objective response rate (ORR), duration of response (DoR), time to death or distant metastasis (TTDM) and safety. Between May 2014 and April 2016, a total of 713 patients were randomized of whom 709 received consolidated treatment (473 durvalumab and 236 placebo).
During ESMO 2017, results from a pre-planned interim analysis at 14.5 months were presented. The median PFS in this analysis was 16.8 months with durvalumab, which was significantly longer than the 5.6 months seen with placebo (HR[95%CI]: 0.52[0.42–0.65]; p< 0.0001). At 12- and 18-month, the PFS rates were 55.9% versus 35.3% and 44.2% versus. 27.0% for durvalumab and placebo respectively. Also the secondary endpoints were significantly better among durvalumab treated patients. With durvalumab 28.4% of patients had an objective response as compared to 16.0% with placebo (p< 0.001). The median DoR was not reached with durvalumab consolidation therapy and was 13.8 months in the control arm. Finally, also the median TTDM was significantly longer with durvalumab (23.2 versus 14.6 months; stratified HR[95%CI]: 0.52[0.39–0.69]; p< 0.0001). Data for OS were immature and will be analyzed after a longer period of follow-up.
Treatment-related adverse events occurred in 68% of patients in the durvalumab group compared to 53% in the placebo group (grade 3/4 32.0% versus 27.8%). The rate of specific immune-mediated adverse events was 24% with durvalumab and 8% with placebo. Severe pneumonitis (grade 3/4) occurred in 3.4% and 2.6% of patients on durvalumab and placebo, respectively. Treatment had to be discontinued due to pneumonitis in 6.3% of patients on durvalumab and in 4.3% of the placebo treated patients. Overall, 15.4% of durvalumab treated patients had to discontinue therapy due to adverse events as compared to 9.8% in the placebo arm.
In summary, PACIFIC demonstrated durvalumab to be a reasonably well-tolerated treatment with a manageable safety profile that delays disease progression by 11 months in this setting. As such, PD-L1 inhibition after chemoradiation appears to be a new option for patients with locally advanced, unresectable stage III lung cancer. It will be important to see the impact on overall survival after a longer follow-up.
Paz-Ares L, Villegas A, Daniel D, et al. PACIFIC: A double-blind, placebo-controlled Phase III study of durvalumab after chemoradiation therapy (CRT) in patients with Stage III, locally advanced, unresectable NSCLC. Presented at ESMO 2017, Abstract LBA1_PR.