Historically, outcomes had been poor in patients who received CRT for unresectable stage III NSCLC, with only 15–30 percent of patients remaining alive at 5 years and a median overall survival (OS) of ≤28 months. [World J Clin Oncol 2017;8:1-20; Int J Radiat Oncol Biol Phys 2017;99(Suppl):S105]

Efforts to identify systemic therapies with curative potential after CRT were proven ineffective, with median survival ranging from 18 months to 23 months. [J Clin Oncol 2015;33:2660-2666; Cancer Treat Rev 2018;66:114-121; J Thorac Oncol 2013;8:1181-1189; J Clin Oncol 2008;26:2450-2456; J Clin Oncol 2008;26:5755-5760] Results of the PACIFIC study were game-changing in the management of patients with unresectable stage III NSCLC following CRT. [N Engl J Med 2018;379:2342-2350; N Engl J Med 2017;377:1919-1929]

PACIFIC: Durvalumab after CRT in unresectable stage III NSCLC

PACIFIC was a phase III, multicentre, double-blind study that evaluated the efficacy and safety of consolidation therapy with durvalumab in patients with unresectable stage III NSCLC after definitive platinum-based concurrent CRT. Eligible patients were ≥18 years of age, with a WHO performance status of 0–1, did not have disease progression after CRT, and had their last radiation dose within 1–42 days before randomization. Assessment of tumour PD-L1 status was not mandated. [N Engl J Med 2018;379:2342-2350; N Engl J Med 2017;377:1919-1929]

Patients were randomized in a 2:1 ratio to receive durvalumab 10 mg/kg (n=476) or matching placebo (n=237) every 2 weeks for up to 12 months. The coprimary endpoints were OS and progression-free survival (PFS) by blinded independent central review using Response Evaluation Criteria in Solid Tumours (RECIST) v1.1. Key secondary endpoints included objective response rate (ORR), duration of response (DoR), time to death or distant metastasis, safety, and patient-reported outcomes. (Figure 1)

Primary analyses: Significant improvements in OS and PFS

In the primary analyses, a 32 percent improvement in OS was observed with durvalumab vs placebo (median, not reached vs 28.7 months; stratified hazard ratio [HR], 0.68; 99.73 percent confidence interval [CI], 0.47 to 0.997; p=0.0025). Median PFS was 16.8 months with durvalumab vs 5.6 months with placebo, corresponding to a 48 percent reduction in the risk of progression or death (stratified HR, 0.52; 95 percent CI, 0.42 to 0.65; p<0.001). [N Engl J Med 2018;379:2342-2350; N Engl J Med 2017;377:1919-1929]

Time to death or distant metastasis was longer with durvalumab vs placebo (median, 28.3 months vs 16.2 months; stratified HR, 0.53; 95 percent CI, 0.41 to 0.68). Time to first subsequent therapy or death and time to second subsequent therapy or death were also longer with durvalumab vs placebo. ORR was 30.0 percent vs 17.8 percent, while median DoR was not reached vs 18.4 months.

Durvalumab exhibited a manageable safety profile and had no adverse impact on patient-reported outcomes. Serious adverse events were reported in 29.1 percent of patients in the durvalumab arm vs 23.1 percent of those in the placebo arm. The rate of grade 3/4 pneumonitis/radiation pneumonitis was 3.4 percent vs 2.1 percent.

Based on the promising efficacy and safety results of the PACIFIC study, durvalumab became the first and only immunotherapy approved by the US FDA as consolidation therapy in patients with unresectable stage III NSCLC whose disease has not progressed following concurrent platinum-based CRT. [https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-durvalumab-after-chemoradiation-unresectable-stage-iii-nsclc] The PACIFIC regimen has also become the standard of care in this disease setting. [NCCN guidelines: Non-Small Cell Lung Cancer, Version 8.2020]

4-year update: Sustained OS and PFS benefits

“The OS benefit with durvalumab was sustained in the preplanned 4-year analysis,” said investigator Professor Corinne Faivre-Finn of the University of Manchester and The Christie NHS Foundation Trust, Manchester, UK. “Median OS in the durvalumab arm was reached for the first time and was 47.5 months compared with 29.1 months with placebo [stratified HR, 0.71; 95 percent, 0.57 to 0.88]. The estimated 4-year OS rate was 49.6 percent vs 36.3 percent.” (Figure 2) [Faivre-Finn C, et al, ESMO 2020, abstract LBA49]

“More than one-third of patients in the durvalumab arm were alive without disease progression at 4 years. The estimated 4-year PFS rate was 35.3 percent in patients receiving durvalumab vs 19.5 percent in those receiving placebo,” she reported. “Median PFS was 17.2 months vs 5.6 months [stratified HR, 0.55; 95 percent CI, 0.44 to 0.67].” (Figure 3)

The OS and PFS benefits with durvalumab were consistent across prespecified subgroups, including sex, age, smoking status, NSCLC disease stage, tumour histology, prior definitive chemotherapy, and response to prior therapy. (Figure 4)

Conclusion

“Consolidation therapy with durvalumab after concurrent CRT, the PACIFIC standard-of-care regimen, continued to demonstrate durable PFS and sustained OS benefits in the 4-year preplanned exploratory analysis of the PACIFIC study. The results were consistent with the significant benefits in these endpoints reported at the primary analyses,” concluded Faivre-Finn. “Median OS in the durvalumab arm was reached for the first time and was 47.5 months, with 4-year OS and PFS rates of 49.6 percent [vs 36.3 percent with placebo] and 35.3 percent [vs 19.5 percent with placebo], respectively.”

“Ongoing studies are investigating the concurrent use of immune checkpoint inhibitors with CRT in patients with unresectable stage III NSCLC, which may further transform the treatment landscape in this setting,” she suggested.