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PACIFIC 4-year update: Sustained survival benefits with durvalumab after CRT in unresectable stage III NSCLC

Prof. Corinne Faivre-Finn
University of Manchester
The Christie NHS Foundation Trust, Manchester
UK
30 Nov 2020
Consolidation therapy with the PD-L1 inhibitor durvalumab (Imfinzi®, AstraZeneca) following chemoradiation therapy (CRT) has become the standard of care in patients with unresectable stage III non-small-cell lung cancer (NSCLC), based on primary results of the PACIFIC study. The 4-year update of the study, presented recently at the European Society for Medical Oncology Virtual Congress 2020 (ESMO 2020), demonstrated durable and sustained survival benefits that were consistent with those reported in the primary analyses.

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)

HK-AST-322mo_01

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]

HK-AST-322mo_02

“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)

HK-AST-322_03

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)

HK-AST-322_04

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.


 

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Most Read Articles
Prof. Corinne Faivre-Finn, 30 Nov 2020
Consolidation therapy with the PD-L1 inhibitor durvalumab (Imfinzi®, AstraZeneca) following chemoradiation therapy (CRT) has become the standard of care in patients with unresectable stage III non-small-cell lung cancer (NSCLC), based on primary results of the PACIFIC study. The 4-year update of the study, presented recently at the European Society for Medical Oncology Virtual Congress 2020 (ESMO 2020), demonstrated durable and sustained survival benefits that were consistent with those reported in the primary analyses.
Dr. Roy Herbst, Dr. David Spigel, 09 Jul 2020
The third-generation EGFR-tyrosine kinase inhibitor (EGFR-TKI) osimertinib is a standard of care in patients with EGFR-positive advanced non-small-cell lung cancer (NSCLC). Results of the ADAURA study, presented at the American Society of Clinical Oncology 2020 Virtual Scientific Programme (ASCO 2020), support earlier use of osimertinib in the adjuvant setting, with superior disease-free survival (DFS) in patients who underwent complete resection of stage IB/II/IIIA EGFR-positive NSCLC. 
Prof. Mark Shackleton, 01 Apr 2020
In recent years, the focus on immuno-oncology has generated a wealth of compelling evidence supporting the use of immune checkpoint inhibitors – in particular those targeting the programmed death-ligand 1 (PD-L1) or PD-1 pathway. At the 8th Oncology Summit organized by the Hong Kong Society of Clinical Oncology, Professor Mark Shackleton of Alfred Health and Monash University, Australia, discussed recent advances in immunotherapy for the management of metastatic Merkel cell carcinoma (MCC) with a focus on the role of the PD-L1 inhibitor avelumab.  
Dr. Keith Wong, 30 Nov 2020
The B-cell lymphoma-2 (BCL-2) inhibitor, venetoclax, has demonstrated promising efficacy in relapsed/refractory chronic lymphocytic leukaemia (CLL). However, the associated risk of tumour lysis syndrome (TLS) in certain patients necessitates prophylactic measures and close monitoring. In an interview with MIMS Oncology, Dr Keith Wong from the haematology department of a public hospital in Hong Kong discussed important treatment considerations for patients with CLL, and highlighted prophylactic and supportive measures established at his hospital to mitigate the risk of TLS complications associated with venetoclax-based therapy.