Real-World PFS Benefit Reported With Durvalumab Regimen in Unresectable Stage III NSCLC

Nicolas Girard, MD, PhD

The median real-world progression-free survival (PFS) with durvalumab (Imfinzi) was higher compared with the median PFS reported in the durvalumab arm of the phase 3 PACIFIC trial (NCT02125461) in patients with stage III non–small cell lung cancer (NSCLC), although challenges with real-world data collection could indicate that the real-world benefit observed is overestimated, according to findings from the PACIFIC-R trial (NCT03798535) that were presented during the 2021 ESMO Congress.¹

At a median follow-up of 23 months (range, 0-35.6), the median PFS was 21.7 months (95% CI, 19.2-24.5) in the full analysis set of the PACIFIC-R trial (n = 1399) compared with 16.9 months (95% CI, 13-23.9) in the durvalumab arm of the PACIFIC trial (n = 476). The 12-month PFS rates were 62.4% vs 55.7%, respectively, and the 24-month PFS rates were 48.2% vs 45%, respectively.

Moreover, the real-world efficacy of durvalumab after chemoradiation among analyzed subgroups was generally consistent with that observed in analyses of the PACIFIC trial.

“The median real-world PFS in this study was higher than that reported in PACIFIC, [but] obviously there are methodological limits in such comparison,” lead study author Nicolas Girard, MD, PhD, a professor of respiratory medicine at Versailles Saint Quentin University and head of the Curie-Montsouris Thorax Institute, in Paris, France, said during a presentation of the data.

On February 16, 2018, the FDA approved durvalumab for the treatment of patients with unresectable stage III NSCLC whose disease has not progressed following concurrent platinum-based chemotherapy and radiation therapy.²

Findings from the randomized PACIFIC trial, which led to the regulatory decision, demonstrated significant overall survival (OS) and PFS improvement with durvalumab compared with placebo in patients with unresectable stage III NSCLC. Five-year survival outcomes from the study showed that the median OS was 47.5 months (95% CI, 38.1-52.9) with durvalumab vs 29.1 months (95% CI, 22.1-35.1) with placebo (HR, 0.72; 95% CI, 0.59-0.89).³ The median PFS was 16.9 months (95% CI, 13-23.9) vs 5.6 months (4.8-7.7), respectively (HR, 0.55; 95% CI, 0.45-0.68).

The PACIFIC-R study assessed the real-world efficacy of durvalumab in patients included in an expanded access program (EAP).

The study evaluated patients with unresectable stage III NSCLC regardless of tumor PD-L1 expression. Patients could not have evidence of disease progression following definitive platinum-based chemoradiation therapy to be eligible for inclusion.

At an index date between September 2017 and December 2018, patients were started on 10 mg/kg of intravenous durvalumab every 2 weeks through the EAP.

Retrospective data were collected at different time points from patient’s medical records. The trial utilized a 5-year observation period to evaluate disease evolution. Overall, 1399 patients were included in the full analysis set. Patients were from 290 active clinical trial sites in 11 participating countries, including France (n = 342), Spain (n = 244), Australia (n = 165), the Netherlands (n = 155), Belgium (n = 118), Italy (n = 116), Israel (n = 92), Germany (n = 62), the United Kingdom (n = 54), Norway (n = 36), and Switzerland (n = 15).

The dual primary end point of the study was investigator-assessed PFS and OS, with key secondary end points including demographics, disease characteristics, prior therapy, PFS/OS by subgroups, and adverse effects (AEs) of special interest.

At EAP inclusion, patients were a median age of 66 years (range, 26-88) and most were 75 years or age or younger (89.6%). The majority of patients were male (67.5%), former smokers (59.5%), and had an ECOG or World Health Organization performance status of 0 (51.4%). Most patients had stage IIIB/C disease (51%) and nonsquamous histology (63.1%).

The majority of patients received concurrent chemoradiotherapy (76.6%) vs sequential chemoradiotherapy (14.3%) or other chemoradiotherapy (9.1%).

Additionally, most evaluable patients (n = 967) had PD-L1–positive disease (PD-L1 ≥1%; 72.5%).

The median time to durvalumab initiation from the end of radiation therapy was 56 days, and patients received durvalumab treatment for a median of 335 days, which translated to approximately 11 months. A proportion of patients (20.1%) received durvalumab for more than 12 months and 4.4% for more than 14 months. Finally, patients received a median of 22 durvalumab infusions; 7.1% received more than 26 infusions.

By subgroup, the data showed the median PFS was 22.4 months (95% CI, 18.7-25.5) in the PD-L1 1% or greater population vs 16.3 months (95% CI, 11.7-23.2) in the PD-L1 less than 1% population (median PFS 25.2 months [95% CI, 14-27.3] in PD-L1–inconsistent population).

The median PFS was 23.7 months (95% CI, 20.2-26.5) in patients with stage IIIA disease vs 19.2 months (95% CI, 15.8-24.2) in patients with stage IIIB/C disease. By histology, the median PFS was 25.3 months (95% CI, 22-26.9) in patients with nonsquamous NSCLC vs 14.7 months (95% CI, 12.8-19) in patients with squamous NSCLC. Finally, by chemoradiation type, the median PFS was 23.7 months (95% CI, 20.1-25.8) with concurrent chemoradiation vs 19.4 months (95% CI, 12.4-25.3) with sequential chemoradiation.

Regarding safety in the full study analysis cohort, reasons for durvalumab discontinuation included patient decision (n = 20; 1.4%), AEs (n = 233; 16.7%), completed treatment (n = 659; 47.1%), disease progression (n = 377; 26.9%), and death (n = 21; 1.5%). Other reasons for discontinuation included missing data (n = 2), unspecified reasons (n = 68), lost to follow-up (n = 3), and ongoing durvalumab treatment at the time of data extraction (n = 16). The median time from durvalumab start to treatment discontinuation was 6.1 months, 2.8 months, 12 months, 5.1 months, and 1.9 months, respectively.

Additionally, pneumonitis and interstitial lung disease (ILD) was the most common toxicity that led to treatment discontinuation among patients. The AE led to permanent discontinuation in 9.5% (n = 133) of patients and temporary interruption in 5.2% (n = 73) of patients.

Pneumonitis and ILD was observed in 17.9% (n = 250) of patients. Of these events, 4% (n = 56) were mild, 8.4% (n = 118) were moderate, 2.9% (n = 41) were severe, and 0.4% (n = 5) were life threatening or fatal.

The median time to onset of pneumonitis or ILD from durvalumab initiation was 2.5 months, and corticosteroids were required in 71.3% of events.

Girard and coauthors noted that the real-world PFS benefit is likely overestimated because:

1. Germany and the United Kingdom did not collect data on early deaths (n = 50) that occurred prior to study enrollment,
2. RECIST criteria for tumor assessment is heterogenous across countries,
3. Assessments for progression in the real-world setting may not be completed as frequently or consistently as in clinical trials, and
4. The COVID-19 pandemic could have resulted in fewer hospital visits for patients.

“The future read outs of OS will provide further insight into the effectiveness of this regimen,” concluded Girard.

References

1. Girard N, Smit HJM, Sibille A, et al. PACIFIC-R real-world study: treatment duration and interim analysis of progression-free survival in unresectable stage III NSCLC patients treated with durvalumab after chemoradiotherapy. Presented at: 2021 ESMO Congress; September 16-21, 2021; virtual. Abstract 1171MO.
2. FDA approves durvalumab after chemoradiation for unresectable stage III NSCLC. News release. FDA. February 16, 2018. Accessed September 21, 2021. https://bit.ly/3EFpXO3
3. Spigel DR, Faivre-Finn C, Gray JE, et al. Five-year survival outcomes with durvalumab after chemoradiotherapy in unresectable stage III NSCLC: an update from the PACIFIC trial. J Clin Oncol. 2021;39(suppl 15):8511. doi:10.1200/JCO.2021.39.15_suppl.8511