With a median follow-up of 23 months (range 0â35.6), the median PFS was 21.7 months (95% CI, 19.2â24.5) in the full analysis set of the PACIFIC-R study (n = 1399) compared to 16.9 months (95% CI, 13â23.9) in the durvalumab arm of the PACIFIC study (n = 476). The PFS rates after 12 months were 62.4% vs. 55.7% and the PFS rates after 24 months were 48.2% vs. 45%.
In addition, the actual efficacy of durvalumab after chemoradiotherapy in the subgroups analyzed was generally consistent with that seen in the PACIFIC study analyzes.
“The median real PFS in this study was higher than that reported in PACIFIC, [but] Obviously there are methodological limitations in making such a comparison, âsaid lead study author Nicolas Girard, MD, PhD, professor of respiratory medicine at Versailles Saint Quentin University and director of the Curie Montsouris Thorax Institute in Paris, France, during a presentation by 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 after concomitant platinum-based chemotherapy and radiation therapy.2
The results of the randomized PACIFIC study that led to the approval decision showed a significant improvement in overall survival (OS) and PFS with durvalumab compared with placebo in patients with unresectable stage III NSCLC. The study 5-year survival results showed the median OS was 47.5 months (95% CI 38.1-52.9) with durvalumab versus 29.1 months (95% CI 22.1-35 , 1) with placebo was (HR 0.72; 95% CI, 0.59â0.89). 3 The median PFS was 16.9 months (95% CI 13â23.9) vs. 5.6 Months (4.8-7.7) (HR 0.55; 95% CI 0.45-0.68).
The PACIFIC-R study evaluated the efficacy of durvalumab in practice in patients enrolled in an extended access program (EAP).
The study looked at patients with stage III unresectable NSCLC, regardless of tumor PD-L1 expression. After definitive platinum-based chemoradiotherapy, patients could have no evidence of disease progression to be eligible for inclusion.
On an index date between September 2017 and December 2018, patients were started with 10 mg / kg intravenous durvalumab every 2 weeks via the EAP.
Retrospective data were collected from the patient’s medical records at various times. The study used an observation period of 5 years to assess the development of the disease. A total of 1399 patients were included in the full analysis set. Patients were from 290 active clinical trial centers in 11 participating countries including France (n = 342), Spain (n = 244), Australia (n = 165), Netherlands (n = 155), Belgium (n = 118), Italy (n = 116), Israel (n = 92), Germany (n = 62), Great Britain (n = 54), Norway (n = 36) and Switzerland (n = 15).
The dual primary endpoint of the study was investigator-assessed PFS and OS, with the most important secondary endpoints demographics, disease characteristics, previous therapy, PFS / OS by subgroup and side effects (AEs) being of particular interest.
At the time of enrollment in the EAP, the median patients were 66 years old (range 26-88) and most were 75 years or younger (89.6%). The majority of patients were male (67.5%), ex-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 non-squamous histology (63.1%).
The majority of patients received concurrent chemoradiotherapy (76.6%) vs. sequential chemoradiotherapy (14.3%) or other chemoradiotherapy (9.1%).
In addition, most of the evaluable patients (n = 967) had a PD-L1-positive disease (PD-L1 â¥ 1%; 72.5%).
The median time to start durvalumab from the end of radiation therapy was 56 days, and patients received durvalumab treatment for a median of 335 days, which corresponds to approximately 11 months. Some of the patients (20.1%) received durvalumab for more than 12 months and 4.4% for more than 14 months. Finally, the patients received a median of 22 durvalumab infusions; 7.1% received more than 26 infusions.
By subgroup, the data showed that the median PFS was 22.4 months (95% CI 18.7-25.5) in the PD-L1 population with 1% or greater versus 16.3 months (95% CI , 11.7-23.2) in the PD-L1 population of less than 1% of the 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, 20.2â26.5) in patients with stage IIIA disease vs. 19.2 months (95% CI, 15.8â24.2) in patients with Stage IIIB / C disease. According to histology, the median PFS was 25.3 months (95% CI 22â26.9) in patients with non-squamous NSCLC vs. 14.7 months (95% CI 12.8â19) in patients with squamous cell carcinoma. Finally, the median PFS by chemoradiotherapy type was 23.7 months (95% CI, 20.1-25.8) with concurrent chemoradiotherapy vs. 19.4 months (95% CI, 12.4-25.3) with sequential chemoradiotherapy.
With regard to safety in the cohort of the full study analysis, the reasons for discontinuing durvalumab included the patient’s decision (n = 20; 1.4%), AEs (n = 233; 16.7%), treatment completed (aft = 659; 47.1%), disease progression (n = 377; 26.9%) and death (n = 21; 1.5%). Further reasons for discontinuation were missing data (n = 2), unspecified reasons (n ââ= 68), lost follow-up (n = 3), and ongoing durvalumab treatment at the time of data extraction (n = 16). The median times from starting durvalumab to discontinuing treatment were 6.1 months, 2.8 months, 12 months, 5.1 months and 1.9 months, respectively.
In addition, pneumonitis and interstitial lung disease (ILD) were the most common toxicities that led patients to discontinue treatment. The AE led to permanent discontinuation in 9.5% (n = 133) of the patients and to a temporary interruption in 5.2% (n = 73) of the patients.
Pneumonitis and ILD were observed in 17.9% (n = 250) of the patients. Of these events, 4% (n = 56) were mild, 8.4% (n = 118) moderate, 2.9% (n = 41) severe, and 0.4% (n = 5) life-threatening or fatal.
The median time to onset of pneumonitis or ILD after initiating durvalumab treatment was 2.5 months and corticosteroids were required in 71.3% of events.
Girard and co-authors found that the real PFS benefit is likely overestimated for the following reasons:
- Germany and the UK did not collect data on early deaths (n = 50) that occurred prior to enrollment,
- The RECIST criteria for tumor assessment are heterogeneous in the countries
- Real-world progression assessments may not be performed as frequently or consistently as in clinical trials, and
- The COVID-19 pandemic could have resulted in fewer hospital visits for patients.
“The future OS ads will provide further insight into the effectiveness of this regime,” Girard concluded.
Girard N., Smit HJM, Sibille A, et al. PACIFIC-R Real World Study: Treatment Duration and Interim Progression-Free Survival Analysis in Unresectable Stage III NSCLC Patients Treated with Durvalumab After Chemoradiation. Presented at: ESMO Congress 2021; 16.-21. September 2021; virtual. Summary 1171MO.
FDA approves durvalumab after chemoradiation for unresectable stage III NSCLC. Press release. FDA. February 16, 2018. Retrieved September 21, 2021. https://bit.ly/3EFpXO3
Spigel DR, Faivre-Finn C, Gray JE, et al. Five-year survival results with durvalumab after chemoradiotherapy for unresectable stage III NSCLC: an update from the PACIFIC study. J Clin Oncol. 2021; 39 (Supplement 15): 8511. doi: 10.1200 / JCO.2021.39.15_suppl.8511