The PACIFIC study showed that the addition of the programmed cell death ligand 1 (PD-L1) inhibitor durvalumab (Imfinzi) following chemoradiotherapy for patients with unresectable stage III non–small cell lung cancer (NSCLC) dramatically improved progression-free survival compared with placebo. These results, presented at the European Society for Medical Oncology (ESMO) 2017 Congress and published simultaneously in The New England Journal of Medicine, were hailed as practice-changing for this group of potentially curable patients.1 At the time, experts said that overall survival results of the trial would be needed to support further the use of durvalumab for this indication.
In light of the efficacy of durvalumab in this setting, it is important to assess patients’ experience of this new treatment. Durvalumab did not appear to have a negative impact on key symptoms of lung cancer, physical function, and global health status or quality of life, according to the results of a subanalysis of the PACIFIC trial based on patient-reported outcomes.2 These new findings were presented at the 2017 International Association for the Study of Lung Cancer (IASLC) World Conference on Lung Cancer in Yokohama, Japan.
We are pleased to see that adding durvalumab for 12 months after chemoradiation did not compromise quality of life.— Rina Hui, MD
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“PACIFIC was an impressive study showing that durvalumab was superior to placebo, achieving a median improvement in progression-free survival of 11 months. This is the first study to bring PD-L1 treatment to early-stage NSCLC after standard chemoradiation. Durvalumab was well tolerated in the study, but we really need to hear the patients’ experience,” said Rina Hui, MD, of Westmead Hospital, University of Sydney, Australia.
“The take-home message from this study is that quality of life is maintained on durvalumab compared with active surveillance. Changes from baseline for key symptoms were minimal in both arms. There was no difference between the two arms in the time to improvement or the time to deterioration for most symptoms, except for appetite loss and dysphagia. We are pleased to see that adding durvalumab for 12 months after chemoradiation did not compromise quality of life. These findings support the value of durvalumab in earlier-stage NSCLC,” she stated.
Lecia Sequist, MD, MPH
Lecia Sequist, MD, MPH, a thoracic oncologist at -Massachusetts General Hospital Cancer Center in Boston, commented on the study: “The PACIFIC study results from ESMO were practice-changing, and seeing at the World Conference of Lung Cancer that patient-reported outcomes are not any worse with durvalumab after chemoradiation offers further reassurance about implementing this strategy as the new standard of care. The National Comprehensive Cancer Network® (NCCN®) Guidelines have already been updated to include a year of adjuvant durvalumab after curative-intent chemoradiation for inoperable stage III lung cancer.”
Key Findings From PACIFIC Trial
The PACIFIC trial, conducted at 235 centers in 26 countries, randomized 713 patients in a 2:1 ratio to receive durvalumab or placebo for 12 months. All patients had stage III unresectable NSCLC treated with chemoradiotherapy.
A preplanned interim analysis at 14.5 months showed that median progression-free survival was 16.8 months in the durvalumab arm vs 5.6 months with placebo—representing a 48% reduction in the likelihood of disease progression favoring the PD-L1 inhibitor (hazard ratio, 0.52, P < .0001).
At 18 months, progression-free survival rates were 44.2% for durvalumab and 22% for placebo. Overall survival will be presented when the data become more mature.
Progression-free survival favored durvalumab for all patient subgroups, including PD-L1–positive and –negative patients. Patients in the trial were unselected for PD-L1 expression, but tumor tissue was collected for analysis. Both PD-L1–positive and PD-L1–negative patients had a progression-free survival benefit. Durvalumab reduced the risk of disease progression or death by 41% compared with placebo in PD-L1–negative patients (< 25% expression) and by 59% in PD-L1–positive patients (≥ 25% expression).
The durvalumab-treated patients experienced fewer metastatic or new lesions than placebo patients. The median time to death or distant metastasis was 23.2 months with durvalumab vs 14.6 months with placebo (P < .001).
No new safety signals were reported with durvalumab.
Key lung cancer symptoms, physical function, and global health status/quality of life were assessed by the European Organisation for Research and Treatment of Cancer (EORTC) Quality-of-Life Questionnaire (QLQ-30) version 3 and its lung cancer module, QLQ-Lung Cancer-13. Patients completed these questionnaires at baseline, week 4, week 8 and every 8 weeks until week 48, then every 12 weeks until disease progression. Patients who discontinued the study due to disease progression had their final assessment on day 30 after the last dose of drug.
At baseline, the durvalumab and placebo groups had similar key symptom frequency (ie, cough, dyspnea, chest pain, fatigue, appetite loss), physical function, and global health status/quality of life. Key symptom scores and physical functioning as well as global health status/quality of life remained stable in both arms of the study, with no significant differences in changes from baseline.
Within each of the two arms, clinically relevant improvements were observed at week 48 for dysphagia and alopecia. The magnitude of improvement was similar between the two arms. Dr. Hui attributed this finding to resolution of the effects of chemotherapy. Other symptom domains remained stable throughout the study.
The odds of improvement in appetite loss were greater with durvalumab vs placebo, with no between-arm differences in improvement rates for functioning or other symptoms. No differences between durvalumab and placebo were observed in the time to deterioration of most functioning domains and symptoms, except for a longer time to deterioration of “other pain” with durvalumab. However, no difference was observed between the arms for more detailed assessment of pain, chest pain, and shoulder pain.
Paul Bunn, MD
At a press conference held in conjunction with the IASLC meeting, session moderator Paul Bunn, MD, Distinguished Professor, Division of Medical Oncology, University of Colorado School of Medicine, Denver, pointed out that biomarkers are needed for predicting which patients will respond.
“At 2 years, about 40% had not progressed yet, but 60% had progressed. We want to be able to select patients most likely to benefit. PD-L1 expression and tumor burden have been studied as biomarkers in metastatic disease. In this trial, all comers [for PD-L1 expression] were enrolled, and there was no difference in progression-free survival benefit according to PD-L1 expression. At this moment, PD-L1 status does not select patients who may benefit more from durvalumab. But other biomarkers, such as mutational load or immunosignature, may be studied in the future. Right now, there are no biomarkers to select patients. All [unresectable stage III NSCLC] patients may have a possible benefit,” Dr. Bunn stated.
This study was supported by AstraZeneca. ■
DISCLOSURE: Dr. Hui has received advisory board fees from AstraZeneca, Merck Sharp and Dohme, and Novartis; speaker honorarium from Merck Sharp and Dohme; and accommodation expenses from Roche. Dr. -Sequist is on the advisory board of -Genentech, Pfizer, AstraZeneca, and BMS. Dr. Bunn has received advisory board fees from AstraZeneca, Merck, BMS, and Genentech.
1. Antonia SJ, Villegas A, Daniel D, et al: Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer. N Engl J Med. 2017 377:1919-1929, 2017.
2. Hui R, Ozguroglu M, Daniel D, et al: Patient-reported outcomes with durvalumab after chemoradiation in locally advanced unresectable NSCLC: Data from Pacific. 2017 IASLC World Conference on Lung Cancer. Abstract PL 02-02. Presented October 17, 2017.
Michael Boyer, MBBS, PhD
Formal discussant of this trial, Michael Boyer, MBBS, PhD, a medical oncologist at Sydney Cancer Centre, Royal Prince Alfred Hospital, Camperdown, Australia, was enthusiastic about these results, with the caveat that overall survival data are needed.