DISCUSSION
pneumonitis, tumor, malignancy, 6‐week, cancer, PD‐L1
PNEUMONITIS, TUMOR, CANCER, DISEASE, STAGE II NSCLC, REGRESSION
In this study, we evaluated the eligibility of patients with stage III NSCLC for the PACIFIC trial, reasons for ineligibility, and the impact on outcomes in a real‐world setting at two Australian tertiary hospitals. There were several key findings. First, we noted that a significant proportion of our patient cohort who proceeded to definitive chemoradiotherapy (44%) were ineligible for the PACIFIC trial. Second, trial eligibility resulted in improved outcome regardless of receipt of durvalumab. Third, a subset of ineligible patients who received durvalumab had similar outcomes to trial‐eligible patients who received durvalumab.Our study demonstrated that only 56% of patients treated with definitive chemoradiotherapy and 30% of all patients with stage III NSCLC were eligible for the PACIFIC trial. This data is in keeping with a previous retrospective cohort series of definitive chemoradiation patients in Japan, Canada, Korea, and Germany which found that 65%, 60%, 56%, and 50% of patients, respectively, were eligible for durvalumab.This has given rise to concern about the generalizability of the PACIFIC trial results to real‐world populations, including our cohort. Compared to the PACIFIC study, in our cohort, patients were older and mostly commenced durvalumab treatment >42 days following the completion of chemoradiotherapy. In the PACIFIC study, PFS and OS were defined as time from randomization, which could occur up to 42 days following completion of radiotherapy. Although in our study, PFS and OS were defined as the time from completion of radiotherapy, the survival outcomes compare favorably to the results from this study.Patients ineligible for the PACIFIC trial had shorter median PFS (9.7 months) and OS (18.4 months). The detrimental effect on OS was maintained even when patients with progressive disease were excluded (Despite ineligibility for the PACIFIC trial, 17 patients (30%) received durvalumab treatment. Most of these patients were ineligible due to history of another malignancy. In this small group of patients there was no detrimental impact on outcomes seen when compared to trial‐eligible patients who received durvalumab. Only two patients ceased treatment early, one due to declining performance status and one due to pneumonitis. Few studies have evaluated the impact of cancer treatment among trial‐eligible patients. In a Korean study in which 56% of patients were ineligible for the PACIFIC trial, mostly related to radiotherapy dose, favorable PFS was demonstrated with durvalumab use in the ineligible patients (PFS not reached vs. 9.6 months, In univariate analysis, in addition to trial eligibility, the strongest factor associated with survival outcome was receipt of radiation dose <54 Gy. Multivariate regression analysis demonstrated a trend to worse outcomes with receipt of radiation dose <54 Gy. In the RTOG 7301 study, compared to lower doses of radiotherapy, 60 Gy in 30 daily fractions over a 6‐week period was associated with improved tumor response.Unexpectedly, univariate and multivariate regression analysis demonstrated improved PFS and OS with negative PD‐L1‐expression. The PACIFIC trial was not designed or powered to evaluate the effect of PD‐L1 expression on outcome, but post hoc analyses demonstrated that there was a significant improvement in all subgroups except for patients with PD‐L1 < 1%.The strengths of this study are that it provides a real‐world description of a cohort with stage III NSCLC and outcomes in two Australian tertiary centres and adds to the increasing body of real‐world evidence in this space. Although we agree with previous studies that trial eligibility criteria should be broadened to reflect routine clinical practice, in the absence of this, real‐world data can help to bridge this gap. We confirm that trial eligibility is associated with improved prognosis in keeping with several other real‐world studies.