PACIFIC Led to Subtle but Swift Adoption of Concurrent Chemoradiation and Durvalumab in Stage III NSCLC

An increase in the use of concurrent chemoradiation followed by durvalumab (Imfinzi) was found in patients with stage III non–small cell lung cancer (NSCLC) who were treated at 3 Dutch centers in The Netherlands between 2015 and 2019, according to findings from a retrospective analysis published in the Journal of Thoracic Oncology.¹

The results showed that, between 2015 to 2017 and 2018 to 2019, the proportion of patients who received concurrent chemoradiation increased from 34% to 42% (P = .02) and the use of sequential chemoradiation declined from 21% to 16% (P = .05).

Moreover, after 2018, 57% of the patients who received concurrent chemoradiation (n = 90/159) received adjuvant durvalumab. This rate was constant between 2018 and 2019, dropping only to 56% (P = .979).

“Our real-world data are consistent with other reports indicating only between 34% and 73% of patients receive durvalumab after concurrent chemoradiation,” lead study author Merle Ronden, MD, PhD candidate at Amsterdam University Medical Center, and co-authors wrote in the study publication. “Our study highlights the gap between guideline-recommended treatments and real-world care of patients with stage III NSCLC, and it also demonstrates a timely incorporation of evidence-based medicine into oncology practice,” Ronden added in a statement.

The standard of care for patients with unresectable stage III NSCLC is definitive, concurrent chemoradiation followed by durvalumab based on the significant improvements in progression-free survival and overall survival shown with the regimen in this population in the pivotal, phase 3 PACIFIC trial (NCT02125461).²

The regimen was then approved by the European Medicines Agency (EMA) and the FDA in 2018. Per the EMA approval, durvalumab could be prescribed following concurrent chemoradiation or short-course radiation therapy. However, practice patterns in this setting have been shown to vary between countries.

To determine to what degree and whether practice patterns changed when durvalumab became available, investigators studied treatment patterns from 3 Dutch regional thoracic multidisciplinary tumor boards, spanning 7 hospitals, between 2015 and 2019.

Radical-intent treatment was defined by concurrent chemoradiation and multimodal treatment that included surgery.

Among the 855 eligible patients that were identified, 475 presented between 2015 and 2017 and 380 presented between 2018 and 2019.

The majority (n = 811; 95%) of eligible patients were presented at a thoracic multidisciplinary tumor board. Radical-intent treatment was recommended for 63% (n = 510) of the patients who were presented at the tumor board. However, only 52% (n = 424) received radical-intent treatment.

Between 2015 and 2017, 46% of patients underwent radical-intent treatment, which increased to 55% between 2018 and 2019 (P = .007) because of an increase in the use of concurrent chemoradiation (P = .023). A similar increase in the rate of concurrent chemoradiation was observed in all 3 regions.

“An indication of the potential impact of the PACIFIC study is the significant increase observed in patients undergoing concurrent chemoradiation at all 3 regions from 2018 to 2019, with a significant decrease of patients undergoing short-course radiation therapy,” wrote the study authors.

The radical-intent treatment that was recommended consisted of surgery in 13% of patients, of which 42% (n = 45) underwent surgery plus concurrent chemoradiation; concurrent chemoradiation in 38% of patients; sequential short-course radiation therapy in 19% of patients; radiation therapy of at least 50 Gy in 9% of patients; palliative care in 22% of patients; and unknown treatment in 1% of patients.

Across all regions, the median patient age was 69 years in the 2015 to 2017 cohort and 70 years in the 2018 to 2019 cohort. Approximately half of patients in both cohorts were at least 70 years of age, representing 48% (n = 226) and 52% (n = 198) of patients in the 2015 to 2017 and 2018 to 2019 cohorts, respectively.

Moreover, most patients in both cohorts were male, had a World Health Organization (WHO) performance status of 0 or 1, adenocarcinoma, and American Joint Committee on Cancer stage IIIA disease.

The most common reasons for not undergoing radical-intent treatment were poor performance status (n = 24; 29%), patient refusal (n = 24; 29%), comorbidity (n = 12; 15%), early toxicity (n = 7); 9%, tumor size (n = 5; 6%), disease progression (n = 5; 6%), death (n = 3; 4%), a tumor found to be unresectable during surgery (n = 3; 4%), age (n = 2; 2%), tumor necrosis (n = 2; 2%), lack of social support (n = 1; 1%), lack of tumor response after the first course of chemotherapy (n = 1; 1%), and unknown reasons (n = 2; 4%).

Characteristics that predicted for not undergoing radical-intent treatment were age of at least 70 years, WHO performance score of at least 2, Charlson comorbidity index of at least 2 excluding age, forced expiratory volume in 1 second less than 80% of the predicted value, N3 disease, and treatment between 2015 and 2017.

The rates of early-onset toxicity and 1-year mortality were comparable during both time spans. However, a sizable decrease in the number of patients who received at least 3 cycles of chemotherapy during chemoradiation was reported between periods from 72% to 60%, with an increase of patients receiving 2 cycles of chemotherapy from 28% to 40% (P = .005).

“As previous reports suggested that increasing use of concurrent chemoradiation can be associated with higher rates of mortality in patients with comorbidity or aged 70 years or older, it is reassuring that no corresponding increases in 90-day or 1-year mortality were observed in the radical-intent treatment cohorts in the later periods,” wrote the study authors.

Among patients who received durvalumab with at least 1 year of follow-up (n = 59), 59% received at least 20 cycles of the PD-L1 inhibitor. Reasons for not recommending adjuvant durvalumab consisted of patient refusal (n = 12), performance status (n = 10), disease progression (n = 10), comorbidity (n = 9), death (n = 8), not being recommended in local guidelines (n = 6), PD-1 expression of less than 1% (n = 5), COVID-19 (n = 1), pneumonitis (n = 1), and unknown reasons (n = 10).

Eight patients received durvalumab after short-course radiation therapy. No differences between regions were observed in the rates of durvalumab administration (P = .237).

Factors associated with a failure to receive adjuvant durvalumab following chemoradiation were an age of at least 70 years (P = .003), diabetes mellitus (P = .015) and receipt of short-course radiation therapy (P = .000).

“Our findings suggest that there is room for multidisciplinary tumor boards to increase the rate of use of concurrent chemoradiation for stage III NSCLC. The findings also highlight the need for novel clinical trials to address the unmet needs of patients who cannot receive treatment with radical intent, in an era of significant advances in systemic therapies for NSCLC,” concluded the study authors.

References

1. Ronden MI, Bahce I, Claessens NJM, et al. The impact of the availability of immunotherapy on patterns of care in stage III NSCLC: a Dutch multicenter analysis. J Thorac Oncol. 2021;2(7):100195. doi:10.1016/j.jtocrr.2021.100195
2. 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