Implications of pneumonitis after chemoradiation and durvalumab for locally advanced non-small cell lung cancer

Abstract

Background: Consolidation durvalumab improved overall survival (OS) in locally advanced non-small cell lung cancer (LA-NSCLC) treated with chemoradiotherapy (CRT) in the PACIFIC trial; however, pneumonitis was increased with durvalumab. We sought to examine real-world outcomes with the PACIFIC paradigm, especially factors associated with pneumonitis, using a multi-institutional review. Methods: Patients with LA-NSCLC treated with CRT followed by durvalumab from January 2017-February 2019 were identified at 2 institutions. We characterized demographics, tumor factors, radiotherapy, and duration of durvalumab. We examined pneumonitis outcomes including re-challenge success, with secondary endpoints of progression-free survival (PFS) and OS. Results: Thirty-four patients were included with median follow-up of 12 months (range, 3 to 20 months); 94% had stage III disease. The cumulative grade >2 pneumonitis rate was 26.5% with 2 patients developing grade 3 pneumonitis and no grade 4/5 events. Median time to pneumonitis after RT was 2.4 months (range, 0 to 4.9 months). Pneumonitis management included median prednisone dose of 60 mg for median taper of 6 weeks with durvalumab held for median of 4.5 weeks (range, 2 to 8 weeks); 70% of pneumonitis patients received durvalumab re-challenge, with pneumonitis recurring in 14% of patients. 3-month and 6-month pneumonitis-free-survival were 76.9% and 73.6%, respectively; 9-and 12-month OS were 96% (75.1-99.8%), 86.6% (63.5-95.5%), respectively; 9-and 12-month PFS were 68% (47.5-82.5%), 48.7% (25.3-68.3%). Pneumonitis development did not significantly impact PFS or OS (P>0.05).Conclusions: Among LA-NSCLC patients treated with CRT followed by consolidation durvalumab, more than 25% developed symptomatic pneumonitis. In this small case series, pneumonitis did not appear to negatively impact survival, and durvalumab re-challenge appeared feasible after pneumonitis treatment with steroids.

Association Between the Early Discontinuation of Durvalumab and Poor Survival in Patients With Stage III NSCLC

“… 1 Recent data suggest that durvalumab rechallenge may be feasible in patients who develop pneumonitis. 5 Therefore, strong consideration of durvalumab rechallenge may be warranted in patients who develop pneumonitis who received less than 4 months of therapy. In addition, anti–programmed death-ligand 1 rechallenge has been found feasible across a range of immune-related AEs 6 , 7 ; therefore, given the substantial survival benefit of durvalumab, consideration should be given to rechallenge in patients who receive minimal therapy regardless of the specific AE.…”

Adding Base-Excision Repair Inhibitor TRC102 to Standard Pemetrexed–Platinum–Radiation in Patients with Advanced Nonsquamous Non–Small Cell Lung Cancer: Results of a Phase I Trial

“…© 2021 American Association for Cancer clincancerres.aacrjournals.org Downloaded from grade 3-4 radiation pneumonitis with placebo. However, recent data show that in real world practice, grade 3 or higher pneumonitis is somewhat more frequent than this, at 6.5%, with 1.5% of patients experiencing fatal pneumonitis [34]. Other reports also showed increased rates of grade 3 pneumonitis with the addition of durvalumab, 14.3% compared to 3.4% that was reported in the PACIFIC trial.…”

A Canadian Perspective on the Challenges for Delivery of Curative-Intent Therapy in Stage III Unresectable Non-Small Cell Lung Cancer

“…In the PACIFIC trial, any grade pneumonitis occurred at a rate of 33.9% in patients receiving durvalumab, with grade ≥ 3 pneumonitis occurring in 3.4% (24.8 and 2.6% in the placebo arm, respectively) [10]. Real-world data have reported frequencies of any grade and grade ≥ 3 pneumonitis of 20-80% and approximately 6%, respectively, with some studies reporting pneumonitis as a negative prognostic factor for survival [18,57,59,60]. Pneumonitis is a particularly concerning immune-related adverse event in patients with stage III lung cancer, as prior radiotherapy may act synergistically to increase its risk of occurrence [61].…”

“…To optimize patient outcomes, patient education on pneumonitis symptoms, and early diagnosis and intervention with an MDT, is essential [61]. Re-challenge with durvalumab can be considered after resolution of symptoms; however, guidelines on safely re-challenging are limited [60]. In two small retrospective studies, re-challenge with durvalumab was shown to be feasible, leading to pneumonitis recurrence in 14 and 29% of patients [59,60].…”

“…Re-challenge with durvalumab can be considered after resolution of symptoms; however, guidelines on safely re-challenging are limited [60]. In two small retrospective studies, re-challenge with durvalumab was shown to be feasible, leading to pneumonitis recurrence in 14 and 29% of patients [59,60]. To optimize patient outcomes, the decision of durvalumab re-challenge should be made with an MDT.…”