Symptomatic Pneumonitis With Durvalumab After Concurrent Chemoradiotherapy in Unresectable Stage III NSCLC

Abstract

Introduction: In the placebo-controlled, phase 3 PACIFIC trial, durvalumab significantly prolonged progression-free survival (PFS) (p < 0.0001) and overall survival (OS) (p = 0.00251) in patients with unresectable stage III NSCLC and no progression after platinum-based concurrent chemoradiotherapy (cCRT). Pneumonitis or radiation pneumonitis (PRP) was common in both arms. We report exploratory analyses evaluating the association of symptomatic (grade ≥2) PRP (G2+PRP) with baseline factors and clinical outcomes.

Methods: Patients with WHO performance status of 0 or 1 were randomized (2:1) to 12 months of durvalumab or placebo, 1 to 42 days after cCRT. Associations between baseline factors and on-study G2+PRP in durvalumab-treated patients were investigated using univariate and multivariate logistic regression. PFS and OS were analyzed using Cox proportional hazards models adjusted for time-dependent G2+PRP plus covariates for randomization stratification factors without and with additional baseline factors.

Results: On-study G2+PRP occurred in 94 of 475 (19.8%) and 33 of 234 patients (14.1%) on durvalumab and placebo, respectively (median follow-up, 25.2 mo); grade greater than or equal to 3 PRP was uncommon (4.6% and 4.7%, respectively). Time to onset and resolution of G2+PRP was similar with durvalumab and placebo. Univariate and multivariate analyses identified patients treated in Asia, those with stage IIIA disease, those with performance status of 1, and those who had not received induction chemotherapy as having a higher risk of G2+PRP. PFS and OS benefit favoring durvalumab versus placebo was maintained regardless of time-dependent G2+PRP.

Conclusions: Factors associated with higher risk of G2+PRP with durvalumab after cCRT were identified. Clinical benefit was maintained regardless of on-study G2+PRP, suggesting the risk of this event should not deter the use of durvalumab in eligible patients with unresectable stage III NSCLC.

Keywords: Durvalumab; Immunotherapy; Locally advanced NSCLC; Pulmonary toxicity; Radiotherapy.

Figure 1

CONSORT Diagram. Shown are data collected up to March 22, 2018, the last data cutoff for which safety data (including pneumonitis or RT-pneumonitis) was analyzed. Patients who completed (protocol-defined) 12 months’ durvalumab or placebo are those for whom the electronic case report form revealed that they had received the maximum number of cycles of study treatment. ^aTwo patients who were randomized to placebo erroneously received one dose of durvalumab and were included in the durvalumab as-treated population. RT, radiotherapy.

Figure 2

Univariate analyses of baseline factors potentially associated with grade greater than or equal to 2 pneumonitis or RT-pneumonitis in durvalumab-treated patients. ^aSeventeen patients were excluded from the analyses due to missing data for stage and/or best response to prior therapy. ^bThe OR of grade ≥2 pneumonitis or RT-pneumonitis occurrence was derived using logistic regression; an OR for group A versus group B of <1 implies lower risk of grade ≥2 pneumonitis or RT-pneumonitis for group A relative to group B. ^cAge at randomization. ^dCOPD was analyzed as a grouped term comprising diagnoses of COPD, bronchitis chronic, emphysema, and obstructive airways disorder. CI, confidence interval; COPD, chronic obstructive pulmonary disease; CR, complete response; CT, chemotherapy; OR, odds ratio; PR, partial response; RT, radiotherapy; SD, stable disease; PS, performance status.

Figure 3

Study treatment exposure by presence or absence of grade greater than or equal to 2 pneumonitis or RT-pneumonitis in patients who received (A) durvalumab and (B) placebo. RT, radiotherapy.