Durvalumab for Stage III EGFR-Mutated NSCLC After Definitive Chemoradiotherapy

Abstract

Introduction: In 2018, durvalumab was approved by the U.S. Food and Drug Administration as consolidation immunotherapy for patients with stage III NSCLC after definitive chemoradiotherapy (CRT). However, whether durvalumab benefits patients with EGFR-mutated NSCLC remains unknown.

Methods: We conducted a multi-institutional retrospective analysis of patients with unresectable stage III EGFR-mutated NSCLC who completed concurrent CRT. Kaplan-Meier analyses evaluated progression-free survival (PFS) between patients who completed CRT with or without durvalumab.

Results: Among 37 patients, 13 initiated durvalumab a median of 20 days after CRT completion. Two patients completed 12 months of treatment, with five patients discontinuing durvalumab owing to progression and five owing to immune-related adverse events (irAEs). Of 24 patients who completed CRT without durvalumab, 16 completed CRT alone and eight completed CRT with induction or consolidation EGFR tyrosine kinase inhibitors (TKIs). Median PFS was 10.3 months in patients who received CRT and durvalumab versus 6.9 months with CRT alone (log-rank p = 0.993). CRT and EGFR TKI was associated with a significantly longer median PFS (26.1 mo) compared with CRT and durvalumab or CRT alone (log-rank p = 0.023). Six patients treated with durvalumab initiated EGFR TKIs after recurrence, with one developing grade 4 pneumonitis on osimertinib.

Conclusions: In this study, patients with EGFR-mutated NSCLC did not benefit with consolidation durvalumab and experienced a high frequency of irAEs. Patients who initiate osimertinib after durvalumab may be susceptible to incident irAEs. Consolidation durvalumab should be approached with caution in this setting and concurrent CRT with induction or consolidation EGFR TKIs further investigated as definitive treatment.

Keywords: Concurrent chemoradiotherapy; Durvalumab; EGFR TKI; EGFR mutation; Osimertinib.

Figure 1.

Molecular features of the EGFR-mutated NSCLC cohort (N = 37). OncoPrint summarizes the definitive treatment regimen that patients received, PD-L1 expression, and co-occurring mutations in the upper panel and EGFR mutation subtypes or copy number variation in the lower panel. Each column represents one patient. The bar graphs and percentages correspond to the frequencies of the EGFR mutations across the cohort. Amp, amplification; CRT, chemoradiotherapy; del, deletion; ins, insertion; PD-L1, programmed death-ligand 1; VUS, variant of unknown significance; wo, without.

Figure 2.

Time intervals surrounding consolidation durvalumab and EGFR TKI initiation. (A) The median time from CRT completion to durvalumab initiation was 20 days (IQR: 17-49; 2.9 wk). (B) Patients received a median of six cycles (IQR: 4-14) of durvalumab. (C) Median time from durvalumab initiation to severe irAE was 95 days (IQR: 33-151). (D) Median time from the last durvalumab dose to EGFR TKI initiation was 71 days (IQR: 51-168). *Patient completed 12 months of consolidation durvalumab but only 24 cycles were recorded in the available documentation. **One patient experienced a severe irAE (colitis) a few days after completing the second cycle of durvalumab; thus, the patient was included in the 0- to 30-day bin and a close approximation (20 d) was used when calculating the median time to severe irAE. ***One patient initiated osimertinib 588 days after the last dose of durvalumab and experienced an incident grade 4 pneumonitis while on osimertinib. CRT, chemoradiotherapy, IQR, interquartile range, irAE, immune-related adverse event; TKI, tyrosine kinase inhibitor.

Figure 3.

PFS after chemoradiotherapy with or wo durvalumab. (A) Median PFS among patients who completed CRT and durvalumab versus CRT wo durvalumab was 10.3 months versus 22.8 months (log-rank p = 0.180). (B) Median PFS among patients who completed CRT alone versus CRT and durvalumab versus CRT and induction or consolidation EGFR TKI was 6.9 months versus 10.3 months versus 26.1 months (log-rank p = 0.023). CRT, chemoradiotherapy; PFS, progression-free survival; TKI, tyrosine kinase inhibitor; wo, without.