Severe immune-related adverse events are common with sequential PD-(L)1 blockade and osimertinib

Abstract

Background: Concurrent programmed death-ligand-1 (PD-(L)1) plus osimertinib is associated with severe immune related adverse events (irAE) in epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer (NSCLC). Now that PD-(L)1 inhibitors are routinely used as adjuvant and first-line treatments, sequential PD-(L)1 inhibition followed by osimertinib use may become more frequent and have unforeseen serious toxicity.

Methods: We identified patients with EGFR-mutant NSCLC who were treated with PD-(L)1 blockade and EGFR- tyrosine kinase inhibitors (TKIs), irrespective of drug or sequence of administration (total n = 126). Patient records were reviewed to identify severe (NCI-CTCAE v5.0 grades 3-4) toxicity.

Results: Fifteen percent [6 of 41, 95% confidence interval (CI) 7% to 29%] of all patients treated with sequential PD-(L)1 blockade followed later by osimertinib developed a severe irAE. Severe irAEs were most common among those who began osimertinib within 3 months of prior PD-(L)1 blockade (5 of 21, 24%, 95% CI 10% to 45%), as compared with >3-12 months (1 of 8, 13%, 95% CI 0% to 50%), >12 months (0 of 12, 0%, 95% CI 0% to 28%). By contrast, no severe irAEs were identified among patients treated with osimertinib followed by PD-(L)1 (0 of 29, 95% CI 0% to 14%) or PD-(L)1 followed by other EGFR-TKIs (afatinib or erlotinib, 0 of 27, 95% CI 0% to 15%). IrAEs occurred at a median onset of 20 days after osimertinib (range 14-167 days). All patients with irAEs required steroids and most required hospitalization.

Conclusion: PD-(L)1 blockade followed by osimertinib is associated with severe irAE and is most frequent among patients who recently received PD-(L)1 blockade. No irAEs were observed when osimertinib preceded PD-(L)1 blockade or when PD-(L)1 was followed by other EGFR-TKIs. This association appears to be specific to osimertinib, as no severe irAEs occurred with administration of other EGFR-TKIs.

Keywords: EGFR; PD-1; TKI; irAE; osimertinib.

Figure 1

Sequential programmed death-ligand-1 (PD-(L)1) blockade and osimertinib schema of patients who developed severe immune-related adverse events. (A) Flow diagram of clinical course of six patients treated with PD-1 inhibitors followed by osimertinib who developed severe immune-related adverse events. Patient 1, 3, and 6 received other lines of therapy before PD-(L)1 blockade. (B) Patients who developed severe immune-related adverse events. osi, osimertinib; PD1, PD-(L)1 inhibitor; IO, immunotherapy.

Figure 2

Temporal association heatmap and bar diagram of programmed death-ligand-1 (PD-(L)1) blockade and osimertinib. (A) Frequency of severe immune-related adverse events on osimertinib over time interval since last dose of PD-(L)1 inhibitor. Heatmap is displayed with red color shade (online) signifying highest density of events (white color signifies no events). Dashed blue lines (online) under x-axis signify patient end of treatment without experiencing severe immune-related adverse events and red dashed lines (online) above x-axis represent events. Number of patients at risk of severe immune-related adverse events are list below x-axis at 6-month intervals and represented by black dotted line on figure. (B) Frequency of severe immune-related adverse events by epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) since last dose of PD-(L)1 inhibitor.