Despite Encouraging Activity of Osimertinib + Durvalumab, Safety Profile Warrants Further Investigation

Osimertinib in combination with durvalumab demonstrated encouraging clinical activity, but the combination was associated with high rates of toxicities, a study presented at the European Lung Cancer Conference (ELCC) 2016 has shown.¹

Osimertinib is a potent, selective, irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that has demonstrated efficacy in tumors with EGFR mutations and T790M resistance mutations. Durvalumab is a selective, IgG1 monoclonal antibody that blocks programmed death-ligand 1 (PD-L1) and CD80 with high affinity.

Researchers designed the multi-arm, phase 1b TATTON trial to assess the efficacy, tolerability, and safety of the combination. The study was conducted in 2 parts: dose escalation in EGFR-TKI pre-treated patients and dose expansion in EGFR-TKI treatment-naïve patients. All participants received osimertinib 80 mg orally daily plus durvalumab 3 mg/kg or 10 mg/kg intravenously every 2 weeks during the dose-escalation part or 10 mg/kg every 2 weeks during the dose-expansion portion.

In terms of efficacy, 12 patients in the dose-escalation part and 8 in the dose-expansion part achieved a partial response. Nine and 2, respectively, had stable disease.

The most common adverse events were nausea (39%), vomiting (39%), anemia (35%), and diarrhea (35%) among the 23 patients treated in the dose-escalation portion. The most frequently reported adverse events among the 11 treated in the dose-expansion phase were interstitial lung disease (64%), diarrhea (55%), and nausea (45%).

In total, approximately 38% of patients developed interstitial lung disease, of which 5 cases were grade 3 or 4. Most cases of interstitial lung disease were managed with corticosteroids and there were no fatalities. The median time to onset of interstitial lung disease was 69 days.

Because there appeared to be an increased incidence of interstitial lung disease with the combination of osimertinib and durvalumab compared with either agent alone, this arm is currently on hold.

Reference

1. Ahn M, Yang J, Yu H, et al. Osimertinib combined with durvalumab in EGFR-mutant non-small cell lung cancer: results from the TATTON phase 1b trial. Oral presentation at: European Lung Cancer Conference 2016; April 13-16, 2016; Geneva, Switzerland.