A Phase 1 study of gefitinib combined with durvalumab in EGFR TKI-naive patients with EGFR mutation-positive locally advanced/metastatic non-small-cell lung cancer

• Published in: British journal of cancer Vol. 124; no. 2; pp. 383 - 390
• Main Authors: Creelan, Benjamin C., Yeh, Tammie C., Kim, Sang-We, Nogami, Naoyuki, Kim, Dong-Wan, Chow, Laura Q. M., Kanda, Shintaro, Taylor, Rosemary, Tang, Weifeng, Tang, Mei, Angell, Helen K., Roudier, Martine P., Marotti, Marcelo, Gibbons, Don L.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 19.01.2021; Nature Publishing Group
• Subjects: 631/67/1059/2325; 631/67/1059/602; 631/67/1612/1350; 631/67/1857; Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal - administration & dosage; Antibodies, Monoclonal - adverse effects; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Biomedical and Life Sciences; Biomedicine; Cancer Research; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - genetics; Cytolysis; Drug Resistance; Epidemiology; Epidermal growth factor receptors; ErbB Receptors - genetics; Female; Gefitinib; Gefitinib - administration & dosage; Gefitinib - adverse effects; Humans; Immunogenicity; Immunotherapy; Inhibitor drugs; Lung cancer; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Lymphocytes T; Male; Metastases; Middle Aged; Molecular Medicine; Monoclonal antibodies; Mutation; Non-small cell lung carcinoma; Oncology; PD-L1 protein; Pharmacokinetics; Progression-Free Survival; Protein-tyrosine kinase; Small cell lung carcinoma; Targeted cancer therapy; Toxicity; Tumors
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/s41416-020-01099-7

Background EGFR tyrosine kinase inhibitors (TKIs) induce cytolysis and release of tumour proteins, which can stimulate antigen-specific T cells. The safety and efficacy of durvalumab and gefitinib in combination for TKI-naive patients with advanced EGFR m NSCLC was evaluated. Methods This Phase 1 open-label, multicentre trial (NCT02088112) was conducted in 56 patients with NSCLC. Dose expansion permitted TKI-naive patients, primarily with activating L858R or Ex19del EGFR m. Arms 1 + 1a received concurrent therapy; Arm 2 received 4 weeks of gefitinib induction followed by concurrent therapy. Results From dose escalation, the recommended dose of durvalumab was 10 mg/kg Q2W with 250 mg QD gefitinib. Pharmacokinetics were as expected, consistent with inhibition of soluble PD-L1 and no treatment-emergent immunogenicity. In dose expansion, 35% of patients had elevated liver enzymes leading to drug discontinuation. In Arms 1 + 1a, objective response rate was 63.3% (95% CI: 43.9–80.1), median progression-free survival (PFS) was 10.1 months (95% CI: 5.5–15.2) and median response duration was 9.2 months (95% CI: 3.7–14.0). Conclusions Durvalumab and gefitinib in combination had higher toxicity than either agent alone. No significant increase in PFS was detected compared with historical controls. Therefore, concurrent PD-L1 inhibitors with gefitinib should be generally avoided in TKI-naive patients with EGFR m NSCLC.