Benjamin C Creelan1, Tammie C Yeh2, Sang-We Kim3, Naoyuki Nogami4, Dong-Wan Kim5, Laura Q M Chow6, Shintaro Kanda7, Rosemary Taylor8, Weifeng Tang9, Mei Tang9, Helen K Angell10, Martine P Roudier10, Marcelo Marotti8, Don L Gibbons11. 1. Department of Thoracic Oncology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, FOB-1, Tampa, FL, 33612, USA. Ben.Creelan@moffitt.org. 2. Translational Medicine, Oncology R&D, AstraZeneca, 35 Gatehouse Drive, Waltham, MA, 02451, USA. 3. Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, South Korea. 4. Department of Thoracic Oncology, National Hospital Organization Shikoku Cancer Center, 160 Minami-Umemoto-cho, Matsuyama City, 791-0280, Japan. 5. Department of Internal Medicine, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea. 6. Department of Medicine, Division of Oncology, University of Washington/Seattle Cancer Care Alliance, Seattle, WA, 98109, USA. 7. Department of Comprehensive Cancer Therapy, Shinshu University School of Medicine, 3-1-1 Asahi Matsumoto, Nagano, 390-8621, Japan. 8. Oncology, AstraZeneca, Academy House, 132-136 Hills Road, Cambridge, CB2 8PA, UK. 9. Clinical Pharmacology and Safety Assessment, AstraZeneca, One Medimmune Way, 101 ORD, 2001D, Gaithersburg, MD, 20878, USA. 10. Translational Medicine, Oncology R&D, AstraZeneca, Darwin Building, Unit 310, Cambridge Science Park, Milton Road, Cambridge, CB4 0WG, UK. 11. Departments of Thoracic/Head and Neck Medical Oncology and Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX, 77030, USA.
Abstract
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 EGFRm 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 EGFRm. 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 EGFRm NSCLC.
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 EGFRm 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 EGFRm. 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 EGFRm NSCLC.
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