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

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.

Conflict of interest statement

B.C.C. has received institutional research grants/supplies from Biodesix, Boehringer Ingelheim, Bristol-Myers Squibb, Iovance Biotherapeutics, Neogenomics and Prometheus; participated in speaker bureaus for Achilles, AstraZeneca, Bristol-Myers Squibb, Foundation Medicine, F. Hoffmann-La Roche AG, Gilead and Takeda; and has participated in advisory boards for AbbVie, BergenBio, Bristol-Myers Squibb and GlaxoSmithKline. T.C.Y., R.T., W.T. and H.K.A. are employees or contracted employees of AstraZeneca and may be shareholders of AstraZeneca. S.-W.K. has received clinical research support from AstraZeneca, Boehringer Ingelheim and Eli Lilly. N.N. has received research grants from AstraZeneca, Boehringer Ingelheim, Chugai Pharmaceutical, Kyowa Hakko Kirin, ONO Pharmaceutical and Taiho Pharmaceutical and personal fees from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Chugai Pharmaceutical, Eli Lilly Japan, Kyowa Hakko Kirin, Meiji Seika Pharma, Merck Sharp & Dohme, Nikkei Business Publications, ONO Pharmaceutical, Pfizer Japan, Reno Medical and Taiho Pharmaceutical. D.-W.K’s institution has received research funding from Alpha Biopharma, AstraZeneca/MedImmune, Hanmi, Janssen, Merus, Mirati Therapeutics, MSD, Novartis, ONO Pharmaceutical, Pfizer Inc., Roche/Genentech, Takeda, TP Therapeutics, Xcovery and Yuhan. L.Q.M.C. is an employee of the University of Texas, Austin and a former employee of the University of Washington/Seattle Cancer Care Alliance. L.Q.M.C’s institution has received research funding from Alkermes, AstraZeneca/MedImmune, Bristol-Myers Squibb, Dynavax, Eli Lilly, Genentech, Incyte, Merck, Novartis, Pfizer Inc., Seattle Genetics and VentiRx; and the University of Washington/Seattle Cancer Care Alliance received institutional funding from AstraZeneca for this study. L.Q.M.C. has received honoraria from Amgen and has participated in advisory boards for Alkermes, Amgen, AstraZeneca, Bristol-Myers Squibb, Dynavax, Genentech, Merck, Novartis, Pfizer Inc., Sanofi Genzyme, Seattle Genetics, Synthorx and Takeda. S.K. has received research grant funding from AbbVie, AstraZeneca and ONO Pharmaceutical; honoraria from AstraZeneca, Bristol-Myers Squibb, Chugai Pharmaceutical, Novartis and ONO Pharmaceutical; and has participated in advisory boards for AstraZeneca. M.T. is an employee of Astellas Pharma US and a former employee of AstraZeneca. M.P.R. is an employee of the Institute for Prostate Cancer Research and a former employee of AstraZeneca. M.M. is a former employee of AstraZeneca. D.L.G. has received research grants from AstraZeneca, Janssen Research & Development and Takeda; has participated in advisory boards for AstraZeneca, GlaxoSmithKline and Sanofi; and has received travel expenses from AstraZeneca. D.L.G’s institution has received compensation for conducting the study.

Figures

Fig. 1. Study design.

d days, EGFR epidermal growth factor receptor, IV intravenous, N number of patients assigned to treatment, NSCLC non-small cell lung cancer, QD once daily, Q2W once every 2 weeks, TKI tyrosine kinase inhibitor.

Fig. 2. Adverse events of special interest by CTCAE grade (safety population, dose escalation and expansion).

Maximum CTCAE grade is shown for all cohorts, including Cohort A (N = 3), Cohort B (N = 7), Japan Cohort (N = 6), Arm 1 (N = 10), Arm 1a (N = 20) and Arm 2 (N = 10). CTCAE Common Terminology Criteria for Adverse Events, N number of patients assigned to treatment.

Fig. 3. Progression-free survival and duration of response.

a Overall and b by PD-L1 expression (tumour response analysis set). PD-L1 TC expression (high: ≥20%; low/negative: <20%) was determined at baseline. CI confidence interval, DoR duration of response, NC not calculable, PD-L1 programmed cell death ligand-1, PFS progression-free survival, TC tumour cell.

Fig. 4. PFS for individual patients in the dose-expansion phase (tumour response analysis set).

Baseline PD-L1 TC ≥20% was indicative of high PD-L1 expression. AE adverse event, EGFR epidermal growth factor receptor, H high (PD-L1 TC ≥20%), L low/negative (PD-L1 TC