A phase III, randomized, open-label study of ASP8273 versus erlotinib or gefitinib in patients with advanced stage IIIB/IV non-small-cell lung cancer

R J Kelly, F A Shepherd, A Krivoshik, F Jie, L Horn, R J Kelly, F A Shepherd, A Krivoshik, F Jie, L Horn

Abstract

Background: ASP8273, a novel, small molecule, irreversible tyrosine kinase inhibitor (TKI) specifically inhibits the epidermal growth factor receptor (EGFR) in patients with activating mutations or EGFR T790M resistance mutations. The current study examines the efficacy, safety, and tolerability of ASP8273 versus erlotinib or gefitinib in patients with non-small-cell lung cancer (NSCLC) with activating EGFR mutations not previously treated with an EGFR inhibitor.

Patients and methods: This global, phase III, open-label, randomized study evaluated ASP8273 versus erlotinib/gefitinib in patients with locally advanced, metastatic, or unresectable stage IIIB/IV NSCLC with activating EGFR mutations. They were ineligible if they received prior chemotherapy for metastatic disease. The primary end point was progression-free survival (PFS), and secondary end points included overall survival, investigator-assessed PFS, best overall response rate (ORR), disease control rate, duration of response (DoR), and the safety/tolerability profile.

Results: Patients (n = 530) were randomized 1 : 1 to receive ASP8273 (n = 267) or erlotinib/gefitinib (n = 263). Patient demographics between both treatment groups were generally balanced. Median PFS was 9.3 months (95% CI 5.6-11.1 months) for patients receiving ASP8273 and 9.6 months (95% CI 8.8-NE) for the erlotinib/gefitinib group, with a hazard ratio of 1.611 (P = 0.992). The ORR in the ASP8273 group was 33% (95% CI 27.4-39.0) versus 47.9% (95% CI 41.7-54.1) in the erlotinib/gefitinib group. Median DoR was similar for both groups (9.2 months for ASP8273 versus 9.0 months for erlotinib/gefitinib). More grade ≥3 treatment-emergent adverse events (TEAEs) occurred in patients receiving ASP8273 than in those receiving erlotinib/gefitinib (54.7% versus 43.5%). An independent data monitoring committee carried out an interim safety analysis and recommended discontinuing the study due to toxicity and limited predicted efficacy of ASP8273 relative to erlotinib/gefitinib.

Conclusions: First-line ASP8273 did not show improved PFS or equivalent toxicities versus erlotinib/gefitinib.

Clinicaltrial.gov number: NCT02588261.

Keywords: ASP8273; EGFR inhibitor; non-small-cell lung cancer; phase III clinical trial.

© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society for Medical Oncology.

Figures

Figure 1.
Figure 1.
Patient disposition.
Figure 2.
Figure 2.
Progression-free survival (FAS). CI, confidence interval; FAS, full analysis set.

References

    1. Bell DW, Lynch TJ, Haserlat SM. et al. Epidermal growth factor receptor mutations and gene amplification in non-small-cell lung cancer: molecular analysis of the IDEAL/INTACT gefitinib trials. JCO 2005; 23(31): 8081–8092.
    1. Ladanyi M, Pao W.. Lung adenocarcinoma: guiding EGFR-targeted therapy and beyond. Mod Pathol 2008; 21(Suppl 2): S16–S22.
    1. Herbst RS, Heymach JV, Lippman SM.. Lung cancer. N Engl J Med 2008; 359(13): 1367–1380.
    1. Esposito L, Conti D, Ailavajhala R. et al. Lung cancer: are we up to the challenge? Curr Genomics 2010; 11(7): 513–518.
    1. Ohashi K, Maruvka YE, Michor F, Pao W.. Epidermal growth factor receptor tyrosine kinase inhibitor-resistant disease. JCO 2013; 31(8): 1070–1080.
    1. Soria JC, Ohe Y, Vansteenkiste J. et al. Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N Engl J Med 2018; 378(2): 113–125.
    1. Murakami H, Nokihara H, Hayashi H. et al. Clinical activity of ASP8273 in Asian patients with non-small-cell lung cancer with EGFR activating and T790M mutations. Cancer Sci 2018; 109(9): 2852–2862.
    1. Azuma K, Nishio M, Hayashi H. et al. ASP8273 tolerability and antitumor activity in tyrosine kinase inhibitor-naive Japanese patients with EGFR mutation-positive non-small-cell lung cancer. Cancer Sci 2018; 109(8): 2532–2538.
    1. Yu HA, Spira A, Horn L. et al. A phase I, dose escalation study of oral ASP8273 in patients with non-small cell lung cancers with epidermal growth factor receptor mutations. Clin Cancer Res 2017; 23(24): 7467–7473.
    1. Califano R, Tariq N, Compton S. et al. Expert consensus on the management of adverse events from EGFR tyrosine kinase inhibitors in the UK. Drugs 2015; 75(12): 1335–1348.
    1. Tan J, Li M, Zhong W. et al. Tyrosine kinase inhibitors show different anti-brain metastases efficacy in NSCLC: a direct comparative analysis of icotinib, gefitinib, and erlotinib in a nude mouse model. Oncotarget 2017; 8: 98771–98781.
    1. Cross DA, Ashton SE, Ghiorghiu S. et al. AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer. Cancer Discov 2014; 4(9): 1046–1061.
    1. Walter AO, Sjin RT, Haringsma HJ. et al. Discovery of a mutant-selective covalent inhibitor of EGFR that overcomes T790M-mediated resistance in NSCLC. Cancer Discov 2013; 3(12): 1404–1415.
    1. Khozin S, Blumenthal GM, Jiang X. et al. U.S. Food and Drug Administration approval summary: erlotinib for the first-line treatment of metastatic non-small cell lung cancer with epidermal growth factor receptor exon 19 deletions or exon 21 (L858R) substitution mutations. Oncologist 2014; 19(7): 774–779.
    1. Douillard JY, Ostoros G, Cobo M. et al. First-line gefitinib in Caucasian EGFR mutation-positive NSCLC patients: a phase-IV, open-label, single-arm study. Br J Cancer 2014; 110(1): 55–62.
    1. Iressa (Gefitinib) [Prescribing Information]. Wilmington, DE: AstraZeneca Pharmaceuticals LP 2018.
    1. Terceva (Erlotinib) [Prescribing Information]. Northbrook, IL: Astellas Pharma US, Inc. 2016.

Source: PubMed

Sponsoren und Mitarbeiter

Krankheiten

Drogeninterventionen

3
Abonnieren