TATTON: a multi-arm, phase Ib trial of osimertinib combined with selumetinib, savolitinib, or durvalumab in EGFR-mutant lung cancer.

Abstract

BACKGROUND:

Osimertinib is a potent, third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI). The multi-arm phase Ib TATTON study (NCT02143466) was designed to assess the safety and tolerability of osimertinib in combination with other targeted therapies: selumetinib (MEK1/2 inhibitor), savolitinib (MET-TKI), or durvalumab [anti-programmed cell death ligand 1 (anti-PD-L1) monoclonal antibody].

PATIENTS AND METHODS:

Patients with advanced EGFR-mutant non-small-cell lung cancer and disease progression on a prior EGFR-TKI were enrolled and allocated to dose-escalating cohorts combining osimertinib 80 mg orally (p.o.) once a day with selumetinib (25-75 mg p.o. twice a day; continuous or intermittent), savolitinib (600-800 mg p.o. once a day), or durvalumab (3-10 mg/kg intravenous every 2 weeks).

RESULTS:

At data cut-off (28 February 2018), 77 patients were enrolled and received osimertinib plus selumetinib (n = 36), savolitinib (n = 18), or durvalumab (n = 23). Most common adverse events (any grade), occurring in ≥20% of patients across dose groups, were: selumetinib arm-diarrhea (75%), rash (58%), nausea (47%); savolitinib arm-nausea (67%), rash (56%), vomiting (50%); durvalumab arm-rash (48%), vomiting (43%), diarrhea (39%). Dose-limiting toxicities were reported in the selumetinib 25 mg (n = 1), 50 mg (n = 1), and 75 mg (n = 4) continuous-dose groups, savolitinib 600 mg (n = 1) and 800 mg dose groups (n = 2), and durvalumab 10 mg/kg (n = 1) dose group. The objective response rate was 42% (95% confidence interval 26% to 59%), 44% (22% to 69%), and 43% (23% to 66%) in the selumetinib, savolitinib, and durvalumab arms, respectively.

CONCLUSION:

Our results demonstrate the feasibility of combining osimertinib 80 mg with selumetinib or savolitinib at identified tolerable, active doses. A combination of osimertinib with durvalumab was not feasible due to increased reporting of interstitial lung disease. Osimertinib-based combination therapies represent a compelling approach now being further investigated.

CLINICAL TRIALS NUMBER:

NCT02143466.

• Authors: G R Oxnard, J C-H Yang, H Yu, S-W Kim, H Saka, L Horn, K Goto, Y Ohe, H Mann, K S Thress, M M Frigault, K Vishwanathan, D Ghiorghiu, S S Ramalingam, M-J Ahn
• Journal: Annals of oncology : official journal of the European Society for Medical Oncology (Ann Oncol) Vol. 31 Issue 4 Pg. 507-516 (04 2020) ISSN: 1569-8041 [Electronic] England
• PMID: 32139298 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.

Chemical References

• AZD 6244
• Acrylamides
• Aniline Compounds
• Antibodies, Monoclonal
• Benzimidazoles
• Protein Kinase Inhibitors
• Pyrazines
• Triazines
• durvalumab
• 1-(1-(imidazo(1,2-a)pyridin-6-yl)ethyl)-6-(1-methyl-1H-pyrazol-4-yl)-1H-(1,2,3)triazolo(4,5-b)pyrazine
• osimertinib
• EGFR protein, human
• ErbB Receptors

Topics

• Acrylamides
• Aniline Compounds (therapeutic use)
• Antibodies, Monoclonal (adverse effects)
• Antineoplastic Combined Chemotherapy Protocols (adverse effects)
• Benzimidazoles
• Carcinoma, Non-Small-Cell Lung (drug therapy, genetics)
• ErbB Receptors (genetics)
• Humans
• Lung Neoplasms (drug therapy, genetics)
• Mutation
• Protein Kinase Inhibitors (adverse effects)
• Pyrazines
• Triazines