Due to copyright issues, an electronic copy of the thesis must be ordered from the faculty. For the faculty to have time to process the order, the order must be received by the faculty at the latest 2 days before the public defence. Orders received later than 2 days before the defence will not be processed. After the public defence, please address any inquiries regarding the thesis to the candidate.
Trial Lecture – time and place
See Trial Lecture.
Adjudication committee
- First opponent: Assistant Professor Mikael Johansson, Umeå University, Sweden
- Second opponent: Senior Consultant Karin A. Semb, Vestfold Hospital Trust,
- Third member and chair of the evaluation committee: Associate Professor Gunnar Einvik, University of Oslo
Chair of the Defence
Associate Professor Lars Fjellbirkeland, University of Oslo
Principal Supervisor
Professor Odd Terje Brustugun, University of Oslo
Summary
Patients with metastatic non-small cell lung cancer harbouring an EGFR-mutation are treated with tyrosine kinase inhibitors (TKIs), usually with initial response. However, resistance develops in virtually all patients. The most prevalent mechanism of resistance to first- and second-generation drugs is the emergence of a second EGFR-mutation, T790M.
In this thesis, we investigated the efficacy of osimertinib, a third-generation TKI which targets T790M, in a phase II clinical trial with 199 patients. We aimed to assess the activity of the drug in second or later lines in patients with and without T790M, in patients with brain metastases and in patients who had uncommon EGFR-mutations.
We found that in the T790M-positive group, 60% had objective response, median progression-free survival was 10.8 months and overall survival 22.5 months. The T790M-negative patients, who to date have few treatment options other than chemotherapy-containing regimens, benefited to some extent with 28% objective response rate and a median progression-free survival of 5.1. months.
T790M-positive patients with brain metastases had durable intracranial disease control and intracranial progression-free survival. However, T790M-negative patients with brain metastases had a poorer outcome with an intracranial progression-free survival of 3.5 months.
Furthermore, a small group of patients with uncommon EGFR-mutations had moderate effect of the drug and we identified a subgroup of patients with a combination of two rare mutations who seemed to have prolonged benefit of osimertinib.
Overall, the patients had clinical benefit from osimertinib except for a subgroup with T790M-negative disease and brain metastases. In this trial, Nordic patients accessed an additional line of treatment, which at the time of study conduct, was not approved within the public health service. This work also proved the feasibility of conducting trials in low-prevalence areas through Nordic collaboration.
Additional information
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