Osimertinib in non-small cell lung cancer with uncommon EGFR-mutations: a post-hoc subgroup analysis with pooled data from two phase II clinical trials

Inger Johanne Zwicky Eide; Simone Stensgaard; Åslaug Helland; Simon Ekman; Anders Mellemgaard; Karin Holmskov Hansen; Saulius Cicenas; Jussi Koivunen; Bjørn Henning Grønberg; Boe Sandahl Sørensen; Odd Terje Brustugun

doi:10.21037/tlcr-21-995

Osimertinib in non-small cell lung cancer with uncommon EGFR-mutations: a post-hoc subgroup analysis with pooled data from two phase II clinical trials

Transl Lung Cancer Res. 2022 Jun;11(6):953-963. doi: 10.21037/tlcr-21-995.

Authors

Inger Johanne Zwicky Eide^{1

2

3}, Simone Stensgaard⁴, Åslaug Helland^{2

3

5}, Simon Ekman⁶, Anders Mellemgaard⁷, Karin Holmskov Hansen⁸, Saulius Cicenas⁹, Jussi Koivunen¹⁰, Bjørn Henning Grønberg^{11

12}, Boe Sandahl Sørensen⁴, Odd Terje Brustugun^{1

2

3}

Affiliations

¹ Section of Oncology, Vestre Viken Hospital Trust, Drammen, Norway.
² Department of Cancer Genetics, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.
³ Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
⁴ Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark.
⁵ Department of Oncology, Oslo University Hospital, Oslo, Norway.
⁶ Department of Oncology-Pathology, Karolinska Institutet, Thoracic Oncology Center, Karolinska University Hospital, Stockholm, Sweden.
⁷ Herlev Hospital, Copenhagen, Denmark.
⁸ Odense University Hospital, Odense, Denmark.
⁹ National Cancer Institute, Vilnius University Faculty of Medicine, Vilnius, Lithuania.
¹⁰ Oulu University Hospital, University of Oulu, Medical Research Center Oulu, Oulu, Finland.
¹¹ Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway.
¹² Department of Oncology, St. Olav's Hospital, Trondheim University Hospital, Trondheim, Norway.

Abstract

Background: Osimertinib is standard of care for EGFR-mutated non-small cell lung cancer (NSCLC) patients. The efficacy of the drug in patients with mutations other than the common deletion in exon 19 and L858R in exon 21 is largely unknown.

Methods: We identified patients with uncommon EGFR-mutations from two prospective clinical phase II, single-arm studies for previously treated patients and untreated patients, respectively, and pooled data for this analysis. All patients received treatment with osimertinib 80 mg daily until radiological progression or death. The primary endpoint of both trials was objective response rate (ORR), with progression-free survival (PFS), overall survival (OS) and intracranial efficacy as key secondary endpoints. Circulating tumour DNA (ctDNA) was analysed before and two weeks after treatment initiation in the first line cohort.

Results: Of 299 enrolled patients in the two trials, 21 patients with uncommon mutations were identified; 12 patients had a single mutation (G719X or L861Q), one patient had L861Q and an exon 20 insertion, and 8 patients had compound mutations with G719X and either L861Q or S768I. Three of the 10 pretreated patients had the T790M resistance mutation. ORR was 47.6% and disease control rate (DCR) 85.7%. The median duration of response (DoR) was 7.9 months. Among 11 patients treated with osimertinib in first line, ORR was 63.6% vs. 30.0% of 10 previously treated patients. The median PFS was 5.5 months in both groups. Patients with G719X-compound mutations had a higher response rate (62.5% vs. 38.5%), a longer median PFS (13.7 vs. 3.5 months) and median OS (29.3 vs. 7.5 months) than patients with other mutations. Most first line treated patients (81.8%) displayed a reduction in ctDNA after two weeks of treatment.

Conclusions: Osimertinib demonstrates activity in patients with uncommon EGFR-mutations, and especially for G719X-compound mutations.

Keywords: Osimertinib; T790M; circulating tumour DNA (ctDNA); uncommon EGFR mutations.

Grants and funding

27398C0007/ES/NIEHS NIH HHS/United States