Reference Detail

Ref Type

Journal Article

PMID

(31839416)

Authors

Zhao J, Lin G, Zhuo M, Fan Z, Miao L, Chen L, Zeng A, Yin R, Ou Y, Shi Z, Yin J, Gao W, Chen J, Zhou X, Zeng Y, Liu X, Xu H, Chen R, Xia X, Carbone DP

Title

Next-generation sequencing based mutation profiling reveals heterogeneity of clinical response and resistance to osimertinib.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Lung cancer (Amsterdam, Netherlands)	141		2020 Mar	114-118	Lung Cancer

URL

Abstract Text

The 3rd generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR TKI) osimertinib has shown promising efficacy both in EGFR-mutant, T790M positive non-small cell lung cancer (NSCLC) patients who have become resistant to 1st or 2nd generation EGFR TKIs and patients with sensitizing EGFR mutations as the first line therapy. However, the degree and duration of response to osimertinib are heterogeneous. We hypothesized that the concurrent genomic landscape of these tumors could play a role in clinical outcomes and/or mechanisms of resistance.We conducted a retrospective multicenter study of lung cancer patients who had developed resistance to osimertinib. Genomic profiling was done for all the patients by using targeted next-generation sequencing encompassing 59-1021 cancer-related genes.Known EGFR-dependent resistant mutations and activation of alternative pathways were identified in 44 % of all the patients with great heterogeneity. Gain-of-function mutations of CTNNB1 were highly enriched in our cohort. Some other putative resistance mechanisms to osimertinib, such as the recurrent EGFR V834 L mutation, were also identified. Moreover, pathogenic mutations of TP53 were negatively related to the efficacy of osimertinib. To sum up, heterogeneity of resistance to osimertinib was not only manifested by inter-individual differences, but also embodied in its intra-individual diversity.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
TP53 mutant	lung non-small cell carcinoma	not predictive	Osimertinib	Clinical Study - Cohort	Actionable	In a retrospective analysis, patients with non-small cell lung cancer harboring TP53 mutations at treatment discontinuation of Tagrisso (osimertinib) had shorter time to treatment discontinuation (6.5 vs 11.5 months, p=0.0029) compared to patients with wild-type TP53 (PMID: 31839416).	31839416
CTNNB1 S37F	lung non-small cell carcinoma	predicted - resistant	Osimertinib	Case Reports/Case Series	Actionable	In a retrospective analysis, activating CTNNB1 mutations including S37F/C (n=5), D32V (n=1), G34V (n=1), and T41I (n=1) were identified in 8 of 100 patients with non-small cell lung cancer at treatment discontinuation of Tagrisso (osimertinib) (PMID: 31839416).	31839416
CTNNB1 G34V	lung non-small cell carcinoma	predicted - resistant	Osimertinib	Case Reports/Case Series	Actionable	In a retrospective analysis, activating CTNNB1 mutations including S37F/C (n=5), D32V (n=1), G34V (n=1), and T41I (n=1) were identified in 8 of 100 patients with non-small cell lung cancer at treatment discontinuation of Tagrisso (osimertinib) (PMID: 31839416).	31839416
CTNNB1 T41I	lung non-small cell carcinoma	predicted - resistant	Osimertinib	Case Reports/Case Series	Actionable	In a retrospective analysis, activating CTNNB1 mutations including S37F/C (n=5), D32V (n=1), G34V (n=1), and T41I (n=1) were identified in 8 of 100 patients with non-small cell lung cancer at treatment discontinuation of Tagrisso (osimertinib) (PMID: 31839416).	31839416
CTNNB1 S37C	lung non-small cell carcinoma	predicted - resistant	Osimertinib	Case Reports/Case Series	Actionable	In a retrospective analysis, activating CTNNB1 mutations including S37F/C (n=5), D32V (n=1), G34V (n=1), and T41I (n=1) were identified in 8 of 100 patients with non-small cell lung cancer at treatment discontinuation of Tagrisso (osimertinib) (PMID: 31839416).	31839416
CTNNB1 D32V	lung non-small cell carcinoma	predicted - resistant	Osimertinib	Case Reports/Case Series	Actionable	In a retrospective analysis, activating CTNNB1 mutations including S37F/C (n=5), D32V (n=1), G34V (n=1), and T41I (n=1) were identified in 8 of 100 patients with non-small cell lung cancer at treatment discontinuation of Tagrisso (osimertinib) (PMID: 31839416).	31839416
PTEN inact mut	lung non-small cell carcinoma	predicted - resistant	Osimertinib	Case Reports/Case Series	Actionable	In a retrospective analysis, inactivating PTEN mutations were identified in 3 of 100 patients with non-small cell lung cancer at treatment discontinuation of Tagrisso (osimertinib) (PMID: 31839416).	31839416
CTNNB1 act mut	lung non-small cell carcinoma	predicted - resistant	Osimertinib	Case Reports/Case Series	Actionable	In a retrospective analysis, activating CTNNB1 mutations including S37F/C (n=5), D32V (n=1), G34V (n=1), and T41I (n=1) were identified in 8 of 100 patients with non-small cell lung cancer at treatment discontinuation of Tagrisso (osimertinib) (PMID: 31839416).	31839416
BRAF act mut	lung non-small cell carcinoma	predicted - resistant	Osimertinib	Case Reports/Case Series	Actionable	In a retrospective analysis, activating BRAF mutations were identified in 4 of 100 patients with non-small cell lung cancer at treatment discontinuation of Tagrisso (osimertinib) (PMID: 31839416).	31839416
PIK3CA act mut	lung non-small cell carcinoma	predicted - resistant	Osimertinib	Case Reports/Case Series	Actionable	In a retrospective analysis, activating PIK3CA mutations were identified in 6 of 100 patients with non-small cell lung cancer at treatment discontinuation of Tagrisso (osimertinib) (PMID: 31839416).	31839416
TP53 inact mut	lung non-small cell carcinoma	not predictive	Osimertinib	Clinical Study - Cohort	Actionable	In a retrospective analysis, patients with non-small cell lung cancer harboring inactivating TP53 mutations at treatment discontinuation of Tagrisso (osimertinib) had shorter time to treatment discontinuation (5 vs 11.5 months, p=0.0005) compared to patients with wild-type TP53 (PMID: 31839416).	31839416
NRAS act mut	lung non-small cell carcinoma	predicted - resistant	Osimertinib	Case Reports/Case Series	Actionable	In a retrospective analysis, activating NRAS mutations were identified in 1 of 100 patients with non-small cell lung cancer at treatment discontinuation of Tagrisso (osimertinib) (PMID: 31839416).	31839416