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Sensitizing and T790M mutant EGFR tyrosine kinase inhibition

CompoundOsimertinib

Area under investigation

EGFRm NSCLC

Scientific PillarTumor Drivers & Resistance Mechanisms

Target Overview

Targeted inhibition of tumors harboring activating mutations in epidermal growth factor receptor (EGFR) has helped to advance the treatment approach for advanced non-small cell lung carcinoma (NSCLC).

While the majority of these activating mutations also sensitize EGFR (EGFRm) to effective targeting by early-generation EGFR-tyrosine kinase inhibitors (TKIs), the emergence of a secondary resistance mutation (EGFR T790M) results in treatment-refractory NSCLC disease progression. Approximately 51%-68% of tumors that progress on a first- and second-generation EGFR TKI are EGFR T790M mutation positive.1-7

Compound Overview

Osimertinib is a third-generation, irreversible, CNS-active EGFR-TKI designed to selectively target both EGFR-sensitizing (ie, T790M, L858R and exon 19 deletion) and EGFR T790M-resistance mutations.1,8

Osimertinib is being clinically evaluated in EGFRm-containing NSCLC.

Mechanism of Action

  • Mechanism of Action

References

1. Cross DA, Ashton SE, Ghiorghiu S, et al. Cancer Discov. 2014;4(9):1046-1061. 2. Yu HA, Arcila ME, Rekhtman N, et al. Clin Cancer Res. 2013;19(8):2240-2247. 3. Oxnard GR, Arcila ME, Sima CS, et al. Clin Cancer Res. 2011;17(6):1616-1622. 4. Sun JM, Ahn MJ, Choi YL, et al. Lung Cancer. 2013;82(2):294-298. 5. Arcila ME, Oxnard GR, Nafa K, et al. Clin Cancer Res. 2011;17(5):1169-1180. 6. Kuiper JL, Heideman DA, Thunnissen E, et al. Lung Cancer. 2014;85(1):19-24. 7. Li W, Ren S, Li J, et al. Lung Cancer. 2014;84(3):295-300. 8. Planchard D, Jänne PA, Cheng Y, et al. N Engl J Med. 2023;389(21):1935-1948.

Target Overview

Targeted inhibition of tumors harboring activating mutations in epidermal growth factor receptor (EGFR) has helped to advance the treatment approach for advanced non-small cell lung carcinoma (NSCLC).

While the majority of these activating mutations also sensitize EGFR (EGFRm) to effective targeting by early-generation EGFR-tyrosine kinase inhibitors (TKIs), the emergence of a secondary resistance mutation (EGFR T790M) results in treatment-refractory NSCLC disease progression. Approximately 51%-68% of tumors that progress on a first- and second-generation EGFR TKI are EGFR T790M mutation positive.1-7

Compound Overview

Osimertinib is a third-generation, irreversible, CNS-active EGFR-TKI designed to selectively target both EGFR-sensitizing (ie, T790M, L858R and exon 19 deletion) and EGFR T790M-resistance mutations.1,8

Osimertinib is being clinically evaluated in EGFRm-containing NSCLC.

Mechanism of Action

  • Mechanism of Action

References

1. Cross DA, Ashton SE, Ghiorghiu S, et al. Cancer Discov. 2014;4(9):1046-1061. 2. Yu HA, Arcila ME, Rekhtman N, et al. Clin Cancer Res. 2013;19(8):2240-2247. 3. Oxnard GR, Arcila ME, Sima CS, et al. Clin Cancer Res. 2011;17(6):1616-1622. 4. Sun JM, Ahn MJ, Choi YL, et al. Lung Cancer. 2013;82(2):294-298. 5. Arcila ME, Oxnard GR, Nafa K, et al. Clin Cancer Res. 2011;17(5):1169-1180. 6. Kuiper JL, Heideman DA, Thunnissen E, et al. Lung Cancer. 2014;85(1):19-24. 7. Li W, Ren S, Li J, et al. Lung Cancer. 2014;84(3):295-300. 8. Planchard D, Jänne PA, Cheng Y, et al. N Engl J Med. 2023;389(21):1935-1948.

Clinical trial information


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ADAURA2 trial overview

Tumor

EGFRm Stage IA2-IA3 NSCLC following complete tumor resection

Trial Identifier

NCT05120349

Phase

III

Stage

Resectable Stage I-III

Regimen

Osimertinib; placebo

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NeoADAURA trial overview

Tumor

EGFRm resectable stage II-IIIB N2 NSCLC

Trial Identifier

NCT04351555

Phase

III

Stage

Resectable Stage II-III

Regimen

Osimertinib; PtCh ± osimertinib

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ORCHARD trial overview

Tumor

Advanced/metastatic EGFRm NSCLC with disease progression following 1L therapy with osimertinib

Trial Identifier

NCT03944772

Phase

II

Stage

Advanced/metastatic NSCLC

Regimen

Osimertinib + (savolitinib or gefitinib or necitumumab or alectinib or selpercatinib or pemetrexed + PtCh or selumetinib or Dato-DXd); durvalumab + pemetrexed + carboplatin; durvalumab + etoposide + PtCh

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SAFFRON trial overview

Tumor

Locally advanced or metastatic EGFRm, MET overexpressed and/or amplified (IHC3+/≥90% and/or FISH10+) NSCLC that progressed on 1L or 2L osimertinib therapy

Trial Identifier

NCT05261399

Phase

III

Stage

Metastatic, ≥2L

Regimen

Osimertinib + savolitinib; pemetrexed + PtCh

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Savolitinib, partnered with HUTCHMED

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SAVANNAH trial overview

Tumor

EGFRm and MET overexpressed and/or amplified (IHC3+/≥90% and/or FISH10+), locally advanced or metastatic NSCLC that progressed following 1L osimertinib treatment

Trial Identifier

NCT03778229

Phase

II

Stage

Metastatic, ≥2L

Regimen

Osimertinib + savolitinib; placebo + savolitinib

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Savolitinib, partnered with HUTCHMED

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TROPION-Lung14 trial overview

Tumor

Advanced/metastatic, or recurrent, EGFRm (Ex19del and/or L858R) nonsquamous NSCLC, 1L

Trial Identifier

NCT06350097

Phase

III

Stage

Advanced/metastatic NSCLC

Regimen

Osimertinib + Dato-DXd; osimertinib

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TROPION-Lung15 trial overview

Tumor

Advanced/metastatic EGFRm NSCLC with disease progression on prior osimertinib therapy

Trial Identifier

NCT06417814

Phase

III

Stage

Advanced/metastatic NSCLC

Regimen

Dato-DXd + osimertinib; Dato-DXd; pemetrexed + carboplatin or cisplatin followed by pemetrexed

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Abbreviations

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  • 1L

    first line

  • 2L

    second line

  • ADC

    antibody drug conjugate

  • AE

    adverse event

  • AUC

    area under the curve

  • BICR

    blinded independent central review

  • CNS

    central nervous system

  • CPR

    complete pathological response

  • CRC

    colorectal cancer

  • CRT

    chemoradiotherapy

  • CT

    chemotherapy

  • CTCAE

    Common Terminology Criteria for Adverse Events

  • ctDNA

    circulating tumor DNA

  • DCR

    disease control rate

  • DFS

    disease-free survival

  • DoR

    duration of response

  • ECG

    electrocardiogram

  • ECOG PS

    Eastern Cooperative Oncology Group Performance Score

  • EFS

    event-free survival

  • EGFR

    epidermal growth factor receptor

  • EGFRm

    epidermal growth factor receptor mutation

  • EGFRwt

    epidermal growth factor receptor wild type

  • EORTC QLQ-C30

    European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire

  • Ex19del

    exon 19 deletion

  • FISH

    fluorescence in situ hybridization

  • FISH10+

    fluorescence in situ hybridization (MET copy ≥10)

  • Gy

    gray

  • HBV

    hepatitis B virus

  • HCV

    hepatitis C virus

  • HIV

    human immunodeficiency virus

  • HNSCC

    head and neck squamous cell carcinoma

  • HRQoL

    health-related quality of life

  • IASLC

    International Association For The Study Of Lung Cancer

  • ICR

    independent central review

  • IHC3+/≥90%

    3+ immunohistochemistry overexpression in 90% of tumor cells

  • ILD

    interstitial lung disease

  • IV

    intravenous

  • L858R

    exon 21 L858R point mutation

  • MET

    hepatocyte growth factor receptor

  • NEC

    large cell neuroendocrine carcinoma

  • NSCLC

    non-small cell lung cancer

  • OD

    once daily

  • ORR

    overall or objective response rate

  • OS

    overall survival

  • PD

    progressive disease

  • PFS

    progression-free survival

  • PFS2

    time to second progression or death

  • PFS24

    PFS at 24 months from randomization

  • PK

    pharmacokinetics

  • PO

    per oral

  • PS

    phosphatidylserine

  • PtCh

    platinum-based chemotherapy

  • Q*W

    every * weeks

  • Q3W

    every 3 weeks

  • QD

    once daily

  • R

    randomization

  • RECIST

    Response Evaluation Criteria in Solid Tumors

  • RECIST v1.1

    Response Evaluation Criteria in Solid Tumors version 1.1

  • RT

    radiotherapy

  • SBRT

    stereotactic body radiation therapy

  • SCLC

    small cell lung cancer

  • SoC

    standard of care

  • TDT

    time to discontinuation or death

  • TFST

    time to first subsequent therapy

  • TKI

    tyrosine kinase inhibitor

  • TNM

    tumor node metastasis staging

  • TNM8

    Tumor Node Metastasis 8th edition

  • tSCLC

    transformed small cell lung cancer

  • TSST

    time to start of second subsequent therapy

  • TTD

    time to treatment discontinuation

  • TTDM

    time to death or distant metastases

  • TTP

    time to progression

  • WHO

    World Health Organization

  • WHO PS

    World Health Organization performance status

  • WT

    wild type

Some compounds herein refer to selected AstraZeneca pipeline products still under development. AstraZeneca pipeline products are investigational products and, as such, are not approved by the US Food & Drug Administration (FDA), the European Medicines Agency (EMA) or any other regulatory agency for the uses under investigation. Information regarding these investigational products should, under no circumstances, be regarded as a recommendation for their use or of their safety or efficacy.

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Veeva ID: Z4-84958 US-109129 DE-92568 Last Updated October 20263/26
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