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MET inhibition

CompoundSavolitinib

Area under investigation

Advanced solid tumors, EGFRm NSCLC, Gastric cancer, MET-driven NSCLC, RCC

Scientific PillarTumor Drivers & Resistance Mechanisms

 

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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

Visit ct.gov

Savolitinib, partnered with HUTCHMED

Study Design

Inclusion criteria

The key inclusion criteria are1

  • Participant must be ≥18 years (≥ 19 years of age in South Korea) at the time of signing the informed consent. All genders are permitted
  • Histologically or cytologically confirmed locally advanced or metastatic NSCLC which is not amenable to curative therapy
  • Must have at least one documented sensitizing EGFR mutation: exon 19 deletion, L858R mutation, and/or T790M
  • Documented radiologic progression on first- or second-line treatment with osimertinib as the most recent anti-cancer therapy
  • Mandatory provision of FFPE tumor tissue
  • MET overexpression and/or amplification in tumor specimen collected following progression on prior osimertinib treatment
  • Adequate haematological, liver, renal and cardiac functions, and coagulation parameters
  • ECOG performance status of 0 or 1
  • At least one measurable lesion not previously irradiated (RECIST v1.1 requirements)

 

Reference:

1. Study NCT05261399. ClinicalTrials.gov website

Exclusion criteria

The key exclusion criteria are1

  • Predominant squamous NSCLC and small cell lung cancer
  • Prior or current treatment with a third-generation EGFR-TKI other than osimertinib
  • Prior or current treatment with savolitinib or another MET inhibitors
  • Spinal cord compression or brain metastases, unless asymptomatic and are stable
  • History or active leptomeningeal carcinomatosis
  • Unresolved toxicities from any prior therapy greater than CTCAE Grade 1 and prior platinum-therapy related Grade 2 neuropathies at the time of starting study intervention with the exception of alopecia and hemoglobin ≥ 9.0 g/dL
  • Active/unstable cardiac diseases currently or within the last 6 months, clinically significant ECG abnormalities and/or factors/medications that may affect QTc intervals
  • History of liver cirrhosis of any origin and clinical stage, or history of other serious liver disease or chronic disease with relevant liver involvement
  • Known serious active infections including, but not limited to, tuberculosis, or HIV, HBV or HCV or gastrointestinal disease
  • Receipt of live attenuated vaccine (including against COVID-19) within 30 days prior to the first dose of study intervention
  • Past medical history of ILD, drug-induced ILD, radiation pneumonitis, which required steroid treatment, or any evidence of clinically active ILD
  • Participants currently receiving medications or herbal supplements known to be strong inducers of cytochrome P450 (CYP)3A4 or strong inhibitors of CYP1A2

Study Locator

Explore further trial details, understand eligibility criteria and speak to clinical trial navigators for the SAFFRON trial via the Lung Cancer Study Locator website.

Visit Study Locator

SAFFRON Overview Modal

SAFFRON trial overview

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Target Overview

Aberrant activation of the MET receptor tyrosine kinase pathway through mutation, protein overexpression or gene amplification has been implicated in oncogenesis and tumor cell growth.1,2

Alterations in MET signaling are associated with lung cancer, papillary renal cell carcinoma, gastric cancer, and colorectal cancer.3-6

MET overexpression and/or amplification is an acquired resistance mechanism to early generation EGFR-TKIs and osimertinib in EGFRm NSCLC.7,8

 

Compound Overview

Savolitiniba is an investigational potent and selective MET inhibitor that is being clinically evaluated as a potential treatment for NSCLC cancer and other cancers.

aSavolitinib, partnered with HUTCHMED.

Mechanism of Action

  • Mechanism of Action

Figure adapted from Eder JP, Vande Woude GF, Boerner SA, et al. Clin Cancer Res. 2009;15(7):2207-2214.

References

1. Organ SL, Tsao MS. Ther Adv Med Oncol. 2011;3(1 suppl):S7-S19. 2. Maroun CR, Rowlands T. Pharmacol Ther. 2014;142(3):316-338. 3. Olivero M, Valente G, Bardelli A, et al. Int J Cancer. 1999;82(5):640-643. 4. Schmidt L, Junker K, Nakaigawa N, et al. Oncogene. 1999;18(14):2343-2350. 5. Sierra JR, Tsao MS. Ther Adv Med Oncol. 2011;3(1 suppl):S21-S35. 6. Bardelli A, Corso S, Bertotti A, et al. Cancer Discov. 2013;3(6):658-673. 7. Piotrowska Z, Thress K, Mooradian M, et al. Poster presented at: American Society of Clinical Oncology 2017; June 2-6, 2017; Chicago, IL. Abs 9020. 8. Yu HA, Arcila ME, Rekhtman N, et al. Clin Cancer Res. 2013;19(8):2240-2247.

 

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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

Visit ct.gov

Savolitinib, partnered with HUTCHMED

Study Design

Inclusion criteria

The key inclusion criteria are1

  • Participant must be ≥18 years (≥ 19 years of age in South Korea) at the time of signing the informed consent. All genders are permitted
  • Histologically or cytologically confirmed locally advanced or metastatic NSCLC which is not amenable to curative therapy
  • Must have at least one documented sensitizing EGFR mutation: exon 19 deletion, L858R mutation, and/or T790M
  • Documented radiologic progression on first- or second-line treatment with osimertinib as the most recent anti-cancer therapy
  • Mandatory provision of FFPE tumor tissue
  • MET overexpression and/or amplification in tumor specimen collected following progression on prior osimertinib treatment
  • Adequate haematological, liver, renal and cardiac functions, and coagulation parameters
  • ECOG performance status of 0 or 1
  • At least one measurable lesion not previously irradiated (RECIST v1.1 requirements)

 

Reference:

1. Study NCT05261399. ClinicalTrials.gov website

Exclusion criteria

The key exclusion criteria are1

  • Predominant squamous NSCLC and small cell lung cancer
  • Prior or current treatment with a third-generation EGFR-TKI other than osimertinib
  • Prior or current treatment with savolitinib or another MET inhibitors
  • Spinal cord compression or brain metastases, unless asymptomatic and are stable
  • History or active leptomeningeal carcinomatosis
  • Unresolved toxicities from any prior therapy greater than CTCAE Grade 1 and prior platinum-therapy related Grade 2 neuropathies at the time of starting study intervention with the exception of alopecia and hemoglobin ≥ 9.0 g/dL
  • Active/unstable cardiac diseases currently or within the last 6 months, clinically significant ECG abnormalities and/or factors/medications that may affect QTc intervals
  • History of liver cirrhosis of any origin and clinical stage, or history of other serious liver disease or chronic disease with relevant liver involvement
  • Known serious active infections including, but not limited to, tuberculosis, or HIV, HBV or HCV or gastrointestinal disease
  • Receipt of live attenuated vaccine (including against COVID-19) within 30 days prior to the first dose of study intervention
  • Past medical history of ILD, drug-induced ILD, radiation pneumonitis, which required steroid treatment, or any evidence of clinically active ILD
  • Participants currently receiving medications or herbal supplements known to be strong inducers of cytochrome P450 (CYP)3A4 or strong inhibitors of CYP1A2

Study Locator

Explore further trial details, understand eligibility criteria and speak to clinical trial navigators for the SAFFRON trial via the Lung Cancer Study Locator website.

Visit Study Locator

SAFFRON Overview Modal

SAFFRON trial overview

Take me to ClinicalTrials.Gov

You are now leaving the AstraZeneca Oncology Portfolio.
You have selected a link that will take you to a site maintained by a third party.

Click ‘Cancel’ to return back or ‘Continue’ to proceed.

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SAFFRON Study Modal

SAFFRON trial overview

Take me to Study Locator

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Click ‘Cancel’ to return back or ‘Continue’ to proceed.

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Abbreviations

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  • 1L

    first line

  • 2L

    second line

  • 4EBP1

    eukaryotic translation initiation factor 4E binding protein 1

  • AKT

    protein kinase B/also known as PKB

  • DCR

    disease control rate

  • DoR

    duration of response

  • EGFR

    epidermal growth factor receptor

  • EGFRm

    epidermal growth factor receptor mutation

  • ERK

    extracellular signal-regulated kinase

  • FAK

    focal adhesion kinase

  • FH

    fumarate hydratase

  • FISH10+

    fluorescence in situ hybridization (MET copy ≥10)

  • GAB1

    GRB2-associated binding protein 1 of 40 kDa

  • GRB2

    growth factor receptor-bound protein 2

  • HGF

    hepatocyte growth factor

  • IHC3+/≥90%

    3+ immunohistochemistry overexpression in 90% of tumor cells

  • IV

    intravenous

  • MEK

    mitogen-activated protein kinase

  • MET

    hepatocyte growth factor receptor

  • mTORC

    mammalian target of rapamycin complex

  • NEC

    large cell neuroendocrine carcinoma

  • NSCLC

    non-small cell lung cancer

  • ORR

    overall or objective response rate

  • OS

    overall survival

  • PAK

    p21 activated kinase

  • PD

    progressive disease

  • PFS

    progression-free survival

  • PFS2

    time to second progression or death

  • PI3K

    phosphoinositide 3-kinase

  • pRCC

    papillary renal cell carcinoma

  • PtCh

    platinum-based chemotherapy

  • Q4W

    every 4 weeks

  • R

    randomization

  • RAC

    Ras-related c3 botulinum toxin substrate

  • RAF

    rapidly accelerated fibrosarcoma

  • RAS

    GTPase protein family that includes KRAS, HRAS, and NRAS

  • RECIST

    Response Evaluation Criteria in Solid Tumors

  • S6K

    S6 kinase

  • SoC

    standard of care

  • SOS

    son of sevenless

  • TKI

    tyrosine kinase inhibitor

  • tSCLC

    transformed small cell lung cancer

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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