CarcinomaPhase 2SAVANNAHNCT03778229
Osimertinib Plus Savolitinib in EGFRm+/MET+ NSCLC Following Prior Osimertinib
A Phase 2 study testing Osimertinib and Savolitinib in people with Carcinoma, run by AstraZeneca at 90 sites in 13 countries.
Trial summary
This study (the SAVANNAH study) will investigate the efficacy of osimertinib in combination with savolitinib in participants with epidermal growth factor receptor mutation positive (EGFRm+) and mesenchymal epithelial transition factor positive (MET+), locally advanced or metastatic non-small cell lung cancer (NSCLC)… Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Carcinoma
- What is being tested?
- Osimertinib and Savolitinib
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 367 participants
- Where
- 90 sitesin 13 countries
- Study dates
- 9 Jan 2019to 31 Mar 2027
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Participants must be ≥18 years of age (≥20 years of age in Japan). All genders are permitted.
- Histologically or cytologically confirmed locally advanced or metastatic EGFRm+ NSCLC harbouring an EGFR mutation known to be associated with EGFR tyrosine kinase inhibitor (TKI) sensitivity and permitted in the osimertinib national label (such as either exon 19 deletion and/or L858R) which is not amenable to curative therapy.
- Documented radiologic disease progression on first-line (1L) osimertinib.
- MET amplification and/or overexpression (FISH10+ and/or IHC90+) as determined by FISH (central) and IHC (central) testing on tumour sample collected following progression on 1L osimertinib treatment.
- Available tumour sample for central MET FISH and IHC analysis or willingness to collect additional sample for central testing which fulfils the following requirements:
- Obtained following progression on previous osimertinib therapy;
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- obtained within 2 years of submission for MET analysis;
- sufficient tissue to meet the minimum tissue requirement defined in the current Laboratory Manual.
- At least 1 lesion, not previously irradiated, not biopsied during the screening period, that can be accurately measured at baseline as ≥10 mm in the longest diameter (except lymph nodes which must have short axis ≥15 mm) with computed tomography (CT) or magnetic resonance imaging (MRI) which is suitable for accurate repeated measurements. If only 1 measurable lesion exists, it is acceptable to be used as long as baseline tumour assessment scans are done at least 14 days after the screening tumour sample collection is performed.
- Prior lines of therapy in locally advanced/metastatic setting: Only prior 1L osimertinib treatment in metastatic setting is permitted.
- Adequate haematological function defined as:
- Absolute neutrophil count ≥1500/μL
- Haemoglobin ≥9 g/dL (no transfusion in the past 2 weeks)
- Platelets ≥100,000/μL (no transfusion in the past 10 days)
- Adequate liver function
- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 x upper limit of normal (ULN) with total bilirubin (TBL) ≤ ULN OR
- TBL > ULN to ≤1.5x ULN with ALT and AST ≤ ULN
- Adequate renal function - defined as a serum creatinine <1.5 times the institutional ULN OR a glomerular filtration rate ≥50 mL/min. Confirmation of creatinine clearance is only required when creatinine is only required when creatinine is >1.5 times ULN.
- Adequate coagulation parameters: INR <1.5 and activated partial thromboplastin time <1.5 x ULN unless participants are receiving therapeutic anti coagulation which affects these parameters.
- Participants with known tumour thrombus or deep vein thrombosis are eligible if clinically stable on low molecular weight heparin for ≥2 weeks. The use of direct oral anticoagulants such as apixaban/rivaroxaban will be accepted as treatment for cancer related thromboembolism treatment. The use of warfarin for oral anticoagulation is not recommended.
- Eastern Cooperative Oncology Group (ECOG)/World Health Organization (WHO) performance status of 0 or 1 with no deterioration over the previous 2 weeks and a minimum life expectancy of 12 weeks.
- Females must be using highly effective contraceptive measures, should not be breast feeding and must have a negative pregnancy test if of childbearing potential, or must have evidence of non-childbearing potential.
- Males with a female partner of childbearing potential should be willing to use barrier contraception during the study and for 6 months following discontinuation of study drug.
Who cannot join
- Unresolved toxicities from any prior therapy greater than common terminology criteria for adverse events (CTCAE) Grade 1 at the time of starting study treatment with the exception of alopecia and Grade 2 prior platinum therapy related neuropathy.
- As judged by the investigator, active gastrointestinal disease or other condition that will interfere significantly with the absorption, distribution, metabolism, or excretion of oral therapy (eg, ulcerative disease, uncontrolled nausea, vomiting, diarrhoea Grade ≥2, malabsorption syndrome or previous significant bowel resection).
- Any of the following cardiac diseases currently or within the last 6 months:
- Unstable angina pectoris
- Congestive heart failure (New York Heart Association [NYHA] ≥Grade 2)
- Acute myocardial infarction
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- Stroke or transient ischemic attack
- Uncontrolled hypertension (blood pressure [BP] ≥150/95 mmHg despite medical therapy).
- Mean resting correct QT interval (QTcF) >470 msec for women and >450 msec for men at Screening, obtained from 3 ECGs using the screening clinic ECG machine derived QTcF value.
- Any factors that may increase the risk of QTcF prolongation or risk of arrhythmic events such as heart failure, chronic hypokalaemia not correctable with supplements, congenital or familial long QT syndrome, family history of unexplained sudden death under 40 years of age in first-degree relatives or any concomitant medication known to prolong the QT interval and cause Torsade de Pointes.
- Any clinically important abnormalities in rhythm, conduction or morphology of resting ECGs, eg, complete left bundle branch block, third degree heart block, second degree heart block, P-R interval >250 msec.
- Acute coronary syndrome
- Wide field radiotherapy (including therapeutic radioisotopes such as strontium 89) administered ≤28 days or limited field radiation for palliation ≤7 days prior to starting study drug or has not recovered from side effects of such therapy.
- Major surgical procedures ≤28 days of beginning study drug or minor surgical procedures ≤7 days
- Evidence of severe or uncontrolled systemic diseases, including renal transplant, active bleeding diatheses or uncontrolled hypertension, which in the investigator's opinion makes it undesirable for the participant to participate
- Active hepatitis B or C or known serious active infection e.g. tuberculosis or human immunodeficiency virus. Viral testing is not required for assessment of eligibility for the study.
- Known serious active infection including, but not limited to, tuberculosis, or human immunodeficiency virus (positive human immunodeficiency virus 1/2 antibodies).
- Presence of other active cancers, or history of treatment for invasive cancer, within the last 5 years. Participants with Stage I cancer who have received definitive local treatment at least 3 years previously, and are considered unlikely to recur are eligible. All participants with previously treated in situ carcinoma (ie, non-invasive) are eligible, as are participants with history of non-melanoma skin cancer.
- Spinal cord compression or brain metastases unless asymptomatic, stable and not requiring steroids for at least 2 weeks prior to start of study treatment.
- Past medical history of interstitial lung disease (ILD), drug-induced ILD, radiation pneumonitis which required steroid treatment, or any evidence of clinically active ILD.
- History of liver cirrhosis of any origin and clinical stage; or history of other serious liver disease or chronic disease with relevant liver involvement, with or without normal liver function tests (LFTs),
- Prior or current treatment with a 3rd generation EGFR-TKI other than osimertinib
- Prior or current treatment with savolitinib or another MET inhibitor (eg, foretinib, crizotinib, cabozantinib, onartuzumab, capmatinib).
- Any cytotoxic chemotherapy, investigational agents or other anticancer drugs for the treatment of advanced NSCLC from a previous treatment regimen or clinical study within 14 days prior to the first dose of study treatment with the exception of monotherapy osimertinib which may continue uninterrupted during screening.
- Participants currently receiving (or unable to stop use prior to receiving the first dose of study treatment) medications or herbal supplements known to be strong inducers of CYP3A4, strong inhibitors of CYP1A2 within 3 weeks of the first dose of study treatment (including St John's Wort).
- Participation in another clinical study with a cytotoxic, investigational product (IP), or other anticancer drug for the treatment of advanced NSCLC if received IP from that study within 14 days of the first dose of study treatment.
- Known hypersensitivity to the active or inactive excipients of osimertinib or savolitinib or drugs with a similar chemical structure or class.
Trial locations and contacts
90 sites in 13 countries.
90 sites in 13 countries
United States11 sites
Research Site
Baltimore, Maryland, 21201
Research Site
Boston, Massachusetts, 02215
Research Site
Brooklyn, New York, 11220
Research Site
La Jolla, California, 92093
Research Site
Los Angeles, California, 90024
Research Site
Philadelphia, Pennsylvania, 19111
Research Site
Pittsburgh, Pennsylvania, 15232
Research Site
Rochester, Minnesota, 55905
Research Site
Sacramento, California, 95817
Research Site
Seattle, Washington, 98109
Research Site
Washington D.C., District of Columbia, 20016
Brazil10 sites
Research Site
Barretos, 14784-400
Research Site
Curitiba, 80810-050
Research Site
Goiânia, 74093-300
Research Site
Porto Alegre, 90540-140
Research Site
Porto Alegre, 90610-000
Research Site
Rio de Janeiro, 22271-110
Research Site
Salvador, 41950-640
Research Site
São José do Rio Preto, 15090-000
Research Site
São Paulo, 01246-000
Research Site
São Paulo, 01509-900
Japan10 sites
Research Site
Fukuoka, 812-8582
Research Site
Hiroshima, 730-8518
Research Site
Kanazawa, 920-8641
Research Site
Nagoya, 464-8681
Research Site
Niigata, 951-8566
Research Site
Sapporo, 003-0804
Research Site
Sayama, 589-8511
Research Site
Sunto-gun, 411-8777
Research Site
Wakayama, 641-8510
Research Site
Yokohama, 241-0815
Italy9 sites
Research Site
Avellino, 83100
Research Site
Florence, 50134
Research Site
Milan, 20133
Research Site
Milan, 20141
Research Site
Orbassano, 10043
Research Site
Padova, 35128
Research Site
Parma, 43126
Research Site
Perugia, 06132
Research Site
Peschiera del Garda, 37019
Taiwan9 sites
Research Site
Hsinchu, 300
Research Site
Kaohsiung City, 83301
Research Site
New Taipei City, 23561
Research Site
Taichung, 402
Research Site
Taichung, 40705
Research Site
Tainan, 70403
Research Site
Taipei, 10002
Research Site
Taipei, 112
Research Site
Taoyuan, 333
South Korea7 sites
Research Site
Goyang-si, 10408
Research Site
Seongnam-si, 13620
Research Site
Seoul, 03080
Research Site
Seoul, 03722
Research Site
Seoul, 05505
Research Site
Seoul, 06351
Research Site
Suwon, 16247
Spain7 sites
Research Site
Córdoba, 14004
Research Site
Donostia / San Sebastian, 20014
Research Site
Madrid, 28041
Research Site
Madrid, 28046
Research Site
Málaga, 29010
Research Site
Valencia, 46026
Research Site
Zaragoza, 50009
Canada6 sites
Research Site
Calgary, Alberta, T2N 5G2
Research Site
Edmonton, Alberta, T6G 1Z2
Research Site
Newmarket, Ontario, L3Y 2P9
Research Site
North York, Ontario, M2K 1E1
Research Site
Toronto, Ontario, M4N 3M5
Research Site
Toronto, Ontario, M5G 2M9
Denmark6 sites
Research Site
Aalborg, 9100
Research Site
Herlev, 2730
Research Site
København Ø, 2100
Research Site
Næstved, 4700
Research Site
Odense, 5000
Research Site
Vejle, 7100
France6 sites
Research Site
Dijon, 21079
Research Site
Marseille, 13915
Research Site
Nantes, 44093
Research Site
Paris, 75020
Research Site
Paris, 75248
Research Site
Rennes, 35033
India4 sites
Research Site
Bangalore, 560064
Research Site
Chennai, 600035
Research Site
Kolkata, 700160
Research Site
New Delhi, 110085
Chile3 sites
Research Site
Santiago, 7500713
Research Site
Santiago, 7520349
Research Site
Santiago, 8420383
Vietnam2 sites
Research Site
Hà Nội, 100000
Research Site
Ho Chi Minh City, 700000
About this study
Official title: A Phase II Study Assessing the Efficacy of Osimertinib in Combination With Savolitinib in Patients With EGFRm+ and MET+, Locally Advanced or Metastatic Non-Small Cell Lung Cancer Who Have Progressed Following Treatment With Osimertinib (The SAVANNAH Study)
This study (the SAVANNAH study) will investigate the efficacy of osimertinib in combination with savolitinib in participants with epidermal growth factor receptor mutation positive (EGFRm+) and mesenchymal epithelial transition factor positive (MET+), locally advanced or metastatic non-small cell lung cancer (NSCLC) who have progressed following treatment with osimertinib.
Read the detailed description
The combination of osimertinib with savolitinib in this study (the SAVANNAH study) will explore if the combination will overcome MET-amplification as a mechanism of resistance. The SAVANNAH study will investigate the efficacy of osimertinib in combination with savolitinib in participants with EGFRm+ and MET-amplified/overexpressed, locally advanced or metastatic NSCLC who have progressed following treatment with osimertinib.
Eligible participants will be those with histologically or cytologically confirmed diagnosis of EGFRm+, MET amplified/overexpressed (≥10 MET gene copies by fluorescence in situ hybridisation [FISH10+] and/or ≥90% of tumour cells staining at 3+ intensity by immunohistochemistry [IHC90+]) NSCLC that is locally advanced or metastatic and is not amenable to further surgery or radiotherapy with curative intent. The disease must have progressed following treatment with first line osimertinib. Participants must have confirmation of MET-amplified/overexpressed tumour by central fluorescence in situ hybridisation (FISH) and immunohistochemistry (IHC) testing (requirements summarised in the main body of the protocol and fully explained in the Central Laboratory Manual). Participants must not have received prior or current treatment with savolitinib or another MET inhibitor.
All participants confirmed as eligible will begin treatment on Day 1 with osimertinib + savolitinib combination therapy or placebo to osimertinib + savolitinib. Treatment will continue in 28 day cycles until either objective disease progression by investigator per RECIST 1.1 is assessed, unacceptable toxicity occurs, consent is withdrawn or another discontinuation criterion is met.
- Conditions
- Carcinoma
- Being tested
- Osimertinib, Savolitinib, Placebo
- Keywords
- Non Small Cell Lung Cancer, epidermal growth factor receptor mutation positive, hepatocyte growth factor receptor, savolitinib, Osimertinib, AZD9291, AZD6094, volitinib
- Medical subject headings
- Carcinoma, Carcinoma, Non-Small-Cell Lung
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
OsimertinibDrug
Participants will receive oral osimertinib tablets as stated in the arm descripation.
SavolitinibDrug
Participants will receive oral savolitinib tablets as stated in the arm descripation.
PlaceboDrug
Participants will receive oral placebo tablets as stated in the arm descripation.
| Study group | Role | What they receive |
|---|---|---|
| Savo 300 mg QD + osi | Experimental | All participants assigned to savolitinib 300 mg qd + osimertinib and who have received >=1 dose of either study drug. Receives: Drug: Osimertinib; Drug: Savolitinib |
| Savo 300 mg BID + osi | Experimental | All participants assigned to savolitinib 300 mg bid + osimertinib and who received >=1 dose of either study treatment. Receives: Drug: Osimertinib; Drug: Savolitinib |
| Savo 600 mg QD + osi | Experimental | All participants assigned to savolitinib 600 mg qd + osimertinib and who received >=1 dose of either study treatment. Receives: Drug: Osimertinib; Drug: Savolitinib |
| Savo 300 mg BID Monotherapy | Placebo comparator | All participants assigned to savolitinib 300 mg bid + placebo and who received >=1 dose of either study treatment. Receives: Drug: Savolitinib; Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Objective Response Rate (ORR) by Investigator Assessment; Target Population Analysis Set
Percentage of participants with a confirmed Objective Response (OR) per Response Evaluation Criteria In Solid Tumors (RECIST 1.1). OR includes Complete Response (CR: disappearance of all target lesions) or Partial Response (PR: ≥30% decrease in target lesion diameters). OR must be recorded at one visit and confirmed by repeat imaging at least 4 weeks later, with no disease progression between initial and confirmation visits.
Measured: Time from randomization/first dose of study treatment to progression or last evaluable assessment in the absence of progressionuntil the end of the study, or an approximate maximum of 5.6 years
Objective Response Rate (ORR) by Investigator Assessment; 300 mg QD Safety Analysis Set
Percentage of participants with a confirmed OR per RECIST 1.1. OR includes Complete Response (CR: disappearance of all target lesions) or Partial Response (PR: ≥30% decrease in target lesion diameters). OR must be recorded at one visit and confirmed by repeat imaging at least 4 weeks later, with no disease progression between initial and confirmation visits.
Measured: Time from randomization/first dose of study treatment to progression or last evaluable assessment in the absence of progression until the end of the study, or an approximate maximum of 5.6 years
Secondary outcomes (47)
Objective Response Rate (ORR) by BICR Assessment; Target Population Analysis Set
Percentage of participants with a confirmed OR per RECIST 1.1. OR includes Complete Response (CR: disappearance of all target lesions) or Partial Response (PR: ≥30% decrease in target lesion diameters). OR must be recorded at one visit and confirmed by repeat imaging at least 4 weeks later, with no disease progression between initial and confirmation visits.
Measured: Time from randomization/first dose of study treatment to progression or last evaluable assessment in the absence of progression until the end of the study, or an approximate maximum of 6.4 years
Duration of Response (DoR) by Investigator Assessment; Target Population Analysis Set
Median time of response for participants with an investigator assessed confirmed objective response per RECIST1.1.
Measured: From date of first confirmed objective response to progressive disease in accordance with RECIST1.1 or death from any cause, whichever came first; assessed for up to 6.4 years
Duration of Response (DoR) by BICR Assessment; Target Population Analysis Set
Median time of response for participants with an investigator assessed confirmed objective response per RECIST1.1.
Measured: From date of first confirmed objective response to progressive disease in accordance with RECIST1.1 or death from any cause, whichever came first; assessed for up to 6.4 years
Progression-free Survival (PFS) by Investigator Assessment; Target Population Analysis Set
Median progression-free survival (PFS) was measured by investigator assessment using RECIST 1.1 and the Kaplan-Meier method. Progressive disease (PD) per RECIST 1.1 is defined as at least a 20% increase in the sum of target lesion diameters (with an absolute increase of ≥5 mm); unequivocal progression of non-target lesions, which may result from marked progression in a single lesion or multiple lesions; or the appearance of one or more unequivocal new lesions.
Measured: Time from randomization/start of study treatment to investigator assess progressive disease per RECIST1.1 or death, assessed for up to 6.4 years
Progression-free Survival (PFS) by BICR Assessment; Target Population Analysis Set
Median PFS was measured by BICR assessment using RECIST 1.1 and the Kaplan-Meier method. PD per RECIST 1.1 is defined as at least a 20% increase in the sum of target lesion diameters (with an absolute increase of ≥5 mm); unequivocal progression of non-target lesions, which may result from marked progression in a single lesion or multiple lesions; or the appearance of one or more unequivocal new lesions.
Measured: Time from randomization/start of study treatment to BICR assessed progressive disease per RECIST1.1 or death, assessed for up to 6.4 years
Overall Survival (OS); Target Population Analysis Set
Overall Survival (OS) from all-cause mortality.
Measured: Time from randomization/start of study treatment to all-cause death, assessed for up to 6.4 years
Objective Response Rate (ORR) by Investigator Assessment; Contribution of Components Analysis Set
Percentage of participants with a confirmed OR per RECIST 1.1. OR includes Complete Response (CR: disappearance of all target lesions) or Partial Response (PR: ≥30% decrease in target lesion diameters). OR must be recorded at one visit and confirmed by repeat imaging at least 4 weeks later, with no disease progression between initial and confirmation visits.
Measured: Time from randomization/first dose of study treatment to progression or last evaluable assessment in the absence of progressionuntil the end of the study, or an approximate maximum of 5.6 years
Objective Response Rate (ORR) by BICR Assessment; Contribution of Components Analysis Set
Percentage of participants with a confirmed OR per RECIST 1.1. OR includes Complete Response (CR: disappearance of all target lesions) or Partial Response (PR: ≥30% decrease in target lesion diameters). OR must be recorded at one visit and confirmed by repeat imaging at least 4 weeks later, with no disease progression between initial and confirmation visits.
Measured: Time from randomization/first dose of study treatment to progression or last evaluable assessment in the absence of progressionuntil the end of the study, or an approximate maximum of 6.4 years
Duration of Response (DoR) by Investigator Assessment; Contribution of Components Analysis Set
Median time of response for participants with an investigator assessed confirmed objective response per RECIST1.1.
Measured: From date of first confirmed objective response to progressive disease in accordance with RECIST1.1 or death from any cause, whichever came first; assessed for up to 6.4 years
Duration of Response (DoR) by BICR Assessment; Contribution of Components Analysis Set
Median time of response for participants with an investigator assessed confirmed objective response per RECIST1.1.
Measured: From date of first confirmed objective response to progressive disease in accordance with RECIST1.1 or death from any cause, whichever came first; assessed for up to 6.4 years
Progression-free Survival (PFS) by Investigator Assessment; Contribution of Components Analysis Set
Median PFS was measured by investigator assessment using RECIST 1.1 and the Kaplan-Meier method. PD per RECIST 1.1 is defined as at least a 20% increase in the sum of target lesion diameters (with an absolute increase of ≥5 mm); unequivocal progression of non-target lesions, which may result from marked progression in a single lesion or multiple lesions; or the appearance of one or more unequivocal new lesions.
Measured: Time from randomization/start of study treatment to investigator assess progressive disease per RECIST1.1 or death, assessed for up to 6.4 years
Progression-free Survival (PFS) by BICR Assessment; Contribution of Components Analysis Set
Median PFS was measured by BICR assessment using RECIST 1.1 and the Kaplan-Meier method. PD per RECIST 1.1 is defined as at least a 20% increase in the sum of target lesion diameters (with an absolute increase of ≥5 mm); unequivocal progression of non-target lesions, which may result from marked progression in a single lesion or multiple lesions; or the appearance of one or more unequivocal new lesions.
Measured: Time from randomization/start of study treatment to BICR assessed progressive disease per RECIST1.1 or death, assessed for up to 6.4 years
Objective Response Rate (ORR) by Investigator Assessment; Safety Analysis Set
Percentage of participants with a confirmed OR per RECIST 1.1. OR includes Complete Response (CR: disappearance of all target lesions) or Partial Response (PR: ≥30% decrease in target lesion diameters). OR must be recorded at one visit and confirmed by repeat imaging at least 4 weeks later, with no disease progression between initial and confirmation visits.
Measured: Time from randomization/first dose of study treatment to progression or last evaluable assessment in the absence of progressionuntil the end of the study, or an approximate maximum of 5.6 years
Objective Response Rate (ORR) by BICR Assessment; Safety Analysis Set
Percentage of participants with a confirmed OR per RECIST 1.1. OR includes Complete Response (CR: disappearance of all target lesions) or Partial Response (PR: ≥30% decrease in target lesion diameters). OR must be recorded at one visit and confirmed by repeat imaging at least 4 weeks later, with no disease progression between initial and confirmation visits.
Measured: Time from randomization/first dose of study treatment to progression or last evaluable assessment in the absence of progressionuntil the end of the study, or an approximate maximum of 6.4 years
Duration of Response (DoR) by Investigator Assessment; Safety Analysis Set
Median time of response for participants with an investigator assessed confirmed objective response per RECIST1.1.
Measured: From date of first confirmed objective response to progressive disease in accordance with RECIST1.1 or death from any cause, whichever came first; assessed for up to 6.4 years
Duration of Response (DoR) by BICR Assessment; Safety Analysis Set
Median time of response for participants with an investigator assessed confirmed objective response per RECIST1.1.
Measured: From date of first confirmed objective response to progressive disease in accordance with RECIST1.1 or death from any cause, whichever came first; assessed for up to 5.6 years
Overall Survival (OS); Safety Analysis Set
Overall Survival (OS) from all-cause mortality
Measured: Time from randomization/start of study treatment to all-cause death, assessed for up to 6.4 years
Progression-free Survival (PFS) by Investigator Assessment; Safety Analysis Set
Median progression-free survival (PFS) was measured by investigator assessment using RECIST 1.1 and the Kaplan-Meier method. Progressive disease (PD) per RECIST 1.1 is defined as at least a 20% increase in the sum of target lesion diameters (with an absolute increase of ≥5 mm); unequivocal progression of non-target lesions, which may result from marked progression in a single lesion or multiple lesions; or the appearance of one or more unequivocal new lesions.
Measured: Time from randomization/start of study treatment to investigator assess progressive disease per RECIST1.1 or death, assessed for up to 5.6 years
Progression-free Survival (PFS) by BICR Assessment; Safety Analysis Set
Median progression-free survival (PFS) was measured by BICR assessment using RECIST 1.1 and the Kaplan-Meier method. Progressive disease (PD) per RECIST 1.1 is defined as at least a 20% increase in the sum of target lesion diameters (with an absolute increase of ≥5 mm); unequivocal progression of non-target lesions, which may result from marked progression in a single lesion or multiple lesions; or the appearance of one or more unequivocal new lesions.
Measured: Time from randomization/start of study treatment to BICR assessed progressive disease per RECIST1.1 or death, assessed for up to 5.6 years
Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs)
An adverse event (AE) is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious adverse event (SAE) is an AE resulting in any of the following outcomes or deemed medically significant for any other reason: death; initial or prolonged inpatient hospitalization; life threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. The TEAEs are defined as events present at baseline that worsened in intensity after administration of study drug or events absent at baseline that emerged after administration of study drug.
Measured: Day 1 through 5.95 years (maximum observed duration)
Number of Participants With Treatment Discontinuation Due to TEAEs
Number of participants with treatment discontinuation due to TEAEs is reported. An AE is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship.
Measured: Day 1 through 5.95 years (maximum observed duration)
Number of Participants With Abnormal Clinical Laboratory Findings Reported as TEAEs
Number of participants with abnormal clinical laboratory findings reported as TEAEs are reported. Abnormal clinical laboratory parameters are defined as any abnormal finding during analysis of hematology, clinical chemistry, coagulation, urinalysis and liver function tests.
Measured: Day 1 through 5.95 years (maximum observed duration)
Number of Participants With Abnormal Echocardiograpm (ECHO) and Electrocardiogram (ECG) Parameters Reported as TEAEs
Number of participants with abnormal ECHO and ECG parameters reported as TEAEs are reported. Abnormal ECHO and ECG parameters are defined as any abnormal finding during analysis of ECHO and ECG, respectively.
Measured: Day 1 through 5.95 years (maximum observed duration)
Number of Participants With Abnormal Vital Signs Reported as TEAEs
Number of participants with abnormal vital signs reported as TEAEs are reported. Abnormal vital signs are defined as any abnormal finding in the vital sign parameters (blood pressure, pulse, heart rate, temperature and respiration rate).
Measured: Day 1 through 5.95 years (maximum observed duration)
Plasma Concentrations of Osimertinib
Plasma concentration of osimertinib collected over time are reported. The lower limit of quantification (LLOQ) for osimertinib was 0.05 nM.
Measured: Pre-dose, 1 and 3 hours post-dose on Day 1 of Cycles 1 and 2; pre-dose and 1, 3, 4, and 6 hours post-dose on Day 1 of Cycle 3
Plasma Concentrations of AZ5104 (Osimertinib Metabolite)
Plasma concentration of AZ5104 (metabolite of osimertinib) collected over time are reported. The LLOQ for AZ5104 was 0.0515 nM.
Measured: Pre-dose, 1 and 3 hours post-dose on Day 1 of Cycles 1 and 2; pre-dose and 1, 3, 4, and 6 hours post-dose on Day 1 of Cycle 3
Plasma Concentrations of Savolitinib
Plasma concentration of savolitinib collected over time are reported. The LLOQ for savolitinib was 1 ng/mL.
Measured: Pre-dose, 1 and 3 hours post-dose on Day 1 of Cycles 1 and 2; pre-dose and 1, 3, 4, and 6 hours post-dose on Day 1 of Cycle 3
Plasma Concentrations of M2 (Savolitinib Metabolite)
Plasma concentration of M2 (savolitinib metabolite) collected over time are reported. The LLOQ for M2 was 1 ng/mL.
Measured: Pre-dose, 1 and 3 hours post-dose on Day 1 of Cycles 1 and 2; pre-dose and 1, 3, 4, and 6 hours post-dose on Day 1 of Cycle 3
Plasma Concentrations of M3 (Savolitinib Metabolite)
Plasma concentration of M3 (savolitinib metabolite) collected over time are reported. The LLOQ for M3 was 1 ng/mL.
Measured: Pre-dose, 1 and 3 hours post-dose on Day 1 of Cycles 1 and 2; pre-dose and 1, 3, 4, and 6 hours post-dose on Day 1 of Cycle 3
Absolute Change in Clearance of Circulating Tumor Deoxyribonucleic Acid (ctDNA) After 6-weeks of Therapy; Target Population Analysis Set
The mean ctDNA absolute change from baseline to Week 6 was reported. The absolute change in ctDNA at Week 6 was obtained for each participant by the difference between the EGFR mutation ctDNA allele frequencies at Week 6 and at baseline.
Measured: Baseline (last non-missing assessment prior to randomisation/first dose) and Week 6
Percentage Change in Clearance of ctDNA After 6-weeks of Therapy; Target Population Analysis Set
The mean ctDNA percentage change from baseline to Week 6 was reported. The percentage change is calculated as the difference between the allele frequency of EGFR sensitizing mutations in ctDNA at Week 6 and the ctDNA at baseline divided by the allele frequency of EGFR sensitizing mutations in ctDNA at baseline multiplied by one hundred (i.e., [Week 6 - baseline]/baseline × 100).
Measured: Baseline (last non-missing assessment prior to randomisation/first dose) and Week 6
Absolute Change in Clearance of ctDNA After 6-weeks of Therapy; Safety Analysis Set
The mean ctDNA absolute change from baseline to Week 6 was reported. The absolute change in ctDNA at Week 6 was obtained for each participant by the difference between the EGFR mutation ctDNA allele frequencies at Week 6 and at baseline.
Measured: Baseline (last non-missing assessment prior to randomisation/first dose) and Week 6
Percentage Change in Clearance of ctDNA After 6-weeks of Therapy; Safety Analysis Set
The mean ctDNA percentage change from baseline to Week 6 was reported. The percentage change is calculated as the difference between the allele frequency of EGFR sensitizing mutations in ctDNA at Week 6 and the ctDNA at baseline divided by the allele frequency of EGFR sensitizing mutations in ctDNA at baseline multiplied by one hundred (i.e., [Week 6 - baseline]/baseline × 100).
Measured: Baseline (last non-missing assessment prior to randomisation/first dose) and Week 6
ORR by Investigator Assessment in Participants With FISH10+ and/or IHC90+ Mutation Who Have Progressed Following Treatment With 1L Osimertinib; Safety Analysis Set
Percentage of participants with FISH10+ and/or IHC90+ mutation with a confirmed OR per RECIST 1.1. OR includes Complete Response (CR: disappearance of all target lesions) or Partial Response (PR: ≥30% decrease in target lesion diameters). OR must be recorded at one visit and confirmed by repeat imaging at least 4 weeks later, with no disease progression between initial and confirmation visits.
Measured: Time from randomization/first dose of study treatment to progression or last evaluable assessment in the absence of progression until the end of the study, or an approximate maximum of 6.4 years
DoR by Investigator Assessment in Participants With FISH10+ and/or IHC90+ Mutation Who Have Progressed Following Treatment With 1L Osimertinib; Safety Analysis Set
Median time of response for participants with FISH10+ and/or IHC90+ mutation with an investigator assessed confirmed objective response per RECIST1.1.
Measured: From date of first confirmed objective response to progressive disease in accordance with RECIST1.1 or death from any cause, whichever came first; assessed for up to 6.4 years
PFS by Investigator Assessment in Participants With FISH10+ and/or IHC90+ Mutation Who Have Progressed Following Treatment With 1L Osimertinib; Safety Analysis Set
Median PFS was measured in participants with FISH10+ and/or IHC90+ mutation by investigator assessment using RECIST 1.1 and the Kaplan-Meier method. The PD per RECIST 1.1 is defined as at least a 20% increase in the sum of target lesion diameters (with an absolute increase of ≥5 mm); unequivocal progression of non-target lesions, which may result from marked progression in a single lesion or multiple lesions; or the appearance of one or more unequivocal new lesions.
Measured: Time from randomization/start of study treatment to investigator assess progressive disease per RECIST1.1 or death, assessed for up to 6.4 years
OS in Participants With FISH10+ and/or IHC90+ Mutation Who Have Progressed Following Treatment With 1L Osimertinib; Safety Analysis Set
OS from all-cause mortality in participants with FISH10+ and/or IHC90+ mutation and who have progressed following treatment with 1L osimertinib.
Measured: Time from randomization/start of study treatment to all-cause death, assessed for up to 6.4 years
ORR by Investigator Assessment in Participants With FISH10+ and/or IHC90+ Mutation Who Have Progressed Following Treatment With >=2L Osimertinib; Safety Analysis Set
Percentage of participants with FISH10+ and/or IHC90+ mutation with a confirmed OR per RECIST 1.1 following treatment with >=2L osimertinib. OR includes Complete Response (CR: disappearance of all target lesions) or Partial Response (PR: ≥30% decrease in target lesion diameters). OR must be recorded at one visit and confirmed by repeat imaging at least 4 weeks later, with no disease progression between initial and confirmation visits.
Measured: Time from randomization/first dose of study treatment to progression or last evaluable assessment in the absence of progression until the end of the study, or an approximate maximum of 6.4 years
DoR by Investigator Assessment in Participants With FISH10+ and/or IHC90+ Mutation Who Have Progressed Following Treatment With >=2L Osimertinib; Safety Analysis Set
Median time of response for participants with FISH10+ and/or IHC90+ mutation with an investigator assessed confirmed objective response per RECIST1.1 following treatment with >=2L osimertinib.
Measured: From date of first confirmed objective response to progressive disease in accordance with RECIST1.1 or death from any cause, whichever came first; assessed for up to 6.4 years
PFS by Investigator Assessment in Participants With FISH10+ and/or IHC90+ Mutation Who Have Progressed Following Treatment With >=2L Osimertinib; Safety Analysis Set
Median PFS was measured in participants with FISH10+ and/or IHC90+ mutation following treatment with >=2L osimertinib by investigator assessment using RECIST 1.1 and the Kaplan-Meier method. PD per RECIST 1.1 is defined as at least a 20% increase in the sum of target lesion diameters (with an absolute increase of ≥5 mm); unequivocal progression of non-target lesions, which may result from marked progression in a single lesion or multiple lesions; or the appearance of one or more unequivocal new lesions.
Measured: Time from randomization/start of study treatment to investigator assess progressive disease per RECIST1.1 or death, assessed for up to 6.4 years
OS in Participants With FISH10+ and/or IHC90+ Mutation Who Have Progressed Following Treatment With >=2L Osimertinib; Safety Analysis Set
OS from all-cause mortality in participants with FISH10+ and/or IHC90+ mutation and who have progressed following treatment with >=2L osimertinib.
Measured: Time from randomization/start of study treatment to all-cause death, assessed for up to 6.4 years
Mean Change From Baseline in European Organisation for Research and Treatment of Cancer (EORTC) 30-item Core Quality-of-life Questionnaire (QLQ-C30); Target Population Analysis Set
The EORTC-QLQ-C30 consists of 30 questions that can be combined to give 5 functional scales (physical, role, cognitive, emotional, social), 3 symptom scales (fatigue, pain, nausea/vomiting), 6 individual items (dyspnea, insomnia, appetite loss, constipation, diarrhea, financial difficulties) and a global measure of health status. QoL issues are assessed using a 4-point scale (1=not at all, 2=a little, 3=quite a bit, 4=very much) except 2 questions which are between 1 (Very Poor) and 7 (Excellent). An outcome variable consisting of a score from 0 to 100 is derived for each scale/item and global health status/QoL. Higher scores on global health status and functioning scales indicate better health status/function. Higher scores on symptom scales indicate greater symptom burden.
Measured: Baseline and Cycle 8 Day 1
Mean Change From Baseline in EORTC QLQ-C30 in Participants With FISH10+ and/or IHC90+ Mutation; Safety Analysis Set
The EORTC-QLQ-C30 consists of 30 questions that can be combined to give 5 functional scales (physical, role, cognitive, emotional, social), 3 symptom scales (fatigue, pain, nausea/vomiting), 6 individual items (dyspnea, insomnia, appetite loss, constipation, diarrhea, financial difficulties) and a global measure of health status. QoL issues are assessed using a 4-point scale (1=not at all, 2=a little, 3=quite a bit, 4=very much) except 2 questions which are between 1 (Very Poor) and 7 (Excellent). An outcome variable consisting of a score from 0 to 100 is derived for each scale/item and global health status/QoL. Higher scores on global health status and functioning scales indicate better health status/function. Higher scores on symptom scales indicate greater symptom burden.
Measured: Baseline and Cycle 8 Day 1
Mean Change From Baseline in EORTC QLQ-C30 in Participants With FISH5+ and/or IHC50+ Mutation; Safety Analysis Set
The EORTC-QLQ-C30 consists of 30 questions that can be combined to give 5 functional scales (physical, role, cognitive, emotional, social), 3 symptom scales (fatigue, pain, nausea/vomiting), 6 individual items (dyspnea, insomnia, appetite loss, constipation, diarrhea, financial difficulties) and a global measure of health status. QoL issues are assessed using a 4-point scale (1=not at all, 2=a little, 3=quite a bit, 4=very much) except 2 questions which are between 1 (Very Poor) and 7 (Excellent). An outcome variable consisting of a score from 0 to 100 is derived for each scale/item and global health status/QoL. Higher scores on global health status and functioning scales indicate better health status/function. Higher scores on symptom scales indicate greater symptom burden.
Measured: Baseline and Cycle 8 Day 1
Mean Change From Baseline in EORTC Quality-of-life Questionnaire Lung Cancer 13 (QLQ-LC13); Target Population Analysis Set
The QLQ-LC13 is a lung cancer specific module comprising 13 questions to assess lung cancer symptoms (cough, haemoptysis, dyspnoea and site-specific pain), treatment related side-effects (sore mouth, dysphagia, peripheral neuropathy and alopecia) and pain medication. All items are assessed using a Likert four-point scale (1= not at all to 4 = very much). An outcome variable consisting of a score from 0 to 100 will be derived for each of the symptom scales/items. The outcome variable is derived by taking the average of items contributing to a scale or the value of an individual item and applying a linear transformation to standardize the score, so that scores range from 0 to 100. Higher scores represent greater symptom burden.
Measured: Baseline and Cycle 8 Day 1
Mean Change From Baseline in EORTC QLQ-LC13 in Participants With FISH10+ and/or IHC90+ Mutation; Safety Analysis Set
The QLQ-LC13 is a lung cancer specific module comprising 13 questions to assess lung cancer symptoms (cough, haemoptysis, dyspnoea and site-specific pain), treatment related side-effects (sore mouth, dysphagia, peripheral neuropathy and alopecia) and pain medication. All items are assessed using a Likert four-point scale (1= not at all to 4 = very much). An outcome variable consisting of a score from 0 to 100 will be derived for each of the symptom scales/items. The outcome variable is derived by taking the average of items contributing to a scale or the value of an individual item and applying a linear transformation to standardize the score, so that scores range from 0 to 100. Higher scores represent greater symptom burden.
Measured: Baseline and Cycle 8 Day 1
Mean Change From Baseline in EORTC QLQ-LC13 in Participants With FISH5+ and/or IHC50+ Mutation; Safety Analysis Set
The QLQ-LC13 is a lung cancer specific module comprising 13 questions to assess lung cancer symptoms (cough, haemoptysis, dyspnoea and site-specific pain), treatment related side-effects (sore mouth, dysphagia, peripheral neuropathy and alopecia) and pain medication. All items are assessed using a Likert four-point scale (1 = not at all to 4 = very much). An outcome variable consisting of a score from 0 to 100 will be derived for each of the symptom scales/items. The outcome variable is derived by taking the average of items contributing to a scale or the value of an individual item and applying a linear transformation to standardize the score, so that scores range from 0 to 100. Higher scores represent greater symptom burden.
Measured: Baseline and Cycle 8 Day 1
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted19 Dec 2018
- Study start9 Jan 2019
- Primary completion23 Aug 2024
- Study completion31 Mar 2027 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for CarcinomaStudies of the same condition, open and under way.
- More trials run by AstraZenecaThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- Under Protocol versions 1-6 the study model was single arm (open-label). Starting protocol version 7 participants will be randomised in a double blinded manner to receive savolitinib in combination with osimertinib or savolitinib with placebo to osimertinib with crossover option upon disease progression assessed by Investigator.
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 367 participants (actual)
Sponsor and investigators
- Lead sponsor
- AstraZeneca
- Sponsor type
- Industry (pharma, biotech, devices)
- Collaborators
- Hutchison Medipharma Limited
- Responsible party
- Sponsor
- Investigators
- Lecia V Sequist, MD MPH, Principal investigator, Massachusetts General HospitalMyung-Ju Ahn, MD, Principal investigator, Samsung Medical Centre Sungkyunkwan University School of Medicine
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03778229
- Sponsor's protocol ID
- D5084C00007
- Other IDs
- 2018-003012-51, 2018
- Acronym
- SAVANNAH
- Status last verified
- Oct 2026
- First submitted
- 30 Nov 2018
- Last updated
- 2 Nov 2026
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: Qualified researchers can request access to anonymized individual participant-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All request will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
Publications
de Marinis F, Kim TM, Bonanno L, Cheng S, Kim SW, Tiseo M, Chu Q, Proto C, Sacher A, Luo YH, Novello S, Hao D, Baik C, Bazhenova L, Lee JS, Cho BC, Cadranel J, Diep TB, Metro G, Narayanan P, Yoneshima Y, de Castro Carpeno J, Baldotto C, Yang JC, Sequist LV, Levy B, Hartmaier R, Igwegbe I, Poole L, Xu W, Ahn MJ. A plain language summary of the SAVANNAH study: savolitinib plus osimertinib in patients with EGFR-mutated advanced non-small cell lung cancer with MET overexpression and/or amplification whose cancer had grown or spread on osimertinib. Future Oncol. 2026 Jul;22(17):2013-2025. doi: 10.1080/14796694.2026.2692029. Epub 2026 Jul 16.
PubMed 42460617Yang JC, Chen YM, Batra U, Do KH, Sitthideatphaiboon P, Danchaivijitr P, Lee KY, Chindaprasirt J, Yang CT, Chang GC, Charoentum C, Ungtrakul T, Moran JIH, Hartmaier R, Igwegbe I, Gont A, Haskins M, Xu W, Riess JW. Savolitinib Plus Osimertinib in Epidermal Growth Factor Receptor-Mutated, MET-Amplified Advanced Non-Small Cell Lung Cancer: A Randomized Phase II trial. Clin Lung Cancer. 2026 Jan;27(1):38-46. doi: 10.1016/j.cllc.2025.10.018. Epub 2025 Oct 22.
PubMed 41308232Schmid S, Fruh M, Peters S. Targeting MET in EGFR resistance in non-small-cell lung cancer-ready for daily practice? Lancet Oncol. 2020 Mar;21(3):320-322. doi: 10.1016/S1470-2045(19)30859-9. Epub 2020 Feb 3. No abstract available.
PubMed 32027845
Study at a glance
From the registry record, last updated by the sponsor on 2 Nov 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase II Study Assessing the Efficacy of Osimertinib in Combination With Savolitinib in Patients With EGFRm+ and MET+, Locally Advanced or Metastatic Non-Small Cell Lung Cancer Who Have Progressed Following Treatment With Osimertinib (The SAVANNAH Study)
- ClinicalTrials.gov ID
- NCT03778229
- Acronym / sponsor ID
- SAVANNAH / D5084C00007
- Conditions
- Carcinoma
- Keywords
- Non Small Cell Lung Cancer, epidermal growth factor receptor mutation positive, hepatocyte growth factor receptor, savolitinib, Osimertinib, AZD9291, AZD6094, volitinib
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Active, not recruiting
- Enrolment
- 367 participants (actual)
- Lead sponsor
- AstraZenecaIndustry (pharma, biotech, devices)
- Collaborators
- Hutchison Medipharma Limited
- Study start
- 9 Jan 2019 (actual)
- Primary completion
- 23 Aug 2024 (actual)
- Study completion
- 31 Mar 2027 (estimated)
- First posted
- 19 Dec 2018 (actual)
- Results
- Posted 10 Feb 2026
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This study (the SAVANNAH study) will investigate the efficacy of osimertinib in combination with savolitinib in participants with epidermal growth factor receptor mutation positive (EGFRm+) and mesenchymal epithelial transition factor positive (MET+), locally advanced or metastatic non-small cell lung cancer (NSCLC) who have progressed following treatment with osimertinib.
Detailed description
The combination of osimertinib with savolitinib in this study (the SAVANNAH study) will explore if the combination will overcome MET-amplification as a mechanism of resistance. The SAVANNAH study will investigate the efficacy of osimertinib in combination with savolitinib in participants with EGFRm+ and MET-amplified/overexpressed, locally advanced or metastatic NSCLC who have progressed following treatment with osimertinib.
Eligible participants will be those with histologically or cytologically confirmed diagnosis of EGFRm+, MET amplified/overexpressed (≥10 MET gene copies by fluorescence in situ hybridisation [FISH10+] and/or ≥90% of tumour cells staining at 3+ intensity by immunohistochemistry [IHC90+]) NSCLC that is locally advanced or metastatic and is not amenable to further surgery or radiotherapy with curative intent. The disease must have progressed following treatment with first line osimertinib. Participants must have confirmation of MET-amplified/overexpressed tumour by central fluorescence in situ hybridisation (FISH) and immunohistochemistry (IHC) testing (requirements summarised in the main body of the protocol and fully explained in the Central Laboratory Manual). Participants must not have received prior or current treatment with savolitinib or another MET inhibitor.
All participants confirmed as eligible will begin treatment on Day 1 with osimertinib + savolitinib combination therapy or placebo to osimertinib + savolitinib. Treatment will continue in 28 day cycles until either objective disease progression by investigator per RECIST 1.1 is assessed, unacceptable toxicity occurs, consent is withdrawn or another discontinuation criterion is met.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 4
- Model description
- Under Protocol versions 1-6 the study model was single arm (open-label). Starting protocol version 7 participants will be randomised in a double blinded manner to receive savolitinib in combination with osimertinib or savolitinib with placebo to osimertinib with crossover option upon disease progression assessed by Investigator.
| Arm | Type | Receives |
|---|---|---|
| Savo 300 mg QD + osi | Experimental | Drug: Osimertinib, Drug: SavolitinibAll participants assigned to savolitinib 300 mg qd + osimertinib and who have received >=1 dose of either study drug. |
| Savo 300 mg BID + osi | Experimental | Drug: Osimertinib, Drug: SavolitinibAll participants assigned to savolitinib 300 mg bid + osimertinib and who received >=1 dose of either study treatment. |
| Savo 600 mg QD + osi | Experimental | Drug: Osimertinib, Drug: SavolitinibAll participants assigned to savolitinib 600 mg qd + osimertinib and who received >=1 dose of either study treatment. |
| Savo 300 mg BID Monotherapy | Placebo comparator | Drug: Savolitinib, Drug: PlaceboAll participants assigned to savolitinib 300 mg bid + placebo and who received >=1 dose of either study treatment. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (23 listed)
- Participants must be ≥18 years of age (≥20 years of age in Japan). All genders are permitted.
- Histologically or cytologically confirmed locally advanced or metastatic EGFRm+ NSCLC harbouring an EGFR mutation known to be associated with EGFR tyrosine kinase inhibitor (TKI) sensitivity and permitted in the osimertinib national label (such as either exon 19 deletion and/or L858R) which is not amenable to curative therapy.
- Documented radiologic disease progression on first-line (1L) osimertinib.
- MET amplification and/or overexpression (FISH10+ and/or IHC90+) as determined by FISH (central) and IHC (central) testing on tumour sample collected following progression on 1L osimertinib treatment.
- Available tumour sample for central MET FISH and IHC analysis or willingness to collect additional sample for central testing which fulfils the following requirements:
Key exclusion criteria (27 listed)
- Unresolved toxicities from any prior therapy greater than common terminology criteria for adverse events (CTCAE) Grade 1 at the time of starting study treatment with the exception of alopecia and Grade 2 prior platinum therapy related neuropathy.
- As judged by the investigator, active gastrointestinal disease or other condition that will interfere significantly with the absorption, distribution, metabolism, or excretion of oral therapy (eg, ulcerative disease, uncontrolled nausea, vomiting, diarrhoea Grade ≥2, malabsorption syndrome or previous significant bowel resection).
- Any of the following cardiac diseases currently or within the last 6 months:
- Unstable angina pectoris
- Congestive heart failure (New York Heart Association [NYHA] ≥Grade 2)
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| OsimertinibParticipants will receive oral osimertinib tablets as stated in the arm descripation. | Drug | Savo 300 mg BID + osi, Savo 300 mg QD + osi, Savo 600 mg QD + osi |
| SavolitinibParticipants will receive oral savolitinib tablets as stated in the arm descripation. | Drug | Savo 300 mg BID + osi, Savo 300 mg BID Monotherapy, Savo 300 mg QD + osi, Savo 600 mg QD + osi |
| PlaceboParticipants will receive oral placebo tablets as stated in the arm descripation. | Drug | Savo 300 mg BID Monotherapy |
Primary outcome
Objective Response Rate (ORR) by Investigator Assessment; Target Population Analysis Set
Time frame: Time from randomization/first dose of study treatment to progression or last evaluable assessment in the absence of progressionuntil the end of the study, or an approximate maximum of 5.6 years
Percentage of participants with a confirmed Objective Response (OR) per Response Evaluation Criteria In Solid Tumors (RECIST 1.1). OR includes Complete Response (CR: disappearance of all target lesions) or Partial Response (PR: ≥30% decrease in target lesion diameters). OR must be recorded at one visit and confirmed by repeat imaging at least 4 weeks later, with no disease progression between initial and confirmation visits.
Objective Response Rate (ORR) by Investigator Assessment; 300 mg QD Safety Analysis Set
Time frame: Time from randomization/first dose of study treatment to progression or last evaluable assessment in the absence of progression until the end of the study, or an approximate maximum of 5.6 years
Percentage of participants with a confirmed OR per RECIST 1.1. OR includes Complete Response (CR: disappearance of all target lesions) or Partial Response (PR: ≥30% decrease in target lesion diameters). OR must be recorded at one visit and confirmed by repeat imaging at least 4 weeks later, with no disease progression between initial and confirmation visits.
47 secondary outcomes
Objective Response Rate (ORR) by BICR Assessment; Target Population Analysis Set
Time frame: Time from randomization/first dose of study treatment to progression or last evaluable assessment in the absence of progression until the end of the study, or an approximate maximum of 6.4 years
Duration of Response (DoR) by Investigator Assessment; Target Population Analysis Set
Time frame: From date of first confirmed objective response to progressive disease in accordance with RECIST1.1 or death from any cause, whichever came first; assessed for up to 6.4 years
Duration of Response (DoR) by BICR Assessment; Target Population Analysis Set
Time frame: From date of first confirmed objective response to progressive disease in accordance with RECIST1.1 or death from any cause, whichever came first; assessed for up to 6.4 years
Progression-free Survival (PFS) by Investigator Assessment; Target Population Analysis Set
Time frame: Time from randomization/start of study treatment to investigator assess progressive disease per RECIST1.1 or death, assessed for up to 6.4 years
Progression-free Survival (PFS) by BICR Assessment; Target Population Analysis Set
Time frame: Time from randomization/start of study treatment to BICR assessed progressive disease per RECIST1.1 or death, assessed for up to 6.4 years
Overall Survival (OS); Target Population Analysis Set
Time frame: Time from randomization/start of study treatment to all-cause death, assessed for up to 6.4 years
Objective Response Rate (ORR) by Investigator Assessment; Contribution of Components Analysis Set
Time frame: Time from randomization/first dose of study treatment to progression or last evaluable assessment in the absence of progressionuntil the end of the study, or an approximate maximum of 5.6 years
Objective Response Rate (ORR) by BICR Assessment; Contribution of Components Analysis Set
Time frame: Time from randomization/first dose of study treatment to progression or last evaluable assessment in the absence of progressionuntil the end of the study, or an approximate maximum of 6.4 years
Duration of Response (DoR) by Investigator Assessment; Contribution of Components Analysis Set
Time frame: From date of first confirmed objective response to progressive disease in accordance with RECIST1.1 or death from any cause, whichever came first; assessed for up to 6.4 years
Duration of Response (DoR) by BICR Assessment; Contribution of Components Analysis Set
Time frame: From date of first confirmed objective response to progressive disease in accordance with RECIST1.1 or death from any cause, whichever came first; assessed for up to 6.4 years
Progression-free Survival (PFS) by Investigator Assessment; Contribution of Components Analysis Set
Time frame: Time from randomization/start of study treatment to investigator assess progressive disease per RECIST1.1 or death, assessed for up to 6.4 years
Progression-free Survival (PFS) by BICR Assessment; Contribution of Components Analysis Set
Time frame: Time from randomization/start of study treatment to BICR assessed progressive disease per RECIST1.1 or death, assessed for up to 6.4 years
Objective Response Rate (ORR) by Investigator Assessment; Safety Analysis Set
Time frame: Time from randomization/first dose of study treatment to progression or last evaluable assessment in the absence of progressionuntil the end of the study, or an approximate maximum of 5.6 years
Objective Response Rate (ORR) by BICR Assessment; Safety Analysis Set
Time frame: Time from randomization/first dose of study treatment to progression or last evaluable assessment in the absence of progressionuntil the end of the study, or an approximate maximum of 6.4 years
Duration of Response (DoR) by Investigator Assessment; Safety Analysis Set
Time frame: From date of first confirmed objective response to progressive disease in accordance with RECIST1.1 or death from any cause, whichever came first; assessed for up to 6.4 years
Duration of Response (DoR) by BICR Assessment; Safety Analysis Set
Time frame: From date of first confirmed objective response to progressive disease in accordance with RECIST1.1 or death from any cause, whichever came first; assessed for up to 5.6 years
Overall Survival (OS); Safety Analysis Set
Time frame: Time from randomization/start of study treatment to all-cause death, assessed for up to 6.4 years
Progression-free Survival (PFS) by Investigator Assessment; Safety Analysis Set
Time frame: Time from randomization/start of study treatment to investigator assess progressive disease per RECIST1.1 or death, assessed for up to 5.6 years
Progression-free Survival (PFS) by BICR Assessment; Safety Analysis Set
Time frame: Time from randomization/start of study treatment to BICR assessed progressive disease per RECIST1.1 or death, assessed for up to 5.6 years
Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs)
Time frame: Day 1 through 5.95 years (maximum observed duration)
Number of Participants With Treatment Discontinuation Due to TEAEs
Time frame: Day 1 through 5.95 years (maximum observed duration)
Number of Participants With Abnormal Clinical Laboratory Findings Reported as TEAEs
Time frame: Day 1 through 5.95 years (maximum observed duration)
Number of Participants With Abnormal Echocardiograpm (ECHO) and Electrocardiogram (ECG) Parameters Reported as TEAEs
Time frame: Day 1 through 5.95 years (maximum observed duration)
Number of Participants With Abnormal Vital Signs Reported as TEAEs
Time frame: Day 1 through 5.95 years (maximum observed duration)
Plasma Concentrations of Osimertinib
Time frame: Pre-dose, 1 and 3 hours post-dose on Day 1 of Cycles 1 and 2; pre-dose and 1, 3, 4, and 6 hours post-dose on Day 1 of Cycle 3
Plasma Concentrations of AZ5104 (Osimertinib Metabolite)
Time frame: Pre-dose, 1 and 3 hours post-dose on Day 1 of Cycles 1 and 2; pre-dose and 1, 3, 4, and 6 hours post-dose on Day 1 of Cycle 3
Plasma Concentrations of Savolitinib
Time frame: Pre-dose, 1 and 3 hours post-dose on Day 1 of Cycles 1 and 2; pre-dose and 1, 3, 4, and 6 hours post-dose on Day 1 of Cycle 3
Plasma Concentrations of M2 (Savolitinib Metabolite)
Time frame: Pre-dose, 1 and 3 hours post-dose on Day 1 of Cycles 1 and 2; pre-dose and 1, 3, 4, and 6 hours post-dose on Day 1 of Cycle 3
Plasma Concentrations of M3 (Savolitinib Metabolite)
Time frame: Pre-dose, 1 and 3 hours post-dose on Day 1 of Cycles 1 and 2; pre-dose and 1, 3, 4, and 6 hours post-dose on Day 1 of Cycle 3
Absolute Change in Clearance of Circulating Tumor Deoxyribonucleic Acid (ctDNA) After 6-weeks of Therapy; Target Population Analysis Set
Time frame: Baseline (last non-missing assessment prior to randomisation/first dose) and Week 6
Percentage Change in Clearance of ctDNA After 6-weeks of Therapy; Target Population Analysis Set
Time frame: Baseline (last non-missing assessment prior to randomisation/first dose) and Week 6
Absolute Change in Clearance of ctDNA After 6-weeks of Therapy; Safety Analysis Set
Time frame: Baseline (last non-missing assessment prior to randomisation/first dose) and Week 6
Percentage Change in Clearance of ctDNA After 6-weeks of Therapy; Safety Analysis Set
Time frame: Baseline (last non-missing assessment prior to randomisation/first dose) and Week 6
ORR by Investigator Assessment in Participants With FISH10+ and/or IHC90+ Mutation Who Have Progressed Following Treatment With 1L Osimertinib; Safety Analysis Set
Time frame: Time from randomization/first dose of study treatment to progression or last evaluable assessment in the absence of progression until the end of the study, or an approximate maximum of 6.4 years
DoR by Investigator Assessment in Participants With FISH10+ and/or IHC90+ Mutation Who Have Progressed Following Treatment With 1L Osimertinib; Safety Analysis Set
Time frame: From date of first confirmed objective response to progressive disease in accordance with RECIST1.1 or death from any cause, whichever came first; assessed for up to 6.4 years
PFS by Investigator Assessment in Participants With FISH10+ and/or IHC90+ Mutation Who Have Progressed Following Treatment With 1L Osimertinib; Safety Analysis Set
Time frame: Time from randomization/start of study treatment to investigator assess progressive disease per RECIST1.1 or death, assessed for up to 6.4 years
OS in Participants With FISH10+ and/or IHC90+ Mutation Who Have Progressed Following Treatment With 1L Osimertinib; Safety Analysis Set
Time frame: Time from randomization/start of study treatment to all-cause death, assessed for up to 6.4 years
ORR by Investigator Assessment in Participants With FISH10+ and/or IHC90+ Mutation Who Have Progressed Following Treatment With >=2L Osimertinib; Safety Analysis Set
Time frame: Time from randomization/first dose of study treatment to progression or last evaluable assessment in the absence of progression until the end of the study, or an approximate maximum of 6.4 years
DoR by Investigator Assessment in Participants With FISH10+ and/or IHC90+ Mutation Who Have Progressed Following Treatment With >=2L Osimertinib; Safety Analysis Set
Time frame: From date of first confirmed objective response to progressive disease in accordance with RECIST1.1 or death from any cause, whichever came first; assessed for up to 6.4 years
PFS by Investigator Assessment in Participants With FISH10+ and/or IHC90+ Mutation Who Have Progressed Following Treatment With >=2L Osimertinib; Safety Analysis Set
Time frame: Time from randomization/start of study treatment to investigator assess progressive disease per RECIST1.1 or death, assessed for up to 6.4 years
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 2 Nov 2026.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 42460617de Marinis F, Kim TM, Bonanno L, Cheng S, Kim SW, Tiseo M, Chu Q, Proto C, Sacher A, Luo YH, Novello S, Hao D, Baik C, Bazhenova L, Lee JS, Cho BC, Cadranel J, Diep TB, Metro G, Narayanan P, Yoneshima Y, de Castro Carpeno J, Baldotto C, Yang JC, Sequist LV, Levy B, Hartmaier R, Igwegbe I, Poole L, Xu W, Ahn MJ. A plain language summary of the SAVANNAH study: savolitinib plus osimertinib in patients with EGFR-mutated advanced non-small cell lung cancer with MET overexpression and/or amplification whose cancer had grown or spread on osimertinib. Future Oncol. 2026 Jul;22(17):2013-2025. doi: 10.1080/14796694.2026.2692029. Epub 2026 Jul 16.
- Derived from this study: PubMed 41308232Yang JC, Chen YM, Batra U, Do KH, Sitthideatphaiboon P, Danchaivijitr P, Lee KY, Chindaprasirt J, Yang CT, Chang GC, Charoentum C, Ungtrakul T, Moran JIH, Hartmaier R, Igwegbe I, Gont A, Haskins M, Xu W, Riess JW. Savolitinib Plus Osimertinib in Epidermal Growth Factor Receptor-Mutated, MET-Amplified Advanced Non-Small Cell Lung Cancer: A Randomized Phase II trial. Clin Lung Cancer. 2026 Jan;27(1):38-46. doi: 10.1016/j.cllc.2025.10.018. Epub 2025 Oct 22.
- Derived from this study: PubMed 32027845Schmid S, Fruh M, Peters S. Targeting MET in EGFR resistance in non-small-cell lung cancer-ready for daily practice? Lancet Oncol. 2020 Mar;21(3):320-322. doi: 10.1016/S1470-2045(19)30859-9. Epub 2020 Feb 3. No abstract available.
- Redacted Statistical Analysis Plan (SAP)Link provided by the sponsor.
- Redacted CSR SynopsisLink provided by the sponsor.
- Redacted CSPLink provided by the sponsor.
- Individual participant dataSharing planned: Yes. Qualified researchers can request access to anonymized individual participant-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All request will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Lecia V Sequist, MD MPH principal investigator
Massachusetts General Hospital
Myung-Ju Ahn, MD principal investigator
Samsung Medical Centre Sungkyunkwan University School of Medicine
90 sites in 13 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Osimertinib and Savolitinib in people with Carcinoma, run by AstraZeneca at 90 sites in 13 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 23 inclusion and 27 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: under way, not looking for participants, as of the sponsor's last update on 2 Nov 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 90 sites in United States, Brazil, Japan, Italy, Taiwan and 8 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 10 Feb 2026). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Objective Response Rate (ORR) by Investigator Assessment; Target Population Analysis Set (time frame: Time from randomization/first dose of study treatment to progression or last evaluable assessment in the absence of progressionuntil the end of the study, or an approximate maximum of 5.6 years). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03778229, which also lists 3 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 2 Nov 2026.