Osimertinib Plus Savolitinib in EGFRm+/MET+ NSCLC Following Prior Osimertinib (SAVANNAH)

• ClinicalTrials.gov Identifier: NCT03778229
• Recruitment Status: Recruiting
• First Posted: December 19, 2018
• Last Update Posted: April 11, 2024
• Sponsor: AstraZeneca
• Collaborator: Hutchison MediPharma
• Information provided by (Responsible Party): AstraZeneca

Study Description

Brief Summary:

This study (the SAVANNAH study) will investigate the efficacy of osimertinib in combination with savolitinib in patients with EGFRm+ and MET+, locally advanced or metastatic NSCLC who have progressed following treatment with osimertinib

Condition or disease	Intervention/treatment	Phase
Carcinoma	Drug: osimertinib; Drug: savolitinib; Drug: placebo	Phase 2

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 patients with EGFRm+ and MET-amplified/overexpressed, locally advanced or metastatic NSCLC who have progressed following treatment with osimertinib.

Eligible patients will be those with histologically or cytologically confirmed diagnosis of EGFRm+, MET amplified/overexpressed (FISH10+ and/or 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. Patients must have confirmation of MET-amplified/overexpressed tumour by central FISH and IHC testing (requirements summarised in the main body of the protocol and fully explained in the Central Laboratory Manual). Patients must not have received prior or current treatment with savolitinib or another MET inhibitor.

All patients 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objective disease progression by investigator per RECIST 1.1 is assessed, unacceptable toxicity occurs, consent is withdrawn or another discontinuation criterion is met.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

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 360 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment

Intervention Model Description

Under Protocol versions 1-6 the study model was single arm (open-label).

Starting protocol version 7 patients 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 (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• 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.
• Actual Study Start Date: January 9, 2019
• Estimated Primary Completion Date: August 23, 2024
• Estimated Study Completion Date: May 28, 2025

Arms and Interventions

Arm	Intervention/treatment
Experimental: osimertinib + savolitinib; osimertinib + savolitinib	Drug: osimertinib; osimertinib (80 mg oral OD).; Drug: savolitinib; savolitinib (300 mg oral OD or 300 mg oral BID or 600 mg oral OD)
Placebo Comparator: placebo + savolitinib; placebo + savolitinib	Drug: savolitinib; savolitinib (300 mg oral OD or 300 mg oral BID or 600 mg oral OD); Drug: placebo; placebo to osimertinib (oral OD)

Outcome Measures

Primary Outcome Measures :

1. Objective response rate (ORR) by investigator assessment in accordance with RECIST 1.1 [ Time Frame: The primary (ORR) analysis for the study will be performed at 6 months after the last patient under CSP version 7.0 has been randomised to treatment. ]
   To determine the efficacy of savolitinib (300 mg bid) in combination with osimertinib in patients with EGFRm+ and MET amplified/overexpressed (FISH10+ and/or IHC90+), locally advanced or metastatic NSCLC who have progressed following treatment with 1L osimertinib
2. Objective response rate (ORR) by investigator assessment in accordance with RECIST 1.1 [ Time Frame: The primary (ORR) analysis for the study will be performed at 6 months after the last patient under CSP version 7.0 has been randomised to treatment. ]
   To determine the efficacy of savolitinib (300 mg od) in combination with osimertinib in patients with EGFRm+, MET amplified/overexpressed (FISH5+ and/or IHC50+), locally advanced or metastatic NSCLC who have progressed following osimertinib.

Secondary Outcome Measures :

1. Duration of Response (DoR) by investigator assessment in accordance with RECIST 1.1. [ Time Frame: Up to 15 months after the last patient under CSP version 7.0 has been randomised to treatment ]
   To determine the efficacy of savolitinib (300 mg bid) in combination with osimertinib in patients with EGFRm+ and MET amplified/overexpressed (FISH10+ and/or IHC90+), locally advanced or metastatic NSCLC who have progressed following treatment with 1L osimertinib.
2. Progression-free survival (PFS) by investigator assessment in accordance with RECIST 1.1. [ Time Frame: Up to 15 months after the last patient under CSP version 7.0 has been randomised to treatment ]
   To determine the efficacy of savolitinib (300 mg bid) in combination with osimertinib in patients with EGFRm+ and MET amplified/overexpressed (FISH10+ and/or IHC90+), locally advanced or metastatic NSCLC who have progressed following treatment with 1L osimertinib.
3. Overall Survival (OS) by all cause mortality. [ Time Frame: Up to 15 months after the last patient under CSP version 7.0 has been randomised to treatment ]
   To determine the efficacy of savolitinib (300 mg bid) in combination with osimertinib in patients with EGFRm+ and MET amplified/overexpressed (FISH10+ and/or IHC90+), locally advanced or metastatic NSCLC who have progressed following treatment with 1L osimertinib.
4. Objective response rate (ORR) by investigator assessment in accordance with RECIST 1.1. [ Time Frame: Up to 15 months after the last patient under CSP version 7.0 has been randomised to treatment ]
   To describe the difference in the efficacy of savolitinib (300 mg bid) in combination with osimertinib and savolitinib (300 mg bid) in combination with placebo in patients with EGFRm+, MET amplified/overexpressed (FISH10+ and/or IHC90+), locally advanced or metastatic NSCLC who have progressed following treatment with 1L osimertinib therapy under CSP version 7.0.
5. Objective response rate (ORR) by investigator assessment in accordance with RECIST 1.1. [ Time Frame: Up to 15 months after the last patient under CSP version 7.0 has been randomised to treatment ]
   To determine the efficacy of savolitinib (300 mg od and 600 mg od, respectively) in combination with osimertinib in patients with EGFRm+, MET amplified/overexpressed (FISH10+ and/or IHC90+), locally advanced or metastatic NSCLC who have progressed following treatment with 1L osimertinib.
6. Duration of Response (DoR) by investigator assessment in accordance with RECIST 1.1. [ Time Frame: Up to 15 months after the last patient under CSP version 7.0 has been randomised to treatment ]
   To determine the efficacy of savolitinib (300 mg od and 600 mg od, respectively) in combination with osimertinib in patients with EGFRm+, MET amplified/overexpressed (FISH10+ and/or IHC90+), locally advanced or metastatic NSCLC who have progressed following treatment with 1L osimertinib.
7. Progression-free survival (PFS) by investigator assessment in accordance with RECIST 1.1. [ Time Frame: Up to 15 months after the last patient under CSP version 7.0 has been randomised to treatment ]
   To determine the efficacy of savolitinib (300 mg od and 600 mg od, respectively) in combination with osimertinib in patients with EGFRm+, MET amplified/overexpressed (FISH10+ and/or IHC90+), locally advanced or metastatic NSCLC who have progressed following treatment with 1L osimertinib.
8. Overall Survival (OS) by all cause mortality. [ Time Frame: Up to 15 months after the last patient under CSP version 7.0 has been randomised to treatment ]
   To determine the efficacy of savolitinib (300 mg od and 600 mg od, respectively) in combination with osimertinib in patients with EGFRm+, MET amplified/overexpressed (FISH10+ and/or IHC90+), locally advanced or metastatic NSCLC who have progressed following treatment with 1L osimertinib.
9. Objective response rate (ORR) by investigator assessment in accordance with RECIST 1.1. [ Time Frame: Up to 15 months after the last patient under CSP version 7.0 has been randomised to treatment ]
   To determine the efficacy of savolitinib (300 mg od, 300 mg bid, and 600 mg od, respectively) in combination with osimertinib in patients with EGFRm+, MET amplified/overexpressed (FISH10+ and/or IHC90+), locally advanced or metastatic NSCLC who have progressed following treatment of ≥ 2L osimertinib.
10. Duration of Response (DoR) by investigator assessment in accordance with RECIST 1.1. [ Time Frame: Up to 15 months after the last patient under CSP version 7.0 has been randomised to treatment ]
    To determine the efficacy of savolitinib (300 mg od, 300 mg bid, and 600 mg od, respectively) in combination with osimertinib in patients with EGFRm+, MET amplified/overexpressed (FISH10+ and/or IHC90+), locally advanced or metastatic NSCLC who have progressed following treatment of ≥ 2L osimertinib.
11. Progression-free survival (PFS) by investigator assessment in accordance with RECIST 1.1. [ Time Frame: Up to 15 months after the last patient under CSP version 7.0 has been randomised to treatment ]
    To determine the efficacy of savolitinib (300 mg od, 300 mg bid, and 600 mg od, respectively) in combination with osimertinib in patients with EGFRm+, MET amplified/overexpressed (FISH10+ and/or IHC90+), locally advanced or metastatic NSCLC who have progressed following treatment of ≥ 2L osimertinib.
12. Overall Survival (OS) by all cause mortality. [ Time Frame: Up to 15 months after the last patient under CSP version 7.0 has been randomised to treatment ]
    To determine the efficacy of savolitinib (300 mg od, 300 mg bid, and 600 mg od, respectively) in combination with osimertinib in patients with EGFRm+, MET amplified/overexpressed (FISH10+ and/or IHC90+), locally advanced or metastatic NSCLC who have progressed following treatment of ≥ 2L osimertinib.
13. Objective response rate (ORR) by investigator assessment in accordance with RECIST 1.1. [ Time Frame: Up to 15 months after the last patient under CSP version 7.0 has been randomised to treatment ]
    To determine the efficacy of savolitinib (300 mg bid, and 600 mg od, respectively) in combination with osimertinib in patients with EGFRm+, MET amplified/overexpressed (FISH5+ and/or IHC50+), locally advanced or metastatic NSCLC who have progressed following osimertinib.
14. Duration of Response (DoR) by investigator assessment in accordance with RECIST 1.1. [ Time Frame: Up to 15 months after the last patient under CSP version 7.0 has been randomised to treatment ]
    To determine the efficacy of savolitinib (300 mg od, 300 mg bid, and 600 mg od, respectively) in combination with osimertinib in patients with EGFRm+, MET amplified/overexpressed (FISH5+ and/or IHC50+), locally advanced or metastatic NSCLC who have progressed following osimertinib.
15. Progression-free survival (PFS) by investigator assessment in accordance with RECIST 1.1. [ Time Frame: Up to 15 months after the last patient under CSP version 7.0 has been randomised to treatment ]
    To determine the efficacy of savolitinib (300 mg od, 300 mg bid, and 600 mg od, respectively) in combination with osimertinib in patients with EGFRm+, MET amplified/overexpressed (FISH5+ and/or IHC50+), locally advanced or metastatic NSCLC who have progressed following osimertinib.
16. Overall Survival (OS) by all cause mortality. [ Time Frame: Up to 15 months after the last patient under CSP version 7.0 has been randomised to treatment ]
    To determine the efficacy of savolitinib (300 mg od, 300 mg bid, and 600 mg od, respectively) in combination with osimertinib in patients with EGFRm+, MET amplified/overexpressed (FISH5+ and/or IHC50+), locally advanced or metastatic NSCLC who have progressed following osimertinib.
17. Objective response rate (ORR) assessed by BICR in accordance with RECIST 1.1 [ Time Frame: Up to 15 months after the last patient under CSP version 7.0 has been randomised to treatment ]
    To determine the efficacy of (1) 300 mg od, 300 mg bid and 600 mg od of savolitinib in combination with osimertinib in patients with EGFRm+ MET amplified/ overexpressed (FISH 10+ and/or IHC90+); (2) 300 mg od, 300 mg bid and 600 mg od of savolitinib in combination with osimertinib in patients with EGFRm+ MET amplified/overexpressed (FISH5+ and/or IHC50+) (3) savolitinib 300 mg bid in combination with osimertinib and savolitinib 300 mg bid in combination with placebo, respectively, in patients with EGFRm+ MET amplified/ overexpressed (FISH10+ and/or IHC90+) following treatment with 1L osimertinib.
18. Duration of Response (DoR) assessed by BICR in accordance with RECIST 1.1 [ Time Frame: Up to 15 months after the last patient under CSP version 7.0 has been randomised to treatment ]
    To determine the efficacy of (1) 300 mg od, 300 mg bid and 600 mg od of savolitinib in combination with osimertinib in patients with EGFRm+ MET amplified/ overexpressed (FISH 10+ and/or IHC90+); (2) 300 mg od, 300 mg bid and 600 mg od of savolitinib in combination with osimertinib in patients with EGFRm+ MET amplified/overexpressed (FISH5+ and/or IHC50+) (3) savolitinib 300 mg bid in combination with osimertinib and savolitinib 300 mg bid in combination with placebo, respectively, in patients with EGFRm+ MET amplified/ overexpressed (FISH10+ and/or IHC90+) following treatment with 1L osimertinib.
19. Progression-free survival (PFS) assessed by BICR in accordance with RECIST 1.1 [ Time Frame: Up to 15 months after the last patient under CSP version 7.0 has been randomised to treatment ]
    To determine the efficacy of (1) 300 mg od, 300 mg bid and 600 mg od of savolitinib in combination with osimertinib in patients with EGFRm+ MET amplified/ overexpressed (FISH 10+ and/or IHC90+); (2) 300 mg od, 300 mg bid and 600 mg od of savolitinib in combination with osimertinib in patients with EGFRm+ MET amplified/overexpressed (FISH5+ and/or IHC50+) (3) savolitinib 300 mg bid in combination with osimertinib and savolitinib 300 mg bid in combination with placebo, respectively, in patients with EGFRm+ MET amplified/ overexpressed (FISH10+ and/or IHC90+) following treatment with 1L osimertinib.
20. Mean change from baseline in the European Organisation for Research and Treatment of Cancer (EORTC) 30-item core quality-of-life questionnaire (QLQ-C30). [ Time Frame: Up to 15 months after the last patient under CSP version 7.0 has been randomised to treatment ]
    To assess the impact of savolitinib and osimertinib on disease related symptoms and health related quality of life (HRQoL) in this patient population.
21. Mean change from baseline in the European Organisation for Research and Treatment of Cancer (EORTC) complementary 13-item quality-of-life questionnaire - lung cancer symptoms questionnaire (QLQ-LC13). [ Time Frame: Up to 15 months after the last patient under CSP version 7.0 has been randomised to treatment ]
    To assess the impact of savolitinib and osimertinib on disease related symptoms and health related quality of life (HRQoL) in this patient population.
22. Plasma concentrations of osimertinib, savolitinib and their metabolites. [ Time Frame: Blood sampling on Cycles 1 and 2 on Day 1 pre-dose, 1 hour and 3 hours post-dose; Day 1 of Cycles 3, 6, and 11; discontinuation visit (if discontinued due to liver toxicity) (One cycle = 28 days) ]
    To evaluate the pharmacokinetics of osimertinib and savolitinib in this patient population.
23. Total clearance in EGFR mutations at 6-weeks after therapy initiation (percentage and absolute change from baseline in EGFR mutation allele frequencies). [ Time Frame: From date of first dose until the date of first documented progression, up to approximately 36 months. ]
    To determine the prevalence of ctDNA clearance after osimertinib and savolitinib treatment in this patient population.
24. AEs, SAEs and discontinuation rate due to AEs, as characterized and graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Event [CTCAE] v5. [ Time Frame: Continuously from first dose to 28 (+/-7) days after discontinuation of study drug, or up to approximately 36 months. ]
    To evaluate the safety and tolerability of savolitinib in combination with osimertinib and savolitinib in combination with placebo.

Other Outcome Measures:

1. CNS PFS by BICR assessments in accordance with RECIST 1.1 [ Time Frame: Up to 15 months after the last patient under CSP version 7.0 has been randomised to treatment ]
   To assess the efficacy of savolitinib plus osimertinib and savolitinib plus placebo, respectively, on CNS metastases in patients with CNS metastases at baseline.
2. The presence/absence of CNS lesions at progression by BICR assessments in accordance with RECIST 1.1 [ Time Frame: Up to 15 months after the last patient under CSP version 7.0 has been randomised to treatment ]
   To assess the efficacy of savolitinib plus osimertinib and savolitinib plus placebo, respectively, on the prevention of CNS metastases in patients without CNS metastases at baseline.
3. PRO CTCAE symptoms [ Time Frame: From date of consent until the date of first documented progression, up to approximately 36 months. ]
   To assess the impact of savolitinib in combination with osimertinib on patient reported treatment-related symptoms.
4. Patient's Global Impression of Severity (PGIS) [ Time Frame: From date of consent until the date of first documented progression, up to approximately 36 months. ]
   To assess patients' overall impression of severity of cancer symptoms. In patients centrally confirmed as MET positive in all patients.
5. EQ-5D-5L [ Time Frame: From date of consent until the date of first documented progression, up to approximately 36 months. ]
   To explore the impact of treatment and disease on health state utility. In patients centrally confirmed as MET positive in all patients.
6. Longitudinal changes in circulating DNA and/or RNA compared with PFS, OS and ORR. [ Time Frame: Blood samples collected at Screening within 28 days before the first dose of study treatment; on day of first dose of study treatment; at discontinuation 7 days after last dose of study treatment. (One cycle = 28 days) ]
   To assess the predictive value of changes in circulating biomarkers on clinical efficacy endpoints.
7. Pharmacogenetic analyses on blood samples. [ Time Frame: Screening within 28 days before first dose; at first dose; 7 days after last dose. (One cycle = 28 days) ]
   To collect and store DNA (according to each country's local and ethical procedures) for future exploratory research into genes/genetic variation that may influence response (ie, distribution, safety, tolerability and efficacy) to study treatments and or susceptibility to disease (optional).
8. Disease relevant or response markers in tumour tissue and circulating tumour DNA/RNA including but not limited to EGFR mutations and MET amplifications. [ Time Frame: Screening within 28 days before first dose; at first dose; 7 days after last dose. Tumour tissue collected during Pre-screening and at treatment discontinuation 7 days after last dose. (One cycle = 28 days) ]
   To collect and store tissue, plasma and serum samples for diagnostic development and exploratory analyses.
9. HLA alleles associated with susceptibility to drug related AEs (such as but not limited to hypersensitivity). [ Time Frame: On first day of study treatment at Cycle 1 Day 1. (One cycle = 28 days) ]
   To collect and store germline DNA for exploration of the role of HLA alleles in developmental toxicity.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion criteria:

• Patients 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 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 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;

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 CT or 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
• ALT, AST ≤2.5 x ULN with 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 patients are receiving therapeutic anti coagulation which affects these parameters.
• Patients 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.
• ECOG/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.

Exclusion Criteria:

• Unresolved toxicities from any prior therapy greater than 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

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 patient 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. Patients with Stage I cancer who have received definitive local treatment at least 3 years previously, and are considered unlikely to recur are eligible. All patients with previously treated in situ carcinoma (ie, non-invasive) are eligible, as are patients 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 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.
• Patients 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.

Contacts and Locations

Contacts

Contact: AstraZeneca Clinical Study Information Center; 1-877-240-9479; information.center@astrazeneca.com

Locations

United States, California

Research Site; Active, not recruiting

La Jolla, California, United States, 92093

Research Site; Active, not recruiting

Los Angeles, California, United States, 90024

Research Site; Active, not recruiting

Sacramento, California, United States, 95817

Research Site; Withdrawn

Santa Rosa, California, United States, 95403

United States, Connecticut

Research Site; Withdrawn

New Haven, Connecticut, United States, 06510

United States, District of Columbia

Research Site; Active, not recruiting

Washington, District of Columbia, United States, 20016

United States, Florida

Research Site; Withdrawn

Boca Raton, Florida, United States, 33486

United States, Maryland

Research Site; Terminated

Baltimore, Maryland, United States, 21201

United States, Massachusetts

Research Site; Withdrawn

Boston, Massachusetts, United States, 02114

Research Site; Withdrawn

Boston, Massachusetts, United States, 02215

Research Site; Terminated

Boston, Massachusetts, United States, 02215

United States, Minnesota

Research Site; Active, not recruiting

Rochester, Minnesota, United States, 55905

United States, New York

Research Site; Active, not recruiting

Brooklyn, New York, United States, 11220

United States, Pennsylvania

Research Site; Terminated

Philadelphia, Pennsylvania, United States, 19111

Research Site; Active, not recruiting

Pittsburgh, Pennsylvania, United States, 15232

United States, Washington

Research Site; Active, not recruiting

Seattle, Washington, United States, 98109

Brazil

Research Site; Active, not recruiting

Barretos, Brazil, 14784-400

Research Site; Active, not recruiting

Curitiba, Brazil, 80810-050

Research Site; Terminated

Goiania, Brazil, 74093-300

Research Site; Completed

Porto Alegre, Brazil, 90540-140

Research Site; Active, not recruiting

Porto Alegre, Brazil, 90610-000

Research Site; Active, not recruiting

Rio de Janeiro, Brazil, 22271-110

Research Site; Active, not recruiting

Salvador, Brazil, 41950-640

Research Site; Completed

Sao Paulo, Brazil, 01509-900

Research Site; Active, not recruiting

São José do Rio Preto, Brazil, 15090-000

Research Site; Active, not recruiting

São Paulo, Brazil, 01246-000

Canada, Alberta

Research Site; Active, not recruiting

Calgary, Alberta, Canada, T2N 4N2

Research Site; Active, not recruiting

Edmonton, Alberta, Canada, T6G 1Z2

Canada, Ontario

Research Site; Active, not recruiting

Newmarket, Ontario, Canada, L3Y 2P9

Research Site; Completed

North York, Ontario, Canada, M2K 1E1

Research Site; Active, not recruiting

Toronto, Ontario, Canada, M4N 3M5

Research Site; Active, not recruiting

Toronto, Ontario, Canada, M5G 2M9

Chile

Research Site; Completed

Santiago, Chile, 7500713

Research Site; Completed

Santiago, Chile, 7520349

Research Site; Completed

Santiago, Chile, 8420383

Denmark

Research Site; Active, not recruiting

Herlev, Denmark, 2730

Research Site; Recruiting

København Ø, Denmark, 2100

Research Site; Completed

Næstved, Denmark, 4700

Research Site; Recruiting

Odense C, Denmark, 5000

Research Site; Recruiting

Vejle, Denmark, 7100

Research Site; Completed

Ålborg, Denmark, 9100

France

Research Site; Completed

Dijon, France, 21079

Research Site; Completed

Marseille Cedex 20, France, 13915

Research Site; Completed

Nantes, France, 44093

Research Site; Completed

Paris Cedex 5, France, 75248

Research Site; Completed

Paris, France, 75020

Research Site; Active, not recruiting

Rennes, France, 35033

India

Research Site; Active, not recruiting

Bangalore, India, 560064

Research Site; Active, not recruiting

Chennai, India, 600035

Research Site; Active, not recruiting

Kolkata, India, 700160

Research Site; Active, not recruiting

New Delhi, India, 110085

Italy

Research Site; Active, not recruiting

Avellino, Italy, 83100

Research Site; Active, not recruiting

Firenze, Italy, 50134

Research Site; Active, not recruiting

Milano, Italy, 20133

Research Site; Active, not recruiting

Milano, Italy, 20141

Research Site; Active, not recruiting

Orbassano, Italy, 10043

Research Site; Active, not recruiting

Padova, Italy, 35128

Research Site; Active, not recruiting

Parma, Italy, 43126

Research Site; Active, not recruiting

Perugia, Italy, 06132

Research Site; Active, not recruiting

Peschiera Del Garda, Italy, 37019

Japan

Research Site; Completed

Fukuoka, Japan, 812-8582

Research Site; Active, not recruiting

Hiroshima-shi, Japan, 730-8518

Research Site; Active, not recruiting

Kanazawa-shi, Japan, 920-8641

Research Site; Active, not recruiting

Nagoya-shi, Japan, 464-8681

Research Site; Completed

Niigata-shi, Japan, 951-8566

Research Site; Completed

Osakasayama, Japan, 589-8511

Research Site; Active, not recruiting

Sapporo-shi, Japan, 003-0804

Research Site; Active, not recruiting

Sunto-gun, Japan, 411-8777

Research Site; Completed

Wakayama-shi, Japan, 641-8510

Research Site; Completed

Yokohama-shi, Japan, 241-0815

Korea, Republic of

Research Site; Active, not recruiting

Goyang-si, Korea, Republic of, 10408

Research Site; Active, not recruiting

Seongnam-si, Korea, Republic of, 13620

Research Site; Active, not recruiting

Seoul, Korea, Republic of, 03080

Research Site; Active, not recruiting

Seoul, Korea, Republic of, 03722

Research Site; Active, not recruiting

Seoul, Korea, Republic of, 05505

Research Site; Active, not recruiting

Seoul, Korea, Republic of, 06351

Research Site; Active, not recruiting

Suwon, Korea, Republic of, 16247

Puerto Rico

Research Site; Withdrawn

Hato Rey, Puerto Rico, 00917

Spain

Research Site; Terminated

Cordoba, Spain, 14004

Research Site; Completed

Madrid, Spain, 28041

Research Site; Active, not recruiting

Madrid, Spain, 28046

Research Site; Active, not recruiting

Málaga, Spain, 29010

Research Site; Recruiting

San Sebastian, Spain, 20014

Research Site; Active, not recruiting

Valencia, Spain, 46026

Research Site; Completed

Zaragoza, Spain, 50009

Taiwan

Research Site; Active, not recruiting

Hsinchu, Taiwan, 300

Research Site; Active, not recruiting

Kaohsiung, Taiwan, 83301

Research Site; Active, not recruiting

New Taipei, Taiwan, 23561

Research Site; Active, not recruiting

Taichung City, Taiwan, 402

Research Site; Active, not recruiting

Taichung, Taiwan, 40705

Research Site; Terminated

Tainan City, Taiwan, 70403

Research Site; Recruiting

Taipei City, Taiwan, 110

Research Site; Active, not recruiting

Taipei, Taiwan, 10002

Research Site; Active, not recruiting

Taipei, Taiwan, 112

Research Site; Active, not recruiting

Taoyuan, Taiwan, 333

Vietnam

Research Site; Active, not recruiting

Ha Noi, Vietnam, 100000

Research Site; Withdrawn

Ha Noi, Vietnam, 100000

Research Site; Terminated

Ho Chi Minh City, Vietnam, 700000

Research Site; Active, not recruiting

Ho Chi Minh, Vietnam, 700000

Sponsors and Collaborators

AstraZeneca

Hutchison MediPharma

Investigators

• Principal Investigator: Lecia V Sequist, MD MPH; Massachusetts General Hospital
• Principal Investigator: Myung-Ju Ahn, MD; Samsung Medical Centre Sungkyunkwan University School of Medicine

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Schmid 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.

• Responsible Party: AstraZeneca
• ClinicalTrials.gov Identifier: NCT03778229
• Other Study ID Numbers: D5084C00007; 2018-003012-51 ( EudraCT Number )
• First Posted: December 19, 2018
• Last Update Posted: April 11, 2024
• Last Verified: April 2024

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: Qualified researchers can request access to anonymized individual patient-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.
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP)
• Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• Access Criteria: When a request has been approved AstraZeneca will provide access to the de-identified individual patient-level data in an approved sponsored tool. Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• URL: https://astrazenecagroup-dt.pharmacm.com/DT/Home

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by AstraZeneca:

Non Small Cell Lung Cancer; epidermal growth factor receptor mutation positive; hepatocyte growth factor receptor; savolitinib; Osimertinib; AZD9291; AZD6094; volitinib

Additional relevant MeSH terms:

Osimertinib; Tyrosine Kinase Inhibitors; Protein Kinase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents