A Study Comparing Savolitinib Plus Osimertinib vs Savolitinib Plus Placebo in Patients With EGFRm+ and MET Amplified Advanced NSCLC (CoC)

A Multi-centre Phase II, Double-Blind, Randomised Study of Savolitinib in Combination With Osimertinib vs Savolitinib in Combination With Placebo in Patients With EGFRm+ and MET Amplified Locally Advanced or Metastatic Non-Small Cell Lung Cancer Who Have Progressed Following Treatment With Osimertinib

This study will compare the activity of the combination of savolitinib and osimertinib against the combination of savolitinib with placebo to osimertinib in patients with Epidermal Growth Factor Receptor Mutation Positive and MET amplified, locally advanced or metastatic non-small cell lung cancer who have progressed following treatment with osimertinib.

Study Overview

• Status: Active, not recruiting
• Conditions: Non-Small Cell Lung Cancer
• Intervention / Treatment: Drug: Osimertinib + Savolitinib; Drug: Savolitinib + Placebo

Detailed Description

Resistance to EGFR-TKIs is a clinical problem. One of the mechanisms for resistance to osimertinib is amplification of the MET receptor tyrosine kinase, which activates downstream intracellular signalling independent of EGFR. This study will explore the individual contribution of savolitinib to MET mediated osimertinib resistance, by assessing the response to dual pathway blockade of EGFRm and MET to overcome MET mediated resistance to osimertinib versus inhibition of the MET pathway alone by investigating the efficacy of savolitinib plus osimertinib versus savolitinib plus placebo to osimertinib (hereafter referred to as placebo) in patients with EGFRm+ and MET amplified, locally advanced or metastatic NSCLC who have progressed following treatment with osimertinib. This is a multi centre, Phase II, double blind, randomised study.

Patients will be randomised in a ratio of 1:1 to receive treatment with savolitinib once daily plus osimertinib once daily or savolitinib once daily plus placebo. Randomisation will be stratified according to the number ofprior lines of therapy (ie, osimertinib monotherapy as first line or ≥ second line [which includes patients who received osimertinib monotherapy before or after chemotherapy]). All patients confirmed as eligible will begin treatment on Day 1 with savolitinib plus osimertinib or savolitinib plus placebo. Treatment will continue once daily in 28 day cycles until either objective PD by RECIST 1.1 is assessed, unacceptable toxicity occurs, consent is withdrawn, or another discontinuation criterion is met.

After progression, patients can be unblinded, and patients initially randomised to the savolitinib plus placebo arm may cross-over to open-label savolitinib plus osimertinib following investigator assessed objective PD to ensure that all patients enrolled may have the opportunity to receive the combination of savolitinib plus osimertinib.

• Study Type: Interventional
• Enrollment (Actual): 30
• Phase: Phase 2

Contacts and Locations

Study Locations

• Argentina
  • Ciudad de Buenos Aires, Argentina, C1120AAT
    • Research Site
• India
  • Delhi, India, 110085
    • Research Site
  • Mumbai, India, 400053
    • Research Site
• Taiwan
  • Taichung, Taiwan, 402
    • Research Site
  • Taipei, Taiwan, 100
    • Research Site
  • Taipei, Taiwan, 235
    • Research Site
  • Taipei, Taiwan, 11217
    • Research Site
  • Taoyuan, Taiwan, 333
    • Research Site
• Thailand
  • Bangkok, Thailand, 10210
    • Research Site
  • Bangkok, Thailand, 10300
    • Research Site
  • Bangkok, Thailand, 10330
    • Research Site
  • Bangkok, Thailand, 10400
    • Research Site
  • Bangkok, Thailand, 10700
    • Research Site
  • Hat Yai, Thailand, 90110
    • Research Site
  • Khon Kaen, Thailand, 40002
    • Research Site
  • Muang, Thailand, 50200
    • Research Site
• United States
  • California
    • Duarte, California, United States, 91010
      • Research Site
    • Sacramento, California, United States, 95817
      • Research Site
• Vietnam
  • Hanoi, Vietnam, 100000
    • Research Site
  • Ho Chi Minh City, Vietnam, 700000
    • Research Site
  • Hà Nội, Vietnam, 100000
    • Research Site

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Patients must be ≥ 18 years of age at the time of signing the informed consent (≥ 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 that is permitted in the osimertinib national label (such as exon 19 deletion and/or L858R), which is not amenable to curative therapy.
• Documented radiologic PD following treatment with osimertinib (osimertinib does not need to be the most recent therapy).
• Have MET amplification as determined by central MET FISH testing on tumour specimen collected following progression on prior osimertinib treatment.
• At least measurable target lesion
• Patients must have received at least one but no more than 3 prior lines of therapy (including investigational therapy) in the locally advanced/metastatic setting.
• Adequate haematological, liver and renal function
• Eastern Cooperative Oncology Group/WHO performance status of 0 or 1 with no deterioration over the previous 2 weeks and a minimum life expectancy of 12 weeks.
• Females of childbearing potential should be willing to use adequate contraceptive measures, should not be breastfeeding, and must have a negative pregnancy test.
• Male patients 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 intervention. Patients should refrain from donating sperm from the start of dosing until 6 months after discontinuing study intervention.

Exclusion Criteria:

• Unresolved toxicities from any prior therapy greater than CTCAE Grade 1 at the time of starting study intervention with the exception of alopecia, haemoglobin ≥ 9 g/dL 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.

• Any of the following cardiac diseases currently or within the last 6 months:

  • Unstable angina pectoris
  • Congestive heart failure (NYHA Grade ≥ 2)
  • Acute myocardial infarction
  • Stroke or transient ischemic attack
  • Uncontrolled hypertension (BP ≥ 150/95 mmHg despite medical therapy).
  • Mean resting corrected 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
  • Any clinically important abnormalities in rhythm, conduction or morphology of resting ECGs.
  • 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 intervention or has not recovered from side effects of such therapy.
• Major surgical procedures ≤ 28 days of beginning study intervention or minor surgical procedures ≤ 7 days. No waiting is required following port-a-cath placement.
• As judged by the Investigator, any evidence of severe or uncontrolled systemic diseases, including renal transplant or active bleeding diatheses, which in the investigator's opinion makes it undesirable for the patient to enter the study or which would jeopardise compliance with the CSP.
• Active HBV (positive HBsAg result) or HCV. Viral testing is not required for assessment of eligibility for the study.
• Known serious active infection including, but not limited to, tuberculosis, or HIV (positive HIV 1/2 antibodies). Testing is not required for assessment of eligibility for the study.
• 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 intervention.
• Past medical history of ILD, drug-induced ILD, radiation pneumonitis, which required steroid treatment, or any evidence of clinically active ILD.
• Prior or current treatment with a 3rd generation EGFR-TKI other than osimertinib.
• Prior or current treatment with savolitinib or another MET inhibitor (for example, foretinib, crizotinib, cabozantinib, onartuzumab, capmatinib).
• Patients who have received ≥ 4 lines of systemic therapy for NSCLC
• Any cytotoxic chemotherapy, investigational agents or other anti cancer 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 intervention 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 intervention) medications or herbal supplements known to be strong inducers of CYP3A4 or strong inhibitors of CYP1A2, or CYP3A4 substrates which have a narrow therapeutic range within 2 weeks of the first dose of study intervention (3 weeks for St John's Wort) will be excluded. All patients must try to avoid concomitant use of any medications, herbal supplements and/or ingestion of foods with known inducer effects on CYP3A4 during the study and for 3 months later the last dose intake.
• Participation in another clinical study with a cytotoxic, investigational product, or other anti cancer drug for the treatment of advanced NSCLC if received study intervention from that study within 14 days of the first dose of study intervention.
• Known hypersensitivity to the active or inactive excipients of osimertinib or savolitinib or drugs with a similar chemical structure or class.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm A; Savolitinib 300 mg oral QD Osimertinib 80 mg oral QD	Drug: Osimertinib + Savolitinib; Osimertinib 80 mg oral QD Savolitinib 300mg oral QD
Experimental: Arm B; Savolitinib 300 mg oral QD Placebo to Osimertinib 80mg oral QD	Drug: Savolitinib + Placebo; Savolitinib 300mg Oral QD Placebo to Osimertinib 80mg oral QD

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective Response Rate (ORR)	Percentage of evaluable patients with an Investigator-assessed visit response of complete response (CR) or partial response (PR). CR defined as disappearance of all target and non-target lesions and no new lesions. PR defined as >= 30% decrease in the sum of diameters of target lesions (compared to baseline) and no new non-target lesions. Overall Response (OR) = CR + PR.	Tumour assessments every 6 weeks from randomisation up to 24 weeks, then every 8 weeks until objective disease progression (maximum of approximately 25 months)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free Survival (PFS)	PFS is defined as the time from randomisation until the date of objective disease progression or death (by any cause in the absence of progression) regardless of whether the patient withdraws from randomised therapy or receives another anti-cancer therapy prior to progression. Progression (i.e., PD) is defined as at least a 20% increase in the sum of diameters of target lesions (TLs) and an absolute increase of ≥5mm, taking as reference the smallest sum of diameters since treatment started including the baseline sum of diameters.	Tumour assessments every 6 weeks from randomisation up to 24 weeks, then every 8 weeks until objective disease progression (maximum of approximately 25 months)
Duration of Response (DoR)	DoR is defined as the time from the date of first documented response until date of documented progression per RECIST 1.1 as assessed by the investigator or death in the absence of disease progression.	Tumour assessments every 6 weeks from randomisation up to 24 weeks, then every 8 weeks until objective disease progression (maximum of approximately 25 months)
Tumour Size Assessment (TSA)	TSA is defined as the percentage change from baseline in TLs at 12 weeks per RECIST 1.1 as assessed by the investigator.	Baseline and 12 weeks.
Overall Survival (OS)	OS is defined as time from randomisation until the date of death due to any cause.	From the date of randomisation until death due to any cause, assessed up to the data cut-off date (21 December 2022) (maximum of approximately 25 months)
Total Clearance in EGFR Mutations at 6-weeks After Therapy Initiation (Percentage Change From Baseline in EGFR Mutation Allele Frequencies).	To determine the prevalence of ctDNA clearance after savolitinib plus osimertinib or savolitinib plus placebo treatment in this patient population	6-weeks after therapy initiation.
Total Clearance in EGFR Mutations at 6-weeks After Therapy Initiation (Absolute Change From Baseline in EGFR Mutation Allele Frequencies).	To determine the prevalence of ctDNA clearance after savolitinib plus osimertinib or savolitinib plus placebo treatment in this patient population	6-weeks after therapy initiation.
PK Concentration Ratios on Multiple Dosing	The time dependency of the PK on multiple dosing is assessed by the ratio of mean concentrations at the timepoints identified in column one. For example, the Geometric mean ratio for "C3h Cycle2 Day 1 / C3h Cycle 1 Day 1" periods is the geometric mean value for C3h Cycle 2 Day 1 (Stage 2) divided by the geometric mean value for C3h Cycle 1 Day 1 (Stage 1). Because the measurement is a ratio of values, no measures of central tendency are appropriate.	C3h Cycle 2 Day 1/C3h Cycle 1 Day 1; Cpre-dose Cycle 3 Day 1/Cpre-dose Cycle 2 Day 1; Cpre-dose Cycle 6 Day 1/Cpre-dose Cycle 2 Day 1; Cpre-dose Cycle 11 Day 1/Cpre-dose Cycle 2 Day 1. (Each Cycle is 28 days)
AUCss of Savolitinib, Osimertinib and Their Metabolites, (M2 and M3 for Savolitinib; AZ5104 for Osimertinib)	Area under the plasma concentration-time curve at steady state	Cycle 3, Day 1: Pre-dose and 1, 3, 4, and 6 hours post-dose
Cssmax of Savolitinib, Osimertinib and Their Metabolites, (M2 and M3 for Savolitinib; AZ5104 for Osimertinib)	Maximum steady state plasma concentration	Cycle 3, Day 1: Pre-dose and 1, 3, 4, and 6 hours post-dose
Tssmax of Savolitinib, Osimertinib and Their Metabolites, (M2 and M3 for Savolitinib; AZ5104 for Osimertinib)	Time to maximum plasma concentration at steady state	Cycle 3, Day 1: Pre-dose and 1, 3, 4, and 6 hours post-dose
CLss/F of Savolitinib, Osimertinib and Their Metabolites, (M2 and M3 for Savolitinib; AZ5104 for Osimertinib)	To evaluate the PK of savolitinib and osimertinib.	Cycle 3, Day 1 (Each Cycle is 28 days)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
HLA alleles associated with susceptibility to drug related AEs (such as but not limited to hypersensitivity).	To collect and store germline DNA for exploration of the role of HLA alleles in developmental toxicity.	On Cycle 1 Day 1 only (each cycle is 28 days)
Overall survival, in patients who cross over after progression on savolitinib plus placebo	Defined as time from randomisation until the date of death due to any cause	The primary analysis will occur 6 months after the last patient is randomised. The final analysis will occur at the earlier of 18 months after the last patient is randomised or when 70% of patients have progressed or died.

Collaborators and Investigators

• Sponsor: AstraZeneca

Publications and helpful links

Helpful Links

• CSR Synopsis Redacted
• CSP Redacted
• SAP Redacted

Study record dates

Study Major Dates

• Study Start (Actual): September 28, 2020
• Primary Completion (Actual): December 21, 2022
• Study Completion (Estimated): March 30, 2026

Study Registration Dates

• First Submitted: September 1, 2020
• First Submitted That Met QC Criteria: October 27, 2020
• First Posted (Actual): October 28, 2020

Study Record Updates

• Last Update Posted (Actual): February 27, 2026
• Last Update Submitted That Met QC Criteria: February 6, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Keywords: Non-Small Cell Lung Cancer; MET; Carcinoma; EGFR; Locally; Advanced; Metastatic; Osimertinib; Tagrisso; Savolitinib
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Site; Neoplasms; Respiratory Tract Diseases; Neoplasms by Histologic Type; Lung Diseases; Neoplasms, Glandular and Epithelial; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplastic Processes; Lung Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Pathological Conditions, Signs and Symptoms; Carcinoma; Neoplasm Metastasis; Carcinoma, Non-Small-Cell Lung; Tyrosine Kinase Inhibitors; Antineoplastic Agents; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protein Kinase Inhibitors; osimertinib; 1-(1-(imidazo(1,2-a)pyridin-6-yl)ethyl)-6-(1-methyl-1H-pyrazol-4-yl)-1H-(1,2,3)triazolo(4,5-b)pyrazine
• Other Study ID Numbers: D5084C00009; 2020-000813-33 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD 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.

• IPD Sharing 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.

IPD Sharing Access Criteria

When a request has been approved AstraZeneca will provide access to the deidentified 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.

• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No