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.
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daily in 28 day cycles until either objective PD by RECIST 1.1 is assessed, unacceptable toxicity occurs, consent is withdrawn, or another discontinuation criterion is met.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
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
DOUBLE
Enrollment
30
Osimertinib 80 mg oral QD Savolitinib 300mg oral QD
Savolitinib 300mg Oral QD Placebo to Osimertinib 80mg oral QD
Research Site
Duarte, California, United States
Research Site
Sacramento, California, United States
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.
Time frame: Tumour assessments every 6 weeks from randomisation up to 24 weeks, then every 8 weeks until objective disease progression (maximum of approximately 25 months)
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.
Time frame: 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.
Time frame: 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.
Time frame: Baseline and 12 weeks.
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Research Site
Buenos Aires, Argentina
Research Site
Delhi, India
Research Site
Mumbai, India
Research Site
Taichung, Taiwan
Research Site
Taipei, Taiwan
Research Site
Taipei, Taiwan
Research Site
Taipei, Taiwan
Research Site
Taoyuan, Taiwan
...and 11 more locations
Overall Survival (OS)
OS is defined as time from randomisation until the date of death due to any cause.
Time frame: 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
Time frame: 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
Time frame: 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.
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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.
Time frame: Cycle 3, Day 1 (Each Cycle is 28 days)