Non-Small Cell Lung Cancer
Conditions
Keywords
Locally, Advanced, Metastatic, Carcinoma, Non-Small Cell Lung Cancer, Osimertinib, Tagrisso, Savolitinib, MET, EGFR
Brief summary
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.
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daily in 28 day cycles until either objective PD by RECIST 1.1 is assessed, unacceptable toxicity occurs, consent is withdrawn, or another discontinuation criterion is met.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.
Interventions
DRUGOsimertinib + Savolitinib
Osimertinib 80 mg oral QD Savolitinib 300mg oral QD
DRUGSavolitinib + Placebo
Savolitinib 300mg Oral QD Placebo to Osimertinib 80mg oral QD
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Intervention model description
1. Patients will take savolitinib 300mg tablets QD within 15 minutes after the start of a meal except for the day on which PK samples are taken. Patients will take osimertinib 80mg tablet once daily with/without food except for the day on which PK samples are taken. On the day when PK samples are taken both savolitinib & osimertinib will be administered after a meal prepared by the clinic 2. Patients will take savolitinib 300mg tablets QD within 15 minutes after the start of a meal except for the day on which PK samples are taken. Patients will take placebo to osimertinib 80mg tablet once daily with/without food except for the day on which PK samples are taken. On the day when PK samples are taken both savolitinib & placebo to osimertinib will be administered within 15 minutes after a meal prepared by the clinic In addition to comparing the ORR between groups, this study will also assess safety and tolerability, DoR, DCR, OS, PFS and other measures of antitumor activity
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) | Tumour assessments every 6 weeks from randomisation up to 24 weeks, then every 8 weeks until objective disease progression (maximum of approximately 25 months) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS) | Tumour assessments every 6 weeks from randomisation up to 24 weeks, then every 8 weeks until objective disease progression (maximum of approximately 25 months) | 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. |
| Duration of Response (DoR) | Tumour assessments every 6 weeks from randomisation up to 24 weeks, then every 8 weeks until objective disease progression (maximum of approximately 25 months) | 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 Size Assessment (TSA) | Baseline and 12 weeks. | TSA is defined as the percentage change from baseline in TLs at 12 weeks per RECIST 1.1 as assessed by the investigator. |
| Overall Survival (OS) | 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) | OS is defined as time from randomisation until the date of death due to any cause. |
| Total Clearance in EGFR Mutations at 6-weeks After Therapy Initiation (Percentage Change From Baseline in EGFR Mutation Allele Frequencies). | 6-weeks after therapy initiation. | To determine the prevalence of ctDNA clearance after savolitinib plus osimertinib or savolitinib plus placebo treatment in this patient population |
| Total Clearance in EGFR Mutations at 6-weeks After Therapy Initiation (Absolute Change From Baseline in EGFR Mutation Allele Frequencies). | 6-weeks after therapy initiation. | To determine the prevalence of ctDNA clearance after savolitinib plus osimertinib or savolitinib plus placebo treatment in this patient population |
| PK Concentration Ratios on Multiple Dosing | 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) | 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. |
| AUCss of Savolitinib, Osimertinib and Their Metabolites, (M2 and M3 for Savolitinib; AZ5104 for Osimertinib) | Cycle 3, Day 1: Pre-dose and 1, 3, 4, and 6 hours post-dose | Area under the plasma concentration-time curve at steady state |
| Cssmax of Savolitinib, Osimertinib and Their Metabolites, (M2 and M3 for Savolitinib; AZ5104 for Osimertinib) | Cycle 3, Day 1: Pre-dose and 1, 3, 4, and 6 hours post-dose | Maximum steady state plasma concentration |
| Tssmax of Savolitinib, Osimertinib and Their Metabolites, (M2 and M3 for Savolitinib; AZ5104 for Osimertinib) | Cycle 3, Day 1: Pre-dose and 1, 3, 4, and 6 hours post-dose | Time to maximum plasma concentration at steady state |
| CLss/F of Savolitinib, Osimertinib and Their Metabolites, (M2 and M3 for Savolitinib; AZ5104 for Osimertinib) | Cycle 3, Day 1 (Each Cycle is 28 days) | To evaluate the PK of savolitinib and osimertinib. |
Countries
Argentina, India, Taiwan, Thailand, United States, Vietnam
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Savolitinib Plus Osimertinib Savolitinib 300 mg oral QD
Osimertinib 80 mg oral QD | 14 |
| Savolitinib Plus Placebo Savolitinib 300 mg oral QD
Placebo to Osimertinib 80mg oral QD | 16 |
| Total | 30 |
Baseline characteristics
| Characteristic | Savolitinib Plus Osimertinib | Savolitinib Plus Placebo | Total |
|---|---|---|---|
| Age, Continuous | 56.2 Years STANDARD_DEVIATION 11.42 | 62.5 Years STANDARD_DEVIATION 10.02 | 59.6 Years STANDARD_DEVIATION 10.98 |
| Race/Ethnicity, Customized Asian | 12 Participants | 15 Participants | 27 Participants |
| Race/Ethnicity, Customized Not reported | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Other | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 1 Participants | 0 Participants | 1 Participants |
| Sex: Female, Male Female | 7 Participants | 9 Participants | 16 Participants |
| Sex: Female, Male Male | 7 Participants | 7 Participants | 14 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 5 / 14 | 7 / 16 |
| other Total, other adverse events | 13 / 14 | 16 / 16 |
| serious Total, serious adverse events | 4 / 14 | 3 / 16 |
Outcome results
Primary
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)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Savolitinib Plus Osimertinib | Objective Response Rate (ORR) | 57.1 Percentage of participants |
| Savolitinib Plus Placebo | Objective Response Rate (ORR) | 12.5 Percentage of participants |
Secondary
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
Population: All patients with PK data are analysed for savolitinib, osimertinib and their metabolites
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Savolitinib Plus Osimertinib | AUCss of Savolitinib, Osimertinib and Their Metabolites, (M2 and M3 for Savolitinib; AZ5104 for Osimertinib) | Savolitinib | 7875 h*ng/mL | Geometric Coefficient of Variation 37.54 |
| Savolitinib Plus Osimertinib | AUCss of Savolitinib, Osimertinib and Their Metabolites, (M2 and M3 for Savolitinib; AZ5104 for Osimertinib) | M2 | 2630 h*ng/mL | Geometric Coefficient of Variation 48.8 |
| Savolitinib Plus Osimertinib | AUCss of Savolitinib, Osimertinib and Their Metabolites, (M2 and M3 for Savolitinib; AZ5104 for Osimertinib) | Osimertinib | 12910 h*ng/mL | Geometric Coefficient of Variation 50.8 |
| Savolitinib Plus Osimertinib | AUCss of Savolitinib, Osimertinib and Their Metabolites, (M2 and M3 for Savolitinib; AZ5104 for Osimertinib) | AZ5104 | 1086 h*ng/mL | Geometric Coefficient of Variation 70.8 |
| Savolitinib Plus Osimertinib | AUCss of Savolitinib, Osimertinib and Their Metabolites, (M2 and M3 for Savolitinib; AZ5104 for Osimertinib) | M3 | 966.7 h*ng/mL | Geometric Coefficient of Variation 49.07 |
| Savolitinib Plus Placebo | AUCss of Savolitinib, Osimertinib and Their Metabolites, (M2 and M3 for Savolitinib; AZ5104 for Osimertinib) | Savolitinib | 11890 h*ng/mL | Geometric Coefficient of Variation 37.56 |
| Savolitinib Plus Placebo | AUCss of Savolitinib, Osimertinib and Their Metabolites, (M2 and M3 for Savolitinib; AZ5104 for Osimertinib) | M2 | 3516 h*ng/mL | Geometric Coefficient of Variation 44.43 |
| Savolitinib Plus Placebo | AUCss of Savolitinib, Osimertinib and Their Metabolites, (M2 and M3 for Savolitinib; AZ5104 for Osimertinib) | M3 | 1348 h*ng/mL | Geometric Coefficient of Variation 42.37 |
Secondary
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)
Population: All patients with PK data are analysed for savolitinib, osimertinib and their metabolites
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Savolitinib Plus Osimertinib | CLss/F of Savolitinib, Osimertinib and Their Metabolites, (M2 and M3 for Savolitinib; AZ5104 for Osimertinib) | AZ5104 | 0.1475 L/h | Geometric Coefficient of Variation 70.8 |
| Savolitinib Plus Osimertinib | CLss/F of Savolitinib, Osimertinib and Their Metabolites, (M2 and M3 for Savolitinib; AZ5104 for Osimertinib) | M3 | 310.3 L/h | Geometric Coefficient of Variation 49.07 |
| Savolitinib Plus Osimertinib | CLss/F of Savolitinib, Osimertinib and Their Metabolites, (M2 and M3 for Savolitinib; AZ5104 for Osimertinib) | Osimertinib | 0.01241 L/h | Geometric Coefficient of Variation 50.8 |
| Savolitinib Plus Osimertinib | CLss/F of Savolitinib, Osimertinib and Their Metabolites, (M2 and M3 for Savolitinib; AZ5104 for Osimertinib) | Savolitinib | 38.10 L/h | Geometric Coefficient of Variation 37.54 |
| Savolitinib Plus Osimertinib | CLss/F of Savolitinib, Osimertinib and Their Metabolites, (M2 and M3 for Savolitinib; AZ5104 for Osimertinib) | M2 | 114.1 L/h | Geometric Coefficient of Variation 48.8 |
| Savolitinib Plus Placebo | CLss/F of Savolitinib, Osimertinib and Their Metabolites, (M2 and M3 for Savolitinib; AZ5104 for Osimertinib) | Savolitinib | 25.23 L/h | Geometric Coefficient of Variation 37.56 |
| Savolitinib Plus Placebo | CLss/F of Savolitinib, Osimertinib and Their Metabolites, (M2 and M3 for Savolitinib; AZ5104 for Osimertinib) | M3 | 222.5 L/h | Geometric Coefficient of Variation 42.37 |
| Savolitinib Plus Placebo | CLss/F of Savolitinib, Osimertinib and Their Metabolites, (M2 and M3 for Savolitinib; AZ5104 for Osimertinib) | M2 | 85.32 L/h | Geometric Coefficient of Variation 44.43 |
Secondary
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
Population: All patients with PK data are analysed for savolitinib, osimertinib and their metabolites
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Savolitinib Plus Osimertinib | Cssmax of Savolitinib, Osimertinib and Their Metabolites, (M2 and M3 for Savolitinib; AZ5104 for Osimertinib) | AZ5104 | 51.23 ng/mL | Geometric Coefficient of Variation 70.14 |
| Savolitinib Plus Osimertinib | Cssmax of Savolitinib, Osimertinib and Their Metabolites, (M2 and M3 for Savolitinib; AZ5104 for Osimertinib) | M3 | 129.0 ng/mL | Geometric Coefficient of Variation 34.9 |
| Savolitinib Plus Osimertinib | Cssmax of Savolitinib, Osimertinib and Their Metabolites, (M2 and M3 for Savolitinib; AZ5104 for Osimertinib) | Savolitinib | 1282 ng/mL | Geometric Coefficient of Variation 35.65 |
| Savolitinib Plus Osimertinib | Cssmax of Savolitinib, Osimertinib and Their Metabolites, (M2 and M3 for Savolitinib; AZ5104 for Osimertinib) | M2 | 351.0 ng/mL | Geometric Coefficient of Variation 39.91 |
| Savolitinib Plus Osimertinib | Cssmax of Savolitinib, Osimertinib and Their Metabolites, (M2 and M3 for Savolitinib; AZ5104 for Osimertinib) | Osimertinib | 678.3 ng/mL | Geometric Coefficient of Variation 50.8 |
| Savolitinib Plus Placebo | Cssmax of Savolitinib, Osimertinib and Their Metabolites, (M2 and M3 for Savolitinib; AZ5104 for Osimertinib) | M3 | 213.9 ng/mL | Geometric Coefficient of Variation 36.08 |
| Savolitinib Plus Placebo | Cssmax of Savolitinib, Osimertinib and Their Metabolites, (M2 and M3 for Savolitinib; AZ5104 for Osimertinib) | Savolitinib | 2058 ng/mL | Geometric Coefficient of Variation 32 |
| Savolitinib Plus Placebo | Cssmax of Savolitinib, Osimertinib and Their Metabolites, (M2 and M3 for Savolitinib; AZ5104 for Osimertinib) | M2 | 581.5 ng/mL | Geometric Coefficient of Variation 21.19 |
Secondary
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)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Savolitinib Plus Osimertinib | Duration of Response (DoR) | 30.57 Weeks |
| Savolitinib Plus Placebo | Duration of Response (DoR) | NA Weeks |
Secondary
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)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Savolitinib Plus Osimertinib | Overall Survival (OS) | NA Months |
| Savolitinib Plus Placebo | Overall Survival (OS) | 13.37 Months |
Secondary
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)
Population: Geometric mean ratios provided for three different visit combinations
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Savolitinib Plus Osimertinib | PK Concentration Ratios on Multiple Dosing | C3h Cycle 2 Day 1 / C3h Cycle 1 Day 1 | 0.8812 Geometric mean ratio |
| Savolitinib Plus Osimertinib | PK Concentration Ratios on Multiple Dosing | Cpre-dose Cycle 3 Day 1 / Cpre-dose Cycle 2 Day 1 | 0.8650 Geometric mean ratio |
| Savolitinib Plus Osimertinib | PK Concentration Ratios on Multiple Dosing | Cpre-dose Cycle 6 Day 1 / Cpre-dose Cycle 2 Day 1 | 0.6352 Geometric mean ratio |
| Savolitinib Plus Placebo | PK Concentration Ratios on Multiple Dosing | C3h Cycle 2 Day 1 / C3h Cycle 1 Day 1 | 1.081 Geometric mean ratio |
| Savolitinib Plus Placebo | PK Concentration Ratios on Multiple Dosing | Cpre-dose Cycle 3 Day 1 / Cpre-dose Cycle 2 Day 1 | 1.032 Geometric mean ratio |
| Savolitinib Plus Placebo | PK Concentration Ratios on Multiple Dosing | Cpre-dose Cycle 6 Day 1 / Cpre-dose Cycle 2 Day 1 | 1.068 Geometric mean ratio |
Secondary
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)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Savolitinib Plus Osimertinib | Progression-free Survival (PFS) | 7.36 Months |
| Savolitinib Plus Placebo | Progression-free Survival (PFS) | 1.64 Months |
Secondary
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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Savolitinib Plus Osimertinib | Total Clearance in EGFR Mutations at 6-weeks After Therapy Initiation (Absolute Change From Baseline in EGFR Mutation Allele Frequencies). | -17.4 Allele Frequency | Standard Deviation 17.59 |
| Savolitinib Plus Placebo | Total Clearance in EGFR Mutations at 6-weeks After Therapy Initiation (Absolute Change From Baseline in EGFR Mutation Allele Frequencies). | -2.9 Allele Frequency | Standard Deviation 2.93 |
Secondary
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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Savolitinib Plus Osimertinib | Total Clearance in EGFR Mutations at 6-weeks After Therapy Initiation (Percentage Change From Baseline in EGFR Mutation Allele Frequencies). | -93.6 Allele Frequency | Standard Deviation 11.03 |
| Savolitinib Plus Placebo | Total Clearance in EGFR Mutations at 6-weeks After Therapy Initiation (Percentage Change From Baseline in EGFR Mutation Allele Frequencies). | -62.7 Allele Frequency | Standard Deviation 48.73 |
Secondary
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
Population: All patients with PK data are analysed for savolitinib, osimertinib and their metabolites
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Savolitinib Plus Osimertinib | Tssmax of Savolitinib, Osimertinib and Their Metabolites, (M2 and M3 for Savolitinib; AZ5104 for Osimertinib) | M2 | 3.00 h |
| Savolitinib Plus Osimertinib | Tssmax of Savolitinib, Osimertinib and Their Metabolites, (M2 and M3 for Savolitinib; AZ5104 for Osimertinib) | Osimertinib | 4.00 h |
| Savolitinib Plus Osimertinib | Tssmax of Savolitinib, Osimertinib and Their Metabolites, (M2 and M3 for Savolitinib; AZ5104 for Osimertinib) | AZ5104 | 4.00 h |
| Savolitinib Plus Osimertinib | Tssmax of Savolitinib, Osimertinib and Their Metabolites, (M2 and M3 for Savolitinib; AZ5104 for Osimertinib) | Savolitinib | 3.00 h |
| Savolitinib Plus Osimertinib | Tssmax of Savolitinib, Osimertinib and Their Metabolites, (M2 and M3 for Savolitinib; AZ5104 for Osimertinib) | M3 | 3.00 h |
| Savolitinib Plus Placebo | Tssmax of Savolitinib, Osimertinib and Their Metabolites, (M2 and M3 for Savolitinib; AZ5104 for Osimertinib) | M2 | 1.05 h |
| Savolitinib Plus Placebo | Tssmax of Savolitinib, Osimertinib and Their Metabolites, (M2 and M3 for Savolitinib; AZ5104 for Osimertinib) | Savolitinib | 3.00 h |
| Savolitinib Plus Placebo | Tssmax of Savolitinib, Osimertinib and Their Metabolites, (M2 and M3 for Savolitinib; AZ5104 for Osimertinib) | M3 | 1.05 h |
Secondary
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.
Population: Patients with either a tumour size recorded at 12 weeks or enough information to impute a value.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Savolitinib Plus Osimertinib | Tumour Size Assessment (TSA) | -35.0 Percentage change | Standard Deviation 29.62 |
| Savolitinib Plus Placebo | Tumour Size Assessment (TSA) | 8.5 Percentage change | Standard Deviation 38.95 |