Savolitinib Plus Osimertinib Versus Platinum-based Doublet Chemotherapy in Participants With Non-Small Cell Lung Cancer Who Have Progressed on Osimertinib Treatment

Study Overview
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Brief Summary
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Clinical study to investigate the efficacy and safety of savolitinib in combination with osimertinib versus platinum-based doublet chemotherapy in participants with EGFR mutated, MET-overexpressed and/or amplified, locally advanced or metastatic NSCLC who have progressed on treatment with Osimertinib.

Detailed Description
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This is a multicentre, Phase III, randomised, open-label study to investigate the efficacy and safety of savolitinib administered orally in combination with osimertinib versus platinum-based doublet chemotherapy in participants with EGFR mutated, MET-overexpressed and/or amplified, locally advanced or metastatic NSCLC who have progressed on first- or second-line treatment with osimertinib as the most recent therapy. Approximately 324 participants with EGFR mutated, MET-overexpressed and/or amplified, locally advanced or metastatic NSCLC will be randomly assigned to study intervention with 1:1 ratio. Patients will be treated until either objective progression of disease (PD) by Response Evaluation Criteria in Solid Tumours 1.1 (RECIST 1.1) is assessed by the investigator, unacceptable toxicity occurs, consent is withdrawn, or another discontinuation criterion is met.

Official Title
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A Phase III, Randomised, Open-Label Study of Savolitinib in Combination With Osimertinib Versus Platinum-Based Doublet Chemotherapy in Participants With EGFR Mutated, MET-Overexpressed and/or Amplified, Locally Advanced or Metastatic Non-Small Cell Lung Cancer Who Have Progressed on Treatment With Osimertinib (SAFFRON).

Conditions
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Carcinoma, Non-Small-Cell Lung

Intervention / Treatment
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* Drug: Savolitinib
* Drug: Osimertinib
* Drug: Pemetrexed
* Drug: Cisplatin
* Drug: Carboplatin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Provision of signed and dated written ICF prior to any mandatory and non-mandatory study-specific procedures, sampling and analyses. Participant must be ≥18 years (≥ 20 years of age in Japan) at the time of signing the informed consent. All genders are permitted. Histologically or cytologically confirmed locally advanced or metastatic NSCLC which is not amenable to curative therapy. Must have at least one documented sensitising EGFR mutation: exon19 deletion, L858R mutation, and/or T790M. Documented radiologic progression on first- or second-line treatment with osimertinib as the most recent anti-cancer therapy. Mandatory provision of FFPE tumour tissue. MET overexpression and/or amplification in tumour specimen collected following progression on prior osimertinib treatment. Measurable disease as defined by RECIST 1.1. Adequate haematological, liver, renal and cardiac functions, and coagulation parameters. ECOG performance status of 0 or 1. Exclusion Criteria: Predominant squamous NSCLC, and small cell lung cancer. Prior or current treatment with a third-generation EGFR-TKI other than Osimertinib. Prior or current treatment with savolitinib or another MET inhibitors. Spinal cord compression or brain metastases, unless asymptomatic and are stable. History or active leptomeningeal carcinomatosis. Unresolved toxicities from any prior therapy greater than CTCAE Grade 1 with the exception of alopecia, haemoglobin ≥ 9.0 g/dL, and Grade 2 prior platinum-therapy related neuropathy. Active/unstable cardiac diseases currently or within the last 6 months, clinically significant ECG abnormalities, and/or factors/medications that may affect QTc intervals. History of liver cirrhosis of any origin and clinical stage; or history of other serious liver disease or chronic disease with relevant liver involvement. Known serious active infection including, but not limited to, tuberculosis, or HIV, HBV or HCV or gastrointestinal disease. Receipt of live attenuated vaccine (including against COVID-19) within 30 days prior to the first dose of study intervention. Past medical history of ILD, drug-induced ILD, radiation pneumonitis, which required steroid treatment, or any evidence of clinically active ILD. Participants currently receiving medications or herbal supplements known to be strong inducers of cytochrome P450 (CYP)3A4 or strong inhibitors of CYP1A2.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 130 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Chemotherapy<br>Pemetrexed (500 mg/m2) with either cisplatin (75 mg/m2) or carboplatin (AUC5) on Day 1 of 21-day cycles (Q3W) for 4 cycles, followed by pemetrexed maintenance (500 mg/m2) Q3W | Drug: Pemetrexed<br>* Pemetrexed (500 mg/m2) Administrative route : IV infusion<br>* Other names: NAP;Drug: Cisplatin<br>* Cisplatin (75 mg/m2) or Administrative route : IV infusion<br>* Other names: NAP;Drug: Carboplatin<br>* Carboplatin (AUC5) Administrative route : IV infusion<br>* Other names: NAP;|
| Experimental: Savolitinib + Osimertinib<br>300 mg savolitinib BID plus 80 mg osimertinib QD | Drug: Savolitinib<br>* 300 mg savolitinib (3 × 100 mg tablets twice daily) Administrative route : oral<br>* Other names: AZD6094, HMPL-504, volitinib;Drug: Osimertinib<br>* 80 mg osimertinib (1 × 80 mg tablet once daily) Administrative route : oral<br>* Other names: AZD9291, Tagrisso;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival (PFS) / savolitinib + osimertinib versus platinum doublet chemotherapy in participants with EGFR mutated, MET-overexpressed and/or amplified, locally advanced or metastatic NSCLC who have progressed on osimertinib. | Defined as time from randomisation until progression per RECIST 1.1 as assessed by BICR, or death due to any cause. PFS is assessed by Investigator. | Approximately 55 months post first subject randomized | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) /savolitinib + osimertinib versus platinum doublet chemotherapy in participants with EGFR mutated, MET-overexpressed and/or amplified locally advanced or metastatic NSCLC who have progressed on treatment with osimertinib. | Defined as time from randomisation until the date of death due to any cause. | Approximately 55 months post first subject randomized. | 
| Progression-free survival (PFS) / savolitinib + osimertinib versus platinum doublet chemotherapy in participants with EGFR mutated, MET-overexpressed, locally advanced or metastatic NSCLC who have progressed on treatment with osimertinib. | Defined as time from randomisation until progression per RECIST 1.1 as assessed by BICR, or death due to any cause. PFS is assessed by Investigator. | Approximately 55 months post first subject randomized | 
| Overall Survival (OS) / savolitinib in combination with osimertinib versus platinum doublet chemotherapy in participants with EGFR mutated, MET-overexpressed by IHC, locally advanced or metastatic NSCLC who have progressed on treatment with osimertinib. | Defined as time from randomisation until the date of death due to any cause. | Approximately 55 months post first subject randomized | 
| Objective response rate (ORR) savolitinib + osimertinib versus platinum doublet chemotherapy in participants with EGFR mutated, MET-overexpressed and/or amplified locally advanced or metastatic NSCLC who have progressed on treatment with osimertinib. | ORR defined as the proportion of participants who have BOR of a CR or PR, as determined by BICR per RECIST 1.1. | Approximately 55 months post first subject randomized | 
| Participant-reported pulmonary core symptoms / savolitinib + osimertinib versus platinum doublet chemotherapy in participants with EGFR mutated, MET-overexpressed and/or amplified, locally advanced or metastatic NSCLC who have progressed on osimertinib. | TTD in pulmonary core symptoms (dyspnoea, cough, and chest pain) as measured by the NSCLC-SAQ. TTD is defined as the time from randomisation until the date of deterioration. | Approximately 55 months post first subject randomized | 
| Pharmacokinetics (PK) of savolitinib. | Plasma concentrations of savolitinib and its metabolites. | 6 weeks after last patient dosed | 
| Disease control rate (DCR) / savolitinib + osimertinib versus platinum doublet chemotherapy in participants with EGFR mutated, MET-overexpressed and/or amplified locally advanced or metastatic NSCLC who have progressed on treatment with osimertinib. | DCR defined as the proportion of participants who have BOR of a CR, PR, or stable disease, as determined by BICR per RECIST 1.1. | Approximately 55 months post first subject randomized | 
| Time to discontinuation of treatment (TDT) or death / savolitinib + osimertinib vs platinum doublet chemotherapy in participants with EGFR mutated, MET-overexpressed and/or amplified locally advanced or metastatic NSCLC who have progressed on osimertinib | TDT or death is defined as the time from date of randomisation to the earlier of the date of study intervention discontinuation or death. | Approximately 55 months post first subject randomized | 
| Tumor shrinkage / savolitinib + osimertinib versus platinum doublet chemotherapy in participants with EGFR mutated, MET-overexpressed and/or amplified locally advanced or metastatic NSCLC who have progressed on treatment with osimertinib. | Tumour shrinkage defined as percentage change in tumour size in accordance with RECIST 1.1. | Approximately 55 months post first subject randomized | 
| Duration of response (DoR) / savolitinib + osimertinib versus platinum doublet chemotherapy in participants with EGFR mutated, MET-overexpressed and/or amplified locally advanced or metastatic NSCLC who have progressed on treatment with osimertinib. | DoR defined as the time from the date of first documented response until date of documented progression per RECIST 1.1 as assessed by BICR, or death in the absence of disease progression. | Approximately 55 months post first subject randomized | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Savolitinib, Osimertinib, EGFR, Amplified, Metastatic, MET Driven, carcinoma, NSCLC, overexpressed