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

Phase 3Active Not RecruitingNCT05261399

AstraZeneca345 enrolled

Overview

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.

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Criteria in Solid Tumours 1.1 (RECIST 1.1) is assessed by the investigator, unacceptable toxicity occurs, consent is withdrawn, or another discontinuation criterion is met.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

345

Conditions

Carcinoma Non-Small-Cell Lung

Interventions

SavolitinibDRUG

300 mg savolitinib (3 × 100 mg tablets twice daily) Administrative route : oral

OsimertinibDRUG

80 mg osimertinib (1 × 80 mg tablet once daily) Administrative route : oral

PemetrexedDRUG

Pemetrexed (500 mg/m2) Administrative route : IV infusion

Eligibility

Sex: ALLMin age: 18 YearsMax age: 130 Years

Medical Language ↔ Plain English

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 (≥ 19 years of age in South Korea) 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 and prior platinum-therapy related Grade 2 neuropathies with the exception of alopecia and haemoglobin ≥ 9.0 g/dL. * 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.

Locations (226)

Outcomes

Primary Outcomes

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.

Time frame: Approximately 36.5 months post first subject randomized

Secondary Outcomes

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.

Time frame: Approximately 36.5+18 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.

Time frame: 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.

Time frame: 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.

Data from ClinicalTrials.gov

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Cisplatin (75 mg/m2) Administrative route : IV infusion

CarboplatinDRUG

Carboplatin (AUC5) Administrative route : IV infusion

Research Site

Orlando, Florida, United States

Research Site

Honolulu, Hawaii, United States

Research Site

New Brunswick, New Jersey, United States

Research Site

New York, New York, United States

Research Site

Nashville, Tennessee, United States

Research Site

Buenos Aires, Argentina

Research Site

CABA, Argentina

Research Site

Florida, Argentina

Research Site

La Rioja, Argentina

Research Site

Rosario, Argentina

...and 216 more locations

ORR defined as the proportion of participants who have BOR of a CR or PR, as determined by BICR per RECIST 1.1.

Time frame: Approximately 55 months post first subject randomized

Savolitinib+osimertinib vs platinum doublet chemotherapy in terms of BICR-assessed CNS endpoints in participants with EGFR mutated, MET overexpressed and/or amplified, locally advanced or metastatic NSCLC progressed on treatment with osimertinib

CNS PFS, defined as the time from randomisation until the date of CNS progression assessed per CNS modified RECIST v1.1 by BICR or death.

Time frame: Approximately 55 months post first subject randomized

CNS ORR defined as the proportion of participants who have a BOR in the CNS by BICR assessment.

Time frame: Approximately 55 months post first subject randomized

CNS DoR defined as the time from the date of first documented response in the CNS until the date of objective CNS progression as assessed by BICR or death in the absence of disease progression.

Time frame: 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.

Time frame: Approximately 55 months post first subject randomized

Pharmacokinetics (PK) of savolitinib.

Plasma concentrations of savolitinib and its metabolites.

Time frame: Approximately 36.5 months post first subject randomized

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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: Approximately 55 months post first subject randomized