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toxicity occurs, consent is withdrawn, or another discontinuation criterion is met.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.
- 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.
- 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
- Any clinically important abnormalities in rhythm, conduction or morphology of
- 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.