| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| EGFR Mutated, MET-Overexpressed and/or Amplified, Locally Advanced or Metastatic Non-Small Cell Lung Cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
| Non-Small Cell Lung Cancer |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10029514 |
| E.1.2 | Term | Non-small cell lung cancer NOS |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To determine the efficacy of savolitinib in combination with osimertinib versus platinum doublet chemotherapy by assessment of PFS in participants with EGFR mutated, MET-overexpressed and/or amplified, locally advanced or metastatic NSCLC who have progressed on treatment with osimertinib. |
|
| E.2.2 | Secondary objectives of the trial |
To determine the efficacy of savolitinib in combination with osimertinib versus platinum doublet chemotherapy by assessment of:
1) OS (MET-overexpressed and/or amplified)
2) PFS by BICR (MET-overexpressed by IHC)
3) OS (MET-overexpressed by IHC)
4) PFS by Investigator (MET-overexpressed and/or amplified)
5) ORR, DoR, DCR, TDT or death, and tumour shrinkage, (MET-overexpressed and/or amplified).
6) To assess participant-reported pulmonary core symptoms of NSCLC.
7) To evaluate the PK of savolitinib.
8) To evaluate the safety and tolerability of savolitinib in combination with osimertinib versus platinum doublet chemotherapy. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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. |
|
| E.4 | Principal exclusion criteria |
- 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. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
PFS as defined as time from randomisation until progression per RECIST 1.1 as assessed by BICR, or death due to any cause in participants with centrally confirmed MET IHC+ and/or MET FISH+ status (FAS).
The comparison will include all randomised participants, as
randomised, regardless of whether the participant withdraws from randomised therapy, receives another anti-cancer therapy, or clinically progresses prior to RECIST 1.1 progression. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Approximately 55 months post first subject randomized. |
|
| E.5.2 | Secondary end point(s) |
1) Overall survival defined as time from randomisation until the date of death due to any cause.
2) Progression-free survival defined as time from randomisation until progression per RECIST 1.1 as assessed by BICR, or death due to any cause in centrally confirmed MET IHC+ population of FAS (FAS-IHC+).
3) Overall survival defined as time from randomisation until the date of death due to any cause in FAS-IHC+.
4) Progression-free survival defined as time from randomization until progression per RECIST 1.1 as assessed by investigator, or death due to any cause in centrally confirmed MET IHC+ population of FAS (FAS-IHC+).
5)
-Objective response rate will be based on BOR defined as the proportion of participants who have BOR of a CR or PR, as determined by BICR per RECIST 1.1.
-Duration of response 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.
-Disease control rate 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 to discontinuation of treatment or death is defined as the time from date of randomisation to the earlier of the date of study intervention discontinuation (i.e., discontinuation of the last study intervention in the combination) or death.
-Tumour shrinkage defined as percentage change in tumour size in accordance with RECIST 1.1.
6)
-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.
7) Plasma concentrations of savolitinib and its metabolites in the PK Analysis Set.
8) Safety and tolerability will be evaluated in terms of AEs, SAEs, discontinuation rate due to AEs and deaths; clinical chemistry/haematology including LFTs; ECHOs/MUGAs, ECGs, ECOG performance status and vital signs in the Safety Analysis Set. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1) to 5) and 7) Approximately 55 months post first subject randomized.
6) 6 weeks after last patient dosed. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| The tolerability, resistance and sensitivity to treatment. |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| pemetrexed, cisplatin, carboplatin |
|
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 8 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 65 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Argentina |
| Chile |
| Switzerland |
| Taiwan |
| Australia |
| Austria |
| Belgium |
| Brazil |
| Bulgaria |
| Canada |
| China |
| Denmark |
| France |
| Germany |
| Greece |
| Israel |
| Italy |
| Japan |
| Korea, Republic of |
| Poland |
| Russian Federation |
| Spain |
| Thailand |
| Turkey |
| United Kingdom |
| United States |
| Viet Nam |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
The end of the study is defined as the last expected visit/contact of the last participant
undergoing the study including overall survival (OS). |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 4 |
| E.8.9.1 | In the Member State concerned days | 12 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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