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).

Official Summary

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.

Eligibility Requirements

• Minimum Age: 18 Years
• Maximum Age: 130 Years

Study Design

• Study Type: INTERVENTIONAL
• Allocation: RANDOMIZED
• Model: PARALLEL
• Masking: NONE
• Enrollment: 345 participants

Study Arms

• Chemotherapy (ACTIVE_COMPARATOR)
  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
• Savolitinib + Osimertinib (EXPERIMENTAL)
  300 mg savolitinib BID plus 80 mg osimertinib QD

Interventions

• DRUG: Savolitinib — 300 mg savolitinib (3 × 100 mg tablets twice daily) Administrative route : oral
• DRUG: Osimertinib — 80 mg osimertinib (1 × 80 mg tablet once daily) Administrative route : oral
• DRUG: Pemetrexed — Pemetrexed (500 mg/m2) Administrative route : IV infusion
• DRUG: Cisplatin — Cisplatin (75 mg/m2) Administrative route : IV infusion
• DRUG: Carboplatin — Carboplatin (AUC5) Administrative route : IV infusion

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. (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. (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. (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. (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. (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 (Approximately 55 months post first subject randomized)

Eligibility Criteria

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.

Trial Locations

• 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 10 more locations

Study Officials

• Shun Lu, Prof,MD,PhD, — PRINCIPAL_INVESTIGATOR
  Shanghai Chest Hospital, Shanghai JiaoTong University, #241 Huai Hai Road (west), Shanghai, China.

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