Savolitinib + Osimertinib for Non-Small Cell Lung Cancer

(SAFFRON Trial)

Recruiting at 277 trial locations

Overseen By AstraZeneca Lung Cancer Study Locator Service

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: AstraZeneca

Must be taking: Osimertinib

Must not be taking: MET inhibitors, CYP3A4 inducers

Disqualifiers: Squamous NSCLC, Brain metastases, Cardiac diseases, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: 3

Duration: Until disease progression or unacceptable toxicity

324 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial is testing a new drug combination for lung cancer patients whose previous treatment didn't work. The new drugs aim to block two pathways that help cancer grow, potentially making the treatment more effective.

Will I have to stop taking my current medications?

The trial does not specify if you must stop taking your current medications, but you cannot participate if you are taking medications or supplements that strongly affect certain liver enzymes (CYP3A4 or CYP1A2).

What data supports the effectiveness of the drug combination Savolitinib and Osimertinib for non-small cell lung cancer?

Research shows that the combination of Savolitinib and Osimertinib is effective in treating non-small cell lung cancer, as demonstrated in a phase Ib trial. Additionally, Osimertinib alone has been shown to significantly prolong progression-free survival in patients with specific genetic mutations in non-small cell lung cancer. ^{1 2 3 4 5}

Is the combination of Savolitinib and Osimertinib safe for humans?

Osimertinib, used in combination with Savolitinib, has been studied for non-small cell lung cancer and is generally well tolerated with a manageable safety profile. Common side effects include diarrhea, rash, dry skin, and nail issues, with more severe side effects occurring in a smaller percentage of patients. ^{1 4 5 6 7}

How is the drug combination of Savolitinib and Osimertinib unique for treating non-small cell lung cancer?

The combination of Savolitinib and Osimertinib is unique because it targets both EGFR mutations and MET amplification, which is a common resistance mechanism to Osimertinib alone. This dual approach helps overcome resistance and enhances the effectiveness of treatment in non-small cell lung cancer. ^{1 8 9 10 11}

Research Team

Shun Lu, Prof,MD,PhD,

Principal Investigator

Shanghai Chest Hospital, Shanghai JiaoTong University, #241 Huai Hai Road (west), Shanghai, China.

Eligibility Criteria

This trial is for adults with advanced non-small cell lung cancer (NSCLC) that has worsened despite osimertinib treatment. Participants must have a specific EGFR mutation, MET overexpression/amplification, and be in good physical condition (ECOG 0 or 1). They cannot join if they have brain metastases, heart issues, liver cirrhosis, prior MET inhibitor use, serious infections like HIV/HBV/HCV, or recent live vaccines.

Inclusion Criteria

My lung cancer cannot be cured with surgery or radiation.

Provision of signed and dated written ICF prior to any mandatory and non-mandatory study-specific procedures, sampling and analyses

My cancer showed MET overexpression after treatment with osimertinib.

Exclusion Criteria

I have or had cancer spread to the lining of my brain and spinal cord.

I am not taking strong drugs or supplements that affect liver enzymes.

My brain or spinal tumors are stable and not causing symptoms.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either savolitinib in combination with osimertinib or platinum-based doublet chemotherapy

Until disease progression or unacceptable toxicity

Every 3 weeks for chemotherapy group

Follow-up

Participants are monitored for safety and effectiveness after treatment

Approximately 55 months

Open-label extension (optional)

Participants may opt into continuation of treatment long-term

Long-term

Treatment Details

Interventions

• Carboplatin
• Cisplatin
• Osimertinib
• Pemetrexed
• Savolitinib

Trial Overview The study compares the effectiveness of savolitinib combined with osimertinib against standard platinum-based chemotherapy in treating NSCLC after osimertinib failure. It aims to determine which treatment is safer and works better for patients who meet certain genetic criteria.

Participant Groups

Group I: Savolitinib + Osimertinib Experimental Treatment 2 Interventions

300 mg savolitinib BID plus 80 mg osimertinib QD

Group II: Chemotherapy Active Control 3 Interventions

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

Osimertinib is already approved in United States, European Union for the following indications:

Approved in United States as Tagrisso for:

• Locally advanced or metastatic non-small-cell lung cancer (NSCLC) with EGFR exon 19 deletions or exon 21 L858R mutations
• Metastatic EGFR T790M mutation-positive NSCLC

Approved in European Union as Tagrisso for:

• Locally advanced or metastatic non-small-cell lung cancer (NSCLC) with EGFR exon 19 deletions or exon 21 L858R mutations
• Metastatic EGFR T790M mutation-positive NSCLC

Who Is Running the Clinical Trial?

AstraZeneca

Lead Sponsor

Trials

4,491

Recruited

290,540,000+

Sir Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Dr. Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Medical Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

Findings from Research

In a phase Ib trial, the combination of osimertinib and savolitinib demonstrated effectiveness in treating non-small cell lung cancer, suggesting a potential new treatment strategy.

This trial indicates that combining these two targeted therapies may enhance treatment outcomes for patients with this type of lung cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Non-Small Cell Lung Cancer Responds to Osimertinib plus Savolitinib. [2022]

Osimertinib is a third-generation EGFR tyrosine kinase inhibitor that effectively targets specific mutations in advanced non-small cell lung cancer (NSCLC), including the T790M mutation, leading to significantly longer progression-free survival compared to first-generation EGFR TKIs like erlotinib or gefitinib.

The benefits of osimertinib in prolonging progression-free survival were consistent across all patient groups, regardless of the type of EGFR mutation or the presence of CNS metastases, and it has a generally manageable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Osimertinib as first-line therapy in advanced NSCLC: a profile of its use. Scott, LJ.[2020]

Osimertinib is a third-generation EGFR tyrosine kinase inhibitor specifically designed to target the EGFR T790M mutation, which is a common cause of resistance to first-line EGFR TKIs in advanced non-small-cell lung cancer.

This review highlights the efficacy of osimertinib in clinical trials, demonstrating its ability to effectively treat patients with non-small-cell lung cancer harboring the T790M mutation while minimizing effects on normal EGFR.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Osimertinib making a breakthrough in lung cancer targeted therapy. Zhang, H.[2020]

Osimertinib (Tagrisso) is a targeted therapy approved by the FDA for patients with metastatic non-small cell lung cancer (NSCLC) who have the EGFR T790M mutation and have progressed after previous treatments.

The drug received special designations from the FDA, including breakthrough therapy and priority review, highlighting its significance in treating resistant forms of NSCLC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeting the Gatekeeper: Osimertinib in EGFR T790M Mutation-Positive Non-Small Cell Lung Cancer. Skoulidis, F., Papadimitrakopoulou, VA.[2022]

Osimertinib significantly improves disease-free survival (DFS) in adults with completely resected, early-stage EGFR mutation-positive non-small cell lung cancer (NSCLC), as shown in the pivotal ADAURA trial, regardless of prior adjuvant chemotherapy.

The treatment is well tolerated with a manageable safety profile, and it does not negatively impact health-related quality of life, making it a suitable option for adjuvant therapy in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Osimertinib: A Review in Completely Resected, Early-Stage, EGFR Mutation-Positive NSCLC. Frampton, JE.[2022]

Osimertinib (TAGRISSO) received accelerated FDA approval for treating metastatic non-small cell lung cancer with the EGFR T790M mutation, showing significant tumor response rates of 57% and 61% in two major trials involving 411 patients.

While osimertinib demonstrated promising efficacy, common side effects included diarrhea (42%) and rash (41%), with 28% of patients experiencing severe adverse events, highlighting the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Osimertinib for the Treatment of Metastatic EGFR T790M Mutation-Positive Non-Small Cell Lung Cancer. Khozin, S., Weinstock, C., Blumenthal, GM., et al.[2022]

Osimertinib (Tagrisso) is an approved adjuvant treatment for non-small cell lung cancer patients with specific tumor mutations, highlighting its targeted therapeutic approach.

Common side effects of osimertinib include blood-related issues like leukopenia and thrombocytopenia, as well as gastrointestinal and skin reactions, indicating the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New Adjuvant Drug for Lung Cancer. Aschenbrenner, DS.[2023]

In a patient-derived xenograft mouse model of EGFR mutation-positive non-small cell lung cancer, the combination of osimertinib and savolitinib showed significant antitumor activity, with savolitinib achieving up to 84% tumor regression when combined with a fixed dose of osimertinib.

Savolitinib alone demonstrated substantial antitumor effects, while osimertinib alone had minimal impact, highlighting the potential of savolitinib to overcome resistance mechanisms associated with MET amplification in NSCLC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetic/Pharmacodynamic Analysis of Savolitinib plus Osimertinib in an EGFR Mutation-Positive, MET-Amplified Non-Small Cell Lung Cancer Model. Jones, RDO., Petersson, K., Tabatabai, A., et al.[2023]

In a study of 46 treatment-naive patients with EGFR-mutated advanced non-small cell lung cancer, alternating therapy with osimertinib and afatinib resulted in a median progression-free survival of 21.3 months, indicating promising efficacy despite not meeting the primary endpoint of 12-month progression-free survival probability.

The treatment was generally well-tolerated, with common side effects including diarrhea (73.9%) and rash (63.0%), and only a few cases of serious pneumonitis, suggesting a manageable safety profile for this alternating therapy approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Alternating therapy with osimertinib and afatinib for treatment-naive patients with EGFR-mutated advanced non-small cell lung cancer: A single-group, open-label phase 2 trial (WJOG10818L). Hayashi, H., Yonesaka, K., Nakamura, A., et al.[2022]

In a study of 94 patients with advanced non-small-cell lung cancer (NSCLC) who had previously been treated, osimertinib showed a 47.3% overall objective response rate and a 90.1% disease control rate, indicating its effectiveness in this population.

Patients with the T790M mutation experienced significantly longer progression-free survival (PFS) compared to those without the mutation, highlighting osimertinib's targeted efficacy, especially in those with specific genetic profiles.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-World Data Of Osimertinib In Patients With Pretreated Non-Small Cell Lung Cancer: A Retrospective Study. Mu, Y., Xing, P., Hao, X., et al.[2022]

The combination of osimertinib with selumetinib or savolitinib showed a promising objective response rate of around 42-44% in patients with advanced EGFR-mutant non-small-cell lung cancer, indicating potential efficacy of these combinations.

However, combining osimertinib with durvalumab was not feasible due to a higher incidence of interstitial lung disease, highlighting safety concerns with this particular combination.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

TATTON: a multi-arm, phase Ib trial of osimertinib combined with selumetinib, savolitinib, or durvalumab in EGFR-mutant lung cancer. Oxnard, GR., Yang, JC., Yu, H., et al.[2022]

References

1. United States pubmed.ncbi.nlm.nih.gov

Non-Small Cell Lung Cancer Responds to Osimertinib plus Savolitinib. [2022]

2. New Zealand pubmed.ncbi.nlm.nih.gov

Osimertinib as first-line therapy in advanced NSCLC: a profile of its use. [2020]

3. New Zealand pubmed.ncbi.nlm.nih.gov

Osimertinib making a breakthrough in lung cancer targeted therapy. [2020]

4. United States pubmed.ncbi.nlm.nih.gov

Targeting the Gatekeeper: Osimertinib in EGFR T790M Mutation-Positive Non-Small Cell Lung Cancer. [2022]

5. France pubmed.ncbi.nlm.nih.gov

Osimertinib: A Review in Completely Resected, Early-Stage, EGFR Mutation-Positive NSCLC. [2022]

6. United States pubmed.ncbi.nlm.nih.gov

Osimertinib for the Treatment of Metastatic EGFR T790M Mutation-Positive Non-Small Cell Lung Cancer. [2022]

7. United States pubmed.ncbi.nlm.nih.gov

New Adjuvant Drug for Lung Cancer. [2023]

8. United States pubmed.ncbi.nlm.nih.gov

Pharmacokinetic/Pharmacodynamic Analysis of Savolitinib plus Osimertinib in an EGFR Mutation-Positive, MET-Amplified Non-Small Cell Lung Cancer Model. [2023]

9. Ireland pubmed.ncbi.nlm.nih.gov

Alternating therapy with osimertinib and afatinib for treatment-naive patients with EGFR-mutated advanced non-small cell lung cancer: A single-group, open-label phase 2 trial (WJOG10818L). [2022]

10. New Zealand pubmed.ncbi.nlm.nih.gov

Real-World Data Of Osimertinib In Patients With Pretreated Non-Small Cell Lung Cancer: A Retrospective Study. [2022]

11. England pubmed.ncbi.nlm.nih.gov

TATTON: a multi-arm, phase Ib trial of osimertinib combined with selumetinib, savolitinib, or durvalumab in EGFR-mutant lung cancer. [2022]