Savolitinib + Osimertinib for Non-Small Cell Lung Cancer

(SAFFRON Trial)

Recruiting at 323 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new combination treatment for individuals with non-small cell lung cancer (NSCLC) that has specific genetic changes and has worsened after initial treatment. The study compares the effectiveness and safety of the drugs savolitinib (Orpathys) and osimertinib (Tagrisso) together against standard chemotherapy. It targets patients with specific EGFR mutations and MET overexpression, who have already tried osimertinib without success. Those with non-squamous NSCLC who have seen their condition worsen on osimertinib might be suitable candidates. As a Phase 3 trial, this treatment represents the final step before FDA approval, offering access to potentially groundbreaking therapy.

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).

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that combining savolitinib and osimertinib is generally safe for people. Studies have found that the benefits of using these drugs together can outweigh the risks for many patients, despite potential side effects.

In earlier research with patients who have certain mutations in their lung cancer, this drug pair showed promising results in slowing cancer growth. While new treatments always carry some risks, current evidence suggests that this combination is safe enough for further testing in patients.

In simple terms, the treatment appears safe for people, but like any medication, it may cause some side effects. These findings provide a strong basis for continuing to test this combination in more people. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of savolitinib and osimertinib for non-small cell lung cancer because it targets a unique mechanism that sets it apart from standard treatments like chemotherapy with pemetrexed and platinum-based drugs. Savolitinib is a selective MET inhibitor, which means it specifically blocks the MET receptor, a common culprit in cancer cell growth and spread. When paired with osimertinib, a third-generation EGFR inhibitor, this combination not only tackles the EGFR mutation but also addresses MET-driven resistance, offering a double punch against the cancer. This dual action could lead to more effective and longer-lasting responses than current chemotherapy options.

What evidence suggests that the combination of savolitinib and osimertinib could be effective for non-small cell lung cancer?

Research has shown that using savolitinib with osimertinib, which participants in this trial may receive, is promising for treating non-small cell lung cancer (NSCLC) with certain genetic changes. Studies have found that this combination leads to significant and lasting improvements in patients with NSCLC that has mutations in the EGFR gene. Patients in early studies experienced meaningful benefits, indicating that the treatment effectively targets cancer. Additionally, this combination has successfully managed cancer that has spread to the brain. Overall, evidence suggests that this treatment could be effective for patients whose cancer has specific genetic markers and has worsened after previous osimertinib treatment. Meanwhile, another arm of this trial will involve chemotherapy with pemetrexed and either cisplatin or carboplatin. ^{1 3 4 6 7}

Who Is on the Research Team?

Shun Lu, Prof,MD,PhD,

Principal Investigator

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

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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

Published Research Related to This Trial

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]

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]

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 (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 (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]

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]

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]

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]

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 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 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]

Citations

1.

pubmed.ncbi.nlm.nih.gov

pubmed.ncbi.nlm.nih.gov/40461383/

mutated advanced non-small cell lung cancer with MET ...

Savolitinib 300 mg b.i.d. plus osimertinib demonstrated high, clinically meaningful and durable responses in patients with EGFR-mutated, ...

2.

ascopubs.org

ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.8513

Efficacy and CNS results from a randomized subset of the ...

Efficacy and CNS results from a randomized subset of the phase 2 SAVANNAH study comparing savolitinib (savo) + osimertinib (osi) combination ...

3.

hutch-med.com

hutch-med.com/sanovo-phiii-enrollment-completion/

HUTCHMED Completes Patient Enrollment of SANOVO ...

This Phase III trial is a blinded, randomized, controlled study in previously untreated patients with locally advanced or metastatic NSCLC with ...

4.

clinicaltrials.gov

clinicaltrials.gov/study/NCT05261399

Study Details | NCT05261399 | Savolitinib Plus Osimertinib ...

Clinical study to investigate the efficacy and safety of savolitinib in combination with osimertinib versus platinum-based doublet chemotherapy in ...

5.

astrazeneca-us.com

astrazeneca-us.com/media/press-releases/2025/New-study-results-reinforce-TAGRISSO-osimertinib-as-the-backbone-therapy-for-EGFR-mutated-lung-cancer-across-stages-and-settings.html

New study results reinforce TAGRISSO® (osimertinib) as ...

In LAURA Phase III trial, TAGRISSO continues to demonstrate improved overall survival trend in unresectable, Stage III setting.

6.

pubmed.ncbi.nlm.nih.gov

pubmed.ncbi.nlm.nih.gov/32027846/

Osimertinib plus savolitinib in patients with EGFR mutation- ...

The combination of osimertinib and savolitinib has acceptable risk-benefit profile and encouraging antitumour activity in patients with MET-amplified, EGFR ...

7.

annalsofoncology.org

annalsofoncology.org/article/S0923-7534(25)00157-7/fulltext

Savolitinib plus osimertinib in epidermal growth factor ...

Savolitinib + osimertinib had activity in MET overexpressed/amplified EGFR-mutated NSCLC after progression on osimertinib.