Osimertinib + Savolitinib for Lung Cancer

(SAVANNAH Trial)

Recruiting at 84 trial locations

Overseen By AstraZeneca Clinical Study Information Center

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: AstraZeneca

Must be taking: Osimertinib

Must not be taking: CYP3A4 inducers, CYP1A2 inhibitors

Disqualifiers: Cardiac diseases, Active infections, Others

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: 2

Duration: Up to 15 months

367 Participants Needed

Trial Summary

What is the purpose of this trial?

This study (the SAVANNAH study) will investigate the efficacy of osimertinib in combination with savolitinib in patients with EGFRm+ and MET+, locally advanced or metastatic NSCLC who have progressed following treatment with osimertinib

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 take medications or supplements that strongly affect certain liver enzymes (CYP3A4 and CYP1A2) within 3 weeks of starting the study. It's best to discuss your current medications with the study team.

What data supports the effectiveness of the drug combination Osimertinib and Savolitinib for lung cancer?

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

What safety data exists for Osimertinib and Savolitinib in humans?

Osimertinib has been studied in humans and is generally well tolerated, but common side effects include diarrhea, rash, dry skin, and nail issues. Some serious side effects occurred in about 28% of patients, and a small percentage stopped treatment due to these effects. No new safety concerns were identified in recent studies. ^{1 2 4 6 7}

What makes the drug combination of Osimertinib and Savolitinib unique for lung cancer treatment?

The combination of Osimertinib and Savolitinib is unique because it targets specific genetic mutations in non-small cell lung cancer (NSCLC). Osimertinib is effective against EGFR mutations, while Savolitinib addresses MET amplification, a common resistance mechanism to Osimertinib. This combination helps overcome resistance and enhances treatment effectiveness. ^{2 3 4 8 9}

Research Team

Lecia V. Sequist

Principal Investigator

Massachusetts General Hospital

Myung-Ju Ahn, MD

Principal Investigator

Samsung Medical Centre Sungkyunkwan University School of Medicine

Eligibility Criteria

Adults with advanced non-small cell lung cancer (NSCLC) that has specific mutations (EGFRm+) and MET amplification/overexpression, who have seen their cancer progress after treatment with osimertinib. They must be in good physical condition, not have severe heart issues or uncontrolled hypertension, and women of childbearing potential must use effective contraception.

Inclusion Criteria

- Obtained within 2 years of submission for MET analysis;

- Sufficient tissue to meet the minimum tissue requirement defined in the current Laboratory Manual.

I can provide a tumor sample for testing or am willing to have one taken.

Exclusion Criteria

I have had a recent heart attack or severe chest pain.

My brain or spinal tumors are stable, cause no symptoms, and I haven't needed steroids for 2 weeks.

I have been treated with a MET inhibitor like savolitinib.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

4 weeks

1 visit (in-person)

Treatment

Participants receive osimertinib in combination with savolitinib or placebo in 28-day cycles until disease progression or unacceptable toxicity

Up to 15 months

Monthly visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

1 visit (in-person)

Treatment Details

Interventions

• Osimertinib
• Savolitinib

Trial Overview The trial is testing the effectiveness of combining two drugs: osimertinib and savolitinib versus a placebo for patients whose NSCLC has worsened despite previous osimertinib treatment. The goal is to see if this combination can help control the disease better.

Participant Groups

Group I: osimertinib + savolitinib Experimental Treatment 2 Interventions

osimertinib + savolitinib

Group II: placebo + savolitinib Placebo Group 2 Interventions

placebo + savolitinib

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

Hutchison Medipharma Limited

Industry Sponsor

Trials

104

Recruited

14,000+

Dr. Weiguo Su

Hutchison Medipharma Limited

Chief Executive Officer since 2022

PhD in Chemistry from Harvard University, BSc in Chemistry from Fudan University

Dr. Karen Atkin

Hutchison Medipharma Limited

Chief Medical Officer since 2023

MD from Harvard Medical School

Hutchison MediPharma

Collaborator

Trials

1

Recruited

370+

Findings from Research

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 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]

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]

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) 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 retrospective analysis of 32 patients with EGFR T790M-mutant non-small-cell lung cancer, osimertinib showed a 50% objective response rate and a median progression-free survival of 11.3 months, indicating its efficacy in clinical practice.

The median overall survival was 18.3 months, with better outcomes observed in patients without cerebral metastases and those with better performance status, highlighting the importance of these factors in treatment response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effectiveness of osimertinib in patients with lung adenocarcinoma in clinical practice - the Expanded Drug Access Program in Poland. Knetki-Wróblewska, M., Kowalski, DM., Czyżewicz, G., et al.[2022]

References

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

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

2. France pubmed.ncbi.nlm.nih.gov

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

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

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

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

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

5. 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]

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. Switzerland pubmed.ncbi.nlm.nih.gov

Effectiveness of osimertinib in patients with lung adenocarcinoma in clinical practice - the Expanded Drug Access Program in Poland. [2022]