Osimertinib Plus Savolitinib in EGFRm+/MET+ NSCLC Following Prior Osimertinib

NCT03778229 | Active Not Recruiting Phase 2 Results DMC FDA Drug

• 2 other identifiers: D5084C000072018-003012-51
• Study Type: interventional
• Target: 367
• Locations: 13 countries
• Sites: 90

Brief Summary

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

Conditions

Carcinoma

Keywords

Non Small Cell Lung Cancer; epidermal growth factor receptor mutation positive; hepatocyte growth factor receptor; savolitinib; Osimertinib; AZD9291; AZD6094; volitinib

Outcome Measures

Primary Outcomes (2)

• Objective Response Rate (ORR) by Investigator Assessment; Target Population Analysis Set

  Percentage of subjects with a confirmed Objective Response (OR) per Response Evaluation Criteria In Solid Tumors (RECIST 1.1). OR includes Complete Response (CR: disappearance of all target lesions) or Partial Response (PR: ≥30% decrease in target lesion diameters). OR must be recorded at one visit and confirmed by repeat imaging at least 4 weeks later, with no disease progression between initial and confirmation visits.

  Time from randomization/first dose of study treatment to progression or last evaluable assessment in the absence of progressionuntil the end of the study, or an approximate maximum of 5.6 years.

• Objective Response Rate (ORR) by Investigator Assessment; 300 mg QD Safety Analysis Set

  Percentage of subjects with a confirmed Objective Response (OR) per Response Evaluation Criteria In Solid Tumors (RECIST 1.1). OR includes Complete Response (CR: disappearance of all target lesions) or Partial Response (PR: ≥30% decrease in target lesion diameters). OR must be recorded at one visit and confirmed by repeat imaging at least 4 weeks later, with no disease progression between initial and confirmation visits.

  Time from randomization/first dose of study treatment to progression or last evaluable assessment in the absence of progression until the end of the study, or an approximate maximum of 5.6 years.

Secondary Outcomes (19)

• Objective Response Rate (ORR) by BICR Assessment; Target Population Analysis Set

  Time from randomization/first dose of study treatment to progression or last evaluable assessment in the absence of progression until the end of the study, or an approximate maximum of 5.6 years.

• Duration of Response (DoR) by Investigator Assessment; Target Population Analysis Set

  From date of first confirmed objective response to progressive disease in accordance with RECIST1.1 or death from any cause, whichever came first; assessed for up to 5.6 years.

• Duration of Response (DoR) by BICR Assessment; Target Population Analysis Set

  From date of first confirmed objective response to progressive disease in accordance with RECIST1.1 or death from any cause, whichever came first; assessed for up to 5.6 years.

• Progression-free Survival (PFS) by Investigator Assessment; Target Population Analysis Set

  Time from randomization/start of study treatment to investigator assess progressive disease per RECIST1.1 or death, assessed for up to 5.6 years.

• Progression-free Survival (PFS) by BICR Assessment; Target Population Analysis Set

  Time from randomization/start of study treatment to BICR assessed progressive disease per RECIST1.1 or death, assessed for up to 5.6 years.

Study Arms (2)

osimertinib + savolitinib

EXPERIMENTAL

osimertinib + savolitinib

Drug: osimertinib; Drug: savolitinib

placebo + savolitinib

PLACEBO COMPARATOR

placebo + savolitinib

Drug: savolitinib; Drug: placebo

Interventions

placebo DRUG

placebo to osimertinib (oral OD)

placebo + savolitinib

osimertinib DRUG

osimertinib (80 mg oral OD).

osimertinib + savolitinib

savolitinib DRUG

savolitinib (300 mg oral OD or 300 mg oral BID or 600 mg oral OD)

osimertinib + savolitinib; placebo + savolitinib

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients must be ≥18 years of age (≥20 years of age in Japan). All genders are permitted.
• Histologically or cytologically confirmed locally advanced or metastatic EGFRm+ NSCLC harbouring an EGFR mutation known to be associated with EGFR TKI sensitivity and permitted in the osimertinib national label (such as either exon 19 deletion and/or L858R) which is not amenable to curative therapy.
• Documented radiologic disease progression on 1L osimertinib.
• MET amplification and/or overexpression (FISH10+ and/or IHC90+) as determined by FISH (central) and IHC (central) testing on tumour sample collected following progression on 1L osimertinib treatment.
• Available tumour sample for central MET FISH and IHC analysis or willingness to collect additional sample for central testing which fulfils the following requirements:
• Obtained following progression on previous osimertinib therapy;
• obtained within 2 years of submission for MET analysis;
• sufficient tissue to meet the minimum tissue requirement defined in the current Laboratory Manual.
• At least 1 lesion, not previously irradiated, not biopsied during the screening period, that can be accurately measured at baseline as ≥10 mm in the longest diameter (except lymph nodes which must have short axis ≥15 mm) with CT or MRI which is suitable for accurate repeated measurements. If only 1 measurable lesion exists, it is acceptable to be used as long as baseline tumour assessment scans are done at least 14 days after the screening tumour sample collection is performed.
• Prior lines of therapy in locally advanced/metastatic setting: Only prior 1L osimertinib treatment in metastatic setting is permitted.
• Adequate haematological function defined as:
• Absolute neutrophil count ≥1500/μL
• Haemoglobin ≥9 g/dL (no transfusion in the past 2 weeks)
• Platelets ≥100,000/μL (no transfusion in the past 10 days)
• Adequate liver function

You may not qualify if:

• Unresolved toxicities from any prior therapy greater than CTCAE Grade 1 at the time of starting study treatment with the exception of alopecia and Grade 2 prior platinum therapy related neuropathy.
• As judged by the investigator, active gastrointestinal disease or other condition that will interfere significantly with the absorption, distribution, metabolism, or excretion of oral therapy (eg, ulcerative disease, uncontrolled nausea, vomiting, diarrhoea Grade ≥2, malabsorption syndrome or previous significant bowel resection).
• Any of the following cardiac diseases currently or within the last 6 months:
• Unstable angina pectoris
• Congestive heart failure (New York Heart Association \[NYHA\] ≥Grade 2)
• Acute myocardial infarction
• Stroke or transient ischemic attack
• Uncontrolled hypertension (blood pressure \[BP\] ≥150/95 mmHg despite medical therapy).
• Mean resting correct QT interval (QTcF) \>470 msec for women and \>450 msec for men at Screening, obtained from 3 ECGs using the screening clinic ECG machine derived QTcF value.
• Any factors that may increase the risk of QTcF prolongation or risk of arrhythmic events such as heart failure, chronic hypokalaemia not correctable with supplements, congenital or familial long QT syndrome, family history of unexplained sudden death under 40 years of age in first-degree relatives or any concomitant medication known to prolong the QT interval and cause Torsade de Pointes.
• Any clinically important abnormalities in rhythm, conduction or morphology of resting ECGs, eg, complete left bundle branch block, third degree heart block, second degree heart block, P-R interval \>250 msec.
• Acute coronary syndrome
• Wide field radiotherapy (including therapeutic radioisotopes such as strontium 89) administered ≤28 days or limited field radiation for palliation ≤7 days prior to starting study drug or has not recovered from side effects of such therapy.
• Major surgical procedures ≤28 days of beginning study drug or minor surgical procedures ≤7 days
• Evidence of severe or uncontrolled systemic diseases, including renal transplant, active bleeding diatheses or uncontrolled hypertension, which in the investigator's opinion makes it undesirable for the patient to participate

Sponsors & Collaborators

• AstraZeneca: lead
• Hutchison Medipharma Limited: collaborator

Study Sites (90)

Research Site

La Jolla, California, 92093, United States

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Los Angeles, California, 90024, United States

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Sacramento, California, 95817, United States

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Washington D.C., District of Columbia, 20016, United States

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Baltimore, Maryland, 21201, United States

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Boston, Massachusetts, 02215, United States

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Rochester, Minnesota, 55905, United States

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Brooklyn, New York, 11220, United States

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Philadelphia, Pennsylvania, 19111, United States

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Pittsburgh, Pennsylvania, 15232, United States

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Seattle, Washington, 98109, United States

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Barretos, 14784-400, Brazil

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Curitiba, 80810-050, Brazil

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Goiânia, 74093-300, Brazil

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Porto Alegre, 90540-140, Brazil

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Porto Alegre, 90610-000, Brazil

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Rio de Janeiro, 22271-110, Brazil

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Salvador, 41950-640, Brazil

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São José do Rio Preto, 15090-000, Brazil

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São Paulo, 01246-000, Brazil

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São Paulo, 01509-900, Brazil

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Calgary, Alberta, T2N 5G2, Canada

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Edmonton, Alberta, T6G 1Z2, Canada

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Newmarket, Ontario, L3Y 2P9, Canada

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North York, Ontario, M2K 1E1, Canada

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Toronto, Ontario, M4N 3M5, Canada

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Toronto, Ontario, M5G 2M9, Canada

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Santiago, 7500713, Chile

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Santiago, 7520349, Chile

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Santiago, 8420383, Chile

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Aalborg, 9100, Denmark

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Herlev, 2730, Denmark

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København Ø, 2100, Denmark

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Næstved, 4700, Denmark

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Odense, 5000, Denmark

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Vejle, 7100, Denmark

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Dijon, 21079, France

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Marseille, 13915, France

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Nantes, 44093, France

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Paris, 75020, France

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Paris, 75248, France

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Rennes, 35033, France

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Bangalore, 560064, India

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Chennai, 600035, India

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Kolkata, 700160, India

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New Delhi, 110085, India

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Avellino, 83100, Italy

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Florence, 50134, Italy

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Milan, 20133, Italy

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Milan, 20141, Italy

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Orbassano, 10043, Italy

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Padova, 35128, Italy

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Parma, 43126, Italy

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Perugia, 06132, Italy

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Peschiera del Garda, 37019, Italy

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Fukuoka, 812-8582, Japan

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Hiroshima, 730-8518, Japan

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Kanazawa, 920-8641, Japan

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Nagoya, 464-8681, Japan

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Niigata, 951-8566, Japan

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Sapporo, 003-0804, Japan

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Sayama, 589-8511, Japan

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Sunto-gun, 411-8777, Japan

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Wakayama, 641-8510, Japan

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Yokohama, 241-0815, Japan

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Goyang-si, 10408, South Korea

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Seongnam-si, 13620, South Korea

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Seoul, 03080, South Korea

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Seoul, 03722, South Korea

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Seoul, 05505, South Korea

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Seoul, 06351, South Korea

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Suwon, 16247, South Korea

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Córdoba, 14004, Spain

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Donostia / San Sebastian, 20014, Spain

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Madrid, 28041, Spain

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Madrid, 28046, Spain

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Málaga, 29010, Spain

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Valencia, 46026, Spain

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Zaragoza, 50009, Spain

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Hsinchu, 300, Taiwan

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Kaohsiung City, 83301, Taiwan

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New Taipei City, 23561, Taiwan

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Taichung, 402, Taiwan

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Taichung, 40705, Taiwan

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Tainan, 70403, Taiwan

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Taipei, 10002, Taiwan

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Taipei, 112, Taiwan

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Taoyuan District, 333, Taiwan

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Hà Nội, 100000, Vietnam

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Ho Chi Minh City, 700000, Vietnam

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Related Publications (2)

• Yang JC, Chen YM, Batra U, Do KH, Sitthideatphaiboon P, Danchaivijitr P, Lee KY, Chindaprasirt J, Yang CT, Chang GC, Charoentum C, Ungtrakul T, Moran JIH, Hartmaier R, Igwegbe I, Gont A, Haskins M, Xu W, Riess JW. Savolitinib Plus Osimertinib in Epidermal Growth Factor Receptor-Mutated, MET-Amplified Advanced Non-Small Cell Lung Cancer: A Randomized Phase II trial. Clin Lung Cancer. 2026 Jan;27(1):38-46. doi: 10.1016/j.cllc.2025.10.018. Epub 2025 Oct 22.

  PMID: 41308232 DERIVED

• Schmid S, Fruh M, Peters S. Targeting MET in EGFR resistance in non-small-cell lung cancer-ready for daily practice? Lancet Oncol. 2020 Mar;21(3):320-322. doi: 10.1016/S1470-2045(19)30859-9. Epub 2020 Feb 3. No abstract available.

  PMID: 32027845 DERIVED

Related Links

• Redacted Statistical Analysis Plan (SAP)
• Redacted CSR Synopsis
• Redacted CSP

MeSH Terms

Conditions

Carcinoma; Carcinoma, Non-Small-Cell Lung

Interventions

osimertinib; 1-(1-(imidazo(1,2-a)pyridin-6-yl)ethyl)-6-(1-methyl-1H-pyrazol-4-yl)-1H-(1,2,3)triazolo(4,5-b)pyrazine

Condition Hierarchy (Ancestors)

Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Lung Diseases; Respiratory Tract Diseases

Limitations and Caveats

No limitations or caveats were identified in this analysis.

Results Point of Contact

• Title: Global Clinical Lead
• Organization: AstraZeneca

information.center@astrazeneca.com

1-877-240-9479

Study Officials

• Lecia V Sequist, MD MPH

  Massachusetts General Hospital

  PRINCIPAL INVESTIGATOR

• Myung-Ju Ahn, MD

  Samsung Medical Centre Sungkyunkwan University School of Medicine

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: Under Protocol versions 1-6 the study model was single arm (open-label). Starting protocol version 7 patients will be randomised in a double blinded manner to receive savolitinib in combination with osimertinib or savolitinib with placebo to osimertinib with crossover option upon disease progression assessed by Investigator.

Study Record Dates

• First Submitted: November 30, 2018
• First Posted: December 19, 2018
• Study Start: January 9, 2019
• Primary Completion: August 23, 2024
• Study Completion (Estimated): December 31, 2026
• Last Updated: April 23, 2026
• Results First Posted: February 10, 2026

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP
• Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• Access Criteria: When a request has been approved AstraZeneca will provide access to the de-identified individual patient-level data in an approved sponsored tool. Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

Locations

ES (7); CL (3); FR (6); IT (9); KR (7); VN (2); DK (6); JP (10); BR (10); CA (6); IN (4); US (11); TW (9)