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Osimertinib and Gefitinib in Treating Patients with EGFR Mutant Stage IV Non-small Cell Lung cancer

Trial Status: Active

This randomized phase I / II trial studies the side effects and best dose of osimertinib when given together with gefitinib in treating patients with EGFR mutant stage IV non-small cell lung cancer. Osimertinib and gefitinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Inclusion Criteria

  • Participants must have histologically confirmed stage IV NSCLC (per American Joint Committee on Cancer [AJCC] 7th edition) with either the L858R or exon 19 deletion activating EGFR mutation as identified in a Clinical Laboratory Improvement Act (CLIA)-approved laboratory * Note: recurrent stage IV disease initially diagnosed at an earlier stage is considered eligible, provided prior treatment criteria is met
  • Participants must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as >= 20 mm with conventional techniques or as >= 10 mm with spiral computed tomography (CT) scan, magnetic resonance imaging (MRI), or calipers by clinical exam
  • Participants can have no prior history of any EGFR-directed therapy, including tyrosine kinase inhibitors (TKIs) or antibodies, and must also be chemotherapy and immunotherapy naive; patients who have completed adjuvant or neo-adjuvant chemotherapy or immunotherapy > 6 months ago are considered treatment naive
  • Participants must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
  • Participants must have a life expectancy of greater than 12 weeks
  • Leukocytes >= 3,000/mcL
  • Absolute neutrophil count >= 1,500/mcL
  • Platelets >= 100,000/mcL
  • Hemoglobin > 9.0 g/dL
  • Total bilirubin < 1.5 times the upper limit of normal (ULN) if no liver metastases or < 3 times the ULN in the presence of documented Gilbert’s syndrome (unconjugated hyperbilirubinemia) or liver metastases
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) < 2.5 x institutional upper limit of normal or < 5 times the ULN in the presence of liver metastases
  • Creatinine within upper normal institutional limit OR creatinine clearance >= 50 mL/min/1.73 m^2 for participants with creatinine levels above institutional normal
  • Participants should have biopsy tissue at time of diagnosis available for next-generation sequencing testing at the Dana-Farber Cancer Institute; biopsy can be performed at an outside institution as long as sufficient tissue is available; if next generation sequencing has already been performed prior to study enrollment it does not need to be repeated * Note: Cytology specimen may be acceptable for baseline next generation sequencing (NGS) if tumor cellular content is sufficient and following PI approval. If there is no cytology specimen or tissue sample available for NGS, plasma-based NGS may be acceptable for enrollment following discussion with principal investigator (PI)
  • Participants must be >= 4 weeks since any major surgery (excluding vascular access placement, mediastinoscopy, or biopsies performed by an interventional service)
  • Participants must be >= 2 weeks since any prior radiation, including central nervous system (CNS) radiation
  • Male patients: Willing to use adequate contraception (barrier or abstinence) while on treatment with study drug and for 3 months after finishing treatment
  • Female patients: Willing to use adequate contraception (barrier or abstinence) while on treatment with study drug and for 3 months after finishing treatment
  • Female patients: Must not be pregnant or breast-feeding; women of child-bearing potential must have a negative pregnancy test prior to start of dosing or must have evidence of non-child-bearing potential by fulfilling one of the following criteria at screening: * Post-menopausal defined as aged more than 50 years and amenorrheic for at least 12 months following cessation of all exogenous hormonal treatments * Women under 50 years are considered postmenopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and with luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels in the post-menopausal range for the institution * Documentation of irreversible surgical sterilization by hysterectomy, bilateral oophorectomy, or bilateral salpingectomy but not tubal ligation
  • Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria

  • Prior or ongoing treatment with any of the following: * EGFR targeted therapy (TKI or antibody) or any other targeted therapies targeting the ERBB family * Any cytotoxic chemotherapy, investigational agents, or anticancer drugs for the treatment of metastatic NSCLC
  • Prior radiotherapy within 2 weeks of the first dose of study treatment; patients who have received radiation to more than 25% of the bone marrow are not eligible at any time
  • No uncontrolled central nervous system (CNS) disease, including parenchymal brain metastases, leptomeningeal disease, or spinal cord compression; patients with asymptomatic untreated brain metastases are eligible; patients with treated CNS disease will be allowed to enroll provided they have clinically confirmed stable disease with >= 2 weeks since definitive CNS therapy (radiation or surgery) and >= 2 weeks without systemic steroids; patients may undergo either whole brain radiation or stereotactic radiosurgery prior to study entry
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to gefitinib or osimertinib
  • Patients currently receiving (or unable to stop use prior to receiving the first dose of study treatment) medications or herbal supplements known to be strong inducers of CYP3A4; all patients must try to avoid concomitant use of any medications, herbal supplements and/or ingestion of foods with known inducer effects on CYP3A4
  • Any unresolved toxicities from prior therapy greater than Common Terminology Criteria for Adverse Events (CTCAE) grade 1 at the time of starting study treatment
  • Malignancies within the past 3 years excluding adequately treated basal or squamous cell carcinomas of the skin without local or distant metastases
  • Refractory nausea and vomiting, chronic gastrointestinal diseases, previous significant bowel resection, or any process that compromises the ability to swallow or absorb oral medication
  • Significant medical history or unstable medical comorbidities, including: * Heart disease including congestive heart failure (New York Heart Association [NYHA] grade II or greater); unstable angina; prior myocardial infarction (non-ST elevation myocardial infarction [NSTEMI] or ST elevation myocardial infarction [STEMI]) within 6 months prior to study enrollment; hypertension with a systolic blood pressure of > 150 mm Hg or diastolic blood pressure of > 100 mm Hg while on antihypertensive medication * Any clinically important abnormalities in rhythm, conduction or morphology of resting electrocardiogram (ECG), e.g. complete left bundle branch block, third-degree heart block, second-degree heart block, PR interval > 250 msec, mean resting corrected QT value (QTc) of > 470 msec * Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first degree relatives, or any concomitant medication known to the prolong the QT interval that a patient is unable to stop * Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis which required steroid treatment, or any evidence of clinically active interstitial lung disease * Active bleeding diatheses, which in the investigator’s opinion makes it undesirable for the patient to participate in the trial or which would jeopardize compliance with the protocol * Active infection or ongoing antiviral medication for viral infections including hepatitis B, hepatitis C, or human immunodeficiency virus (HIV); screening for chronic conditions is not required; HIV-positive participants on combination antiretroviral therapy are ineligible
  • Known to be T790M+ (on pre-treatment tumor or plasma) or known germline T790M
  • Active pregnancy or breast-feeding; pregnant women are excluded from this study because the effects of gefitinib and osimertinib on the development of the fetus are unknown, and there is potential for teratogenic or abortifacient effects; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with gefitinib or osimertinib, breastfeeding should be discontinued if the mother is treated with these agents


Beth Israel Deaconess Medical Center
Status: ACTIVE
Contact: Daniel Botelho Costa
Phone: 617-667-9236
Brigham and Women's Hospital
Status: ACTIVE
Contact: Pasi Antero Janne
Phone: 617-632-6036
Dana-Farber Cancer Institute
Status: ACTIVE
Contact: Pasi Antero Janne
Phone: 617-632-6036


I. To determine the feasibility of combining the oral agent gefitinib with the oral agent osimertinib as initial therapy in EGFR TKI naive advanced EGFR mutant positive (EGFRm+) non-small cell lung cancer (NSCLC).

II. To determine the maximum tolerable dose of gefitinib and osimertinib in combination in order to conduct Part 2 of this study in which feasibility of the combination will be assessed. (Part I)


I. To determine the rate of treatment-related grade 3-5 adverse events in patient cohorts treated with concurrent combination gefitinib and osimertinib via the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.

II. To determine the objective response rate and progression-free survival per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 in patient cohorts treated with concurrent combination gefitinib and osimertinib.

III. To estimate overall survival.

IV. To study genomic alterations at diagnosis and disease progression and to identify mechanism(s) of resistance in repeat biopsy at time of disease progression.

V. To serially collect and evaluate circulating free (cf) deoxyribonucleic acid (DNA) to determine the rate of change in EGFR activating mutations (L858R or exon 19 deletion) and evolution of acquired resistance mutations (T790M and C797S) during treatment.

VI. To determine the proportion of patients in whom the EGFR activating mutation (L858R or exon 19 deletion) becomes undetectable in plasma following 2 and 4 months of therapy.


I. To collect and store plasma for potential exploratory research of blood borne biomarkers as factors that may influence the development of resistance in NSCLC and/or outcome to combination gefitinib/osimertinib therapy.

II. To collect and store tumor DNA for future exploratory research into mutations and genetic variation that may influence development of resistance mechanisms and/or response to combination gefitinib/osimertinib therapy.

OUTLINE: This is a phase I dose-escalation study of osimertinib followed by a phase II study.

PHASE I: Patients are randomized into 1 of 2 cohorts.

COHORT A: Patients receive gefitinib orally (PO) once daily (QD) and osimertinib PO QD concurrently daily on days 1-28 for all courses. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. After course 6, courses may repeat every 8 weeks for odd courses in the absence of disease progression or unacceptable toxicity.

COHORT B (CLOSED TO ACCRUAL): Patients receive gefitinib PO QD and osimertinib PO QD on days 1-28 alternating by course. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. After course 6, courses may repeat every 8 weeks for odd courses in the absence of disease progression or unacceptable toxicity. (COHORT TERMINATED JULY 2018)


COHORT C: Patients receive gefitinib PO QD and osimertinib PO QD as in cohort A. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. After course 6, courses may repeat every 8 weeks for odd courses in the absence of disease progression or unacceptable toxicity. Patients who were previously enrolled in cohort B will be given the option to cross over to concurrent osimertinib/gefitinib treatment and receive gefitinib and osimertinib as in cohort A.

After completion of study treatment, patients are followed up at 30 days and every 8 weeks for up to 5 years.

Trial Phase Phase I/II

Trial Type Treatment

Lead Organization
Dana-Farber Harvard Cancer Center

Principal Investigator
Pasi Antero Janne

  • Primary ID 16-627
  • Secondary IDs NCI-2017-00990
  • ID NCT03122717