Osimertinib and Selumetinib in Treating Participants with Stage IV EGFR Mutant Non-Small Cell Lung Cancer
- Participants must have histologically confirmed stage IV non-small cell lung cancer (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 nonnodal 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 for metastatic disease; patients who have completed adjuvant or neo-adjuvant chemotherapy > 6 months ago are considered treatment naive
- Participants must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
- 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])/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 =< 1.5 x institutional upper limit of normal OR creatinine clearance >= 50 mL/min as determined by the Cockcroft-Gault formula
- Participants should have biopsy tissue (or a cell block from a malignant effusion) at time of diagnosis available for targeted next-generation sequencing; the testing does not have to be completed prior to study enrollment; biopsy can be performed at an outside institution as long as sufficient tissue is available * Note: if next generation sequencing has already been performed prior to study enrollment, it does not need to be repeated. Tissue is still requested for central next generation sequencing (NGS)
- 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 4 months after finishing treatment * Female patients: willing to use adequate contraception (barrier or abstinence) at least 2 weeks before receiving any study medication, 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
- 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 advanced NSCLC
- Prior radiotherapy < 2 weeks of the first dose of study treatment
- 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, or any of its excipients, of similar chemical or biologic composition to osimertinib or selumetinib
- Patients currently receiving and unable to stop using medications known to be potent inhibitors or inducers of CYP3A4
- Patients currently receiving and unable to stop high doses of supplemental vitamin E
- 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 and cancer of the cervix in situ
- Refractory nausea and vomiting, chronic gastrointestinal diseases, previous significant bowel resection, or any process that compromises the ability to swallow or absorb oral medication
- 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; previous moderate or severe impairment of left ventricular systolic function (LVEF < 45% on echocardiography or equivalent on multiple-gated acquisition scan [MUGA]) even if full recovery has occurred; prior or current severe valvular heart disease; prior or current cardiomyopathy including but not limited to the following: * Known hypertrophic cardiomyopathy * Known arrhythmogenic right ventricular cardiomyopathy
- Any clinically important abnormalities in rhythm, conduction or morphology of resting electrocardiography (ECG), e.g. complete left bundle branch block, third-degree heart block, second-degree heart block, QT interval corrected by Fridericia’s formula (QTcF) of >= 450 ms in males or >= 450 ms in females
- Any factors that increase the risk of corrected QT interval (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 because of the potential for pharmacokinetic interactions with selumetinib or osimertinib
- Baseline left ventricular ejection fraction (LVEF) below the LLN or of < 455% measured by echocardiography/MUGA; atrial fibrillation with a ventricular rate > 100 bpm on ECG at rest
- Any evidence of severe or uncontrolled systemic diseases, including 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
- Known to be T790M+ (on pre-treatment tumor or plasma) or known germline T790M
- Ophthalmological conditions as follows: * Current or past history of retinal pigment epithelial detachment (RPED)/central serous retinopathy (CSR) or retinal vein occlusion * Uncontrolled glaucoma (irrespective of intraocular pressure [IOP])
- Males and females of reproductive potential who are not using an effective method of birth control and females who are pregnant or breastfeeding or have a positive (urine or serum) pregnancy test prior to study entry * Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with these agents
I. Best objective response rate as determined by Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1.
I. Progression-free survival.
II. Tolerability as measured by the fraction of patients continuing on study therapy at 6 months.
III. Overall survival.
I. To investigate the mechanisms of resistance using serial assessment of cell free deoxyribonucleic acid (DNA).
II. To investigate the potential association in EGFR mutant (L858R or Del 19) cell free DNA and objective response and progression-free survival.
III. Subgroup analysis of efficacy by EGFR mutation (exon 19 and exon 21 L858R).
Participants receive osimertinib orally (PO) once daily (QD) on days 1-28 and selumetinib PO twice daily (BID) intermittently (4 days on, 3 days off), starting on day 1. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, participants are followed up at 30 days and then every 8 weeks for up to 5 years.
Trial Phase Phase II
Trial Type Treatment
Dana-Farber Harvard Cancer Center
Pasi Antero Janne
- Primary ID 17-540
- Secondary IDs NCI-2018-00300
- Clinicaltrials.gov ID NCT03392246