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Osimertinib in Treating Patients with Stage IV EGFR-Mutant Non-small Cell Lung Cancer

Trial Status: Active

This phase II trial studies how well osimertinib works in treating patients with stage IV non-small cell lung cancer who are positive for EGFR mutations. The EGFR gene produces a protein that helps cells divide. Specific changes or mutations in the genetic information can cause abnormal cell division and lead to lung cancer. Patients who have non-small cell lung cancer with an EGFR gene mutation can be treated by drugs called EGFR tyrosine kinase inhibitors. EGFR tyrosine kinase inhibitors such as osimertinib, may stop (or “inhibit”) the effect of the mutation in the EGFR gene and may stop the growth of tumor cells.

Inclusion Criteria

  • 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 from tumor tissue * 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 at baseline, 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 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 * Note: For participants entering study after starting commercial osimertinib, elevations in hepatic transaminases (AST/ALT) and/or total bilirubin < grade 2 at study entry are acceptable
  • Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) < 2.5 x institutional upper limit of normal or < 5 times the ULN in the presence of liver metastases * Note: For participants entering study after starting commercial osimertinib, elevations in hepatic transaminases (AST/ALT) and/or total bilirubin < grade 2 at study entry are acceptable
  • Creatinine =< 1.5 x institutional upper limit of normal OR
  • Creatinine clearance >= 50 mL/min as determined by the Cockcroft-Gault formula
  • Participants must have biopsy tissue at time of diagnosis available and sufficient for targeted next-generation sequencing. The sequencing can be performed at a commercial vendor such as Foundation Medicine. The testing does not have to be completed prior to study enrollment. If the specimen is insufficient a repeat biopsy will need to be performed * Note: Cytology specimen may be acceptable for baseline next generation sequencing (NGS) if tumor cellular content is sufficient and following principal investigator (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 PI * For participants entering study after starting commercial osimertinib: a tissue sample from the time of diagnosis must be available and sufficient for NGS testing. Participants who have had commercial tumor NGS testing performed on their pre-osimertinib treated specimen do not need NGS repeated as part of this study
  • Participants must be willing to undergo a repeat tumor biopsy during study treatment between cycles 4 and 8 (if considered medically safe) and at the time of disease progression
  • Participants must be >= 2 weeks since any major surgery (excluding vascular access placement, mediastinoscopy, or biopsies performed by an interventional service)
  • Male patients should be asked to use barrier contraceptives (i.e., by use of condoms) during sex with all partners who are women of child bearing potential, including pregnant women, during the trial and for a washout period of 4 months. Male patients should avoid procreation for 4 months after completion of trial treatment. Patients should refrain from donating sperm from the start of dosing until 4 months after discontinuing study treatment
  • Female patients (women of child-bearing potential): 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 6 weeks after finishing treatment. Must not be pregnant or breast-feeding. Women of child-bearing potential must have a negative pregnancy test (urine or serum) 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
  • Subjects may enter the study even if they have started treatment using commercial osimertinib. Subjects may enter the study anytime during the first 3 months of receiving commercial osimertinib therapy (up to 84 days of commercial osimertinib before entering the study). In order to enter the study after starting commercial osimertinib, subjects must meet all eligibility criteria listed above, have baseline and follow up imaging available for review for response assessment, and must not have developed disease progression during the first 3 months of commercial osimertinib therapy

Exclusion Criteria

  • Prior or ongoing treatment with any of the following: * EGFR targeted therapy (tyrosine kinase inhibitor [TKI] or antibody) or any other targeted therapies targeting the ERBB family except for subjects receiving first line osimertinib during the first three months of therapy * Any cytotoxic chemotherapy, investigational agents, immunotherapy or anticancer drugs for the treatment of metastatic NSCLC * Note: Patients who have completed adjuvant or neo-adjuvant chemotherapy > 6 months ago are considered treatment naive
  • Prior radiotherapy, including central nervous system (CNS) radiation, within 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 asymptomatic 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
  • Patients currently receiving and unable to stop using medications or herbal supplements known to be potent inducers of CYP3A4
  • Any unresolved toxicities from prior therapy, including commercial osimertinib, 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 segment elevation myocardial infarction [NSTEMI] or ST-segment 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, have normal QT interval on ECG evaluation QT corrected Fridericia (QTcF) of =< 450 ms in males or =< 470 ms in females * 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 and cause Torsades de Pointes 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 * Known 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 osimertinib * Cardiac ejection fraction of < 45% * 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 * Note: testing is not required for study entry
  • 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. Women of child-bearing potential must have a negative pregnancy test prior to start of dosing
  • Pregnant women are excluded from this study because the effects of 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 osimertinib, breastfeeding should be discontinued if the mother is treated with osimertinib


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. Determine the mechanism(s) of resistance to osimertinib through next generation sequencing of post-progression biopsies.


I. To determine the overall response rate to osimertinib as per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.

II. To determine the progression-free survival with osimertinib treatment.

III. To determine overall survival following osimertinib treatment.

IV. To determine toxicity following osimertinib treatment.


I. To develop patient derived xenograft models from osimertinib post-progression biopsies.

II. To investigate the mechanisms of resistance to osimertinib using serial assessment of cell free deoxyribonucleic acid (DNA).

III. To investigate the potential association in the rate of change in EGFR mutant (L858R or Del 19) cell free DNA and objective response and progression-free survival.

IV. To biopsy and study tumor biopsies obtained at the time of maximal response to osimertinib.


Patients receive osimertinib orally (PO) once daily (QD) on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo radiographic assessment every 2 cycles for the first 6 months and then every 3 cycles until disease progression. Patients also undergo tumor biopsy between cycles 4 and 8 and again at the time of progression.

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

Trial Phase Phase II

Trial Type Treatment

Lead Organization
Dana-Farber Harvard Cancer Center

Principal Investigator
Pasi Antero Janne

  • Primary ID 18-070
  • Secondary IDs NCI-2018-02315
  • ID NCT03586453