Clinical Trials /

Osimertinib and Gefitinib in EGFR Inhibitor naïve Advanced EGFR Mutant Lung Cancer



This research study is studying a combination of two drugs as a possible treatment for Non-Small Cell Lung Cancer (NSCLC) with an EGFR mutation. The interventions involved in this study are: - Osimertinib (Tagrisso) - Gefitinib (Iressa)

Related Conditions:
  • Non-Small Cell Lung Carcinoma
Recruiting Status:

Active, not recruiting


Phase 1/Phase 2

Trial Eligibility



  • Brief Title: Osimertinib and Gefitinib in EGFR Inhibitor naïve Advanced EGFR Mutant Lung Cancer
  • Official Title: A Phase 1/2 Study of Osimertinib in Combination With Gefitinib in EGFR Inhibitor naïve Advanced EGFR Mutant Lung Cancer

Clinical Trial IDs

  • ORG STUDY ID: 16-627
  • NCT ID: NCT03122717


  • Non-Small Cell Lung Cancer


GefitinibIressaGefitinib + Osimertinib
OsimertinibTagrissoGefitinib + Osimertinib


This research study is studying a combination of two drugs as a possible treatment for Non-Small Cell Lung Cancer (NSCLC) with an EGFR mutation. The interventions involved in this study are: - Osimertinib (Tagrisso) - Gefitinib (Iressa)

Detailed Description

      This research study is a Phase I clinical trial, which tests the safety of investigational
      drugs and also tries to define the appropriate dose of the investigational drugs to use for
      further studies. "Investigational" means that the drugs are being studied.

      The FDA (the U.S. Food and Drug Administration) has approved gefitinib and osimertinib as
      separate treatment options for this disease. The FDA has not approved the combination of
      these study drugs as a treatment option for this disease.Recently, the FDA approved
      osimertinib as a first-line treatment for patients that have NSCLC with an EGFR mutation,
      that have not received prior treatment for their disease.

      In this research study, the investigators are evaluating the combination of gefitinib and
      osimertinib in patients who have just been diagnosed with non-small cell lung cancer
      containing a mutation in the epidermal growth factor receptor (EGFR) gene.

      Normally, cells in the body divide in an orderly way. However, in cancer cells, this normal
      process of cell division becomes abnormal and allows the cancer cells to grow in a rapid,
      unregulated way. In some patients with lung cancer, this abnormal and rapid growth in the
      cancer cells is drive by a specific change in a gene called the Epidermal Growth Factor
      Receptor (EGFR). This change in the EGFR gene in cancer cells is called a mutation. Patients
      with lung cancer harboring a mutation in EGFR can be treated with specific drugs called EGFR
      inhibitors. However, even though these drugs can be very effective, after a period of time,
      most EGFR tumors will develop resistance to this treatment, most often because of a second
      mutation in EGFR called T790M.

      Right now, patients with newly diagnosed lung cancer with an EGFR mutation would be treated
      with a single EGFR inhibitor. A drug like gefitinib is a standard first treatment for
      patients with this kind of lung cancer. Osimertinib is currently approved only to treat
      patients whose cancers develop resistance to gefitinib (or other similar EGFR inhibitors)
      because of the T790M mutation.

      However, ongoing clinical trials have shown that osimertinib is also effective when used as
      the first treatment in newly diagnosed patients with lung cancer containing an EGFR mutation.
      In addition, laboratory studies have shown that combining EGFR inhibitors may help prevent
      the development of drug resistance.

      The goal of this particular study is to evaluate two different methods of combining gefitinib
      and osimertinib in newly diagnosed patients with EGFR mutations: either with both drugs given
      together on the same day OR an alternating schedule where participants will alternate taking
      one drug at a time every 4 weeks.

      This study will help determine the optimal dosing strategy for combining these two drugs in
      lung cancer patients with EGFR mutations. The study will also follow the clinical response of
      participants treated with the drug combination to monitor how well and how long this strategy
      controls the disease.

Trial Arms

Gefitinib + OsimertinibExperimentalGerfitinib will administered orally at a pre determine dose daily Osimertinib will administered orally at a pre determine dose daily
  • Gefitinib
  • Osimertinib

Eligibility Criteria

        Inclusion Criteria:

          -  Participants must have histologically confirmed stage IV NSCLC (per AJCC 7th edition)
             with either the L858R or exon 19 deletion activating EGFR mutation as identified in a
             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 CT scan, MRI, or calipers by clinical exam.

          -  Participants can have no prior history of any EGFR-directed therapy, including TKIs or
             antibodies, and must also be chemotherapy and immunotherapy naïve. Patients who have
             completed adjuvant or neo-adjuvant chemotherapy or immunotherapy >6 months ago are
             considered treatment naive.

          -  Participants must be aged ≥ 18 years

          -  Participants must have an ECOG performance status of 0-1 (Appendix A)

          -  Participants must have a life expectancy of greater than 12 weeks

          -  Participants must have normal organ and marrow function as defined below:

               -  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 ULN if no liver metastases or < 3 times the ULN
                  in the presence of documented Gilbert's syndrome (unconjugated
                  hyperbilirubinemia) or liver metastases

               -  AST(SGOT)/ALT(SGPT) <2.5 × institutional upper limit of normal or <5 times the
                  ULN in the presence of liver metastases

               -  creatinine within normal institutional limits OR

               -  creatinine clearance ≥50 mL/min/1.73 m2 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 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 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 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

               -  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 LH and 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

          -  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 potent inhibitors of
             CYP3A4 (Appendix B). All patients must try to avoid concomitant use of any
             medications, herbal supplements and/or ingestion of foods with known inducer effects
             on CYP3A4. The full list of medications that would make a patient ineligible are
             provided in Appendix B.

          -  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 (NYHA Grade II or greater);
                  unstable angina; prior myocardial infarction (NSTEMI or 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 ECG, e.g. complete left bundle branch block, third-degree heart block,
                  second-degree heart block, PR interval >250msec, mean resting corrected QT value
                  (QTc) of >470msec

               -  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

               -  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 gefitinib or osimertinib.

               -  ongoing use of warfarin (injectable low-molecular weight heparins are permitted).
                  Patients must be off warfarin for >7 days prior to enrollment

          -  Identification of EGFR T790M in baseline cfDNA analysis

          -  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
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Number of patients completing combination therapy with gefitinib and osimertinib for 6 x 28 day cycles
Time Frame:3 years
Safety Issue:
Description:The feasibility of combination gefitinib/osimertinib dosing will be determined through evaluation of the number of patients in each cohort who are able to remain on combination therapy for 6 x 28 day cycles.

Secondary Outcome Measures

Measure:Rate of treatment-related Grade 3-5 adverse events
Time Frame:3 years
Safety Issue:
Description:CTCAE v4.0 will be used to monitor toxicities in patients on combination therapy with gefitinib and osimertinib.
Measure:Objective response rate
Time Frame:3 years (each cycle is 28 days)
Safety Issue:
Description:RECIST 1.1 measurements of CT scans of the chest/abdomen/pelvis will be measured every 2 cycles on treatment to determine the objective response rate for patients being treated with combination gefitinib and osimertinib.
Measure:Progression free survival
Time Frame:3 years
Safety Issue:
Description:The Kaplan-Meier method will be used to determine the progression-free survival of patients enrolled on protocol and treated with combination gefitinib and osimertinib.
Measure:Overall Survival
Time Frame:3 years
Safety Issue:
Description:Survival follow-up with clinic visits or phone calls will be used to monitor for overall survival from time of study randomization to death from any cause. The Kaplan-Meier method will be used to calculate overall survival.


Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Active, not recruiting
Lead Sponsor:Dana-Farber Cancer Institute

Trial Keywords

  • Non-Small Cell Lung Cancer

Last Updated

November 17, 2020