Randomized Phase II Trial of Osimertinib With or Without Local Consolidation Therapy (LCT) for Patients With EGFR-Mutant Metastatic NSCLC (NORTHSTAR)

Official Summary

This phase II trial studies how well osimertinib, surgery, and radiation therapy work in treating patients with stage IIIB or IV non-small cell lung cancer with EGFR mutations. Osimertinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Giving osimertinib, surgery, and radiation therapy may work better at treating non-small cell lung cancer with EGFR mutations.

Study Design

• Study Type: INTERVENTIONAL
• Allocation: RANDOMIZED
• Model: PARALLEL
• Masking: NONE
• Enrollment: 173 participants

Interventions

• DRUG: Osimertinib — Given PO
• RADIATION: Radiation Therapy — Undergo radiation therapy
• PROCEDURE: Therapeutic Conventional Surgery — Undergo surgery

Primary Outcomes

• Progression free survival (PFS) (From the start date of osimertinib assessed up to 4 years)

Secondary Outcomes

• Overall survival (From the treatment start date assessed up to 4 years)
• Time to progression of target lesions (Up to 4 years)
• Time to appearance of new metastases (Up to 4 years)
• PFS in oligometastatic subgroup (Up to 4 years)
• Incidence of adverse events (Up to 30 days post treatment)

Eligibility Criteria

Inclusion Criteria:

* Histologically or cytologically confirmed non-small cell lung cancer
* Stage IIIB/IV or recurrent non-small cell lung cancer which is not amenable to curative intent therapy
* Patients must have one of the following:

  * NSCLC which harbors EGFR exon 19 deletion or L858R mutation. This subset of patients must be TKI naive; OR
  * NSCLC which harbors an EGFR T790M mutation that was acquired following progression on erlotinib, gefitinib or afatinib. This subset of patients must have not received prior third generation TKI
  * NOTE: EGFR mutation must be documented by a Clinical Laboratory Improvement Amendments (CLIA) certified test
* Eastern Cooperative Oncology Group (ECOG) performance status =\< 1
* Measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
* Candidate for local consolidation therapy to at least one site of disease
* Signed and dated written informed consent prior to admission to the study in accordance with International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH)-Good Clinical Practice (GCP) guidelines and to the local legislation
* Ability to take pills by mouth
* Females of childbearing potential:

  * Must not be breast feeding
  * Must have a negative serum or urine pregnancy test
  * Must agree to use adequate contraception for a minimum of two weeks prior to receiving study medication until 3 months after discontinuation of the study medication

    * NOTE: Acceptable methods of contraception include total and true sexual abstinence, hormonal contraceptives that are not prone to drug-drug interactions (IUS levonorgestrel intra uterine system \[Mirena\], medroxyprogesterone injections \[Depo-Provera\]), copper-banded intra-uterine devices, and vasectomized partner. All hormonal methods of contraception should be used in combination with the use of a condom by their sexual male partner. Females of childbearing potential are defined as those who are not surgically sterile (i.e., bilateral tubal ligation, bilateral oophorectomy, or complete hysterectomy) or postmenopausal (defined as 12 months with no menses without an alternative medical cause)
* Women will be considered post-menopausal if they have been amenorrheic for the past 12 months without an alternative medical cause. The following age-specific requirements must also apply:

  * Women \< 50 years old: they would be considered post-menopausal if they have been amenorrheic for the past 12 months or more following cessation of exogenous hormonal treatments. The levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) must also be in the post-menopausal range (as per the institution)
  * Women \>= 50 years old: they would be considered post-menopausal if they have been amenorrheic for the past 12 months or more following cessation of all exogenous hormonal treatments, or have had radiation-induced oophorectomy with the last menses \> 1 year ago, or have had chemotherapy-induced menopause with \> 1 year interval since last menses, or have had surgical sterilization by either bilateral oophorectomy or hysterectomy
* Non-sterilized males who are sexually active with a female partner of childbearing potential must use adequate contraception for the duration of the study and 3 month after the last dose of study medication. Adequate contraception methods include: birth control pills (e.g. combined oral contraceptive pill), barrier protection (e.g. condom plus spermicide, cervical/vault cap or intrauterine device), and abstinence. Patients should not father a child for 6 months after completion of the study medication. Patients should refrain from donating sperm from the start of dosing until 6 months after discontinuing the study medication. If male patients wish to father children they should be advised to arrange for freezing of sperm samples prior to the start of the study medication
* Life expectancy \>= 12 weeks
* To be eligible for randomization, patients must:

  * Meet all the inclusion criteria
  * Have no progression of disease after 6-12 weeks of osimertinib per RECIST 1.1. To assess for progressive disease patients must have the following imaging:

    * Either a positron emission tomography (PET)/computed tomography (CT) scan or a CT scan of the chest/abdomen/pelvis (or CT chest)
    * A CT scan or a magnetic resonance imaging (MRI) of the brain
  * Have target lesions (lesions that will be treated with LCT if the patient is randomized to that arm). Patients that have a complete response (CR) to front-line osimertinib (e.g. no visible disease to target) will continue to be followed for progression on study but will not be randomized

Exclusion Criteria:

* Previous treatment with osimertinib, or a 3rd generation EGFR TKI. NOTE: Patients who are receiving initial osimertinib (6-12 weeks) outside this study are not excluded
* Patients currently receiving (or unable to stop use prior to receiving the first dose of stud

Trial Locations

• UCSF Medical Center-Mount Zion, San Francisco, California, United States
• University of Colorado, Denver, Colorado, United States
• Memorial Sloan Kettering Cancer Center, New York, New York, United States
• M D Anderson Cancer Center, Houston, Texas, United States

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