PRIMARY OBJECTIVE:
I. To determine whether, in patients with tyrosine kinase inhibitor (TKI) naive or TKI
resistant (acquired T790M) metastatic EGFR mutant non-small cell lung cancer (NSCLC) who do
not progress after 6-12 weeks of induction osimertinib, local consolidative therapy (LCT;
radiotherapy +/- surgical resection) followed by osimertinib prolongs progression-free
survival (PFS) compared with osimertinib alone.
SECONDARY OBJECTIVES:
I. To determine whether osimertinib plus LCT improves time to progression of non-irradiated
lesions (TTP-NIL) and time to appearance of new metastases (TANM) compared with osimertinib
alone.
II. To determine whether osimertinib plus LCT improves the time to progression of target
versus (vs.) non-target lesions compared with osimertinib alone.
III. To determine whether osimertinib plus LCT improves progression-free survival compared
with osimertinib alone in TKI naive EGFR (L8585R/exon 19 deletion) mutant metastatic NSCLC.
IV. To determine whether osimertinib plus LCT improves progression-free survival compared
with osimertinib alone in TKI resistant (acquired T790M) EGFR mutant NSCLC.
V. To determine whether osimertinib plus LCT improves progression-free survival compared with
osimertinib alone in the subgroup of patients with oligometastatic NSCLC (up to 3
metastases).
VI. To assess the safety and tolerability of osimertinib with and without LCT. VII. To
determine whether osimertinib plus LCT improves overall survival (OS) compared with
osimertinib alone.
VIII. To determine if there is a difference in survival outcomes or toxicity by radiation
treatment modality (protons vs. photons).
EXPLORATORY OBJECTIVES:
I. To explore the association of baseline genomic, proteomic and gene expression profiles
(from tumor, germline deoxyribonucleic acid [DNA], and cell free [cf]DNA) with clinical
benefit and in patients treated with osimertinib with or without LCT.
II. To determine modulation of genomic, proteomic and gene expression tumor profiles by
induction osimertinib.
III. To explore osimertinib resistance mechanisms. IV. To determine the immunomodulatory
effects of osimertinib plus LCT.
OUTLINE: Patients are randomized to 1 of 2 groups.
GROUP I (LCT): Patients receive osimertinib orally (PO) once daily (QD) for 6-12 weeks.
Patients then undergo surgery and/or radiation therapy daily for 5 consecutive days every
week for up to 8 weeks. Patients continue osimertinib during and after radiation therapy.
Cycles repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.
GROUP II (NO LCT): Patients receive osimertinib PO QD. Cycles repeat every 4 weeks in the
absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up within 30 days, then every 6
months thereafter.
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 study treatment) medications or herbal supplements known to be potent inducers of
CYP3A4 (at least 3 week prior). All patients must try to avoid concomitant use of any
medications, herbal supplements and/or ingestion of foods with known inducer effects
on CYP3A4
- Patients with symptomatic central nervous system (CNS) metastases who are
neurologically unstable
- Any unresolved toxicities from prior therapy greater than Common Terminology Criteria
for Adverse Events (CTCAE) grade 1 (with the exception of alopecia grade 2) at the
time of starting study treatment
- Any evidence of severe or uncontrolled systemic diseases, including uncontrolled
hypertension and active bleeding diatheses, which in the investigator's opinion makes
it undesirable for the subject to participate in the trial or which would jeopardize
compliance with the protocol, or active infection including hepatitis B, hepatitis C
and human immunodeficiency virus (HIV). Screening for chronic conditions is not
required
- Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to
swallow the formulated product or previous significant bowel resection that would
preclude adequate absorption of osimertinib
- Past medical history of interstitial lung disease (ILD), drug-induced ILD, radiation
pneumonitis which required steroid treatment, or any evidence of clinically active
interstitial lung disease
- Males and females of reproductive potential who are not using and 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
- History of hypersensitivity of osimertinib (or active or inactive excipients of
osimertinib or drugs with a similar chemical structure or class to osimertinib)
- Judgment by the investigator that the patient should not participate in the study if
the patient is unlikely to comply with study procedures, restrictions and requirement
- Absolute neutrophil count < 1,500/mcL
- Platelet < 100,000/mcL
- Hemoglobin < 9.0 g/dL
- Total bilirubin > 1.5 times the upper limit of normal (ULN) if no demonstrable liver
metastases or > 3 times ULN in the presence of documented Gilbert's syndrome or liver
metastases
- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
> 2.5 times ULN or > 5 times ULN if liver metastases are present
- Creatinine clearance < 50 mL/min/1.73 m^2 by Cockcroft-Gault equation
- Any of the following cardiac criteria:
- Mean resting corrected QT interval (corrected QT [QTc] using Fridericia's
formula) > 470 msec
- 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
- 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 prolong the QT
interval
- Patients will be excluded from randomization if they meet any of the following
criteria:
- Any of the exclusion criteria
- Complete response to osimertinib or prior treatment to all visible lesions, such
that no lesion is amenable to LCT. Note that patients can receive palliative
radiation therapy prior to randomization to CNS lesions or those requiring urgent
treatment (e.g. for pain or bleeding), but are only eligible for the study if
they have one site amenable to further radiation therapy. In addition, these
lesions will be counted towards the total number of metastases, and will also be
counted as target lesions
