- Histologically or cytologically confirmed NSCLC-lung adenocarcinoma histology.
- Tumor must harbor an EGFR activating mutation (Exon 21 L858R, Exon 19 deletion, Exon
18 G719X, Exon 21 L861Q).
- Patient must have Stage IV, recurrent or metastatic disease with EGFR mutant disease.
- Patient must have progressive disease on or after osimertinib (any number of prior
treatment is allowed).
- At least one measurable lesion according to RECIST version 1.1
- Age >18 years
- ECOG performance status ≤1
- Patients who received chemotherapy must have recovered (Common Terminology Criteria
for Adverse Events [CTCAE] Grade ≤1) from the acute effects of chemotherapy except for
residual alopecia or Grade 2 peripheral neuropathy prior to randomization. A washout
period of at least 21 days is required between last chemotherapy dose and
randomization (provided the patient did not receive radiotherapy).
- Patients who received adjuvant radiotherapy must have completed and fully recovered
from the acute effects of radiotherapy. A washout period of at least 14 days is
required between end of radiotherapy and randomization.
The patient has adequate organ function for all of the following criteria, as defined
Table 1: Laboratory Value Guidance to Establish Adequate Organ Function System Laboratory
Value Hematologic ANC 1.5 × 109/L Platelets 100 × 109/L Hemoglobin 8 g/dL Patients may
receive erythrocyte transfusions to achieve this hemoglobin level at the discretion of the
investigator. Initial treatment must not begin earlier than the day after the erythrocyte
Hepatic Total bilirubin 1.5 × ULN Patients with Gilbert's syndrome with a total bilirubin
≤2.0 times ULN and direct bilirubin within normal limits are permitted.
ALT and AST 3 × ULN Renal Serum creatinine 1.5 × ULN
Abbreviations: ALT = alanine aminotransferase; ANC = absolute neutrophil count; AST =
aspartate aminotransferase; ULN = upper limit of normal.
- Negative urinary pregnancy test within 7 days prior to entry of study.
- Men and women of child bearing age must agree to contraception methods prior to entry
of study and continue on that for 3 months for women and 6 months for men after last
dose of osimertinib (details will be submitted in actual protocol) and notification of
PI if pregnancy occurs.
- Patients with brain metastases may enroll in this study providing they have been
treated and remain asymptomatic.
- The patient is able to swallow oral medications.
- Chemotherapy or other investigational agent within three weeks prior to the start of
- Radiotherapy within 4 weeks prior to randomization, except as follows:
- Palliative radiation to target organs other than chest or stereotactic radiotherapy to
the chest may be allowed up to 2 weeks prior to treatment with osimertinib and
- Single dose palliative treatment for symptomatic metastasis outside above allowance to
be discussed with sponsor prior to enrolling.
- Major surgery within 4 weeks before starting study treatment or scheduled for surgery
during the projected course of the study.
- Known hypersensitivity to osimertinib or the excipients of any of the trial drugs.
- History or presence of clinically relevant cardiovascular abnormalities such as
uncontrolled hypertension, congestive heart failure NYHA classification of 3, unstable
angina or poorly controlled arrhythmia as determined by the investigator. Myocardial
infarction within 6 months prior to study enrollment.
- Women of child-bearing potential (WOCBP) and men who are able to father a child,
unwilling to be abstinent or use adequate contraception prior to study entry, for the
duration of study participation and for at least 28 days after treatment has ended.
<Note: for osimertinib this must be 28 days, however this may be longer for other
- Female patients of childbearing potential who are nursing or are pregnant or are not
using an acceptable method of birth control, or do not plan to continue using this
method throughout the study and/or do not agree to submit to pregnancy testing
required by this protocol.
- Previous or concomitant malignancies at other sites, except effectively treated
non-melanoma skin cancers, carcinoma in situ of the cervix, ductal carcinoma in situ
or effectively treated malignancy that has been in remission for more than 3 years and
is considered to be cured.
- Known pre-existing interstitial lung disease (patients with previous radiation induced
interstitial lung disease are allowed provided they do not require active treatment
and symptoms attributed to interstitial lung disease have resolved).
- Any history or presence of poorly controlled gastrointestinal disorders that could
affect the absorption of osimertinib (e.g. Crohn's disease, ulcerative colitis,
chronic diarrhea, and malabsorption).
- Active hepatitis B infection (defined as presence of HepB sAg and/ or Hep B DNA),
active hepatitis C infection (defined as presence of Hep C RNA) and/or known HIV
- QTcF > 470 ms on average of 3 ECG recordings
- Leptomeningeal carcinomatosis.
- Patients with controlled CNS metastases are allowed. Radiotherapy or surgery for CNS
metastases must have been completed >2 weeks prior to study entry. Patients must be
neurologically stable, having no new neurologic deficits on clinical examination, and
no new findings on CNS imaging. Steroid use for management of CNS metastases must be
at a stable dose for two weeks preceding study entry.
- The patient has serious preexisting medical condition(s) that would preclude
participation in this study (for example, interstitial lung disease, severe dyspnea at
rest or requiring oxygen therapy, history of major surgical resection involving the
stomach or small bowel, or preexisting Crohn's disease or ulcerative colitis or a
preexisting chronic condition resulting in baseline Grade 2 or higher diarrhea).
- The patient has active bacterial infection (requiring intravenous [IV] antibiotics at
time of initiating study treatment), fungal infection, or detectable viral infection
(such as known human immunodeficiency virus positivity or with known active hepatitis
B or C [for example, hepatitis B surface antigen positive].
- The patient has a personal history of any of the following conditions: syncope of
cardiovascular etiology, ventricular arrhythmia of pathological origin (including, but
not limited to, ventricular tachycardia and ventricular fibrillation), or sudden
- Clinically active interstitial lung disease, radiation pneumonitis requiring steroid
treatment and further entry to be determined on an individual basis.
- Use of medications or supplements known to be major inducers of CYP3A4.
- Comorbidities not limited to unstable angina, congestive heart failure; EKG
abnormalities including but not limited to QT prolongation; gastrointestinal diseases
limiting absorption of oral medications; psychiatric illnesses and other social
situations which may limit participation and compliance on the study.
- Prior CDK4/6 inhibitor treatment is prohibited