Local Ablative Therapy for Treatment of Oligoprogressive, EGFR-Mutated, Non-Small Cell Lung Cancer After Treatment With Osimertinib

Background:

- EGFR tyrosine kinase inhibitors (TKI) have significantly improved the response rate (RR)
and survival in patients with tumors harboring EGFR-sensitizing mutations.

- An invariable consequence of treatment with EGFR-TKIs is the development of acquired
resistance. The most common mechanism of resistance observed in approximately 50% of all
cases is the emergence of a secondary mutation (T790M) in exon 20.

- Osimertinib is a third-generation EGFR-TKI designed to target the T790M mutation, which
has shown impressive responses in both first- and second-line settings.

- Despite these developments, it is almost certain that selection pressure will lead to
the emergence of newer clones that are resistant to treatment with osimertinib. In fact,
a newly identified EGFR mutation (C797S) that results in acquired resistance to
osimertinib has been reported recently.

- The use of local ablative therapies for patients who develop limited metastatic disease
oligoprogressive disease) on EGFR-TKI therapy is promising.

- We hypothesize that following local ablative therapy to treat oligoprogressive disease
after emergence of resistance to AZD9291, osimertinib can be resumed safely and
reinitiation of osimertinib results in additional progression-free survival benefits.

Objectives:

- Determine the safety, tolerability, and efficacy (as assessed by PFS) of re-initiation
of osimertinib following local ablative therapy (LAT) for patients with oligoprogressive
disease after treatment with osimertinib

- Assess mechanisms of acquired resistance to osimertinib

Eligibility:

- Histologically confirmed advanced lung adenocarcinoma with EGFR-sensitizing somatic
mutations or a germline T790M mutation and no prior EGFR tyrosine kinase inhibitor (TKI)
therapy (Cohort 1); OR progressive disease after 1st or 2nd generation EGFR TKI therapy
harboring somatic T790M mutation (Cohort 2); or patients with progressive disease after
treatment with osimertinib who are eligible for local ablative therapy (Cohort 3). If
biopsy for EGFR mutation status confirmation is not clinically feasible, EGFR mutations
may be confirmed by ctDNA analysis using a CLIA certified assay.

- Presence of measurable disease per RECIST version 1.1

- ECOG performance status 0-2

- Adequate end organ function

- If patients are not eligible for LAT, they will be referred for standard of care
chemotherapy as per treating physicians discretion. These patients may also be
considered for other clinical trials.

Design:

- This is a single-institution, open-label phase II trial of osimertinib.

- Eligible patients not previously treated with osimertinib will be treated with
osimertinib daily until disease progression. At the time of progression, patients with
oligoprogressive disease (no more than 5 sites of progressive disease) will be assessed
for LAT.

- If patients are eligible for LAT, osimertinib will be resumed after LAT and they will be
followed for second progression on osimertinib (PFS2).

- If patients progress at the same site where LAT has been performed before, the
progression will be considered to be a result of inadequate ablation and they will be
considered for repeat LAT and again re-challenged with osimertinib if clinically
feasible.

- Tumor samples will be obtained at baseline by a mandatory biopsy. At the time of first
progression on osimertinib if a patient is eligible for surgery as a form of LAT, then a
tissue sample will be obtained for genomic and proteomic studies to identify mechanisms
of acquired resistance. For patients who are not eligible for LAT or a form of LAT that
is not surgery (radiation, radiofrequency ablation, cryoablation), then a mandatory
biopsy will be performed, if clinically safe, to obtain tissue for above studies.

- INCLUSION CRITERIA:

For inclusion in the study subjects should fulfill the following criteria:

- Provision of informed consent prior to any study specific procedures

- Patients (male/female) must be greater than or equal to 18 years of age.

- Patients with histologically confirmed, by the NCI Laboratory of Pathology or by
CLIA-certified Next Generation Sequencing or cobas EGFR Mutation Test v1/2 at an
outside institution, advanced lung adenocarcinoma with EGFR-sensitizing somatic
mutations or a germline T790M mutation (detected histologically or via ctDNA analysis
using a CLIA assay) with:

- No prior EGFR tyrosine kinase inhibitor (TKI) therapy (Cohort 1)

OR

-- Progressive disease after 1st or 2nd generation EGFR TKI therapy harboring somatic T790M
mutation (Cohort 2)

OR

- Progressive disease after treatment with osimertinib who are eligible for local
ablative therapy (Cohort 3)

- Presence of measurable disease per RECIST version 1.1.

- In patients with suspected leptomeningeal disease, the diagnosis of
leptomeningeal disease should be confirmed by the presence of neurological or
imaging signs and/or positive CSF cytology.

- ECOG performance status 0-2.

- No uncontrolled arrhythmia; no myocardial infarction in the last 6 months.

- Females should not be breast feeding and must have a negative pregnancy test
prior to start of dosing if of child-bearing potential 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 old would be consider 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

- Females of child-bearing potential should use reliable methods of contraception
from the time of screening until 3 months after discontinuing osimertinib.
Acceptable methods of contraception include total and true sexual abstinence,
tubal ligation, 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 male sexual partner for
intercourse.

- Male patients should be willing to use barrier contraception. Male patients
should be asked to use barrier contraceptives (i.e., by use of condoms) during
sex with all of their female partners during the trial and for a washout period
of 3 months. Patients should refrain from donating sperm from the start of dosing
until 6 months after discontinuing osimertinib treatment. If male patients wish
to father children they should be advised to arrange for freezing of sperm
samples prior to the start of osimertinib treatment.

- Patient is willing and able to comply with the protocol for the duration of the
study including undergoing treatment and scheduled visits and examinations
including follow up.

EXCLUSION CRITERIA:

Subjects should not enter the study if any of the following exclusion criteria are
fulfilled:

- Any unresolved toxicities from prior therapy greater than Common Terminology Criteria
for Adverse Events (CTCAE) grade 1 at the time of starting study treatment with the
exception of alopecia and grade 2, prior platinum-therapy related neuropathy.

- Treatment with an investigational drug within five half-lives of the compound.

- Major thoracic or abdominal surgery from which the patient has not sufficiently
recovered yet.

- Untreated and uncontrolled second tumor in the past 2 years.

- 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 (at least 1 week prior) and potent inducers of CYP3A4 (at least 3 week prior)
will only be eligible at the PI s discretion.

- 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 patient to participate in the trial or which would jeopardize
compliance with the protocol. Screening for chronic conditions is not required.

- Patients with CNS metastases who are neurologically unstable.

- Past medical history of interstitial lung disease (ILD), drug-induced ILD, radiation
pneumonitis requiring steroid treatment, or any evidence of clinically active ILD

- Inadequate bone marrow reserve or organ function as demonstrated by any of the
following laboratory values:

- Absolute neutrophil count <1 x 10(9)/L

- Platelet count <100 x 10(9)/L

- Hemoglobin <90 g/L

- Alanine aminotransferase >2.5 times the 2.1.2.9.4 upper limit of normal (ULN) if
no demonstrable liver metastases or >5 times ULN in the presence of liver
metastases

- Aspartate aminotransferase >2.5 times ULN if no demonstrable liver metastases or
>5 times ULN in the presence of liver metastases

- Total bilirubin >1.5 times ULN if no liver metastases or >3 times ULN in the
presence of documented Gilbert s Syndrome (unconjugated hyperbilirubinemia) or
liver metastases

- Creatinine >1.5 times ULN concurrent with creatinine clearance <30 ml/min
(measured or calculated by Cockcroft and Gault equation); confirmation of
creatinine clearance is only required when creatinine is >1.5 times ULN

- Any of the following cardiac criteria

- Resting corrected QT interval (QTc using Fredericia s formula) > 480 msec

- 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)

- 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

- Significant symptomatic congestive heart failure, per PI judgement.

- 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

- History of hypersensitivity to osimertinib (or drugs with a similar chemical structure
or class to osimertinib) or any excipients of these agents

- 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 requirements