Targeted Therapy in Treating Patients With Incurable Non-Small Cell Lung Cancer With Genetic Mutations

PRIMARY OBJECTIVES:

I. To estimate the objective response rate among patients with high PD-L1 expressing cancers
after failure of targeted therapy.

SECONDARY OBJECTIVES:

I. To compare the overall survival for patients receiving treatment targeting primary
mutations, secondary mutations, or immunotherapy at the time of progression on tyrosine
kinase inhibitor therapy.

II. To assess the incidence of secondary mutations in this population according to smoking
status.

III. To evaluate the response rates of patients treated using these different approaches.

IV. To correlate outcomes with specific secondary genetic changes.

OUTLINE: Patients are assigned to 1 of 3 treatment arms.

ARM I (PD-L1 >= 50%): Patients receive nivolumab intravenously (IV) over 60 minutes every 2
weeks or pembrolizumab IV every 3 weeks in the absence of disease progression or unacceptable
toxicity.

ARM II (PD-L1 < 50% without secondary oncogenic driver): Patients receive tyrosine kinase
inhibitor therapy orally (PO) targeting the initial oncogenic driver or other treatment for
about 3 weeks.

ARM III (PD-L1 < 50% with secondary oncogenic driver): Patients receive tyrosine kinase
inhibitor therapy PO targeting initial oncogenic driver, a drug targeting the secondary
mutation, or other treatment for about 3 weeks.

After completion of study treatment, patients are followed up for a minimum of 30 days.

Inclusion Criteria:

- Patients must have histologically or cytologically confirmed incurable non-small cell
lung cancer that harbors an activating mutation in EGFR, MET, BRAF, V600E, RET, HER2,
translocation in Alk, or translocation in ROS-1

- Patients must be receiving treatment or planning to start treatment with a tyrosine
kinase inhibitor targeting the activated gene

- Patients may not be receiving the treatment targeting the activated gene as part of a
clinical treatment trial other than the Precision Oncology Trial

- Eastern Cooperative Oncology Group (ECOG) performance status of 0-3

- Total bilirubin =< 1.5 X institutional upper limit of normal

- Aspartate transaminase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine
transaminase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X
institutional upper limit of normal

- Women of child-bearing potential and men must agree to use adequate contraception
(hormonal or barrier method of birth control) prior to study entry and for the
duration of study participation; should a woman become pregnant or suspect she is
pregnant while participating in this study, she should inform her treating physician
immediately

- Ability to understand and the willingness to sign an Institutional Review Board
(IRB)-approved informed consent document

Exclusion Criteria:

- Emergent need for palliative radiation

- Patients may not be receiving any other investigational agents for the treatment of
non-small cell lung cancer

- Uncontrolled intercurrent illness including, but not limited to ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements

- Pregnant women are excluded; breastfeeding should be discontinued