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

Study Overview
=================
Brief Summary
-----------------
This phase II trial studies how well targeted therapy works in treating patients with incurable non-small cell lung cancer with a genetic mutation. Giving drugs that target other genetic mutations or other specific proteins may work better when a patient has cancer caused by a driver mutation and the treatment that targets that mutation stops working.

Detailed Description
-----------------
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.

Official Title
-----------------
Phase II Pilot Study Evaluating Strategies to Overcome Resistance at the Time of Progression for Patients With Non-small Cell Lung Cancers Harboring Major Oncogenic Drivers

Conditions
-----------------
Recurrent Non-Small Cell Lung Carcinoma, Stage IV Non-Small Cell Lung Cancer, EGFR Activating Mutation

Intervention / Treatment
-----------------
* Drug: Chemotherapy
* Biological: Immunotherapy
* Other: Laboratory Biomarker Analysis
* Biological: Nivolumab
* Biological: Pembrolizumab
* Drug: Targeted Molecular Therapy
* Drug: Tyrosine Kinase Inhibitor


Participation Criteria
=================
Eligibility Criteria
-----------------
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
Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I (nivolumab, pembrolizumab)<br>Patients receive nivolumab IV over 60 minutes every 2 weeks or pembrolizumab IV every 3 weeks in the absence of disease progression or unacceptable toxicity. | Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Biological: Nivolumab<br>* Given IV<br>* Other names: Opdivo;Biological: Pembrolizumab<br>* Given IV<br>* Other names: SCH 900475;|
| Experimental: Arm II (kinase inhibitor, chemotherapy, immunotherapy)<br>Patients receive tyrosine kinase inhibitor therapy PO targeting the initial oncogenic driver or other treatment for about 3 weeks. | Drug: Chemotherapy<br>* Receive other treatment<br>* Other names: Chemotherapy, Cancer, General;Biological: Immunotherapy<br>* Receive other treatment<br>* Other names: Immunologically Directed Therapy;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Tyrosine Kinase Inhibitor<br>* Given PO<br>* Other names: TK Inhibitors;|
| Experimental: Arm III (kinase inhibitor, targeted therapy, other treatment)<br>Patients receive tyrosine kinase inhibitor therapy PO targeting initial oncogenic driver, a drug targeting the secondary mutation, or other treatment for about 3 weeks. | Drug: Chemotherapy<br>* Receive other treatment<br>* Other names: Chemotherapy, Cancer, General;Biological: Immunotherapy<br>* Receive other treatment<br>* Other names: Immunologically Directed Therapy;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Targeted Molecular Therapy<br>* Receive drug targeting secondary mutation<br>* Other names: molecularly targeted therapy;Drug: Tyrosine Kinase Inhibitor<br>* Given PO<br>* Other names: TK Inhibitors;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective response rate in patients with high PD-L1 expressing cancers after failure of targeted therapy defined as complete or partial response according to the investigator's assessment | A Simon's two-stage design will be used. | Up to 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of adverse events measured using Common Terminology Criteria for Adverse Events version 4.0 | Toxicities for each group will be estimated and described using counts and frequencies by grade, location and relatedness. | Up to 30 days after the last dose of study treatment | 
| Incidence of mutations in secondary genes for patients with PD-L1 expression < 50% |  | Up to 3 years | 
| Objective response rates for patients without high PD-L1 expressing cancers | Objective response rates will be estimates in the two PD-L1 expression < 50% arms. Confidence intervals for each of these rates will be estimated. An exploratory comparison will be made among the three groups comparing complete response/partial response versus stable disease/progressive disease among the groups using a Fisher's exact test (for the 2x3 table). | Up to 3 years | 
| Objective response rates for the combined population to historical controls receiving second or third line targeted agents | Objective response rates will be estimates in the two PD-L1 expression < 50% arms. Confidence intervals for each of these rates will be estimated. An exploratory comparison will be made among the three groups comparing complete response/partial response versus stable disease/progressive disease among the groups using a Fisher's exact test (for the 2x3 table). | Up to 3 years | 
| Overall survival | Estimated using Kaplan-Meier methods and survival rates will be compared using log-rank tests. | From date of progression on primary targeted treatment to death, assessed up to 3 years | 
| Rate of tobacco use and mutation burden based on PD-L1 expression at time of progression |  | Up to 3 years | 
| Smoking status defined as current, former, never | Whether smoking status is related to the prevalence of any mutations identified (present/absent) will be examined using Cochran-Maentel Haenzel tests. These tests will be performed overall and then separately in the three arms. | At baseline |