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

Phase 2

Terminated

• Conditions: EGFR Activating Mutation; Recurrent Non-Small Cell Lung Carcinoma; Stage IV Non-Small Cell Lung Cancer
• Interventions: Other: Laboratory Biomarker Analysis; Drug: Chemotherapy; Biological: Nivolumab; Biological: Immunotherapy; Biological: Pembrolizumab; Drug: Targeted Molecular Therapy; Drug: Tyrosine Kinase Inhibitor

• Registration Number: NCT02949843
• Lead Sponsor: Wake Forest University Health Sciences

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.

Study Timeline

• Study First Submitted: 2016-10-27
• Study First Submitted QC: 2016-10-27
• Study First Posted: 2016-10-31
• Study Start: 2017-03-10
• Primary Completion: 2018-01-08
• Study Completion: 2021-01-12
• Results First Submitted: 2024-03-06
• Status Verified: 2024-06
• Results First Submitted QC: 2024-06-26
• Last Update Submitted: 2024-06-26
• Results First Posted: 2024-06-28
• Last Update Posted: 2024-06-28

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 19

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

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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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm I (nivolumab, pembrolizumab)	Laboratory Biomarker Analysis	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.
Arm I (nivolumab, pembrolizumab)	Nivolumab	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.
Arm II (kinase inhibitor, chemotherapy, immunotherapy)	Immunotherapy	Patients receive tyrosine kinase inhibitor therapy PO targeting the initial oncogenic driver or other treatment for about 3 weeks.
Arm II (kinase inhibitor, chemotherapy, immunotherapy)	Laboratory Biomarker Analysis	Patients receive tyrosine kinase inhibitor therapy PO targeting the initial oncogenic driver or other treatment for about 3 weeks.
Arm III (kinase inhibitor, targeted therapy, other treatment)	Chemotherapy	Patients receive tyrosine kinase inhibitor therapy PO targeting initial oncogenic driver, a drug targeting the secondary mutation, or other treatment for about 3 weeks.
Arm III (kinase inhibitor, targeted therapy, other treatment)	Immunotherapy	Patients receive tyrosine kinase inhibitor therapy PO targeting initial oncogenic driver, a drug targeting the secondary mutation, or other treatment for about 3 weeks.
Arm III (kinase inhibitor, targeted therapy, other treatment)	Laboratory Biomarker Analysis	Patients receive tyrosine kinase inhibitor therapy PO targeting initial oncogenic driver, a drug targeting the secondary mutation, or other treatment for about 3 weeks.
Arm III (kinase inhibitor, targeted therapy, other treatment)	Targeted Molecular Therapy	Patients receive tyrosine kinase inhibitor therapy PO targeting initial oncogenic driver, a drug targeting the secondary mutation, or other treatment for about 3 weeks.
Arm I (nivolumab, pembrolizumab)	Pembrolizumab	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.
Arm II (kinase inhibitor, chemotherapy, immunotherapy)	Chemotherapy	Patients receive tyrosine kinase inhibitor therapy PO targeting the initial oncogenic driver or other treatment for about 3 weeks.
Arm II (kinase inhibitor, chemotherapy, immunotherapy)	Tyrosine Kinase Inhibitor	Patients receive tyrosine kinase inhibitor therapy PO targeting the initial oncogenic driver or other treatment for about 3 weeks.
Arm III (kinase inhibitor, targeted therapy, other treatment)	Tyrosine Kinase Inhibitor	Patients receive tyrosine kinase inhibitor therapy PO targeting initial oncogenic driver, a drug targeting the secondary mutation, or other treatment for about 3 weeks.

Primary Outcome Measures

Name	Time	Method
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	Up to 1 year after failure of targeted therapy	Objective Response is defined as Complete Response (CR), Partial Response (PR), Stable Disease (SD) or Progressive Disease (PD). This outcome applies only to Arm I. \* Complete Response (CR): Disappearance of all target lesions, \* Partial Response (PR): At least a 30% decrease in the sum of the target lesions Progressive Disease (PD): At least a 20% increase in the sum of the target lesions, Stable Disease (SD): Neither sufficient shrinkage to qualify for partial response nor sufficient increase to qualify for progressive disease

Secondary Outcome Measures

Name	Time	Method
Number of Mutations in Secondary Genes for Patients With PD-L1 Expression < 50%	Up to 1 year after failure of targeted therapy	This outcome applies to only Arms II and III.
Overall Survival	From date of progression on primary targeted treatment to death, assessed up to 3 years.	Estimated using Kaplan-Meier methods and survival rates will be compared using log-rank tests.; Note: Log-rank tests will not be used due to the very low sample size.
Rate of Tobacco Use and Mutation Burden Based on PD-L1 Expression at Time of Progression	Assessed at enrollment into study.	Smoking History was defined as Never, Former or Current
Number of Participants With Adverse Events Measured Using Common Terminology Criteria for Adverse Events Version 4.0	Adverse events were collected following each cycle of treatment (1-4) and up to 30 days after the last dose of study treatment. The average collection time from start of treatment was 7 weeks, with a range of 3 to 11 weeks.	Toxicities for each group will be estimated and described using counts and frequencies by grade, location and relatedness.
Objective Response Rates for Patients Without High PD-L1 Expressing Cancers	Up to 3 years after failure of targeted therapy	Objective response rates will be estimated in the two PD-L1 expression \< 50% arms. At the time of protocol development, the intention was to estimate confidence intervals for each of these rates, and to make an exploratory comparison 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). Due to the low numbers of patients evaluable for response, these analyses were not performed.

Trial Locations

Locations (1)

Comprehensive Cancer Center of Wake Forest University; 🇺🇸 Winston-Salem, North Carolina, United States