EGFR Activating Mutation, Recurrent Non-Small Cell Lung Carcinoma, Stage IV Non-Small Cell Lung Cancer
Conditions
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.
Interventions
DRUGChemotherapy
Receive other treatment
BIOLOGICALImmunotherapy
Receive other treatment
OTHERLaboratory Biomarker Analysis
Correlative studies
BIOLOGICALNivolumab
Given IV
BIOLOGICALPembrolizumab
Given IV
Receive drug targeting secondary mutation
DRUGTyrosine Kinase Inhibitor
Given PO
Sponsors
National Cancer Institute (NCI)
Wake Forest University Health Sciences
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
| 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 |
Countries
United States
Participant flow
Recruitment details
Nineteen patients were enrolled in the study from March 2017 to January 2018. Thirteen patients did not progress on the initial tyrosine kinase inhibitor treatment within one year. The data entered here relate to the six patients who did progress within one year.
Pre-assignment details
Thirteen patients did not progress within one year after treatment with a tyrosine kinase inhibitor and did not continue on the study.
Participants by arm
| Arm | Count |
|---|---|
| Arm I (Nivolumab, 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.
Laboratory Biomarker Analysis: Correlative studies
Nivolumab: Given IV
Pembrolizumab: Given IV | 1 |
| Arm II (Kinase Inhibitor, Chemotherapy, Immunotherapy) Patients receive tyrosine kinase inhibitor therapy PO targeting the initial oncogenic driver or other treatment for about 3 weeks.
Chemotherapy: Receive other treatment
Immunotherapy: Receive other treatment
Laboratory Biomarker Analysis: Correlative studies
Tyrosine Kinase Inhibitor: Given PO | 2 |
| Arm III (Kinase Inhibitor, Targeted Therapy, Other Treatment) Patients receive tyrosine kinase inhibitor therapy PO targeting initial oncogenic driver, a drug targeting the secondary mutation, or other treatment for about 3 weeks.
Chemotherapy: Receive other treatment
Immunotherapy: Receive other treatment
Laboratory Biomarker Analysis: Correlative studies
Targeted Molecular Therapy: Receive drug targeting secondary mutation
Tyrosine Kinase Inhibitor: Given PO | 3 |
| Total | 6 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Withdrawal by Subject | 0 | 1 | 1 |
Baseline characteristics
| Characteristic | Arm I (Nivolumab, Pembrolizumab) | Arm II (Kinase Inhibitor, Chemotherapy, Immunotherapy) | Arm III (Kinase Inhibitor, Targeted Therapy, Other Treatment) | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 1 Participants | 1 Participants | 2 Participants |
| Age, Categorical Between 18 and 65 years | 1 Participants | 1 Participants | 2 Participants | 4 Participants |
| Age, Continuous | 61 years STANDARD_DEVIATION 0 | 54.5 years STANDARD_DEVIATION 17.7 | 63.7 years STANDARD_DEVIATION 3.5 | 60.2 years STANDARD_DEVIATION 9.4 |
| Race/Ethnicity, Customized Race African American (Black) | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Race Asian | 1 Participants | 0 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized Race Caucasian (White) | 0 Participants | 1 Participants | 2 Participants | 3 Participants |
| Region of Enrollment United States | 1 participants | 2 participants | 3 participants | 6 participants |
| Sex: Female, Male Female | 1 Participants | 1 Participants | 2 Participants | 4 Participants |
| Sex: Female, Male Male | 0 Participants | 1 Participants | 1 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 1 | 2 / 2 | 2 / 3 |
| other Total, other adverse events | 1 / 1 | 1 / 1 | 3 / 3 |
| serious Total, serious adverse events | 0 / 1 | 1 / 1 | 2 / 3 |
Outcome results
Primary
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
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
Time frame: Up to 1 year after failure of targeted therapy
Population: This outcome applies only to Arm I.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm I (Nivolumab, Pembrolizumab) | 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 | Partial Response | 1 Participants |
| Arm I (Nivolumab, Pembrolizumab) | 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 | Stable Disease | 0 Participants |
| Arm II (Kinase Inhibitor, Chemotherapy, Immunotherapy) | 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 | Partial Response | 0 Participants |
| Arm II (Kinase Inhibitor, Chemotherapy, Immunotherapy) | 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 | Stable Disease | 0 Participants |
| Arm III (Kinase Inhibitor, Targeted Therapy, Other Treatment) | 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 | Partial Response | 0 Participants |
| Arm III (Kinase Inhibitor, Targeted Therapy, Other Treatment) | 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 | Stable Disease | 0 Participants |
Secondary
Number of Mutations in Secondary Genes for Patients With PD-L1 Expression < 50%
This outcome applies to only Arms II and III.
Time frame: Up to 1 year after failure of targeted therapy
Population: This outcome applies only to Arms II and III; secondary gene mutation testing was not done in Arm I.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm II (Kinase Inhibitor, Chemotherapy, Immunotherapy) | Number of Mutations in Secondary Genes for Patients With PD-L1 Expression < 50% | Alk G1202R plus ROS-1 | 0 Participants |
| Arm II (Kinase Inhibitor, Chemotherapy, Immunotherapy) | Number of Mutations in Secondary Genes for Patients With PD-L1 Expression < 50% | No secondary driver identified | 2 Participants |
| Arm II (Kinase Inhibitor, Chemotherapy, Immunotherapy) | Number of Mutations in Secondary Genes for Patients With PD-L1 Expression < 50% | T790M | 0 Participants |
| Arm III (Kinase Inhibitor, Targeted Therapy, Other Treatment) | Number of Mutations in Secondary Genes for Patients With PD-L1 Expression < 50% | Alk G1202R plus ROS-1 | 1 Participants |
| Arm III (Kinase Inhibitor, Targeted Therapy, Other Treatment) | Number of Mutations in Secondary Genes for Patients With PD-L1 Expression < 50% | No secondary driver identified | 0 Participants |
| Arm III (Kinase Inhibitor, Targeted Therapy, Other Treatment) | Number of Mutations in Secondary Genes for Patients With PD-L1 Expression < 50% | T790M | 2 Participants |
Secondary
Number of Participants With 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.
Time frame: 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.
Population: One patient in Arm II refused additional treatment and was not evaluated for adverse events, although this patient was followed for survival.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm I (Nivolumab, Pembrolizumab) | Number of Participants With Adverse Events Measured Using Common Terminology Criteria for Adverse Events Version 4.0 | 1 Participants |
| Arm II (Kinase Inhibitor, Chemotherapy, Immunotherapy) | Number of Participants With Adverse Events Measured Using Common Terminology Criteria for Adverse Events Version 4.0 | 1 Participants |
| Arm III (Kinase Inhibitor, Targeted Therapy, Other Treatment) | Number of Participants With Adverse Events Measured Using Common Terminology Criteria for Adverse Events Version 4.0 | 3 Participants |
Secondary
Objective Response Rates for Patients Without High PD-L1 Expressing Cancers
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.
Time frame: Up to 3 years after failure of targeted therapy
Population: One patient in Arm II refused additional treatment and is not evaluable for response; one patient in Arm III expired one month after starting secondary treatment and is not evaluable for response.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm I (Nivolumab, Pembrolizumab) | Objective Response Rates for Patients Without High PD-L1 Expressing Cancers | Progressive Disease | 0 Participants |
| Arm I (Nivolumab, Pembrolizumab) | Objective Response Rates for Patients Without High PD-L1 Expressing Cancers | Partial Response | 1 Participants |
| Arm II (Kinase Inhibitor, Chemotherapy, Immunotherapy) | Objective Response Rates for Patients Without High PD-L1 Expressing Cancers | Progressive Disease | 1 Participants |
| Arm II (Kinase Inhibitor, Chemotherapy, Immunotherapy) | Objective Response Rates for Patients Without High PD-L1 Expressing Cancers | Partial Response | 0 Participants |
| Arm III (Kinase Inhibitor, Targeted Therapy, Other Treatment) | Objective Response Rates for Patients Without High PD-L1 Expressing Cancers | Progressive Disease | 1 Participants |
| Arm III (Kinase Inhibitor, Targeted Therapy, Other Treatment) | Objective Response Rates for Patients Without High PD-L1 Expressing Cancers | Partial Response | 1 Participants |
Secondary
Overall Survival
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.
Time frame: From date of progression on primary targeted treatment to death, assessed up to 3 years.
Population: Patient records were reviewed at this time for all six patients.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm I (Nivolumab, Pembrolizumab) | Overall Survival | 36 months |
| Arm II (Kinase Inhibitor, Chemotherapy, Immunotherapy) | Overall Survival | 8.3 months |
| Arm III (Kinase Inhibitor, Targeted Therapy, Other Treatment) | Overall Survival | 2.56 months |
Secondary
Rate of Tobacco Use and Mutation Burden Based on PD-L1 Expression at Time of Progression
Smoking History was defined as Never, Former or Current
Time frame: Assessed at enrollment into study.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm I (Nivolumab, Pembrolizumab) | Rate of Tobacco Use and Mutation Burden Based on PD-L1 Expression at Time of Progression | Currently Smoke | 0 Participants |
| Arm I (Nivolumab, Pembrolizumab) | Rate of Tobacco Use and Mutation Burden Based on PD-L1 Expression at Time of Progression | Never Smoked | 1 Participants |
| Arm I (Nivolumab, Pembrolizumab) | Rate of Tobacco Use and Mutation Burden Based on PD-L1 Expression at Time of Progression | Formerly Smoked | 0 Participants |
| Arm II (Kinase Inhibitor, Chemotherapy, Immunotherapy) | Rate of Tobacco Use and Mutation Burden Based on PD-L1 Expression at Time of Progression | Currently Smoke | 0 Participants |
| Arm II (Kinase Inhibitor, Chemotherapy, Immunotherapy) | Rate of Tobacco Use and Mutation Burden Based on PD-L1 Expression at Time of Progression | Formerly Smoked | 0 Participants |
| Arm II (Kinase Inhibitor, Chemotherapy, Immunotherapy) | Rate of Tobacco Use and Mutation Burden Based on PD-L1 Expression at Time of Progression | Never Smoked | 2 Participants |
| Arm III (Kinase Inhibitor, Targeted Therapy, Other Treatment) | Rate of Tobacco Use and Mutation Burden Based on PD-L1 Expression at Time of Progression | Currently Smoke | 0 Participants |
| Arm III (Kinase Inhibitor, Targeted Therapy, Other Treatment) | Rate of Tobacco Use and Mutation Burden Based on PD-L1 Expression at Time of Progression | Formerly Smoked | 2 Participants |
| Arm III (Kinase Inhibitor, Targeted Therapy, Other Treatment) | Rate of Tobacco Use and Mutation Burden Based on PD-L1 Expression at Time of Progression | Never Smoked | 1 Participants |
Comparison: Null Hypothesis is that each arm has equal rates of smoking history.p-value: 0.6Fisher Exact