Recurrent Lung Non-Small Cell Carcinoma, Stage IV Lung Non-Small Cell Cancer AJCC v7
Conditions
Brief summary
This randomized phase II trial studies how well giving erlotinib hydrochloride and cabozantinib-s-malate alone or in combination works as second or third line therapy in treating patient with stage IV non-small cell lung cancer. Erlotinib hydrochloride and cabozantinib-s-malate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known whether giving erlotinib hydrochloride together with cabozantinib-s-malate is more effective than erlotinib hydrochloride or cabozantinib-s-malate alone in treating non-small cell lung cancer.
Detailed description
PRIMARY OBJECTIVES: I. To compare the progression-free survival (PFS) associated with patients treated with erlotinib (erlotinib hydrochloride) versus (vs) erlotinib plus cabozantinib (cabozantinib-s-malate). II. To compare the PFS associated with patients treated with erlotinib vs cabozantinib. SECONDARY OBJECTIVES: I. To evaluate overall survival in the three treatment arms. II. To evaluate best objective response rate in the three treatment arms. III. To define the toxicity associated with each regimen. IV. To conduct correlative science studies that will help to select predictive biomarkers of response to therapy, including mesenchymal-epidermal transition (MET) expression and potentially other tissue biomarkers, plasma biomarkers, and bone scans. OUTLINE: Patients are randomized to 1 of 3 treatment arms. ARM A (erlotinib): Patients receive erlotinib orally (PO) daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. ARM B (cabozantinib): Patients receive cabozantinib PO daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. ARM C (erlotinib+cabozantinib): Patients receive erlotinib as patients in Arm A and cabozantinib as patients in Arm B. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. ARM Z: Patients achieving disease progression in Arm A or Arm B may receive erlotinib and cabozantinib as patients in Arm C. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 3 months for 2 years and then every 6 months for 3 years.
Interventions
DRUGCabozantinib S-malate
Given PO
DRUGErlotinib Hydrochloride
Given PO
OTHERLaboratory Biomarker Analysis
Correlative studies
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Criteria: * Tumor with a sensitizing mutation in epidermal growth factor receptor (EGFR), defined as follows: * EGFR mutation testing of tumor has been performed and did not demonstrate an EGFR tyrosine kinase inhibitor sensitizing mutation; at minimum, testing for EGFR exon 19 deletion and exon 21 L858R mutations must have been included; OR * EGFR mutation testing has been attempted and is inconclusive (for example, due to lack of sufficient deoxyribonucleic acid \[DNA\] yield); OR * EGFR mutation status is unknown but tumor is positive for at least one alternative driver mutation, i.e: Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation, v-raf murine sarcoma viral oncogene homolog B (BRAF) mutation, human epidermal growth factor receptor 2 (HER2) mutation, ret proto-oncogene (RET) rearrangement/fusion, or one not listed following approval by the study chair prior to registration Inclusion Criteria: * INCLUSION CRITERIA STEP 1: * Cytologically or histologically confirmed non-small cell lung carcinoma (NSCLC) * Predominant non-squamous histology (patients with NSCLC not otherwise specified \[NOS\] are eligible); mixed tumors will be categorized by the predominant cell type; if small cell elements are present the patient is ineligible * Stage IV disease (includes M1a, M1b, or recurrent disease), according to the 7th edition of the lung cancer TNM classification system * Patients must have measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1 criteria; baseline measurements and evaluation of all sites of disease must be obtained within 4 weeks prior to registration * Prior to registration, the investigator/site must confirm that sufficient pathology material representative of patient's cancer is available for submission for MET immunohistochemical (IHC) testing * Patients must have received one or two lines of prior chemotherapy (first line platinum-doublet based chemotherapy plus switch maintenance chemotherapy counts as one line of therapy); prior adjuvant chemotherapy for early stage disease does not count as one line of therapy if 12 months or greater elapsed between completion of adjuvant therapy and initiation of first-line systemic therapy; if less than 12 months elapsed, adjuvant chemotherapy counts as one line of therapy * Any prior chemotherapy (based on administration schedule) must have been completed in greater than or equal to the time frames specified in the protocol * Patients must have discontinued treatment with any other type of investigational agent \>= 4 weeks prior to registration * Patients must have recovered to baseline or Common Terminology Criteria for Adverse Events (CTCAE) v 4.0 =\< grade 1 from toxicity due to all prior therapies except alopecia and other non-clinically significant adverse events (AEs) * Patients with no known brain metastasis at baseline must have baseline brain imaging within 12 weeks prior to study registration not demonstrating brain metastases; patients with brain metastases at baseline must have baseline brain imagining within 4 weeks prior to study registration and meet all of the specific criteria for brain mets listed in the protocol * Radiation related toxicities must have resolved to =\< grade 1 prior to registration * Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status between 0-2 * Patients must have an anticipated life expectancy greater than 3 months * Acceptable bone marrow, renal and hepatic function within 2 weeks prior to registration as defined in the protocol * Patients must have corrected QT interval calculated by the Fridericia formula (QTcF) =\< 500 ms within 28 days before registration * Patients must be able to swallow tablets * INCLUSION CRITERIA STEP 2: * Patients must have met all eligibility requirements for Step 1 at time of registration to Step 1 to be eligible for Step 2 * Patients must have radiographic progressive disease per RECIST v1.1 criteria after \>= 2 courses of therapy on Arm A or Arm B * Patients must be registered to Step 2 within 4 weeks of the last dose of treatment administration from Step 1 * Patients must have an ECOG performance status between 0-2 * Patients must have recovered to baseline (pre-Step 1) or CTCAE version 4.0 \<= grade 1 from toxicity due to all prior therapies except alopecia and other non-clinically significant AEs
Exclusion criteria
*
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS) | Assessed every 3 months if patient is < 2 years from study entry; every 6 months if patient is 2 - 5 years from study entry, up to 5 years | PFS is defined as the time from randomization to documented disease progression or death from any cause, whichever occurred first. Patients who had not experienced an event of interest by the time of analysis were censored at the date of last disease assessment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | Assessed every 3 months if patient is < 2 years from study entry; every 6 months if patient is 2 - 5 years from study entry, up to 5 years | OS is defined as the time from randomization to death from any cause or date of last known alive. |
| Proportion of Patients With Objective Response | Assessed every 3 months if patient is < 2 years from study entry; every 6 months if patient is 2 - 5 years from study entry, up to 5 years | Objective response is defined as complete response (CR) or partial response (PR) evaluated using RECIST v 1.1. CR is defined as disappearance of all lesions and any pathological lymph nodes must have reduction in short axis to \< 10 mm. PR is defined as at least a 30% decrease in the sum of the diameters of target lesions and persistence of one or more non-target lesion(s). |
| Proportion of Patients With MET Positivity | Assessed at baseline | Submission of archival tissue for central MET IHC testing was required for this study, and total MET IHC testing was conducted at the Brigham and Women's Hospital using the c-Met clone CVD13 (arabbit polyclonal). Membranous and cytoplasmic staining were individually scored, and positivity was declared if MET was expressed in either the membrane or cytoplasm. |
| Proportion of Patients With Worst Grade Toxicities of Grade 3 or Higher | Assessed every 4 weeks while on treatment and for 30 days after the end of treatment | — |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORJoel W Neal
ECOG-ACRIN Cancer Research Group
Participant flow
Recruitment details
This study was activated on February 7, 2013 and closed to accrual on July 1, 2014 with final accrual of 125 patients. Among these, a total of 20 patients registered to Step 2.
Participants by arm
| Arm | Count |
|---|---|
| Arm A (Erlotinib) Patients receive erlotinib 150mg PO daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. | 38 |
| Arm B (Cabozantinib) Patients receive cabozantinib 60mg PO daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. | 38 |
| Arm C (Erlotinib+Cabozantinib) Patients receive erlotinib 150mg PO daily and cabozantinib 40mg PO daily. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. | 35 |
| Total | 111 |
Baseline characteristics
| Characteristic | Arm A (Erlotinib) | Arm B (Cabozantinib) | Arm C (Erlotinib+Cabozantinib) | Total |
|---|---|---|---|---|
| Age, Continuous | 68 years | 65 years | 63 years | 66 years |
| Sex: Female, Male Female | 20 Participants | 24 Participants | 17 Participants | 61 Participants |
| Sex: Female, Male Male | 18 Participants | 14 Participants | 18 Participants | 50 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| other Total, other adverse events | 35 / 40 | 40 / 40 | 38 / 39 | 19 / 20 |
| serious Total, serious adverse events | 13 / 40 | 28 / 40 | 28 / 39 | 12 / 20 |
Outcome results
Primary
Progression-free Survival (PFS)
PFS is defined as the time from randomization to documented disease progression or death from any cause, whichever occurred first. Patients who had not experienced an event of interest by the time of analysis were censored at the date of last disease assessment.
Time frame: Assessed every 3 months if patient is < 2 years from study entry; every 6 months if patient is 2 - 5 years from study entry, up to 5 years
Population: Eligible and treated patients
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A (Erlotinib) | Progression-free Survival (PFS) | 1.8 months |
| Arm B (Cabozantinib) | Progression-free Survival (PFS) | 4.3 months |
| Arm C (Erlotinib+Cabozantinib) | Progression-free Survival (PFS) | 4.7 months |
80% CI: [0.25, 0.53]
80% CI: [0.27, 0.55]
Secondary
Overall Survival (OS)
OS is defined as the time from randomization to death from any cause or date of last known alive.
Time frame: Assessed every 3 months if patient is < 2 years from study entry; every 6 months if patient is 2 - 5 years from study entry, up to 5 years
Population: Eligible and treated patients
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A (Erlotinib) | Overall Survival (OS) | 5.1 months |
| Arm B (Cabozantinib) | Overall Survival (OS) | 9.2 months |
| Arm C (Erlotinib+Cabozantinib) | Overall Survival (OS) | 13.3 months |
Secondary
Proportion of Patients With MET Positivity
Submission of archival tissue for central MET IHC testing was required for this study, and total MET IHC testing was conducted at the Brigham and Women's Hospital using the c-Met clone CVD13 (arabbit polyclonal). Membranous and cytoplasmic staining were individually scored, and positivity was declared if MET was expressed in either the membrane or cytoplasm.
Time frame: Assessed at baseline
Population: Eligible and treated patients who had sufficient samples for MET expression analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A (Erlotinib) | Proportion of Patients With MET Positivity | 0.80 proportion of participants |
| Arm B (Cabozantinib) | Proportion of Patients With MET Positivity | 0.81 proportion of participants |
| Arm C (Erlotinib+Cabozantinib) | Proportion of Patients With MET Positivity | 0.96 proportion of participants |
Secondary
Proportion of Patients With Objective Response
Objective response is defined as complete response (CR) or partial response (PR) evaluated using RECIST v 1.1. CR is defined as disappearance of all lesions and any pathological lymph nodes must have reduction in short axis to \< 10 mm. PR is defined as at least a 30% decrease in the sum of the diameters of target lesions and persistence of one or more non-target lesion(s).
Time frame: Assessed every 3 months if patient is < 2 years from study entry; every 6 months if patient is 2 - 5 years from study entry, up to 5 years
Population: Eligible and treated patients
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A (Erlotinib) | Proportion of Patients With Objective Response | 0.03 proportion of participants |
| Arm B (Cabozantinib) | Proportion of Patients With Objective Response | 0.11 proportion of participants |
| Arm C (Erlotinib+Cabozantinib) | Proportion of Patients With Objective Response | 0.03 proportion of participants |
Secondary
Proportion of Patients With Worst Grade Toxicities of Grade 3 or Higher
Time frame: Assessed every 4 weeks while on treatment and for 30 days after the end of treatment
Population: All patients who received protocol therapy
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A (Erlotinib) | Proportion of Patients With Worst Grade Toxicities of Grade 3 or Higher | 0.325 Proportion of participants |
| Arm B (Cabozantinib) | Proportion of Patients With Worst Grade Toxicities of Grade 3 or Higher | 0.70 Proportion of participants |
| Arm C (Erlotinib+Cabozantinib) | Proportion of Patients With Worst Grade Toxicities of Grade 3 or Higher | 0.718 Proportion of participants |