Metastatic Lung Non-Small Cell Carcinoma, Recurrent Lung Non-Small Cell Carcinoma, Stage IVA Lung Cancer AJCC v8, Stage IVB Lung Cancer AJCC v8, Stage IV Lung Cancer AJCC v8
Conditions
Brief summary
This phase II trial studies how well ramucirumab and pembrolizumab work in treating EGFR mutant non-small cell lung cancer that has come back (recurrent) or spread to other places in the body (metastatic) while on systemic therapy. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Ramucirumab, a drug which has anti-angiogenic and pleotropic immunomodulatory effects and may synergize with the effect of an anti-PD-1 agent. The study investigates the effect of targeted anti-antitumor activity of immune checkpoint inhibitor pembrolizumab and immune-suppressive activity of VEGF-inhibitor ramicirumab to evaluate the efficacy and the tolerability of the combination.
Detailed description
PRIMARY OBJECTIVE: I. To evaluate response rate of the combination of ramucirumab and pembrolizumab in EGFR mutant non-small cell lung cancer (NSCLC). SECONDARY OBJECTIVE: I. To evaluate safety, tolerability, and survival for patients receiving pembrolizumab and ramucirumab. EXPLORATORY OBJECTIVE: I. To characterize predictive immunologic biomarkers of response in tissue and peripheral blood of patients receiving ramucirumab and pembrolizumab combination therapy. OUTLINE: Patients receive ramucirumab intravenously (IV) over 60 minutes and pembrolizumab IV over 30 minutes on day 1. Treatment repeats every 21 days for up to 35 cycles in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 30 days, every 3 months for 1 year, and then every 6 months for 1 year.
Interventions
BIOLOGICALPembrolizumab
Given IV
BIOLOGICALRamucirumab
Given IV
Sponsors
Ohio State University Comprehensive Cancer Center
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Adult patients aged ≥18 years 2. Histologically confirmed recurrent or metastatic non-small cell carcinoma of the lung with sensitizing EGFR mutations. Exon 20 resistance mutations will not be permitted but uncommon sensitizing mutations are allowed. 3. Prior Systemic Anticancer Therapy: Neo/adjuvant therapy or prior therapy for locally advanced disease will be permitted. Patients with prior exposure to PD/PD-L1 inhibitors will be excluded. No limit on prior EGFR TKIs (erlotinib, gefitinib, afatinib, dacomitinib or osimertinib). Prior chemotherapy for metastatic disease is permitted only. A 7 day washout period or four half-lives after the last treatment dose, whichever is longer, is required for TKI. A 4 week washout is required for cytotoxic chemotherapy. 4. Measurable disease per RECIST criteria 5. ECOG performance status of 0-1 6. Adequate organ function, hematologic, hepatic, renal and coagulation parameters as defined in the protocol. 7. Because the teratogenicity of ramucirumab is not known, the patient, if sexually active, must be postmenopausal, surgically sterile, or using effective contraception (hormonal or barrier methods). 8. Female patients of childbearing potential must have a negative serum pregnancy test within 72 hours prior to first dose of protocol therapy.
Exclusion criteria
1. Active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment. 2. Known active chronic infections - HIV/AIDS, known active Hepatitis B or C. Known history of Hepatitis B (defined as Hepatitis B surface antigen \[HBsAg\] reactive) or known active Hepatitis C virus (defined as HCV RNA \[qualitative\] is detected) infection. Note: no testing for Hepatitis B and Hepatitis C is required unless mandated by local health authority. 3. Cirrhosis (Child-Pugh B or worse) or cirrhosis with history of hepatic encephalopathy or clinically meaningful ascites resulting from cirrhosis. 4. Prior exposure to ramucirumab. 5. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX-40, CD137). 6. Any Grade 3-4 GI bleeding within 3 months prior to first dose of protocol therapy. 7. History of deep vein thrombosis (DVT), pulmonary embolism (PE), or any other significant thromboembolism (venous port or catheter thrombosis or superficial venous thrombosis are not considered significant) during the 3 months prior to first dose of protocol therapy. 8. Patients receiving dipyridamole, clopidogrel, or similar agents. Once-daily aspirin use (maximum dose 325 mg/day) is permitted. 9. Uncontrolled CNS metastases. Patients with treated brain metastases are eligible if they were clinically stable with regard to neurologic function, off steroids after cranial irradiation (whole brain radiation therapy, focal radiation therapy, and stereotactic radiosurgery) ending at least 2 weeks prior to first dose of study treatment, or after surgical resection performed at least 28 days prior to first dose of study treatment. The patient must have no evidence of Grade ≥1 CNS hemorrhage based on pretreatment MRI or IV contrast CT scan (performed within 28 days before first dose of study treatment). Note: Patients who received systemic therapy that adequately and appropriately treated CNS metastases, including tyrosine kinase inhibitors, are eligible provided that CNS disease control is confirmed by pretreatment MRI within 28 days of receiving first dose of study treatment. 10. Hemoptysis (defined as bright red blood or ≥ 1/2 teaspoon) within 2 months prior to first dose of protocol therapy or with radiographic evidence of intratumor cavitation or has radiologically documented evidence of major blood vessel invasion or encasement by cancer. 11. Uncontrolled or poorly-controlled hypertension (\>160 mmHg systolic or \> 100 mmHg diastolic for \>4 weeks) despite standard medical management. 12. Any arterial thromboembolic events, including but not limited to myocardial infarction, transient ischemic attack, cerebrovascular accident, or unstable angina, within 6 months prior to first dose of protocol therapy. 13. Major surgery within 28 days or device placement within 7 days prior to the first dose of protocol therapy. Patient has elective or planned major surgery to be performed during the course of the clinical trial. 14. Serious or non-healing wound, ulcer, or bone fracture within 28 days of study treatment. 15. Prior history of GI perforation/fistula (within 6 months of first dose of protocol therapy) or risk factors for perforation. 16. Small cell or mixed (small cell/non-small cell) lung cancer 17. Pregnancy or breastfeeding. 18. Has received a live vaccine within 30 days prior to the first dose of study drug. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®) are live attenuated vaccines and are not allowed. 19. History of (non-infectious) pneumonitis that required steroids or has current pneumonitis. 20. History or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject's participation for the full duration of the study, or is not in the best interest of the subject to participate, in the opinion of the treating investigator. 21. Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial. 22. Severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients. 23. Active infection requiring systemic therapy. 24. Known history of active TB (Bacillus Tuberculosis).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate | Up to 2 years | Response rate will be evaluated with computed tomography (CT) scans every 2 cycles and tumor measurements using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. Immune RECIST (iRECIST) will also be assessed. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Clinical Benefit Rate (Complete Response + Partial Response + Stable Disease) | Up to 2 years | Clinical benefit rate will be evaluated with CT scans every 2 cycles and tumor measurements using RECIST 1.1 criteria. iRECIST will also be assessed. |
| Number of Adverse Events | Up to 2 years | Common Terminology Criteria for Adverse Events version 4.0 will be used for adverse event grading. Attributions of causality will be assessed by the primary treating physician. Frequency and severity of adverse events and tolerability of the regimen will be collected and summarized by descriptive statistics for each of the disease cohorts. |
| Progression-free Survival | From the date of study registration to the date of progressive disease, assessed up to 2 years | Kaplan-Meier curves will be calculated to estimate progression-free survival. |
| Overall Survival | From the date of study registration to the date of death, assessed up to 2 years | Kaplan-Meier curves will be calculated to estimate overall survival. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Change in Circulating VEGF Levels | Baseline up to 2 years | Will evaluate correlation with clinical response. A bivariate plot will be used to describe the relationship between response rate and peak VEGF via enzyme-linked immunosorbent assay over time. |
| Circulating Immune Cell Profiles in Response to Treatment and in Relation to Clinical Response | Up to 2 years | Measured using 10-color 65 marker multiplex Clinical Laboratory Improvement Act-certified IMMUNOME flow cytometry profile on peripheral blood samples. For immune cell subpopulation data by flow cytometry, will identify differences between the paired peripheral blood mononuclear cell samples from the same patients. |
| Tumor Immunoprofile | Baseline | Measured by immunohistochemistry, including tumor infiltrating lymphocytes and T cell receptor (TCR) immunosequencing (immunoSEQ) and relationship to clinical outcomes, including response rate. TCR immunoSEQ data will be summarized for each patient for T-cell clonality difference, descriptive statistics and confidence interval will be obtained across patients. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Treatment (Ramucirumab, Pembrolizumab) Patients receive ramucirumab IV over 60 minutes and pembrolizumab IV over 30 minutes on day 1. Treatment repeats every 21 days for up to 35 cycles in the absence of disease progression or unacceptable toxicity.
Pembrolizumab: Given IV
Ramucirumab: Given IV | 6 |
| Total | 6 |
Baseline characteristics
| Characteristic | Treatment (Ramucirumab, Pembrolizumab) |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 4 Participants |
| Age, Categorical Between 18 and 65 years | 2 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 6 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 5 Participants |
| Region of Enrollment United States | 6 participants |
| Sex: Female, Male Female | 3 Participants |
| Sex: Female, Male Male | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 6 / 6 |
| other Total, other adverse events | 6 / 6 |
| serious Total, serious adverse events | 4 / 6 |
Outcome results
Primary
Overall Response Rate
Response rate will be evaluated with computed tomography (CT) scans every 2 cycles and tumor measurements using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. Immune RECIST (iRECIST) will also be assessed.
Time frame: Up to 2 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment (Ramucirumab, Pembrolizumab) | Overall Response Rate | 0 percentage of participants |
Secondary
Clinical Benefit Rate (Complete Response + Partial Response + Stable Disease)
Clinical benefit rate will be evaluated with CT scans every 2 cycles and tumor measurements using RECIST 1.1 criteria. iRECIST will also be assessed.
Time frame: Up to 2 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment (Ramucirumab, Pembrolizumab) | Clinical Benefit Rate (Complete Response + Partial Response + Stable Disease) | 50 percentage of participants |
Secondary
Number of Adverse Events
Common Terminology Criteria for Adverse Events version 4.0 will be used for adverse event grading. Attributions of causality will be assessed by the primary treating physician. Frequency and severity of adverse events and tolerability of the regimen will be collected and summarized by descriptive statistics for each of the disease cohorts.
Time frame: Up to 2 years
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Treatment (Ramucirumab, Pembrolizumab) | Number of Adverse Events | Alkaline phosphatase increased | 2 Number of Events |
| Treatment (Ramucirumab, Pembrolizumab) | Number of Adverse Events | Anemia | 3 Number of Events |
| Treatment (Ramucirumab, Pembrolizumab) | Number of Adverse Events | Hypokalemia | 1 Number of Events |
| Treatment (Ramucirumab, Pembrolizumab) | Number of Adverse Events | Hyponatremia | 9 Number of Events |
| Treatment (Ramucirumab, Pembrolizumab) | Number of Adverse Events | Osteoporosis | 1 Number of Events |
| Treatment (Ramucirumab, Pembrolizumab) | Number of Adverse Events | Pericardial effusion | 1 Number of Events |
| Treatment (Ramucirumab, Pembrolizumab) | Number of Adverse Events | Lymphocyte count decreased | 4 Number of Events |
| Treatment (Ramucirumab, Pembrolizumab) | Number of Adverse Events | Activated partial thromboplastin time prolonged | 4 Number of Events |
| Treatment (Ramucirumab, Pembrolizumab) | Number of Adverse Events | Alanine aminotransferase increased | 3 Number of Events |
| Treatment (Ramucirumab, Pembrolizumab) | Number of Adverse Events | Anorexia | 2 Number of Events |
| Treatment (Ramucirumab, Pembrolizumab) | Number of Adverse Events | Arthralgia | 1 Number of Events |
| Treatment (Ramucirumab, Pembrolizumab) | Number of Adverse Events | Aspartate aminotransferase increased | 4 Number of Events |
| Treatment (Ramucirumab, Pembrolizumab) | Number of Adverse Events | Cognitive impairment | 1 Number of Events |
| Treatment (Ramucirumab, Pembrolizumab) | Number of Adverse Events | Constipation | 2 Number of Events |
| Treatment (Ramucirumab, Pembrolizumab) | Number of Adverse Events | Diarrhea | 1 Number of Events |
| Treatment (Ramucirumab, Pembrolizumab) | Number of Adverse Events | Dysgeusia | 3 Number of Events |
| Treatment (Ramucirumab, Pembrolizumab) | Number of Adverse Events | Dysphagia | 1 Number of Events |
| Treatment (Ramucirumab, Pembrolizumab) | Number of Adverse Events | Dyspnea | 2 Number of Events |
| Treatment (Ramucirumab, Pembrolizumab) | Number of Adverse Events | Edema limbs | 3 Number of Events |
| Treatment (Ramucirumab, Pembrolizumab) | Number of Adverse Events | Encephalopathy | 2 Number of Events |
| Treatment (Ramucirumab, Pembrolizumab) | Number of Adverse Events | Epistaxis | 1 Number of Events |
| Treatment (Ramucirumab, Pembrolizumab) | Number of Adverse Events | Fall | 1 Number of Events |
| Treatment (Ramucirumab, Pembrolizumab) | Number of Adverse Events | Fatigue | 7 Number of Events |
| Treatment (Ramucirumab, Pembrolizumab) | Number of Adverse Events | Generalized muscle weakness | 1 Number of Events |
| Treatment (Ramucirumab, Pembrolizumab) | Number of Adverse Events | Headache | 2 Number of Events |
| Treatment (Ramucirumab, Pembrolizumab) | Number of Adverse Events | Hematuria | 2 Number of Events |
| Treatment (Ramucirumab, Pembrolizumab) | Number of Adverse Events | Hypercalcemia | 1 Number of Events |
| Treatment (Ramucirumab, Pembrolizumab) | Number of Adverse Events | Hyperglycemia | 3 Number of Events |
| Treatment (Ramucirumab, Pembrolizumab) | Number of Adverse Events | Hypernatremia | 1 Number of Events |
| Treatment (Ramucirumab, Pembrolizumab) | Number of Adverse Events | Hypertension | 4 Number of Events |
| Treatment (Ramucirumab, Pembrolizumab) | Number of Adverse Events | Hyperthyroidism | 1 Number of Events |
| Treatment (Ramucirumab, Pembrolizumab) | Number of Adverse Events | Hypoalbuminemia | 5 Number of Events |
| Treatment (Ramucirumab, Pembrolizumab) | Number of Adverse Events | Hypocalcemia | 1 Number of Events |
| Treatment (Ramucirumab, Pembrolizumab) | Number of Adverse Events | Hypoxia | 1 Number of Events |
| Treatment (Ramucirumab, Pembrolizumab) | Number of Adverse Events | Imbalance | 1 Number of Events |
| Treatment (Ramucirumab, Pembrolizumab) | Number of Adverse Events | Infusion related reaction | 1 Number of Events |
| Treatment (Ramucirumab, Pembrolizumab) | Number of Adverse Events | INR increased | 4 Number of Events |
| Treatment (Ramucirumab, Pembrolizumab) | Number of Adverse Events | Bacteriuria | 1 Number of Events |
| Treatment (Ramucirumab, Pembrolizumab) | Number of Adverse Events | Localized Edema | 1 Number of Events |
| Treatment (Ramucirumab, Pembrolizumab) | Number of Adverse Events | Mucositis | 1 Number of Events |
| Treatment (Ramucirumab, Pembrolizumab) | Number of Adverse Events | Myalgia | 1 Number of Events |
| Treatment (Ramucirumab, Pembrolizumab) | Number of Adverse Events | Nausea | 1 Number of Events |
| Treatment (Ramucirumab, Pembrolizumab) | Number of Adverse Events | Neuralgia | 2 Number of Events |
| Treatment (Ramucirumab, Pembrolizumab) | Number of Adverse Events | Pleural effusion | 1 Number of Events |
| Treatment (Ramucirumab, Pembrolizumab) | Number of Adverse Events | Pneumothorax | 1 Number of Events |
| Treatment (Ramucirumab, Pembrolizumab) | Number of Adverse Events | Productive cough | 2 Number of Events |
| Treatment (Ramucirumab, Pembrolizumab) | Number of Adverse Events | Proteinuria | 2 Number of Events |
| Treatment (Ramucirumab, Pembrolizumab) | Number of Adverse Events | Thromboembolic event | 1 Number of Events |
| Treatment (Ramucirumab, Pembrolizumab) | Number of Adverse Events | Rash maculo-papular | 2 Number of Events |
| Treatment (Ramucirumab, Pembrolizumab) | Number of Adverse Events | Nephrotic syndrome | 1 Number of Events |
| Treatment (Ramucirumab, Pembrolizumab) | Number of Adverse Events | Hemoptysis | 2 Number of Events |
| Treatment (Ramucirumab, Pembrolizumab) | Number of Adverse Events | Sinus tachycardia | 1 Number of Events |
| Treatment (Ramucirumab, Pembrolizumab) | Number of Adverse Events | Urinary incontinence | 1 Number of Events |
| Treatment (Ramucirumab, Pembrolizumab) | Number of Adverse Events | Vomiting | 3 Number of Events |
| Treatment (Ramucirumab, Pembrolizumab) | Number of Adverse Events | Weight gain | 3 Number of Events |
| Treatment (Ramucirumab, Pembrolizumab) | Number of Adverse Events | Weight loss | 2 Number of Events |
| Treatment (Ramucirumab, Pembrolizumab) | Number of Adverse Events | Confusion | 1 Number of Events |
Secondary
Overall Survival
Kaplan-Meier curves will be calculated to estimate overall survival.
Time frame: From the date of study registration to the date of death, assessed up to 2 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment (Ramucirumab, Pembrolizumab) | Overall Survival | 7.03 months |
Secondary
Progression-free Survival
Kaplan-Meier curves will be calculated to estimate progression-free survival.
Time frame: From the date of study registration to the date of progressive disease, assessed up to 2 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment (Ramucirumab, Pembrolizumab) | Progression-free Survival | 1.4 months |
Other Pre-specified
Change in Circulating VEGF Levels
Will evaluate correlation with clinical response. A bivariate plot will be used to describe the relationship between response rate and peak VEGF via enzyme-linked immunosorbent assay over time.
Time frame: Baseline up to 2 years
Other Pre-specified
Circulating Immune Cell Profiles in Response to Treatment and in Relation to Clinical Response
Measured using 10-color 65 marker multiplex Clinical Laboratory Improvement Act-certified IMMUNOME flow cytometry profile on peripheral blood samples. For immune cell subpopulation data by flow cytometry, will identify differences between the paired peripheral blood mononuclear cell samples from the same patients.
Time frame: Up to 2 years
Other Pre-specified
Tumor Immunoprofile
Measured by immunohistochemistry, including tumor infiltrating lymphocytes and T cell receptor (TCR) immunosequencing (immunoSEQ) and relationship to clinical outcomes, including response rate. TCR immunoSEQ data will be summarized for each patient for T-cell clonality difference, descriptive statistics and confidence interval will be obtained across patients.
Time frame: Baseline