Brain Metastasis, Melanoma, Non-small Cell Lung Cancer
Conditions
Brief summary
The purpose of this phase 2 trial is to study the activity of pembrolizumab in combination with bevacizumab in patients with untreated brain metastases from melanoma or NSCLC to determine activity and safety of the drug combination. Furthermore, in patients who undergo resection of biopsy of a brain metastasis, we will evaluate biomarkers predictive of treatment benefit, and will also conduct correlative biomarker studies on extra-cerebral specimens in all patients in whom a systemic biopsy is feasible or in archival tumor tissue when available. A total of 53 eligible patients will be enrolled on this trial (40 with melanoma and 13 with NSCLC). Individual cohorts of the study can be stopped if insufficient activity is observed in the first stage of that cohort. The study will accrue for approximately 84 months, and will be open for approximately 12 additional months as patients on study are being followed.
Interventions
DRUGPembrolizumab plus Bevacizumab
Pembrolizumab will be administered on day 1 of every cycle until disease progression or withdrawal from study. Bevacizumab will be administered in addition to pembrolizumab on day 1 of cycles 1, 2, 3, and 4 (or alternative cycles if bevacizumab is held during these cycles). Three weeks constitutes one cycle.
Sponsors
National Cancer Institute (NCI)
Merck Sharp & Dohme LLC
Yale University
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Major Inclusion Criteria: 1. Biopsy proven metastatic melanoma or non-squamous NSCLC with at least one untreated brain metastasis that is at least 5 mm AND twice the MRI slice thickness, but less than 20 mm, which is asymptomatic and not requiring immediate local therapy or steroids. 2. Patients who have had prior resection or biopsy of a CNS metastasis will be required to provide a paraffin embedded specimen from tumor taken at the time of surgery, if available. 3. Patients will be required to undergo biopsy or submit archival tumor tissue from a systemic site of disease for correlative studies. When not feasible, this requirement can be waived after discussion with the principal investigators. 4. PD-L1 expression in tumor tissue from any site determined by the Dako 22C3 assay is required for patients with NSCLC. 5. Adequate organ function. 6. ECOG performance status \< 2. 7. Any number of previous treatments with the exception of previous inhibitors of PD-1 or PD-L1. 8. Life expectancy of at least 3 months. 9. Understanding and willingness to consent. 10. A history of radiotherapy for brain metastases is allowed, but any lesion present at the time of WBRT or included in the stereotactic radiotherapy field will NOT be considered evaluable unless documented to have progressed since treatment. Overall Inclusion Criteria: 1. Biopsy proven metastatic melanoma or non-squamous NSCLC with at least one untreated cerebral metastasis that is at least 5 mm AND twice the MRI slice thickness, but less than 20 mm, that is asymptomatic and does not require local therapy at the time of enrollment (clinically evaluable lesion(s)). An untreated brain metastasis is defined as a lesion not present at the time of whole brain radiation therapy or included in a stereotactic radiotherapy field (or within 2mm of a treated lesion), or any lesion that is new or unequivocally progressing since prior radiation therapy. 2. ECOG performance status \< 2 3. Any number of previous treatments with the exception of previous inhibitors of PD-1, PD-L1, or PD-L2. Other prior systemic therapies must have been administered at least 2 weeks before administration of pembrolizumab; the exception to this is ipilimumab which must have been administered at least 4 weeks prior to the start of pembrolizumab. Patients are not required to have had prior systemic therapy. 4. Life expectancy of at least 3 months 5. A history of previously treated brain metastases is allowed, provided that at least 7 days have lapsed between radiation and initiation of pembrolizumab. Any brain metastasis ≥ 20mm or causing symptoms must be treated with local therapy (i.e. radiation or surgical resection, as clinically appropriate) prior to study enrollment. Any lesion present at the time of WBRT or included in the stereotactic radiotherapy field (or within 2mm of the treated lesion) will NOT be considered evaluable unless it is new or documented to have progressed since treatment. 6. PD-L1 expression \>1% in tumor tissue from any site is required for patients with NSCLC. Tumor tissue can be archival if no intercurrent systemic therapy was administered, however if no archival tissue is available or if intercurrent systemic therapy was administered, then a biopsy must be obtained for PD-L1 testing. PD-L1 expression must be obtained using the Dako 22C3 assay in a CLIA-certified laboratory. PD-L1 expression is not required for patients with melanoma. 7. All patients are required to submit a tumor specimen for analysis (brain or extra-cerebral). A formalin-fixed paraffin-embedded (FFPE) tissue block, or a 4mm punch from an FFPE block must be submitted. If it is not possible to safely obtain a biopsy due to anatomic location of tumors, and no prior tissue is available, this requirement may be waived upon discussion with the study PI or co-PI. 8. Patients must have normal organ and marrow function (as defined in the protocol) at the time of screening. 9. Female subject of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. 10. Female subjects of childbearing potential should be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication. Subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for \> 1 year. 11. Male subjects should agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy. Major
Exclusion criteria
1. Symptomatic brain metastases at the time of initiation of systemic therapy. 2. Other systemic therapy within 14 days of initiation of study drug. 3. Use of corticosteroids to control CNS symptoms. Low-dose steroid use (≤10 mg of prednisone or equivalent) is allowed. 4. Presence of leptomeningeal disease. 5. Presence of active autoimmune disease. Autoimmune thyroid disease will be allowed if thyroid function is within normal range. Overall
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Brain Metastasis Response Rate (BMRR) | up to 2 years from start of treatment | Brain metastasis response rate (BMRR) using modified RECIST (mRECIST) criteria |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Steroid Use | up to 2 years from start of treatment | Number of patients using steroids to control of cerebral edema for greater than 96 hours |
| Overall Response Rate (ORR) | up to 2 years from start of treatment | best overall response rate (ORR) by mRECIST criteria in the brain or RECIST criteria in the body |
| Progression-free Survival (PFS) | up to 9 years from start of treatment or to disease progression | Progression-free survival by mRECIST criteria in the brain or RECIST criteria in the body |
| Safety and Toxicity of Combination Pembrolizumab and Bevacizumab Assessed Using Common Terminology Criteria for Adverse Events v. 4. | up to 2 years from start of treatment | Number of participants that experienced at least 1 treatment related adverse event. |
Other
| Measure | Time frame |
|---|---|
| PD-L1 Expression and Other Potential Predictive Biomarkers in CNS, Tumors and Blood, Correlated With Response to Treatment | 2 years from start of trial |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Untreated Brain Metastases From Melanoma pembrolizumab plus bevacizumab | 37 |
| Untreated Brain Metastases From NSCLC pembrolizumab plus bevacizumab | 4 |
| Total | 41 |
Baseline characteristics
| Characteristic | Untreated Brain Metastases From Melanoma | Untreated Brain Metastases From NSCLC | Total |
|---|---|---|---|
| Age, Continuous | 66 years | 67 years | 66 years |
| Eastern Cooperative Oncology Group (ECOG) performance status 0 | 25 units on a scale | 1 units on a scale | 26 units on a scale |
| Eastern Cooperative Oncology Group (ECOG) performance status 1 | 12 units on a scale | 4 units on a scale | 16 units on a scale |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 1 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 34 Participants | 3 Participants | 37 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 3 Participants | 0 Participants | 3 Participants |
| Mutation Status BRAF Mutant | 16 participants | — | 16 participants |
| Mutation Status BRAF WT | 19 participants | — | 19 participants |
| Mutation Status NRAS Mutant | 4 participants | — | 4 participants |
| Mutation Status Unknown Mutation Status | 2 participants | — | 2 participants |
| Mutation Status Unknown V600 type | 1 participants | — | 1 participants |
| Mutation Status V600E | 9 participants | — | 9 participants |
| Mutation Status V600K | 6 participants | — | 6 participants |
| Number of intracranial target lesions 1-2 | 23 Participants | 4 Participants | 27 Participants |
| Number of intracranial target lesions 3-5 | 14 Participants | 0 Participants | 14 Participants |
| Presence of extracranial metastases No | 5 Participants | 0 Participants | 5 Participants |
| Presence of extracranial metastases Yes | 32 Participants | 4 Participants | 36 Participants |
| Prior local therapy for MBM No | 18 Participants | 3 Participants | 21 Participants |
| Prior local therapy for MBM Yes | 19 Participants | 2 Participants | 21 Participants |
| Prior systemic therapy No | 30 Participants | 4 Participants | 34 Participants |
| Prior systemic therapy Yes | 7 Participants | 0 Participants | 7 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) White | 36 Participants | 3 Participants | 39 Participants |
| Region of Enrollment United States | 37 participants | 5 participants | 42 participants |
| Serum lactate dehydrogenase Elevated levels | 12 Participants | 0 Participants | 12 Participants |
| Serum lactate dehydrogenase Normal levels | 25 Participants | 0 Participants | 25 Participants |
| Sex: Female, Male Female | 10 Participants | 3 Participants | 13 Participants |
| Sex: Female, Male Male | 27 Participants | 1 Participants | 28 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 37 | 0 / 5 |
| other Total, other adverse events | 27 / 37 | 4 / 5 |
| serious Total, serious adverse events | 4 / 37 | 1 / 5 |
Outcome results
Primary
Brain Metastasis Response Rate (BMRR)
Brain metastasis response rate (BMRR) using modified RECIST (mRECIST) criteria
Time frame: up to 2 years from start of treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Untreated Brain Metastases From Melanoma | Brain Metastasis Response Rate (BMRR) | 54.1 percentage of participants |
| Untreated Brain Metastases From NSCLC | Brain Metastasis Response Rate (BMRR) | 75 percentage of participants |
Secondary
Overall Response Rate (ORR)
best overall response rate (ORR) by mRECIST criteria in the brain or RECIST criteria in the body
Time frame: up to 2 years from start of treatment
Population: Denominator for extracranial response is 32 because 5 patients did not have extracranial metastases at baseline
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Untreated Brain Metastases From Melanoma | Overall Response Rate (ORR) | Intracranial | 54.1 percentage of participants |
| Untreated Brain Metastases From Melanoma | Overall Response Rate (ORR) | Extracranial | 56.3 percentage of participants |
| Untreated Brain Metastases From NSCLC | Overall Response Rate (ORR) | Intracranial | 75 percentage of participants |
| Untreated Brain Metastases From NSCLC | Overall Response Rate (ORR) | Extracranial | 75 percentage of participants |
Secondary
Progression-free Survival (PFS)
Progression-free survival by mRECIST criteria in the brain or RECIST criteria in the body
Time frame: up to 9 years from start of treatment or to disease progression
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Untreated Brain Metastases From Melanoma | Progression-free Survival (PFS) | Median overall PFS | 1.2 years |
| Untreated Brain Metastases From Melanoma | Progression-free Survival (PFS) | Median intracranial PFS | 2.2 years |
| Untreated Brain Metastases From NSCLC | Progression-free Survival (PFS) | Median overall PFS | NA years |
| Untreated Brain Metastases From NSCLC | Progression-free Survival (PFS) | Median intracranial PFS | NA years |
Secondary
Safety and Toxicity of Combination Pembrolizumab and Bevacizumab Assessed Using Common Terminology Criteria for Adverse Events v. 4.
Number of participants that experienced at least 1 treatment related adverse event.
Time frame: up to 2 years from start of treatment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Untreated Brain Metastases From Melanoma | Safety and Toxicity of Combination Pembrolizumab and Bevacizumab Assessed Using Common Terminology Criteria for Adverse Events v. 4. | 32 Participants |
| Untreated Brain Metastases From NSCLC | Safety and Toxicity of Combination Pembrolizumab and Bevacizumab Assessed Using Common Terminology Criteria for Adverse Events v. 4. | 3 Participants |
Secondary
Steroid Use
Number of patients using steroids to control of cerebral edema for greater than 96 hours
Time frame: up to 2 years from start of treatment
Population: At time of analysis it was found that data reported by participants was incorrect and could not be used.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Untreated Brain Metastases From Melanoma | Steroid Use | 3 Participants |
| Untreated Brain Metastases From NSCLC | Steroid Use | 1 Participants |
Other Pre-specified
PD-L1 Expression and Other Potential Predictive Biomarkers in CNS, Tumors and Blood, Correlated With Response to Treatment
Time frame: 2 years from start of trial