Pembrolizumab Plus Bevacizumab for Treatment of Brain Metastases in Metastatic Melanoma or Non-small Cell Lung Cancer (NSCLC)

NCT02681549 | Completed Phase 2 Results DMC FDA Drug

• 3 other identifiers: 15120169531511MEL0071R01CA269286-01A1
• Study Type: interventional
• Target: 41
• Locations: 1 country
• Sites: 2

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.

Conditions

Melanoma; Non-small Cell Lung Cancer; Brain Metastasis

Outcome Measures

Primary Outcomes (1)

• Brain Metastasis Response Rate (BMRR)

  Brain metastasis response rate (BMRR) using modified RECIST (mRECIST) criteria

  up to 2 years from start of treatment

Secondary Outcomes (4)

• Steroid Use

  up to 2 years from start of treatment

• Overall Response Rate (ORR)

  up to 2 years from start of treatment

• Progression-free Survival (PFS)

  up to 9 years from start of treatment or to disease progression

• 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

Other Outcomes (1)

• PD-L1 Expression and Other Potential Predictive Biomarkers in CNS, Tumors and Blood, Correlated With Response to Treatment

  2 years from start of trial

Study Arms (2)

Untreated brain metastases from melanoma

EXPERIMENTAL

pembrolizumab plus bevacizumab

Drug: Pembrolizumab plus Bevacizumab

Untreated brain metastases from NSCLC

EXPERIMENTAL

pembrolizumab plus bevacizumab

Drug: Pembrolizumab plus Bevacizumab

Interventions

Pembrolizumab plus Bevacizumab DRUG

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.

Untreated brain metastases from NSCLC; Untreated brain metastases from melanoma

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• 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.
• 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.
• PD-L1 expression in tumor tissue from any site determined by the Dako 22C3 assay is required for patients with NSCLC.
• Adequate organ function.
• ECOG performance status \< 2.
• Any number of previous treatments with the exception of previous inhibitors of PD-1 or PD-L1.
• Life expectancy of at least 3 months.
• Understanding and willingness to consent.
• 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.
• 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.
• ECOG performance status \< 2
• 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.
• Life expectancy of at least 3 months
• 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.

You may not qualify if:

• Symptomatic brain metastases at the time of initiation of systemic therapy.
• Other systemic therapy within 14 days of initiation of study drug.
• Use of corticosteroids to control CNS symptoms. Low-dose steroid use (≤10 mg of prednisone or equivalent) is allowed.
• Presence of leptomeningeal disease.
• Presence of active autoimmune disease. Autoimmune thyroid disease will be allowed if thyroid function is within normal range.
• Symptomatic brain metastases. Any neurologic symptoms present must have resolved with local therapy by the time of administration of study drug.
• Patients with brain metastases for whom complete surgical resection is clinically appropriate.
• Patients with lung cancer with squamous histology.
• Has had prior chemotherapy or targeted small molecule therapy within 2 weeks prior to start of treatment or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to a previously administered agent. Previous radiation to extracranial sites may be completed at any time prior to initiation of pembrolizumab.
• Note: If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.
• Has had prior treatment with any other anti-PD-1 or PD-L1 or PD-L2 agent.
• The use of corticosteroids to control cerebral edema or treat neurologic symptoms will not be allowed, and patients who previously required corticosteroids for symptom control must be off steroids for at least 1 week prior to treatment on day 1 of cycle 1. Low-dose steroid use (≤10 mg of prednisone or equivalent) as corticosteroid replacement therapy is allowed
• Has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier.
• Presence of leptomeningeal disease
• Has 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.

Sponsors & Collaborators

• Yale University: lead
• National Cancer Institute (NCI): collaborator
• Merck Sharp & Dohme LLC: collaborator

Study Sites (2)

Smilow Cancer Hospital at Yale New Haven

New Haven, Connecticut, 06510, United States

Location

Moffitt Cancer Center

Tampa, Florida, 33612, United States

Location

Related Publications (1)

• Weiss SA, Djureinovic D, Wei W, Tran T, Austin M, Markowitz J, Eroglu Z, Khushalani NI, Hegde U, Cohen J, Sznol M, Anderson G, Johnson B, Piteo C, Mahajan A, Adeniran A, Jilaveanu L, Goldberg S, Chiang V, Forsyth P, Kluger HM. Phase II Trial of Pembrolizumab in Combination With Bevacizumab for Untreated Melanoma Brain Metastases. J Clin Oncol. 2025 May 10;43(14):1685-1694. doi: 10.1200/JCO-24-02219. Epub 2025 Mar 6.

  PMID: 40048689 DERIVED

MeSH Terms

Conditions

Melanoma; Carcinoma, Non-Small-Cell Lung; Brain Neoplasms

Interventions

pembrolizumab; Bevacizumab

Condition Hierarchy (Ancestors)

Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Neoplasms by Site; Skin Diseases; Skin and Connective Tissue Diseases; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Lung Diseases; Respiratory Tract Diseases; Central Nervous System Neoplasms; Nervous System Neoplasms; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Limitations and Caveats

At time of analysis it was found that data reported by participants for the Steroid Use outcome was incorrect and therefore unreliable and could not be used.

Results Point of Contact

• Title: Harriet Kluger, MD
• Organization: Harvey and Kate Cushing Professor of Medicine (Oncology) and of Dermatology; Director, Yale SPORE in Skin Cancer, Yale Cancer Center

harriet.kluger@yale.edu

(203) 200-6622

Study Officials

• Harriett Kluger, MD

  Yale University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: February 9, 2016
• First Posted: February 12, 2016
• Study Start: May 1, 2016
• Primary Completion: September 11, 2024
• Study Completion: March 31, 2025
• Last Updated: August 7, 2025
• Results First Posted: August 7, 2025

Record last verified: 2025-07

Data Sharing

• IPD Sharing: Will not share

Locations

US (2)