Long-Term Survival of Patients With Melanoma With Active Brain Metastases Treated With Pembrolizumab on a Phase II Trial

Harriet M. Kluger, MD; Veronica Chiang, MD; Amit Mahajan, MD; Christopher R. Zito, PhD; Mario Sznol, MD; Thuy Tran, MD, PhD; Sarah A. Weiss, MD; Justine V. Cohen; James Yu, MD; Upendra Hegde, MD; Elizabeth Perrotti; Gail Anderson; Amanda Ralabate, RN; Yuval Kluger, PhD; Wei Wei, PhD; Sarah B. Goldberg, MD; Lucia B. Jilaveanu, MD, PhD

Disclosures

J Clin Oncol. 2019;37(1):52-60. 

In This Article

Abstract and Introduction

Abstract

Purpose: Pembrolizumab is active in melanoma, but activity in patients with untreated brain metastasis is less established. We present long-term follow-up of pembrolizumab-treated patients with new or progressing brain metastases treated on a phase II clinical trial (ClinicalTrials.gov identifier: NCT02085070).

Patients and Methods: We enrolled 23 patients with melanoma with one or more asymptomatic, untreated 5- to 20-mm brain metastasis not requiring corticosteroids; 70% of patients had prior systemic therapy. Pembrolizumab was administered for up to 24 months. Brain metastasis response, the primary end point, was assessed by modified Response Evaluation Criteria in Solid Tumors (RECIST). Pretreatment tumors were analyzed for T-cell infiltrate and programmed death ligand 1.

Results: Six patients (26%) had a brain metastasis response. Eight patients (35%) did not reach a protocol evaluation scan and were unevaluable for brain metastasis response as a result of progression or need for radiation. Brain metastasis and systemic responses were concordant, with all ongoing at 24 months. The median progression-free and overall survival times were 2 and 17 months, respectively. Eleven patients (48%) were alive at 24 months. This included three unevaluable patients. One of these three patients had hemorrhaged, and two had symptoms from perilesional edema requiring radiosurgery, but all three patients remained on commercial pembrolizumab more than 24 months later. None of the 24-month survivors received subsequent BRAF inhibitors. Neurologic adverse events occurred in 65% of patients; all adverse events but one were grade 1 or 2. Three patients had seizures, which were treated with anticonvulsants. Most responders had higher pretreatment tumor CD8 cell density and programmed death ligand 1 expression, whereas all nonresponders did not.

Conclusion: Pembrolizumab is active in melanoma brain metastases with acceptable toxicity and durable responses. Multidisciplinary care is required to optimally manage patients with brain metastases, including consideration of radiation to large or symptomatic lesions, which were excluded in this trial. Two-year survival was similar to patients without brain metastasis treated with anti–programmed cell death 1 agents. Concordant brain and extracerebral responses support use of pembrolizumab to treat small, asymptomatic brain metastases.

Introduction

Immune checkpoint inhibitors have revolutionized cancer care. Ipilimumab, the first approved checkpoint inhibitor for melanoma, inhibits cytotoxic T-cell lymphocyte-4.[1] Inhibitors of programmed cell death 1 (PD-1) or its ligand (PD-L1) were approved for multiple tumor types based on randomized trials.[2–7] Randomized trials, however, excluded patients with untreated brain metastases from melanoma or non–small-cell lung cancer (NSCLC), which occur in more than 50,000 patients per year in the United States.[8]

Melanoma is the solid tumor with the highest propensity for dissemination to the CNS; the incidence at autopsy is up to 70%.[9,10] Brain metastases occur in 30% of patients with metastatic NSCLC, and multifocal disease is common in both malignancies.[11] Although local therapies, particularly surgery and stereotactic radiosurgery (SRS), are effective for isolated lesions, they do not prevent regional or distant recurrences. Whole-brain radiation is typically ineffective for melanoma.[9,10] Therefore, systemic therapies require additional exploration, particularly because many patients have extracerebral disease as well.

Clinical trials have typically excluded patients with brain metastases because of concerns regarding CNS penetration and historically poor prognosis. Landmark trials for melanoma using recently approved drugs enrolled more than 6,000 patients, none with active brain metastasis; brain metastasis–specific trials only enrolled 234 patients (4.1%).[10] Some studies even excluded patients with previously irradiated, stable brain metastases because of concerns about neurologic sequelae.

Given the dramatic responses in melanoma and NSCLC in extracerebral disease, we initiated a phase II trial of pembrolizumab in patients with NSCLC or melanoma and untreated brain metastases (ClinicalTrials.gov identifier: NCT02085070). This trial was initiated before US Food and Drug Administration approval of pembrolizumab with the goal of determining the activity and safety in patients with CNS involvement. Given the importance of the study, we published interim findings from the first 36 patients (18 patients with each disease).[12] Here, we present the final results and long-term follow-up for the full melanoma cohort and tumor-based correlative studies.

Comments

3090D553-9492-4563-8681-AD288FA52ACE

processing....