Pembrolizumab for patients with melanoma or non-small-cell lung cancer and untreated brain metastases: early analysis of a non-randomised, open-label, phase 2 trial

Abstract

Background: Immunotherapy targeting the PD-1 axis has activity in several tumour types. We aimed to establish the activity and safety of the PD-1 inhibitor pembrolizumab in patients with untreated brain metastases from melanoma or non-small-cell lung cancer (NSCLC).

Methods: In this non-randomised, open-label, phase 2 trial, we enrolled patients aged 18 years or older with melanoma or NSCLC with untreated brain metastases from the Yale Cancer Center. Patients had at least one untreated or progressive brain metastasis between 5 and 20 mm in diameter without associated neurological symptoms or the need for corticosteroids. Patients with NSCLC had tumour tissue positive for PD-L1 expression; this was not required for patients with melanoma. Patients were given 10 mg/kg pembrolizumab every 2 weeks until progression. The primary endpoint was brain metastasis response assessed in all treated patients. The trial is ongoing and here we present an early analysis. The study is registered with ClinicalTrials.gov, number NCT02085070.

Findings: Between March 31, 2014, and May 31, 2015, we screened 52 patients with untreated or progressive brain metastases (18 with melanoma, 34 with NSCLC), and enrolled 36 (18 with melanoma, 18 with NSCLC). A brain metastasis response was achieved in four (22%; 95% CI 7-48) of 18 patients with melanoma and six (33%; 14-59) of 18 patients with NSCLC. Responses were durable, with all but one patient with NSCLC who responded showing an ongoing response at the time of data analysis on June 30, 2015. Treatment-related serious and grade 3-4 adverse events were grade 3 elevated aminotransferases (n=1 [6%]) in the melanoma cohort, and grade 3 colitis (n=1 [6%]), grade 3 pneumonitis (n=1 [6%]), grade 3 fatigue (n=1 [6%]), grade 4 hyperkalemia (n=1 [6%]), and grade 2 acute kidney injury (n=1 [6%]) in the NSCLC cohort. Clinically significant neurological adverse events included transient grade 3 cognitive dysfunction and grade 1-2 seizures (n=3 [17%]) in the melanoma cohort.

Interpretation: Pembrolizumab shows activity in brain metastases in patients with melanoma or NSCLC with an acceptable safety profile, which suggests that there might be a role for systemic immunotherapy in patients with untreated or progressive brain metastases.

Funding: Merck and the Yale Cancer Center.

Conflict of interest statement

Conflict of interest statements:

SBG reports grants from Merck, during the conduct of the study; and grants from AstraZeneca and personal fees from Clovis, outside the submitted work. RSH reports other from Merck, outside the submitted work. MS reports grants and personal fees from Merck, during the conduct of the study; personal fees from Bristol-Myers, Genentech-Roche, Astra-Zeneca-Medimmune, Anaeropharma, Merus, Symphogen, Nektar, Amgen, Kyowa-Kirin, Astellas-Agensys, Lion Biotechnologies, Neostem, Seattle Genetics, Novartis, Pfizer,, Vaccinex, Immune Design, Lilly, Prometheus, and Biodesix, and other from Immunova, Intensity, and Amphivena, outside the submitted work; and TRM Oncology, Physicians Education Resource, Imedex, Research to Practice, AcademicCME, Haymarket Media, Dava, Clinical Care Options. JY reports grants from 21st Century Oncology, outside the submitted work. HMK reports grants from Merck, during the conduct of the study; and personal fees from Regeneron, Bioclinica, Promethius and Alexion, outside of the submitted work.

Copyright © 2016 Elsevier Ltd. All rights reserved.

Figures

Figure 1

Characteristics of brain metastasis responses in patients with melanoma or NSCLC who received pembrolizumab. A. Best brain metastasis response by mRECIST in evaluable patients. Bars represent individual patients, with percent change in tumor burden in the brain from baseline to the best response demonstrated by the amplitude of the bars. Bar colors indicate patients with melanoma (gray) or NSCLC (black). The dashed line demonstrates the −30% cut-off that defines an objective response. Stars denote partial responses (PRs) and crosses denote complete responses (CRs). Two patients, one with melanoma and one with NSCLC, had PD despite >30% shrinkage of target lesions due to the development of new brain metastases and unequivocal progression of non-target lesions, respectively. The number of target (and total) untreated lesions among melanoma patients with a CNS response were 1 (1), 2 (6), 3 (5) and 3 (4) and among NSCLC patients 1 (3), 5 (58), 1 (2), 5 (50), 1 (3) and 1 (4). Eight patients were unevaluable in the brain, seven due to rapid systemic progression and one due to intralesional hemorrhage. B. Time to brain metastasis response and duration of therapy. Bars represent individual patients who achieved a brain metastasis response or remained on trial ≥ six months. Ten patients demonstrated an objective response in the brain by mRECIST (four with melanoma and six with NSCLC), and three additional patients remained on therapy ≥ six months due to clinical benefit despite having either disease progression or being unevaluable due to treatment of hemorrhagic lesions in the brain. Black circles indicate the time of first brain metastasis response, and black arrows indicate patients who continued on study treatment (regardless of response) at the time of data analysis.