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.
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.


RESULTS
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.


CONCLUSIONS
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.


BACKGROUND
Merck and the Yale Cancer Center.
Yale University School of Medicine and Yale Cancer Center, New Haven, CT, USA. Electronic address: sarah.goldberg@yale.edu.
Sarah B
SB
Goldberg
Yale University School of Medicine and Yale Cancer Center, New Haven, CT, USA.
Scott N
SN
Gettinger
Yale University School of Medicine and Yale Cancer Center, New Haven, CT, USA.
Amit
A
Mahajan
Yale University School of Medicine and Yale Cancer Center, New Haven, CT, USA.
Anne C
AC
Chiang
Yale University School of Medicine and Yale Cancer Center, New Haven, CT, USA.
Roy S
RS
Herbst
Yale University School of Medicine and Yale Cancer Center, New Haven, CT, USA.
Mario
M
Sznol
New York Presbyterian Hospital, Weill Cornell Medical Center, New York, NY, USA.
Apostolos John
AJ
Tsiouris
Yale University School of Medicine and Yale Cancer Center, New Haven, CT, USA.
Justine
J
Cohen
Yale University School of Medicine and Yale Cancer Center, New Haven, CT, USA.
Alexander
A
Vortmeyer
Yale University School of Medicine and Yale Cancer Center, New Haven, CT, USA.
Lucia
L
Jilaveanu
Yale University School of Medicine and Yale Cancer Center, New Haven, CT, USA.
James
J
Yu
University of Connecticut Health Center, Farmington, CT, USA.
Upendra
U
Hegde
Yale University School of Medicine and Yale Cancer Center, New Haven, CT, USA.
Stephanie
S
Speaker
Yale University School of Medicine and Yale Cancer Center, New Haven, CT, USA.
Matthew
M
Madura
Yale University School of Medicine and Yale Cancer Center, New Haven, CT, USA.
Amanda
A
Ralabate
Yale University School of Medicine and Yale Cancer Center, New Haven, CT, USA.
Angel
A
Rivera
Yale University School of Medicine and Yale Cancer Center, New Haven, CT, USA.
Elin
E
Rowen
Yale University School of Medicine and Yale Cancer Center, New Haven, CT, USA.
Heather
H
Gerrish
Yale University School of Medicine and Yale Cancer Center, New Haven, CT, USA.
Xiaopan
X
Yao
Yale University School of Medicine and Yale Cancer Center, New Haven, CT, USA.
Veronica
V
Chiang
Yale University School of Medicine and Yale Cancer Center, New Haven, CT, USA.
Harriet M
HM
Kluger
D000230:Adenocarcinoma / Q000188:drug therapy / Q000556:secondary; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000556:secondary; D018287:Carcinoma, Large Cell / Q000188:drug therapy / Q000556:secondary; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000556:secondary; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008207:Lymphatic Metastasis; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000473:pathology; D008875:Middle Aged; D009367:Neoplasm Staging; D011379:Prognosis; D012878:Skin Neoplasms / Q000188:drug therapy / Q000473:pathology; D015996:Survival Rate
D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; C582435:pembrolizumab