Phase II Study of Pembrolizumab Finds Activity in Brain Metastases from NSCLC

This phase II study, published in The Lancet Oncology, found that pembrolizumab (Keytruda) has activity in brain metastases from non-small cell lung cancer (NSCLC) that is comparable to its systemic activity, and can result in prolonged survival in a subset of patients.¹

The researchers indicated that studies of combination therapy, such as with other immunotherapies, radiotherapy, or chemotherapy, are warranted to potentially increase the frequency of responses in patients with NSCLC who also have brain metastases.

“We have clearly shown, for the first time, that brain metastasis responds to a targeted immunotherapy treatment for lung cancer,” lead investigator Sarah B. Goldberg, MD, MPH, associate professor of Medical Oncology at Yale Cancer Center, said in a press release.² “In general, we found that the benefit offered by pembrolizumab to the lungs in patients with advanced lung cancer was mirrored in control of their brain tumors. The brain and body response were the same.”

In this open-label, phase II study of patients from the Yale Cancer Center, researchers treated 42 patients between March 31, 2014 and May 21, 2018. Eligible patients were at least 18 years of age with stage IV NSCLC with at least 1 brain metastases 5vmm to 20 mm in size, not previously treated or progressing after previous radiotherapy, demonstrated no neurological symptoms or corticosteroid requirement, and had an Eastern Cooperative Oncology Group performance status less than 2. Modified Response Evaluation Criteria in Solid Tumors (mRECIST) criteria was used to evaluate CNS disease, and systemic disease was not required for participation.

“We did not enroll patients with larger tumors or neurologic issues because, as the first study of this protocol, we did not know if there would be side effects and we did not want to cause harm,” Goldberg explained. “As it turns out, we found the drug was safe, and the neurologic adverse events were very few and unrelated to the drug.”

The patients were treated with 10 mg/kg of pembrolizumab intravenously every 2 weeks. Moreover, the patients were split into 2 cohorts: cohort 1 was for those with PD-L1 expression of at least 1% and cohort 2 was for patients with PD-L1 less than 1% or who were unevaluable. The primary endpoint was the proportion of patients achieving a brain metastasis response of either partial response or complete response, according to mRECIST.

Median follow-up was 8.3 months (IQR 4.5-26.2), and 11 (29.7% [95% CI, 15.9-47.0]) of 37 patients in cohort 1 had a brain metastasis response; there were no responses in cohort 2. Grade 3 or 4 adverse events related to treatment included 2 patients with pneumonitis, and 1 each with constitutional symptoms, colitis, adrenal insufficiency, hyperglycemia, and hypokalemia. Further, serious adverse events related to treatment occurred in 6 (14%) of 42 patients and were pneumonitis (n = 2), acute kidney injury, colitis, hypokalemia, and adrenal insufficiency (n = 1 each). However, there were no treatment-related deaths. 

“Survival in this cohort of patients exceeds the historically documented survival for patients with brain metastasis from non-small cell lung cancer or NSCLC, which is a 2-year survival of about 14%,” said Goldberg. 

An important limitation of the study was that the patient population was heterogeneous, with many patients having had no previous treatment and others having received 1 or more previous lines of therapy, which could have affected the tumor immune milieu. Additionally, most patients only had tissue available from systemic sites of disease, which have a different microenvironment than brain metastasis. The researchers were also unable to assess tumor mutational burden, which has previously been associated with benefit from immunotherapy and might be higher in brain metastases than in other sites of disease. 

Goldberg theorized that with further study and biomarker analysis, “it might make sense for some patients to try a checkpoint inhibitor first to treat both their lung cancer and brain metastasis. Radiation could follow, if necessary.” Though she went on to add that such a change would take time to become a tool used for the treatment of NSCLC brain metastasis. “The standard of care is radiation, and sometimes, whole brain radiation. Further investigation of this therapy is needed.”

References:

1. Goldberg SB, Schalper KA, Gettinger SN, et al. Pembrolizumab for management of patients with NSCLC and brain metastases: long-term results and biomarker analysis from a non-randomized, open-label, phase 2 study. The Lancet Oncology. doi:10.1016/S1470-2045(20)30111-X.

2. First Test Using Immunotherapy Drug to Treat Advanced Lung Cancer Shows Benefit – And Future Promise [news release]. New Haven, Connecticut. Published April 13, 2020. newswise.com/articles/first-test-using-immunotherapy-drug-to-treat-advanced-lung-cancer-shows-benefit-and-future-promise?sc=dwhr&xy=10019792. Accessed April 16, 2020.