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 tumor types. We aimed to determine the efficacy and safety of pembrolizumab in patients with untreated brain metastases. Here we present results from a Phase II trial of the PD-1 inhibitor pembrolizumab in patients with new or progressive brain metastases from melanoma or non-small cell lung cancer (NSCLC). Methods Thirty-six patients were enrolled, 18 with melanoma and 18 with NSCLC. Patients had at least one untreated or progressive brain metastasis between 5 and 20 mm in longest diameter without associated neurologic symptoms or the need for corticosteroids. NSCLC patients had tumor tissue demonstrating PD-L1 expression. Patients were treated with pembrolizumab 10 mg/kg every two weeks until progression, and brain metastasis response was assessed every eight weeks by modified RECIST. The primary endpoint was brain metastasis response rate and the analysis was performed on an intent-to-treat basis. The trial is ongoing and here we present an early analysis. The study is registered with clinicaltrials.gov, number NCT02085070. Findings Brain metastasis response rate was 22% and 33% among patients with melanoma and NSCLC, respectively. Responses were durable, with all but one patient who responded demonstrating an ongoing response at the time of data analysis. Treatment-related serious and grade 3–4 adverse events were rare and included transaminitis, colitis, pneumonitis, fatigue, endocrine abnormalities, and acute kidney injury (1 patient each). Serious neurological adverse events included cognitive dysfunction and seizures (1 and 3 patients, respectively), due to pembrolizumab, metastases or both. Interpretation Pembrolizumab demonstrates activity in brain metastases in patients with melanoma or NSCLC with an acceptable safety profile, indicating that there may be a role for systemic immunotherapy in patients with untreated or progressive brain metastases. Funding Merck and the Yale Cancer Center.

Profiles of brain metastases: Prioritization of therapeutic targets

“…The interaction between the immune system, tumor and the tumor microenvironment has been the focus of intense investigation—specifically the role of the PD‐1/PDL‐1 signaling axis,38 The efficacy of PD‐1 inhibition (i.e., nivolumab and pembrolizumab) as a monotherapy or in combination therapy has shown favorable survival in clinical trials for patients with advanced melanoma and NSCLC 39, 40, 41, 42, 43. However, the role of immune checkpoint inhibitors in the treatment of CNS cancers, including metastasis, is currently being defined,44, 45 and our current results provide further support for these agents in this context.…”

Advances in Experimental Targeted Therapy and Immunotherapy for Patients with Glioblastoma Multiforme

“…The CTLA-4 inhibitor ipilimumab showed activity in patients with brain metastases of melanoma without significant CNS toxicity (128,129). The PD-1 inhibitor pembrolizumab was active in the treatment of brain metastases in patients with melanoma or non-small-cell lung cancer with an acceptable safety profile (130,131). Furthermore, PD-L1 expression level in the tumor tissue was positively associated with the likelihood of clinical benefit with PD-1 inhibitor in nonsmall-cell lung cancer as well as other tumor types (132,133).…”

Immune Checkpoint Blockade: The New Frontier in Cancer Treatment

“…Although the majority of the clinical trials testing ICBs exclude patients with active brain metastases, pembrolizumab was administered to 36 patients with melanoma or NSCLC and untreated or progressive brain metastases in an investigator-initiated phase 2 trial. Relevant reduction in brain metastases was observed in 28% of patients, warranting further investigation of ICBs in this patient population [109]. In the phase 2 CheckMate 204 study, the combination of nivolumab and ipilimumab was administered to 75 patients with advanced melanoma and untreated brain metastases, and provided an intracranial ORR of 55% and an extracranial ORR of 49% [110].…”