Melanoma brain metastases treated with stereotactic radiosurgery and concurrent pembrolizumab display marked regression; efficacy and safety of combined treatment

Abstract

BackgroundBrain metastases are common in patients with metastatic melanoma. With increasing numbers of melanoma patients on anti-PD-1 therapy, we sought to evaluate the safety and initial response of brain metastases treated with concurrent pembrolizumab and radiation therapy.MethodsFrom an institutional database, we retrospectively identified patients with melanoma brain metastases treated with radiation therapy (RT) who received concurrent pembrolizumab. Concurrent treatment was defined as RT during pembrolizumab administration period and up to 4 months after most recent pembrolizumab treatment. Response was categorized by change in maximum diameter on first scheduled follow-up MRI. Lesion and patient specific outcomes including response, lesion control, brain control and overall survival were recorded and descriptively compared to contemporary treatments with RT and concurrent ipilimumab or RT without immunotherapy.ResultsFrom January 2014 through December 2015, we identified 21 patients who received concurrent radiation therapy and pembrolizumab for brain metastases or resection cavities that had at least one scheduled follow-up MRI. Eleven underwent stereotactic radiosurgery (SRS), 7 received hypofractionated radiation and 3 had whole brain treatment (WBRT). All treatments were well tolerated with no observed Grade 4 or 5 toxicities; Grade 3 edema and confusion occurred in 1 patient treated with WBRT after prior SRS. For metastases treated with SRS, at first scheduled follow-up MRI (median 57 days post SRS), 70% (16/23) exhibited complete (CR, n = 8) or partial response (PR, n = 8). The intracranial response rates (CR/PR) for patients treated with SRS and concurrent ipilimumab and SRS without concurrent immunotherapy was 32% and 22%, respectively.ConclusionsConcurrent pembrolizumab with brain RT appears safe in patients with metastatic melanoma, and SRS in particular is effective in markedly reducing the size of brain metastases at the time of first follow-up MRI. These results compare favorably to SRS in combination with ipilimumab and SRS without concurrent immunotherapy.

Non-small cell lung cancer brain metastases and the immune system: From brain metastases development to treatment

“…In general, PD-L1 positive patients have a higher chance for a better [69][70][71][72][73][74][75][76][77][78][79] outcome with anti-PD-(L)1 treatment compared to PD-L1 negative patients [47][48][49]. BM seem to present a clonal population of cells distinct from those in the primary site with somatic mutations that may be driven by the brain microenvironment [50].…”

“…Furthermore, it was not mentioned whether some of these patients also received radiation during or after ICI treatment and whether this also improved efficacy [77]. In melanoma, concurrent administration defined as radiation therapy during pembrolizumab administration period and up to 4 months after most recent pembrolizumab treatment has yielded the highest intracranial ORR [78]. Furthermore, it is not clear whether the improved control of irradiated BM allows patients receiving ICI to benefit maximally from immunotherapy or whether radiation-induced cell death results in an antitumor immune response that enhances ICI.…”

Radiotherapy as a Backbone for Novel Concepts in Cancer Immunotherapy

“…A retrospective analysis of patients treated for brain metastases of malignant melanoma revealed that inhibition of the PD-1 axis was more effective than inhibition of CTLA-4 in combination with external beam radiotherapy and that concurrent dosing (at least 4 weeks within the two treatments) was necessary to induce best responses [163]. Independent retrospective studies and one meta-analysis confirmed these results [145,[164][165][166][167][168][169][170][171] (Table 4), also showing the superiority of combining radiation with PD-1 inhibitors compared to combination with other agents such as v-Raf murine sarcoma viral oncogene homolog B1 (BRAF) or dual specificity mitogen-activated protein kinase kinase (MEK) inhibitors [172,173] (Table 4). One retrospective study showed longer overall survival of patients irradiated more than 16 weeks after initiation of ipilimumab, compared to patients irradiated within 16 weeks of starting ipilimumab treatment [174].…”

The Role of Radiation Oncology in Immuno-Oncology

“…According to a retrospective study, concurrent stereotactic radiosurgery (SRS) and the administration of pembrolizumab for melanoma brain metastases produces a much better response (8/23 with a complete response [CR] and 8/23 with a partial response [PR]) than SRS without concurrent immunotherapy (22%) . The addition of ipilimumab to radiotherapy significantly prolongs the survival of patients with melanoma metastasis to the brain compared with RT alone (median overall survival: 18.3 months vs. 5.3 months) .…”

“…Twenty‐three patients with melanoma brain metastatic lesions were treated with concurrent SRS and pembrolizumab. Marked regression was observed (CR: 8/23 and PR: 8/23) . Concurrent durvalumab and palliative irradiation were employed to treat inoperable or metastatic cancer .…”