Targeted Therapies May Boost SRS Melanoma Metastases Distant Control

Patients receiving single fraction stereotactic radiosurgery may benefit more from targeted molecular or immunological therapy than conventional chemotherapy

medwireNews: Molecular and immunological targeted therapies given with stereotactic radiosurgery (SRS) might help control melanoma brain metastases (MBMs), research suggests.

Patients who were treated with the programmed cell death protein 1 (PD-1) inhibitors pembrolizumab or nivolumab, or with combined dabrafenib and trametinib targeting the BRAF and MEK pathways had better distant MBM control than their counterparts given a conventional chemotherapy agent, the researchers report in the Annals of Oncology.

“These results warrant prospective evaluation of the potential synergistic effect that may take place between immunologic and targeted agents with SRS to improve outcomes in patients with MBMs”, say Jimmy Caudell, from H Lee Moffitt Cancer Center and Research Institute in Tampa, Florida, USA, and co-authors.

The analysis included 96 patients who received 119 single SRS fractions for 314 MBMs between 2007 and 2015 and were followed up for a median of 7.4 months. Most SRS sessions were given during or after systemic therapy.

The primary endpoint of distant MBM control – defined as freedom from development of MBM or leptomeningeal disease outside of the irradiated field – was achieved by 36% and 18% of patients at 6 and 12 months, respectively.

The 6- and 12-month rates differed between patients depending on which systemic therapy they received, from 61% and 38% for those given anti-PD-1 therapy and 53% and 20% for those given combined BRAF/MEK inhibitor treatment, to 26% and 21% for those given the anti-CTLA-4 agent ipilimumab and 30% and 8% for those given the BRAF inhibitor vemurafenib. For patients given conventional chemotherapy, the rates were 15% and 5%, respectively.

Multivariate analysis, taking into consideration the number of metastases and systemic therapy, showed that receipt of anti-PD-1 or BRAF/MEK inhibitor therapy significantly predicted better distant MBM control with SRS than chemotherapy, with hazard ratios (HRs) of 3.1 and 2.1, respectively.

By contrast, the rate of local MBM failure, defined as a 20% or greater radiographical increase in irradiated metastases, did not significantly differ between the treatment groups.

However, progression-free survival was significantly longer with anti-PD-1, anti-CTLA-4 or combined BRAF/MEK inhibitor therapy compared with chemotherapy, with multivariate analysis HRs of 2.7, 2.5 and 2.5, respectively.

And this pattern was also true for overall survival, with corresponding HRs of 3.4, 3.1 and 2.4.

Discussing their findings, the researchers note that patients given anti-PD-1, anti-CTLA-4 and BRAF/MEK inhibitor treatments were given lower doses of SRS than those treated with a BRAF inhibitor or conventional chemotherapy.

“This was due to a shift in the center’s practice towards lower SRS dosing for melanoma metastases”, they explain, noting that “[t]here is the potential that slightly lower dosing may allow immune cells to remain viable positively influencing outcomes.

“In addition, lower SRS doses may preserve intact tumor-associated vasculature to mediate effective trafficking of immune cells from the periphery to the tumor site”, the authors suggest.


Ahmed KA, Abuodeh YA, Echevarria MI, et al. Clinical outcomes of melanoma brain metastases treated with stereotactic radiosurgery and anti-PD-1 therapy, anti-CTLA-4 therapy, BRAF/MEK inhibitors, BRAF inhibitor or conventional chemotherapy. Ann Oncol; Advance online publication 15 September 2016. doi: 10.1093/annonc/mdw417

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