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HOUSTON -- Patients with melanoma brain metastases had better survival if they received radiotherapy (RT) followed by immunotherapy instead of the reverse sequence, a meta-analysis of six published studies showed.

Starting treatment with an immune checkpoint inhibitor (ICI) was associated with a 75-80% increase in the progression-free survival (PFS) hazard ratio and about a 40% increase in the overall survival (OS) hazard ratio, the latter of which did not achieve statistical significance. The findings did not change whether the data were analyzed by random- or fixed-effects methodology, reported Philip Haddad, MD, of LSU Health Shreveport in Louisiana, at the Society for NeuroOncology meeting.

"This is the first and largest meta-analysis to date to show that in patients with melanoma brain metastases, the optimal sequence that impacts patients' survival outcomes is to start with radiation therapy followed by immune checkpoint inhibitors," Haddad said in conclusion.

The findings require validation in additional research, particularly prospective studies, he added.

Based on previously reported data, the study is not new, but a meta-analysis that looks at studies in aggregate "sometimes can be helpful," said Lia Moriguchi Halasz, MD, of Fred Hutch Cancer Center in Seattle.

"[Sequencing] is an important question because patients with brain metastases from melanoma sometimes respond to immunotherapy, and we are not always clear that adding stereotactic radiosurgery is required," Moriguchi Halasz, who is an expert for the American Society for Radiation Oncology (ASTRO), told 名媛直播. "The meta-analysis findings are thought provoking, and suggest we need further study."

"Overall survival for patients who received radiosurgery had only a trend towards better survival. Progression-free survival after radiosurgery is a difficult endpoint to interpret since radiosurgery can also cause inflammation -- radiation treatment effect -- that is hard to distinguish from tumor growth."

No consensus currently exists about the optimal approach to combining immunotherapy and RT for brain metastases.

"This is an important, open question as to what is best for these patients," said Moriguchi Halasz. "Generally, for symptomatic metastases, we consider earlier radiation therapy, given the trials showing response to immunotherapy were often limited to asymptomatic patients who did not require high-dose steroids. However, for asymptomatic patients, it is unclear how these treatments should be sequenced."

Whether the results have applicability to brain metastases from other types of tumors remains to be seen.

"I do think brain metastases from melanoma may be different from brain metastases from other types of cancer," said Moriguchi Halasz. "Melanoma is relatively radioresistant compared to other types of cancer, and thus may respond to a different sequence of therapies. Melanoma is also one of the most immunogenic cancers and may respond in the brain differently to immunotherapy than other cancers."

The rationale for using RT and ICIs together has come from evidence that RT "synergizes with ICIs to promote a more robust anti-tumor immune response," said Lisa Sudmeier, MD, PhD, of Emory University in Atlanta and also an ASTRO expert. "ICIs act by inducing CD8+ T-cell proliferation, activation, and tumor infiltration, most profoundly after the ICI treatment is first started. Tumor infiltration by CD8+ T cells may be enhanced by pre-ICI radiation, which induces the release of cancer neoantigens."

"In theory, however, radiation immediately following initiation of ICIs could inadvertently deplete these recently-activated tumor-infiltrating CD8+ T cells. I therefore generally favor radiation prior to initiating immunotherapy if clinically feasible. This is less of an issue in patients who have already received a few cycles of ICIs (that is, they have not just initiated ICI treatment). Radiation between ICI cycles can be a good option for those patients who need it."

Brain metastases occur in as many as 50% of patients with melanoma and are associated with an "abysmal prognosis," said Haddad. Immunotherapy and RT have been shown to improve OS in patients with melanoma brain metastases, but the optimal sequence for the two therapeutic modalities remains unclear.

In an effort to inform the ongoing discussion, Haddad and colleagues identified six clinical trials with ICIs administered before or after RT for patients with brain metastases from melanoma. The studies were published from 2015 to 2022, and all reported both PFS and OS. Investigators excluded studies that reported aggregate mixed data that included concurrent ICI-RT therapy.

The six studies involved a total of 213 patients. The largest study had 50 patients and the smallest had 14. The patients had a median age of 62, and median follow-up for all patients was 22 months. Most patients received ipilimumab (Yervoy).

The PFS analysis showed that starting treatment with immunotherapy was associated with a hazard ratio (HR) of 1.77 (95% CI 1.21-2.60, P=0.003) by random effects and 1.80 by fixed effects (95% CI 1.27-2.54). All but one of the studies showed a clear detriment when starting with an ICI. The OS analysis yielded an HR of 1.39 by both statistical methods for an ICI-first strategy (95% 0.97-1.99). All of the studies trended toward worse survival associated an ICI-first strategy.

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