Timing and type of immune checkpoint therapy affect the early radiographic response of melanoma brain metastases to stereotactic radiosurgery

Abstract

Background Growing evidence suggests that immunotherapy and radiation therapy can be synergistic in the treatment of cancer. We sought to determine the effect of the relative timing and type of immune checkpoint therapy on response of melanoma brain metastases to treatment with stereotactic radiosurgery (SRS). Methods 75 melanoma patients with 566 brain metastases were treated with both SRS and immunotherapy between 2007 and 2015 at a single institution. Immunotherapy and radiosurgery treatment to any single lesion was considered concurrent if SRS was administered within four weeks of immunotherapy. The impact of timing and type of immunotherapy on lesional response was determined using the Wilcoxon rank sum test to compare median percent lesion volume change at 1.5 months, 3 months, and 6 months after SRS treatment, with significance determined by p=0.0167, per the Bonferroni correction for multiple comparisons. Results Concurrent use of immunotherapy and SRS resulted in significantly greater median percent reduction in lesion volume at 1.5 months (−63.1% vs −43.2%, p<0.0001), 3 months (−83.0% vs −52.8%, p<0.0001), and 6 months (−94.9% vs −66.2%, p<0.0001) compared to non-concurrent therapy. Median percent reduction in lesion volume was also significantly greater for anti-PD-1 than for anti-CTLA-4 at 1.5 months (−71.1% vs −48.2%, p<0.0001), 3 months (−89.3% vs −66.2%, p<0.0001), and 6 months (−95.1% vs −75.9%, p=0.0004). Conclusions Administration of immunotherapy within four weeks of SRS results in improved lesional response of melanoma brain metastases compared to treatment separated by greater than four weeks. Anti-PD-1 therapy also results in greater lesional response than anti-CTLA-4 after SRS.

Improved time to disease progression in the brain in patients with melanoma brain metastases treated with concurrent delivery of radiosurgery and ipilimumab

“…Several retrospective studies have shown that SRS occurring "within 4 mo," "4 weeks" or "14 d" either before or after IT can reduce the volume of metastases and their results have trended toward improved overall survival; however, statistical significance for OS has been difficult to achieve with small, retrospective cohorts, similarly to our study. 22,35 Other potential explanations for the improved survival in this small cohort of patients compared to historic controls are: First, the LC and CR rates achieved were very high, 94.8% and 38%, respectively, which may have led to fewer CNS deaths. Second, additional RT using 5-8 Gy per fraction for extracranial cancer treatment (SBRT) may have played a role in ongoing antigenic priming, as eight of our patients received this modality during their entire treatment course for treatment of systemic disease.…”

“…[9][10][11][27][28][29][30][31][32] We, along with other authors, believe that this synergy is potentiated by a shorter interval between SRS and IT. 22,35 Mechanistic support for this theory comes from a recent study done in mice which demonstrated that when in vivo melanoma tumor cells were treated with Ipi and RT (10-20Gy/1 fraction) together, the mannose-6-phosphate receptor (MPR) was upregulated and tumor cell growth was significantly reduced compared to IT or RT alone (p D 0.0078). 33 When tumors expressed more MPR, then the effects of Ipi-induced CTLs came to fruition through the binding of their products (granzymes) to their receptors (MPR), thereby killing more tumor cells.…”

Diagnosis and treatment of brain metastases from solid tumors: guidelines from the European Association of Neuro-Oncology (EANO)

“…99 Sequence and timing of radiotherapy in relation to ipilimumab have not been fully elucidated. 100,101 To sum up, immunotherapy with ipilimumab has activity in brain metastases from melanoma, and the effects seem similar in intra-and extracranial disease. In patients with symptomatic brain metastases, the effect is smaller, maybe due to corticosteroid treatment or alternatively the generally worse prognosis.…”

Phase I Study of Ipilimumab Combined With Whole-Brain Radiation Therapy or Radiosurgery for Melanoma Patients with Brain Metastases

“…31 In terms post-RT lesion size, reports with combined therapy have been conflicting. Qian et al 8 recently reported results regarding 313 melanoma BMs in 53 patients treated concurrently (defined as RT and IT delivery within 4 weeks of each other).8 IT was as follows: 54 patients (72%) received anti-CTLA-4 and 21 patients (28%) received anti-PD-1. No patients received combination IT.…”

“…It remains unclear the role that this synergism has on toxicity. 8 Activated T-cells and antibodies targeting tumor-associated antigens (TAAs) detected in blood from cancer patients supports an active role for an anti-tumor immune response. 9 T-cell infiltrates in melanoma have prognostic significance, and when identified within nodal metastases, predict benefit in patients treated with neoadjuvant interferon-α-2b.…”