Optimal Sequence of Immunotherapy and Radiation Could Prolong Survival in Melanoma With Brain Metastases

Daniel Pomeranz Krummel, PhD

A possible optimal sequence of radiation therapy and immune checkpoint inhibitors could help to prolong the survival of patients with melanoma who have brain metastases following surgical resection, according to results of a retrospective analysis.¹

Patients with resected melanoma brain metastases who received radiation therapy followed by treatment with an immune checkpoint inhibitor exhibited superior survival outcomes compared with radiation therapy alone or the reverse sequence of therapy. A transcriptome analysis of resected melanoma brain metastases also showed that those who received radiation therapy prior to an immune checkpoint inhibitor demonstrated deregulation of genes involved in apoptotic signaling and key modulators of inflammation.

Additionally, in a preclinical model, radiation therapy followed by PD-L1–directed therapy, specifically, proved to be more effective than immune checkpoint inhibitor first, followed by radiation therapy.

“Specifically, we found that radiation followed by immunotherapy was superior compared to immunotherapy followed by radiation therapy,” Daniel Pomeranz Krummel, PhD, an associate professor with the University of Cincinnati College of Medicine, stated in a press release from his institution.² “More genetic analysis of the tissue revealed that radiation therapy followed by immunotherapy showed that genes causing cell death signaling, usually fighting the cancer, were restricted and key indicators of inflammation were present.”

Investigators utilized an institutional pathology database to access a retrospective analysis from 2010 to 2018 to identify patients with a single resected melanoma brain metastasis who had received central nervous system-directed radiation therapy (n = 8) or immune checkpoint inhibitor and further radiation therapy (n = 17). The majority of patients received adjuvant radiation therapy following resection of the brain metastasis (n = 11) in comparison to resection for local progression following initial radiation therapy (n = 6). The median age of patients in the study is 54 years (range, 34-81) and the majority of patients were male (76.5%).

For those who received a combination of radiation therapy and immune checkpoint inhibitor, investigators examined the different gene expression via RNA sequencing. Requirements for samples included: at least 750 ng RNA, preferred concentration 10 ng/μL, and DV200 > 0.3. Seventeen samples of the original 79 specimens collected met eligibility and had sufficient sequencing.

The radiation therapy used was either stereotactic radiosurgery (SRS; n = 15) or whole-brain radiation therapy (WBRT; n = 2). The median dose/fraction of SRS was 21 Gy/1 fraction (range, 16-32.5 Gy in 1-5 fractions) while WBRT was delivered in 30 Gy/10 fractions and 37.5 Gy/15 fractions, respectively. The survival analysis suggests that those in the radiation therapy/immune checkpoint inhibitor treatment group had an improved outcome (log-rank P = .064). Investigators additionally observed a separation in curves at the 15-month mark for the timing analysis, though it is believed that the small sample size could be a contributing factor.

A differential gene expression analysis of resected melanoma brain metastases from the radiation therapy/immune checkpoint inhibitor, as well as the reverse sequence of therapy showed 48 deregulated genes (false discovery rate cutoff, 0.05). All deregulated genes increased in expression within the radiation therapy/immune checkpoint inhibitor group. An analysis of annotation/pathway enrichment showed a significant (P <.01) enrichment of genes, including NIK (MAP3K14), NFKB, RIPK1, JNK and Akt signaling, and DAB2, which are involved in apoptosis and antiapoptotic signaling.

Investigators examined the different sequences of the combination of radiation therapy and immune checkpoint inhibitor. The best tumor control within the irradiated volume and nonirradiated region was noted for radiation therapy/immune checkpoint inhibitor. No antitumor activity was seen when CD8 T cells were depleted, implying that T cells were needed in order to respond to a PD-L1–directed therapy, which can be utilized in combination with radiation therapy.

“In summary, our current study contributes to increasing evidence that sequencing [radiation therapy] and [immune checkpoint inhibitors] may have differential effects on the outcomes of patients with [melanoma brain metastases], and prospective studies to validate this are reasonable and necessary,” the authors concluded. “We aim to design a prospective clinical study with sufficient patient numbers that would enable us to more fully explore this research and validate the results presented herein based on retrospective, small tissue samples.”

References

1. Pomeranz DA, Nasti TH, Izar B, et al. Impact of sequencing radiation therapy and immune checkpoint inhibitors in the treatment of melanoma brain metastases. Rad Oncol [published online ahead of print February 11, 2020]. doi:10.1016/j.ijrobp.2020.01.043.
2. Study reveals potential new treatment for patients with melanoma. [News release]. UC News. Published February 26, 2020. Accessed July 1, 2020. https://bit.ly/38qj8Ac.