Introduction: Immune checkpoint blockade provides clinical benefit for a substantial proportion of patients with metastatic melanoma; however, early intracranial metastatic progression remains a significant limitation on survival. We hypothesize that early surgical intervention creates an opportunity for improved survival amongst patients undergoing immune checkpoint blockade for metastatic melanoma.
Methods: An IRB approved, single institution retrospective study identified 142 patients with melanoma brain metastases treated with immune checkpoint blockade. Overall survival was calculated from date of diagnosis of brain metastasis until death from any cause. Model building included a prognostic model of overall survival and the effect of sequencing of immunotherapy and surgery on overall survival.
Results: A total of 79 patients underwent surgical resection of intracranial disease. The 2-year overall survival for patients treated with CTLA-4, PD-1 or combinatorial blockade were 19%, 54%, and 57%, respectively. A multivariable Cox proportional hazards model was stratified by the treatment factors of immunotherapy and surgery. Factors associated with increased hazard of death included the development of brain metastases after immunotherapy (HR: 2.05, 95% CI: 1.17 to 3.59, P=0.01), abnormal LDH (HR: 2.16, 95% CI: 1.32 to 3.54, P=0.002), and ECOG performance status greater than 1 (HR: 2.90, 95% CI: 1.55 to 5.43, P=0.004). Amongst patients undergoing surgery, a multivariable Cox proportional hazards model identified age, abnormal LDH, and the timing between immunotherapy, diagnosis of brain metastases, and surgery as predictors of overall survival. In particular, patients who had immunotherapy followed by surgery for brain metastasis had approximately triple the hazard of death compared with patients who had up-front surgery for brain metastasis followed by immunotherapy (HR: 2.96, 95% CI: 1.4 to 6.1, P=0.002).
Conclusions: Amongst patients with treatment naïve melanoma brain metastases, surgical intervention represents an important therapeutic modality offering a bridge towards enhanced efficacy of immunotherapy.
Patient Care: Patients with metastatic melanoma have benefitted from the development of novel immunomodulatory agents that can lead to significant improvement in overall survival. However, many patients continue to fail due to intracranial disease burden. This study identifies that the timing of surgery and immunotherapy for melanoma brain metastases should be considered in clinical decision making and that early neurosurgical intervention prior to initiation of immunotherapy can lead to significant clinical benefit.
Learning Objectives: By the conclusion of this session, participants should be able to:
1) Understand that surgery represents a critical adjunct for patients with intracranial metastases undergoing immunotherapy.
2) Understand that the benefit of neurosurgical intervention in the immunotherapy era appears most evident in immunotherapy naïve patients.
3) Understand that surgical resection of melanoma brain metastases provides the opportunity for subsequent immunotherapy mediated local control and systemic responses.