Local Tumor Treatment in Combination with Systemic Ipilimumab Immunotherapy Prolongs Overall Survival in Patients with Advanced Malignant Melanoma

Abstract

Immune checkpoint inhibition with ipilimumab has revolutionized cancer immunotherapy and significantly improved outcomes of patients with advanced malignant melanoma. Local peripheral treatments (LPT), such as radiotherapy or electrochemotherapy, have been shown to modulate systemic immune responses, and preliminary data have raised the hypothesis that the combination of LPT with systemic immune checkpoint blockade might be beneficial. Clinical data from 127 consecutively treated melanoma patients at four cancer centers in Germany and Switzerland were analyzed. Patients received either ipilimumab (n ¼ 82) or ipilimumab and additional LPT (n ¼ 45) if indicated for local tumor control. The addition of LPT to ipilimumab significantly prolonged overall survival (OS; median OS 93 vs. 42 weeks, unadjusted HR, 0.46; P ¼ 0.0028). Adverse immunerelated events were not increased by the combination treatment, and LPT-induced local toxicities were in most cases mild. In a multivariable Cox regression analysis, we show that the effect of added LPT on OS remained statistically significant after adjusting for BRAF status, tumor stage, tumor burden, and central nervous system metastases (adjusted HR, 0.56; 95% confidence interval, 0.31-1.01, P ¼ 0.05). Our data suggest that the addition of LPT to ipilimumab is safe and effective in patients with metastatic melanoma irrespective of clinical disease characteristics and known risk factors. Induction of antitumor immune responses is most likely the underlying mechanism and warrants prospective validation.

Electrochemotherapy induces apoptotic death in melanoma metastases: a histologic and immunohistochemical investigation

“…Interestingly preliminary data sustain the use of ECT in association with systemic immune checkpoint inhibitors, such as anticytotoxic T lymphocyte-associated antigen-4 or antiprogrammed cell death protein 1 antibodies. The combined concept of local therapy with systemic immune checkpoint inhibition is currently being studied in prospective clinical trials and has the potential to further improve the success of cancer immunotherapy 35,36…”

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

“…17,18,19 One of the larger studies to investigate ipilimumab evaluated 127 patients and demonstrated an OS benefit (93 v. 42 weeks, P=0.0028) for patients who received concomitant IT and RT. 20 Early in vitro studies showing a broad shoulder in the cell survival curves and a high repair rate in melanoma cells have inferred better tumor response with higher radiation doses. 21,22 Moreover, SRS delivery in close proximity to IT yields the possibility of increased immunomodulation which has been hypothesized to have an effect on distant control.…”

In Vivo Irradiation of Mice Induces Activation of Dendritic Cells

“…Most importantly, these immune-modulatory effects are not only restricted locally to the tumor site but manifest at a systemic level [6]. Several clinical observations have been published supporting the immune-stimulatory effect of radiation [7,8]. These findings opened the gate for studies exploring optimal combinations of radiotherapy and immunotherapy in order to achieve a synergistic effect.…”