The role of immunotherapy in combination with oligometastasis-directed therapy: a narrative review

Abstract

Metastatic disease is a significant cause of morbidity and mortality among patients with cancer.Patients with oligometastatic cancer represent a subset of the metastatic population with a limited amount of disease that has metastasized distantly and progresses at a slow pace and thus has the potential to be cured with metastasis-directed local therapy. Recent studies examining the role of metastasis-directed therapy in patients with oligometastatic disease have primarily focused upon treatment with ablative doses of radiation, commonly referred to as stereotactic body radiation therapy (SBRT). While the use of SBRT to treat oligometastases has increased considerably in recent years, the benefit of this approach has yet to be confirmed in phase III randomized controlled trials; moreover, distant failure remains a significant problem in patients with oligometastatic disease treated with SBRT. Given the propensity for distant failure in patients with oligometastatic disease treated with SBRT, there is growing interest in the utility of combining SBRT with systemic agents such as immunotherapy. Immunotherapy, and specifically immune checkpoint blockade (ICB), represents a rapidly evolving systemic therapy option with a growing number of indications among patients with metastatic disease; however, despite its promise, only a minority of patients respond to ICB and among those who do, the majority eventually progress. SBRT and ICB are both dependent upon, and have the ability to shift, the balance between antitumor immune surveillance and immunosuppressive states in the tumor and tumor microenvironment. As a result, it has been speculated that SBRT and ICB have the potential to act synergistically when used in combination. SBRT has been demonstrated to be safe in combination with ICB in studies with short-term follow-up and although additional research is needed, preliminary prospective data support the potential efficacy of this approach. In addition to confirming the safety and efficacy of SBRT in combination with immunotherapy, further studies are needed to determine how to maximize the therapeutic ratio of this treatment paradigm for the full potential of immunotherapy in the oligometastatic population to be realized.

A randomized phase II clinical trial of stereotactic body radiation therapy (SBRT) and systemic pembrolizumab with or without intratumoral avelumab/ipilimumab plus CD1c (BDCA-1)+/CD141 (BDCA-3)+ myeloid dendritic cells in solid tumors

“…Combining ICB and SBRT aims to reduce immunosuppression and induce ICD in the TME, enhancing the anti-tumor immune response. However, prospective trials have not consistently shown significant efficacy improvements [ 18 ]. Implementing stricter selection criteria, like excluding patients with prior radiation at disease progression sites and ensuring optimal performance scores before treatment, may enhance response rates.…”

Radiation and immune checkpoint inhibitors in the treatment of oligometastatic non-small-cell lung cancer: a practical review of rationale, recent data, and research questions

“…Despite adequate local treatment however, OMD patients have a propensity for failing distantly. 24 , 25 Moreover, the first-line SoC treatment for metastatic NSCLC has shifted from cytotoxic chemotherapy to upfront immunotherapy, chemo-immunotherapy, or targeted therapy. 26 For NSCLC patients with synchronous or metachronous OMD who are to receive immunotherapy upfront or at disease progression, it is imperative to carefully consider how and when SABR can be strategically incorporated into this treatment paradigm.…”

“…This creates a form of radioresistance 39 which may be overcome by the administration of a concurrent PD-L1 antibody with RT. 24 , 40 ICI use in combination with RT therefore has the potential to address the challenges of pro-tumor microenvironment changes as well as tumor radioresistance.…”

Reply to J. Widder

“…It may well be that other diseases or novel agent combination under investigation in other phase III trials (NRG-LU002, COMET3, and CORE) will yield different outcomes. 9 For now, BR002 demonstrated that metastasis-specific local therapy for palliation remains the standard of care for breast cancer.…”