Immune Checkpoint Inhibitors and Chemoradiation for Limited-Stage Small Cell Lung Cancer

Abstract

Opinion statementLimited-stage small cell lung cancer (LS-SCLC) is a potentially curable disease. However, most patients develop disease relapse shortly after definitive treatment. The landmark trials IMpower133 and CASPIAN demonstrated a survival benefit with the addition of immunotherapy to first-line platinum/etoposide for extensive-stage small cell lung cancer. Therefore, it is critical to determine whether advancements in overall survival with immunotherapy can be translated earlier into the treatment paradigm for LS-SCLC. Decades of robust preclinical research into the synergism of radiation therapy and immunotherapy set the stage for the combination of these treatment modalities. Recently published data suggests tolerability of single agent immunotherapy concurrent with chemoradiation in LS-SCLC, along with promising efficacy. However, combination immunotherapy in the consolidation setting appears too toxic, although this may be reflective of the dosing schedule rather than inherent to any combination immune checkpoint blockade. Here, we review underlying mechanisms of synergy with the combination of radiation and immunotherapy, the safety and efficacy of respective treatment modalities, and the ongoing trials that are exploring novel therapeutic approaches for LS-SCLC. Pivotal trials in LS-SCLC are ongoing and anticipated to aid in understanding efficacy and safety of immunotherapy with concurrent platinum-based chemoradiotherapy.

Successful management of postoperative tracheal metastasis in small cell lung cancer with radiotherapy and durvalumab: A case report

“…In the CASPIAN trial, treatment of patients with advanced small cell lung cancer with etoposide plus platinum plus durvalumab resulted in a progression‐free interval of 5.1 months and overall survival of 13.0 months. This shows an overall survival improvement of 2–3 months with the addition of immunotherapy to conventional first line therapy 9,10 . Platinum‐etoposide chemotherapy and concurrent radiotherapy with the addition of durvalumab has been reported to improve overall survival and progression‐free interval 10,11 .…”

“…The rationale is the synergistic effect of immunotherapy and radiation. Radiation causes neoantigen release from cancer cells 10,12 . In 1953, Mole observed that after local tumor irradiation, distant nonirradiated sites in the same organism regressed 12 .…”

Small cell bladder carcinoma treated with nivolumab as adjuvant maintenance therapy

“…For advanced-stage or extensive-stage SCLC, combined chemotherapy (platinum-etoposide) and immunotherapy (atezolizumab or durvalumab during and after chemotherapy) has become the new standard first-line treatment 14. An abundance of preclinical data suggests a synergistic benefit to limited-stage SCLC treated with ICIs and radiation therapy 15. Immunohistochemical staining of neuroendocrine bladder tumours, including SCBC, has shown less expression of Programmed cell Death ligand 1 and density of CD8+ T lymphocyte infiltration 16.…”

Challenges and opportunities in the immunotherapy era: balancing expectations with hope in small-cell lung cancer

“…The combination of immunotherapy agents with therapeutic radiation is also being explored in the clinical trial setting in SCLC ( Table 3 ). Radiation causes neoantigen release from cancer cells, and antigen-presenting cells prime T cells to these neoantigens, allowing for T-cell-mediated cytotoxicity of cancer cells 80 ; thus, radiation therapy may potentiate synchronous immunostimulatory and immunosuppressive effects within a tumor site. 81 , 82 However, the phase II STIMULI trial, which examined the use of consolidation nivolumab (1 mg/kg) plus ipilimumab (3 mg/kg) every 3 weeks following primary concurrent chemoradiation (CCRT) therapy did not meet its primary endpoint of PFS benefit, and consolidative ipilimumab with nivolumab was not well tolerated.…”