Over the last decade, immune checkpoint inhibitors, particularly inhibitors of the programmed cell death-1(PD-1)/programmed cell death ligand-1(PD-L1) axis, have transformed the therapeutic landscape in advanced non-small cell lung cancer (NSCLC) without driver mutations. Several PD-1/PD-L1 inhibitors have been demonstrated to provide significant overall survival (OS) benefit than docetaxel as second-line therapy [1–6]. However, treatment efficacy of single agent PD-1/PD-L1 inhibitors is unsatisfactory, with an overall response rate (ORR) around 15%-20% in all comers [7].
Radiotherapy, especially stereotactic body radiotherapy (SBRT), are repeatedly found to enhance anti-tumor immunity and has the potential to synergize with immunotherapy in NSCLC[8, 9]. The underlying molecular mechanisms include induction of immunogenic cell death[10], release of tumor associated antigen (TAA) and cytokines[11–13], and enhance homing of immune cells to tumors[14, 15], thus converting immunologically “cold” tumors to “hot” tumors[16]. In addition, the upregulation of PD-L1 expression on tumor cells induced by radiotherapy makes patients more susceptible to subsequent PD-1/PD-L1 inhibitors, contributing to a higher response rate and longer survival[17]. As radiation-induced antitumor immunity is dose-dependent, SBRT, which delivers a high radiation dose in generally 3 to 5 fractions with high accuracy to single tumor sites, potentially has more potent immune activation effects than conventional radiotherapy[18, 19]. This superiority makes it more favorable for SBRT to combine with PD-1/PD-L1 inhibitors. In the phase II randomized clinical trial PEMBRO-RT, the combination of SBRT (8 Gy × 3 fractions) and Pembrolizumab revealed enhanced antitumor immunity with numerically improved ORR (36% vs. 18%), progression free survival (PFS) (6.6 vs. 1.9 months), and OS (15.9 months vs. 7.6 months) compared to Pembrolizumab alone[20]. Moreover, an individual patient-level meta-analysis of the Pembro-RT trial and MDACC study[21], demonstrated that adding radiotherapy, especially SBRT, to Pembrolizumab, significantly improved out-of-field (abscopal) response rate (ASR) (41.7% vs 19.7%, p = 0.0039), PFS (9.0 vs 4.4 months, p = 0.0450) and OS (19.2 vs 8.7 months, p = 0.0004) in patients with pretreated metastatic NSCLC[22]. However, these results need to be verified in further clinical trials enrolling patients from different races and genetic backgrounds. Meanwhile, the reported efficacy of combining SBRT and PD-1/PD-L1 inhibitor were still unsatisfactory, and novel partners with non-redundant molecular mechanisms are demanded.
Antigen presentation by dendritic cells (DC) and subsequently activing adaptive immune response are indispensable steps in cancer-immune cycle, and granulocyte-macrophage colony stimulating factor (GM-CSF), which plays a pivotal role in the differentiation and maturation of DCs, could serve as potent immune adjuvant or sensitizer[23, 24]. In solid tumors, GM-CSF augments the recruitment and activations of DCs, which helps to eradicate cancer through presenting TAAs to T cells and subsequently initiating the anti-tumor adaptive immune response. This effect was supported by the fact that the GM-CSF induced enhanced antitumor activity disappeared when CD4+ or CD8+ T cells were depleted[25]. In a preclinical study using a B16 melanoma model, the irradiated tumor cells alone could not stimulate significant anti-tumor immunity, while the irradiated cells expressing murine GM-CSF stimulated potent, long-lasting, and specific anti-tumor immunity[25]. A poof-of-concept phase II trial (NCT02474186) enrolling 41 patients with different metastatic solid tumors found that adding GM-CSF to SBRT could induce abscopal response in 11 (26.8%) patients, including 4 patients with advanced NSCLC[26]. Meanwhile, the safety and efficacy of combining radiotherapy and GM-CSF was shown in a phase I/II study in untreated stage III/IV squamous cell cancer of head and neck[27]. All of these data support the synergic cooperation between radiotherapy and GM-CSF in activating the innate immune response against cancer. However, T cell exhaustion remains an obstacle for long term anti-tumor immunity which may be mitigated by PD-1/PD-L1 inhibitors. Hence, triple combination of SBRT, GM-CSF and a PD-1/PD-L1 inhibitor may potentially enhance treatment efficacy of advanced NSCLC, through activation of both innate and adaptive anti-tumor immune response. Nevertheless, the feasibility and efficacy has not been evaluated.
Given the above preclinical and clinical data, we conducted a prospective, multicenter, single-arm, phase II trial assessing the safety and efficacy of triple combination of Sintilimab, a PD-1 inhibitor which had been proven to be effective in advanced NSCLC[28, 29], SBRT and GM-CSF as second-line therapy in sensitizing driver mutation negative metastatic NSCLC. In order to determine the tolerability of this novel triple combination therapy, a safety run-in phase was conducted by monitoring the dose-limiting toxicities (DLTs) in the first 20 enrolled patients and herein we reported the results.