Sintilimab, Stereotactic Body Radiotherapy and Granulocyte-macrophage Colony Stimulating Factor as Second-line Therapy for Advanced Non-small Cell Lung Cancer: Safety Run-in Results of a Multicenter, Single-arm, Phase II Trial

1. Introduction

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.

2. Methods

2.1 Study design

The SWORD trial (NCT04106180) was a single arm, open-label, multicenter, phase II study with a safety run-in phase. Metastatic NSCLC patients without driver mutations who failed first-line standard of care chemotherapy were treated with SBRT in combination with Sintilimab and GM-CSF. Additionally, blood and tissue samples were serially collected for translational research. The trial was designed to enroll fifty-six patients. Sample size was calculated for the following hypothesis: H₀ (null) with an ORR ≤ 20% according to Checkmate 017 and Checkmate 057[5], H₁ (alternative) with an ORR ≥ 38%. If no less than 17 out of the 56 patients evaluated had objective response (CR or PR), then H₀ will be rejected in favor of H₁. This design has at least 90% power to reject H₀ if the ORR was 30% or more with a one-sided type I error rate of 5%. The study schema was presented in Fig. 1 and the protocol of this trial was provided as supplemental material.

2.2 Objectives and endpoints

The trial was designed to evaluate the safety and efficacy of Sintilimab in combination with SBRT and GM-CSF in advanced NSCLC patients previously treated with first-line platinum-based chemotherapy. The primary endpoint was ORR, defined as the proportion of participants with partial response (PR) or complete response (CR) in evaluable patients according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1[30] determined by investigators.

Secondary objectives were safety profiles according to the Common Terminology Criteria for Adverse Events version 5.0 (CTCAE 5.0), ASR, OS and PFS. ASR was defined as the proportion of patients with at least 30% reduction from baseline in the sum of longest diameter of non-irradiated target lesions defined by RECIST 1.1[30]. OS was defined as the time from the date of enrollment until death by any cause. Participants still alive at the time of last follow-up were censored in survival analyses. PFS was measured from the date of enrollment to the date of disease progression (PD) as defined by RECIST 1.1[30] or death due to any cause, whichever occurred first. Participants who did not have disease progression by the time of the last radiographic follow-up were censored in survival analyses.

Additionally, this study collected serial peripheral blood and tissue specimens from the enrolled patients who were willing to participate in the translational research. The relationship between biomarkers generated from these serially collected biological samples, treatment efficacy and treatment-related adverse events (TRAEs) would be extensively analyzed, in order to investigate the molecular mechanisms underlying the synergic effect and primary resistance of this triple combination.

2.3 Study population

Patients could be included if they had histologically confirmed stage IV NSCLC without driver mutations, and had failed (documented progression or intolerable toxicity) first-line platinum-based therapy without PD-1/PD-L1 inhibitors. Driver mutations included epidermal growth factor receptor (EGFR) mutations, anaplastic lymphoma kinase (ALK) or ROS proto-oncogene 1 (ROS-1) translocations. Patients should have at least one lesion (size 1–5 cm) eligible for SBRT (24Gy/3Fx) and at least another measurable lesion as defined by RECIST 1.1[30]. Patients with brain metastasis were eligible if they were asymptomatic, neurologically stable, and off corticosteroids. Key exclusion criteria included patients who had received any PD-1/PD-L1 inhibitors previously.

2.4 Treatment scheme and modalities

Eligible patients were treated with SBRT for one previously unirradiated primary or metastatic lesion (size 1–5 cm), and SBRT was administrated 24 Gy in 3 fractions (8Gy/Fx) once-daily for 3 consecutive days. Patients then received Sintilimab and GM-CSF intravenously (IV) starting within 2 weeks after SBRT completion. Sintilimab 200mg IV was administrated on Day 1 (D1) every 3 weeks until PD, intolerable toxicity, up to 35 cycles (2 years), death, or withdrawal of consent. GM-CSF 125 µg/m² would be given daily for 14 consecutive days (D1-D14) on Cycle 1.

2.5 Treatment evaluation

For patients who received at least one dose of Sintilimab and GM-CSF, treatment visits were performed with a physical examination, laboratory assessments, adverse events (AEs) collections, and concomitant treatments description on D1 of each treatment cycle. In addition, weekly phone calls were made to assess patients’ symptoms. Treatment efficacy was evaluated by radiographic examinations every 9 weeks.

2.6 Safety run-in analysis

Given that the safety profile of SBRT in combination with Sintilimab and GM-CSF has not been evaluated in advanced NSCLC patients, a safety run-in was adopted to ensure that no excessive severe adverse events happened in the treated patients. Accrual was suspended after the inclusion of 20 patients, and safety data for each patient were collected within the first 30 days after the first dose of study drugs to early detect unexpected non-tolerable toxicities. DLT was monitored during the DLT observation window, which was defined as 30 days after the first cycle of protocol treatment. DLT was defined as any grade 3 event lasting more than 7 days other than asymptomatic laboratory abnormalities, any grade 4 event, or any treatment related grade 5 event.

Grading was made according to CTCAE 5.0. At any time during the safety run-in phase, if excessive numbers (≥ 35%) of DLTs were to be seen, the accrual was to be halted and the Data and Safety Monitoring Board (DSMB) was to be convened to decide on the study continuation. In addition, if excessive numbers (≥ 20%) of death were to be seen within 60 days since the initiation of GM-CSF treatment, the study was to close for safety concerns.

2.7 Ethical considerations

Written informed consent was obtained from all patients before performing any study-specific tests or evaluations. The protocol received formal approval by the ethnical Authorities/Committees of all participating academic centers.

2.8 Statistical analysis

TRAEs and DLTs for the first 20 patients enrolled to the safety run-in phase of the trial were summirized by TRAE type, grade, frequency and proportion. These 20 patients were assessed and included for all outcomes using the same schedule and criteria as subsequent patients. The demographic variables of these patients were summarized by median and range for continuous variables and by frequency and percentage for categorical variables. Analyses were performed by the study statisticians using SPSS 21.0 (SPSS, Chicago, IL, USA) and R version 3.5.1 (The R Foundation for Statistical Computing).

3. Results

3.1 Patient characteristics

From 2019/10/16 to 2020/8/8, twenty-two patients were screened and 2 were excluded due to consent withdrawn in one patient and general condition deteriorated rapidly before any treatment initiation in another. Hence, 20 patients were enrolled in the safety run-in phase. The baseline characteristics and SBRT sites of these 20 patients were summarized in Table 1. The majority of patients were male, smoker, Eastern Cooperative Oncology Group (ECOG) performance status 1 and non-squamous NSCLC, with a median age of 61 (range, 32–71). Baseline brain, liver and bone metastasis were present in 2, 4 and 8 patients, respectively. The majority of patients had no less than 3 metastatic organs and all of the patients had more than 5 metastatic lesions.

Table 1

Patient characteristics
Characteristics	Number of patients	%
Age
≤ 60	8	40.0
> 60	12	60.0
Sex
Female	5	25.0
Male	15	75.0
Smoking status
Current/former	13	65.0
Never smoker	7	35.0
ECOG score
0	2	10.0
1	18	90.0
Histology
squamous	8	40.0
Non-squamous	12	60.0
Metastasis at baseline
Brain	2	10.0
Liver	4	20.0
Bone	8	40.0
No. of metastatic organs
< 3	5	25.0
≥ 3	15	75.0
No. of metastatic lesions
≤ 5	0	0.0
> 5	20	100.0
Site of SBRT
Lung	11	55.0
Mediastinal LN	5	25.0
Abdominal LN	1	5.0
Liver	1	5.0
Thoracic vertebra	1	5.0
Pleural nodule	1	5.0
ECOG, Eastern Cooperative Oncology Group; SCC, squamous cell carcinoma; NSCLC, non-small cell lung cancer; SBRT, stereotactic body radiotherapy; LN, lymph node

3.2 Adverse events and DLT observation

No DLT was observed during the DLT observation window. Overall, 18 (90.0%) of the 20 patients experienced TRAEs. The most common TRAEs were fatigue (50%), fever (30%), and ostealgia (20%), and all were grade 1. Grade 2 TRAEs occurred in 4 (40.0%) patients and grade 3 TRAEs (ALT/AST elevation and heart failure) in 2 (10.0%) patients. No patient experienced grade 4 or grade 5 TRAEs. Detailed information of adverse events was summarized in Table 2.

Table 2

Treatment-related adverse events
	Grade 1	Grade 2	Grade 3	Grade 4
Fever	6 (30.0%)	0	0	0
Fatigue	10 (50.0%)	0	0	0
Headache	3 (15.0%)	0	0	0
Ostealgia	4 (20.0%)	0	0	0
Skin rash	2 (10.0%)	0	0	0
Pruritus	2 (10.0%)	0	0	0
Elevation in ALT	0	1 (5.0%)	1 (5.0%)	0
Elevation in AST	0	1 (5.0%)	1 (5.0%)	0
Decreased appetite	2 (10.0%)	0	0	0
Nausea	2 (10.0%)
Diarrhea	2 (10.0%)	0	0	0
Cough	1 (10.0%)	0	0	0
Vomiting	1 (10.0%)	0	0	0
Chest pain	0	1 (5.0%)	0	0
Hypothyroidism	0	1 (5.0%)	0	0
Heart failure	0	1 (5.0%)	1 (5.0%)	0
ALT, alanine aminotransferase; AST, aspartate aminotransferase

3.3 Characteristics of patients experiencing acute heart failure

Two patients experienced acute and transient left heart failure.

Patient 009 was a 62-year-old male, smoker, diagnosed with metastatic squamous cell carcinoma of the right lung in July, 2019. He denied any previous medical history of cardiovascular diseases. After failing first-line chemotherapy consisting of 4 cycles of cisplatin and nab-paclitaxel, he was enrolled into the trial. SBRT was performed to one of the metastatic mediastinal lymph nodes uneventfully, followed by Sintilimab and GM-CSF. Four days after Sintilimab and GM-CSF initiation, the patient complained progressive dyspnea with moist rales in the lungs. Laboratory tests revealed an elevation in pro-BNP (3970pg/ml) and echocardiography found mild pulmonary hypertension. Acute left heart failure (grade 2) was diagnosed by an experienced cardiologist and GM-CSF was stopped. The patient recovered 3 days after administration with diuretics, oxygen therapy and antiasthmatic agents. However, the patient refused to continue the study treatment and was transferred to a local hospital.

Patient 014 was a 71-year-old male, smoker, diagnosed with metastatic squamous cell carcinoma of the right lung in September, 2019. He also denied any past medical history of cardiovascular diseases. Before enrollment, he had been treated with 4 cycles of Carboplatin and Gemcitabine, as well as salvage thoracic radiotherapy. SBRT was performed to one of the metastatic mediastinal lymph nodes successfully, followed by Sintilimab and GM-CSF. Seven days after Sintilimab and GM-CSF initiation, the patient developed severe shortness of breath, fatigue and facial edema. On examination, there were moist rales in the lungs and the oxygen saturation was 86%. Laboratory tests found a significant elevation in pro-BNP (4820pg/ml). Acute left heart failure (grade 3) was diagnosed and GM-CSF was stopped. The patient’s symptoms alleviated 5 days after administration of diuretics and oxygen therapy. This event was considered GM-CSF related only and thus, Sintilimab was given for another 3 cycles, without recurrence of acute heart failure. The best response to the triple therapy was stable disease (SD). However, tumor progressed rapidly after the forth cycle, which eventually led to death.

4. Discussion

PD-1/PD-L1 inhibitors, alone or in combination with other agents, are now standard of care for advanced NSCLC without driver mutations[31]. However, the response rate of PD-1/PD-L1 inhibitor alone is limited and treatment toxicities of combinational modalities already available are frequent[32, 33]. Novel treatment strategies with more potent efficacy and less adverse events are highly needed. Here, we report the preliminary results of safety run-in phase of the prospective, multicenter, phase II trial (SWORD) investigating triple combination of Sintilimab, SBRT and GM-CSF as novel second-line therapy for advanced NSCLC without driver mutations. We found the novel combination safe with manageable TRAEs.

For the first time, we found that triple combination of SBRT, a PD-1 inhibitor and GM-CSF seemed to be safe with mild toxicities. The safety of PD-1/PD-L1 inhibitors in combination with SBRT have been demonstrated in several prospective clinical trials[20, 21, 34, 35], with the frequency of grade 3–5 TRAE ranging from 9.7–30.0% and very few patients developed DLTs. Meanwhile, the combination of SBRT and GM-CSF has also been tested in a prospective trial with acceptable toxicities[26]. However, the feasibility and safety of combining GM-CSF and PD-1/PD-L1 inhibitors have not been reported. In our study, grade 3 TRAE occurred in 10.0% of the patients, without DLT or grade 4–5 TRAEs. Most of the TRAEs were mild and the two grade 3 TRAEs were transient, which could be successfully managed. Taken together, triple combination of Sintilimab, SBRT and GM-CSF in advanced NSCLC was demonstrated to be safe, and the trial continued to recruit participants.

Nevertheless, acute heart failure was an unexpected adverse event in our study. Congestive heart failure was previously reported in clinical trials examining the safety and efficacy of combinational regimens involving GM-CSF among patients with hematological disorders[36, 37] and solid tumors[38]. GM-CSF receptor expression and plasma GM-CSF level were also found to be significantly elevated in end-stage heart failure patients[39, 40]. Mechanically, GM-CSF produced by cardiac fibroblasts could act locally and distally to generate and recruit inflammatory and proteolytic cells, which led to heart failure in mice models[41]. In our study, two patients experienced transient acute left heart failure and recovered quickly after GM-CSF discontinuation and initiation of diuretics. Hence, GM-CSF related heart failure was suspected in these two patients. However, we could not totally rule out the possibility that Sintilimab also had a role in the development of acute heart failure in these two patients. Cardiac toxicities of PD-1/PD-L1 inhibitors rarely developed but have detrimental effects[42, 43], and PD-1/PD-L1 inhibitor related heart failure was anecdotally reported[44–46]. However, the two patients recovered rapidly without glucocorticoids and one of the patients even continued to receive further cycles of Sintilimab without recurrence of heart failure. Hence, acute heart failure should be intensively monitored in patients receiving continuous GM-CSF, especially among those with concurrent PD-1/PD-L1 inhibitors.

Our study has several strengths. Firstly, this was the first prospective, phase II, multicenter study assessing the safety and efficacy of triple combination of a PD-1/PD-L1 inhibitor, SBRT and GM-CSF in advanced solid tumors. Although this was a single-arm study, but there have been several clinical trials testing the efficacy of PD-1/PD-L1 inhibitor alone as second-line therapy in advanced NSCLC with generally consistent results, which could serve as reliable historical control[1–3, 47]. Using these historical controls and experiences from previous studies[20, 21], sample size of our study was dedicatedly designed to have a 90% power to detect the difference. Moreover, data generated from serially collected biological samples could provide valuable information regarding the molecular mechanisms underlying the effective anti-tumor immune response induced by the trial regimen, which could be used to design better combinational treatment strategies for advanced NSCLC. Of note, since tissue samples from the same tumor lesion outside the radiation field both before SBRT and after SBRT (but before initiation of Sintilimab and GM-CSF) were collected, the impact of SBRT on the immune microenvironment of tumor lesions outside the radiation field and its relationship between the so-called “abscopal effect” could be examined, which was largely unknown[48, 49].

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