In the present study, we described the efficacy and safety of immunotherapy combined with radiotherapy in 57 NSCLC patients. Among the evaluable patients, the median OS was 25.9 months, and the median PFS was 10.3 months. The in-field and out-of-field overall response rates were 45.2% and 32.1%, respectively; the disease control rates were 97.6% and 94.3%. Furthermore, the combination of immunotherapy with radiotherapy was well tolerated and was not associated with an increase in the rate of pneumonitis.
Immunotherapy combined with radiotherapy showed longer OS and PFS in our study than in previous studies in which patients received immunotherapy alone, with an OS of 11.8-22.0 months and a PFS of 4.0-9.0 months(18, 19), indicating that combination therapy could be a good strategy in metastatic NSCLC patients. There is growing evidence to suggest that a focus on combining immunotherapy with radiotherapy is warranted. A secondary analysis of the phase I KEYNOTE-001 study assessed 98 patients and suggested that patients who received pembrolizumab and had previously received radiotherapy history had longer PFS (4.4 months vs. 2.1 months, P = 0.019) and OS (10.7 months vs. 5.3 months, P = 0.026) than those who did not receive radiotherapy(20). In the PEMBRO-RT (phase 2, n=76) and MDACC (phase 1/2, n=72) trials, patients with metastatic NSCLC were divided into a pembrolizumab with radiotherapy group and a pembrolizumab alone group(14, 21). Although there were no significant differences in response rates and outcomes when the above two studies were analysed individually, a pooled analysis combining the data from these two randomized trials reported that immunotherapy combined with radiotherapy significantly increased the abscopal response rate and control rate (41.7% vs. 19.7%, P = 0.004; 65.3% vs. 43.4%, P = 0.007, respectively), with higher PFS (9.0 vs. 4.4 months, P = 0.045) and OS (19.2 vs. 8.7 months, P<0.001) (15). Moreover, a systematic review including 18 articles (6 prospective studies) described 1736 patients treated with an ICI-SABR combination; the OS and PFS were 12.4 and 4.6 months, respectively, and abscopal response rates was 41%(22). Collectively, in line with the findings of our study, the addition of radiotherapy to immunotherapy showed great promise for advanced NSCLC.
To further study the ideal radiotherapy timing, number of lesions to be irradiated, and schedule of combined treatment, subgroup analyses were performed. Patients receiving immunotherapy with concurrent radiotherapy showed a trend to have improved PFS and OS compared to those who were given sequential radiotherapy, although the difference did not reach statistical significance. Although several studies attribute outcome benefits to the abscopal effect(23, 24), the exact mechanisms of the concurrent combination are not known and need to be confirmed by future studies with larger sample sizes. In the subgroup analysis of the number of irradiated lesions, multisite radiotherapy was associated with longer PFS than single-site radiotherapy, which was an independent prognostic factor for PFS. However, similar to previous studies(21), the median OS was significantly different. This result may suggest that multisite radiotherapy could prolong systemic lesion control and lead to better prognosis by activating systemic immunity; however, there are many factors affecting OS, such as posterior treatment mode.
A previous study of radiotherapy schemes demonstrated that hypofractionated radiation therapy (HFRT) has a therapeutic advantage compared with conventional fractionated radiation therapy(25). A preclinical study proved that HFRT treatment of the primary tumour could reduce the recruitment of myeloid-derived suppressor cells into tumours and decrease the expression of PD-L1 on those cells, which unleashed the cytotoxicity of CD8+ T cells(26). Although low-dose radiation therapy (LDRT) has an inferior tumour-killing effect, LDRT is conducive to T cell recruitment and reprograms macrophages in the tumour microenvironment(27). Thus, studies to determine which radiotherapy mode can achieve the best combination effect are warranted. In the pooled analysis of the PEMBRO-RT and MDACC trials, the PFS in the SBRT group was significantly longer than that in the traditional radiotherapy group (21.1 vs. 6.8 months, P=0.03)(14). In a retrospective analysis, patients receiving immunotherapy with SRT (n=228) showed a superior OS compared with those receiving a traditional radiation scheme (n=2235) (P <0.001)(28). However, our study found a similar PFS and OS in the SRT and conventional radiotherapy groups. Several factors might be related to the results. First, the relatively small sample size was a limitation for the detection of potentially significant differences. Second, the lack of PD-L1 assay standardization and limited stratification due to the difficulty in obtaining samples from retrospective studies might have affected the results.
There is growing evidence of the encouraging safety profile of immunotherapy combined with radiotherapy. Our study showed no increase in toxicity and a rate of treatment-related AEs of 61.4%, consistent with the range of 50–70% previously reported(29, 30). The incidence of grade 3 AEs was 5.3%. Therefore, administration of immunotherapy combined with radiotherapy does not increase the incidence of AEs in the real world. Pneumonitis is a major concern in lung cancer, and the incidence of pneumonitis was not increased for patients receiving immunotherapy with thoracic radiotherapy. Additionally, patients receiving immunotherapy with concurrent radiotherapy or multisite radiotherapy did not have an increased risk of severe or unexpected toxicities.
This study is limited by its small sample size and retrospective nature. Furthermore, the relationship between PD-L1 expression and outcomes in our combined cohort could not be determined due to the lack of sufficient tissue samples. Additionally, many questions remain about the effect of different radiotherapy doses and fractionation schedules on the magnitude of the immune-boosting effect. Further large-volume, randomized trials are needed to address these unresolved questions.