In this study, we reported the efficacy and safety of combining single-site RT and ICIs in patients with oligometastatic NSCLC. Our study showed that the addition of single-site RT to immunotherapy could improve ORR and PFS with acceptable AEs. Of note, this combination therapy enhance the occurrence of out-of-field (abscopal) response. The favorable clinical outcomes were also observed for patients with brain metastases. Subgroup analysis revealed the younger patients, patients with better physical constitution, patients with less metastatic sites, and patients who received ICIs as first-line therapy benefited more from the combined approach.
Although no matched paired analysis was performed due to the relatively limited sample size, strict inclusion and exclusion criteria were followed to avoid potential bias. Our results showed the clinical features were well-balanced between the two groups. In order to further confirm this conclusion, we also performed a subgroup analysis (including brain metastases and primary tumors radiotherapy). Therefore, we believe our conclusion are interesting enough to warrant large-scale studies.
Oligometastasis with a small disease burden can be classified as an indolent state that is between the extensive and locally advanced stages. Despite having a relatively short follow-up time for patients with oligometastatic NSCLC in the study, anti-PD-1 monotherapy achieved a median PFS of 8.9 months, with an ORR of 31.2%. This was significantly better than the results of the CheckMate 057 and KEYNOTE-001 studies in a second-line setting and was also higher than the median PFS of 6.4 months (KEYNOTE-407) in a first-line setting (Borghaei et al., 2021; Herbst et al., 2016; Paz-Ares et al., 2020). This result suggests that a smaller tumor burden might be necessary in increasing the response to immunotherapy. Local therapy for oligometastatic NSCLC has been shown to improve clinical outcomes in multiple clinical trials (Gomez et al., 2016; Qiu et al., 2017; Weickhardt et al., 2012). RT as a primary local treatment provides local control of the irradiated lesion, and when administered in combination with immunotherapy, enhances antitumor response far outside of the radiation, which is known as the abscopal effect. This phenomenon crucially determines the anti-tumor efficiency of the local RT and ICI combination strategy (Ngwa et al., 2018). However, current strategies designed to test the efficacy of the combination strategy cannot optimally achieve abscopal effects through single-site irradiation in metastatic tumors (Kwon et al., 2014; McBride et al., 2021). In our study, we observed a significant response rate of 50.8% and a out-of-field response rate of 41.3%, which was higher than the ICI alone group (31.2%). Such a trial design is selected for oligometastatic patients with a small disease burden and equally immunogenic tumors that may fully activate the patient’s immune system. In our subgroup analysis, patients with 1–2 vs. 3–4 metastatic sites benefited more from anti-PD-1 treatment plus RT, which further supports the view of a small disease burden in favor of immune responses. In contrast to oligometastatic disease, the heterogeneity of polymetastases means that tumor-associated antigens exposed to RT might not be present at other unirradiated locations, or, if they are present, they might only be recognized in subgroups of the tumor lesion and not in the entire cellular population, making immune clearance at these other unirradiated locations impossible or greatly limited (Easwaran, Tsai, & Baylin, 2014; Heppner & Shekhar, 2014; Sharabi, Lim, DeWeese, & Drake, 2015; Spiotto, Fu, & Weichselbaum, 2016).
Undeniably, more biological and clinical evidence supports the use of comprehensive RT delivered to multiple lesions in combination with immunotherapy. Irradiating multiple sites helps to increase the likelihood of exposure to both shared and exclusive tumor-associated antigens and promptly reduce tumor burden (Brooks & Chang, 2019). A randomized clinical trial from MADCC assessing the effect of combining pembrolizumab with stereotactic body RT showed an out-of-field response rate of 38%, which was much higher than that of PD-1 monotherapy (Welsh et al., 2020). Overall, the use of multisite radiotherapy in combination with immunotherapy could be beneficial to achieve better therapeutic outcomes. However, this approach is not being widely tested in clinical trials, most likely owing to the lack of official guidelines or fear of AEs.
In addition to tumor burden and tumor heterogeneity, there is still no clear consensus on the optimal dosing, timing, or location of RT to increase the response rates of radiated and unirradiated lesions. Promisingly, some clinical practices indicate an important direction for future studies. Several studies have observed that SBRT, with relatively higher doses than conventional RT, is more favorable in combination with PD-1/PD-L1 inhibitors to achieve better survival benefits (Rapoport & Anderson, 2019; Schaue, Ratikan, Iwamoto, & McBride, 2012). However, our result did not indicate that hypofractionated radiation (> 2.0Gy per fraction per day) was more favorable when combined with immunotherapy. In addition, the originally published ETOP NICOLAS Study and PACIFIC trials both demonstrated the efficacy of concurrent and sequential RT combined with PD-1/PD-L1 inhibitors (Peters et al., 2019; Tomasini, Greillier, Boyer, Jeanson, & Barlesi, 2018). Our findings suggested no difference in PFS between the concurrent group and the nonconcurrent group. Based on the limited available data, it seems that the sequencing of the combination treatment makes almost no difference in efficacy as long as the interval is not long. Radiotherapy is a local treatment that acts on both the tumor and the surrounding non-malignant tissues; therefore, the likelihood of a successful immunogenic event is also influenced by the tumor microenvironment, the surrounding tissue or organ, and the nodal characteristics of the irradiated site. For example, irradiation of liver metastases in patients with NSCLC has been shown to result in stronger activation of antitumor immunity than the irradiation of pulmonary metastases (Tang et al., 2017). For liver metastases, our sample size is inadequate for valid analysis. Additionally, the results of our subgroup analyses showed that patients who derived benefit had good prognostic factors, including young age, good body condition, and have received immunotherapy as first-line treatment. Certainly, these optimizations of the ICI combination with RT still need to be validated in prospective clinical trials.
Nevertheless, our study has several limitations. First, this was a retrospective, single-institution analysis with a small sample size, which may introduce selection bias. For example, the percentage of patients with brain metastases in this study was higher than that reported in other studies. Another weakness of our study is the heterogeneity of treatment, including the administration of different PD-1 pathway inhibitors and different RT regimens; this represents a significant confounding factor. Third, because of the relatively short follow-up period, the survival analysis thus is limited to PFS, and the conclusion should be interpreted with caution. Moreover, the PD-L1 status of most of the patients in our study was unknown, making comprehensive subgroup analysis difficult. Nonetheless, we still analyzed the available data, despite being limited.