To our knowledge, this was the first retrospective study to investigate the safety of consolidative TRT after PD-L1 inhibitors with platinum and etoposide treatment. We concluded that using consolidative TRT to manage the residual lesions in the chest after administrating PD-L1 inhibitors with platinum and etoposide was safe and tolerable, which was supported by the fact that the incidence of grade 2 RP was 30% and no grade 3 RP occurred. We did not identify risk factors for grade 2 RP by using univariate and multivariate logistic regression analyses.
It has been reported that the risk of ≥ grade 2 symptomatic pneumonitis ranges from 5–30% with TRT alone or when combined with platinum-based chemotherapy(9–12). The incidence of checkpoint inhibitor-related pneumonitis is lower than 5% in patients who received PD-(L)1 inhibitors alone, in whom the occurrence rate of any grade pneumonitis resulting from PD-L1 inhibitors is 1.3%(13–17). Theoretically, PD-L1 inhibitors combined with TRT will enhance the probability of pneumonitis because radiation can increase the infiltration of inflammatory cells and inflammatory factors inside the tumour of the targeted area. A retrospective study reported that the incidence rate of pneumonitis at any grade was 33.9% in patients with stage III non-small-cell lung cancer who received PD-L1 inhibitors after administration of concurrent chemoradiotherapy, which was considered tolerable for patients(18). Based on the results of previous studies, the dosimetric parameters of our patients were all within the safe range. We considered that receiving consolidative TRT to manage residual lesions in the chest after administration of PD-L1 inhibitors with platinum and etoposide was tolerable because the incidence of grade 2 RP was 30% and no grade 3 RP occurred in our study.
However, there was another retrospective study showing that the occurrence rate of pneumonitis was 48.96% in patients who received consolidative TRT after PD-(L)1 inhibitors with chemotherapy, which indicated that this treatment mode was harmful to patients(19). Comparing the results of this retrospective study with those of our study, we found that 10 (35.7%) patients in the previous study had pulmonary emphysema, and the majority of patients received PD-1 inhibitors rather than PD-L1 inhibitors as used in this study. Previous studies showed that the occurrence rate of pneumonitis after the administration of PD-1 inhibitors was 3.6%, which was higher than that after the administration of PD-L1 inhibitors(20–22). The potential mechanism of the higher incidence of pneumonitis induced by PD-1 inhibitors is unclear but may be explained as follows. Tumour cells achieve immune escape by expressing PD-L1 and PD-L2 receptors, and immune checkpoint inhibitors can enhance antitumor effects by activating immune cells and preventing immune escape. PD-1 inhibitors not only bind with PD-L1 receptors but also with PD-L2 receptors. PD-L1 inhibitors only bind with PD-L1 receptors; they do not influence the PD-L2 pathway, so PD-L1 inhibitors retain their immunomodulatory function and lower the occurrence of autoimmune diseases. Thus, the occurrence rate of RP is lower in patients who received TRT and PD-L1 inhibitors than in patients who received TRT and PD-1 inhibitors.
The mPFS was 9 months for all patients in our study (Fig. 1) and 5.2 months and 5.1 months, respectively, in the Impower133 trial and Caspian trial(4, 5). Among all 20 patients, 17 patients (85%) suffered from disease progression, the brain (50%) and liver (25%) were the most common sites of failure lesions, and only four patients suffered from local failure in the radiation field. The local control rate in the chest was 80%, and the median intrathoracic PFS was 8.85 months. The rate of isolated intrathoracic progression was 15% in our study, compared with 19.8% in the CREST trial. TRT could reduce the occurrence rate of intrathoracic progression. Increasing the dose in the chest may decrease the recurrence rate in the chest. The recurrence rate in the chest was 25.8% in the RTOG0937 trial, which was lower than the 62.5% observed in the CREST trial. The difference between the two trials was the total dose in the chest; the former was 45 Gy/15 f, and the latter was 30 Gy/10 f(23, 24). Moreover, one study showed that a BED (biological effective dose) > 50 Gy was beneficial to overall survival, PFS, and intrathoracic PFS at 1 year(25). We divided the 20 patients into 2 groups according to whether they received BEDs ≥ 50 Gy or BEDs < 50 Gy. However, there was no significant difference between the two groups by statistical analyses perhaps due to the limited number of samples in our study.
In the NRG LU007 (NCT04402788, https://clinicaltrials.gov) trial, patients who were administered 4–6 cycles of platinum and etoposide with or without atezolizumab in first-line treatment were divided into 2 groups according to whether they received radiation therapy (including those with lesions in the chest). The trial was a prospective study and played an important role in confirming the function of TRT after the administration of PD-L1 inhibitors combined with chemotherapy.
This study has some limitations. On the one hand, this was a retrospective study conducted in a single medical centre with a short follow-up time and only 20 patients; thus, we did not identify risk factors for Grade 2 RP after performing statistical analysis. However, only 6 patients (30%) experienced grade 2 RP, and no patients experienced grade 3 or higher pneumonitis. We concluded that it was safe to use consolidative TRT after PD-L1 inhibitors with platinum and etoposide. On the other hand, the follow-up time was short, so most patients did not achieve an overall survival outcome, so we could not analyse the OS of the 20 patients. The mPFS was 9 months for the 20 patients in our study, which was higher than the 5.2 m and 5.1 m observed in the IMpower133 trial and CASPAIN trial, respectively. From these results, we can see that administrating consolidative TRT after PD-L1 inhibitors with platinum and etoposide can improve PFS.
In conclusion, administrating consolidative TRT after PD-L1 inhibitors with platinum and etoposide was safe and tolerable. Thus, we encourage more prospective studies to explore the efficacy and safety of this treatment mode.