To my 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 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 the risk factors of grade 2 RP by using univariate and multivariate logistics regression analyses.
It has been reported that the risk of ≥ grade 2 symptomatic pneumonitis ranges from 5–30% with TRT alone or combined with platinum-based chemotherapy(9–12). Checkpoint Inhibitors-related pneumonitis is lower than 5% in patients who received PD-(L)1 inhibitors alone, in which the occurrence rate of any grade pneumonitis of PD-L1 inhibitors is 1.3%(13–17).Theoretically, PD-L1 inhibitors combing with TRT will enhance the probability of pneumonitis because radiation can increase the infiltration of inflammatory cells and inflammatory factors inside the tumor of targeted area. A retrospective study reported that the incidence rate of any grade pneumonitis was 33.9% in patients with stage III non-small cell lung cancer who received PD-L1 inhibitors after administrating concurrent chemoradiotherapy, which was considered tolerable for patients(18). Compared with the previous studies, the dosimetric parameters of our patients were all within the safe range. We considered that receiving consolidative TRT to manage the residual lesions in chest after administrating PD-L1 inhibitors with platinum and etoposide was tolerable because grade 2 RP was 30% and no grade 3 RP occurred in our study.
But there was one 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). Compared this retrospective study with our study, we found that 10 (35.7%) patients had pulmonary emphysema, and a majority of patients received PD-1 inhibitors rather than PD-L1 inhibitors in this study. Previous studies showed the occurrence rate of pneumonitis after administrating PD-1 inhibitors was 3.6%, it was higher than after administrating PD-L1 inhibitors(20–22). The potential mechanism of the higher incidence of pneumonitis induced by PD-1 inhibitors are unclear, maybe the following can explain it. As we all know, tumor cells achieve immune escape by expressing PD-L1 and PD-L2 receptors, the immune checkpoint inhibitors can enhance anti-tumor effect by activating immune cells, and prevent the immune escape. PD-1 inhibitors not only combine with PD-L1 receptors but also combine with PD-L2 receptors, PD-L1 inhibitors only combine with PD-L1 receptors, they do not influence the PD-L2 pathway, so, PD-L1 inhibitors retain the 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 patients who received TRT and PD-1 inhibitors.
The mPFS was 9 months for all patients in our study (Fig. 1), and respectively were 5.2 months and 5.1 months, correspondingly, in Impower133 trial and Caspian trial(4, 5). Among all 20 patients, 17 patients (85%) suffered from disease progression, the most common failure lesions were brain(50%)and liver༈25%༉, only four patients suffered from local failure in radiation field. Local control rate in chest was 80%, the median intrathoracic PFS was 8.85 months. The rate of isolated intrathoracic progression was 15% in our study, compared with 19.8% in CREST trial. TRT could reduce the occurrence rate of intrathoracic progression. Maybe increasing the dose in chest can decrease the recurrence rate in chest. The recurrence rate in chest was 25.8% in RTOG0937 trial, it was lower than 62.5% in CREST trial. The difference between the two trials was the total dose in chest, the former was 45Gy/15f, the latter was 30Gy/10f(23, 24).Meanwhile, 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 BED ≥ 50 Gy or BED < 50 Gy. But there was no statistical difference between the two groups by statistical analyses, maybe there were limited samples in our study.
In NRG LU007 (NCT04402788, https://clinicaltrials.gov) trial patients who administrating 4–6 cycles platinum and etoposide with or without atezolizumab in first line treatment were divided to 2 groups according to receiving radiation therapy (including the lesion in chest) or not. The trial was a prospective study and played an important role in confirming the function of TRT after administrating PD-L1 inhibitors combine with chemotherapy.
This study has some limitations. On the one hand, this was a retrospective study in a single medical center, short follow-up time and only 20 patients, thus we did not find the risk factors of Grade 2 RP by performing statistical analysis. But there was only 6 patients (30%) experienced Grade 2 RP, no patients experienced grade 3 or higher pneumonitis, we concluded that it was safe by using consolidative TRT after PD-L1 inhibitors with platinum and etoposide. On the other hand, the follow-up time was short, so most of patients did not achieve an overall survival outcome, so we could not analyse the OS of the 20 patients. The mPFS was 9 months of the 20 patients in our study, which was higher than 5.2m and 5.1m of IMpower133 trial and CASPAIN trial respectively. From here 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 implement to explore the efficacy and safety of this treatment mode.