Improved survival outcome with not-delayed radiotherapy and immediate PD-1/PD-L1 inhibitor for non-small-cell lung cancer patients with brain metastases

In this study, we evaluate the outcome of 73 NSCLC patients who receive ICIs and RT to BMs, and investigate the best sequence. While retrospective series have explored this topic in melanoma patients receiving ipilimumab and RT [16], few have reported patient outcomes in NSCLC patients with anti-PD-1 ICI in BMs, and our series represents one of the most comprehensive analyses to date. This study provides several important findings. First, in terms of sequencing of therapy, not-delayed RT maximizes the benefits of synergistic therapy. Second, the benefit of combined modality therapy is maximized when immediate intracranial RT is delivered to ICI naive lesions. Third, not only is the high intracranial response rate in patients undergoing RT and immediate ICI impressive, but early evaluation of this response is predictive of OS. It is important to note that given the difficulty in conducting prospective clinical trials, these results are crucial to optimal patient management.

Numerous studies have demonstrated the survival advantages of RT and ICIs together [1]. Studies on patients with BMs found that RT might change blood–brain barrier functioning and permit the entry of immune cells and ICI into the brain [17‐19]. Recent studies recommend RT combined with ICI to treat patients with BMs [20, 21]. Institutional studies in melanoma with BMs have reported the impact of iRT sequence on survival outcome [22, 23], but few have specifically investigated impact in lung cancer. In our study, which included 73 NSCLC patients with BMs, we discovered that the delayed RT group had inferior survival outcomes, including iLPFS, iDPFS, and OS. Similarly, Schapira and colleagues reported declined iDPFS and OS in 37 patients with delayed RT (defined as within 1mo or 1mo prior to ICIs) [24]. Our study supports their findings in a larger sample size, and provides multiple with more observations, including lesions-specific objective response rate. A large international meta-analysis was published in 2019 [25], this study enrolled melanoma and lung cancer patients with BMs, and revealed that delayed RT predicts the worst OS (1-year OS was 40.7%, 56%,65% for delayed RT, concurrent RT, and upfront RT, P = 0.00045), but there are only 19 BM lesions originated from lung cancer. In keeping with their finding that RT shouldn’t be delayed, our meta-analysis increased the sample size and solely recruited lung cancer patients with BM.

Many trials, including those done by Schapira E et al., Porte J et al., Maike Trommer et al., and Hubbeling et al. used “1 month” as the threshold for “concurrent RT” [24, 26‐28]. In these trials, patients administered with concurrent iRT experienced better survival outcomes than those treated with non-concurrent therapy. The definition of “concurrent ICI” ranges from “within 1 week” [29] to “5.5 months” [30]. Some studies suggest ICI’s half time prior to or after RT as a definition for “concurrent therapy”, which is based on small samples on retrospective studies [13, 7, 31]. We use “x-tile” software, there is a sustaining benefit in iLPFS and OS of “not delayed RT” when we compress the time interval between upfront ICI and following RT from “1 month” to “14 days”. This is the reason why use two weeks as the boundary between concurrent and non-concurrent RT. Similarly, Chen found that patients who received ICI more than two weeks prior to stereotactic radiation had lower OS than the contemporaneous group [32]. Imber et al. also use “2 weeks” as a boundary for delayed and not-delayed RT [33]. Numerous studies have identified and assessed biomarker alterations, such as those in mannose-6-phosphate (MPR) [34], tumor-reactive T cells [35], and PD-L1 [35], to assist in determining the ideal time to provide anti-PD-1/L1 therapy. Hettich’s work shows that ICI is effective early after RT-mediated T-cell induction since CD8+T-cell count peaks after 5 days post-RT and subsequently drops to pre-RT levels following 6Gy 2 fractions [36]. Frey’s work reinforces this finding, following tumor irradiation with 10Gy/2F, it was shown that CD8+T-cells peak at day 8 and decline significantly by day 9 [37]. Together, these findings imply that the optimal definition of “concurrent RT” might be reached by closely monitoring tumor-reactive T cells after radiotherapy.

Patients who received ICIs exhibited prolonged local control and had superior BOR when the gap between iRT and RT was shorter (P = 0.0544). We recommend shortening the time between RT and ICI; in other words, ICI administration schedules shouldn’t be changed while RT is being administered. Other authors found a similar result in favor of immediate delivery. Italian Association of Radiotherapy and Clinical Oncology (AIRO) conducted a sizable multi-institutional retrospective analysis, they showed significant differences when comparing OS in patients treated with interval of iRT ≤ 7 days to those with interval > 7 days (P = 0.007), in favor of short interval group [38]. In contrast to non-immediate ICI, Kotecha found that patients who received immediate ICI had superior BOR [13]. Innovatively, Dagoglu’s case series evaluation revealed that 95.8% of abscopal responses happened in patients who underwent RT right away after immunotherapy [39]. For preclinical studies, Dovediin’s study revealed that anti-PD-L1 drugs started seven days after RT were related to worse survival outcomes than those started on the first or last day [35]. Some studies demonstrated that very close intervals of RT and anti-PD-1 will be able to potentiate early T-cell activation stimulated by RT [21, 40], to some extent accounting for our results.

The relevant limitation is its retrospective nature with a high risk of selection bias, however, we have tried to exclude the strong confounding factors. We only enrolled BM patients from NSCLC and excluded those who have received previous brain radiotherapy. Furthermore, only those who received PD-1/PD-L1 were included. Drawbacks of this study were: firstly, follow-up time bias, as patients who underwent delayed RT were likely to have a much closer frequency of screening MRI and close follow-up. Secondly, even though the baseline characteristics were comparable across groups, patients were not randomly chosen to undergo ICI, stereotactic radiotherapy, or WBRT as their initial course of treatment. Thirdly, chromosomal abnormalities and PD-L1/PD-1 expression were not examined since a significant fraction of patients’ conditions were unknown. Fourth, delayed RT is frequently used for BM progression. These patients are likely to have ICI resistance, and this imbalance might affect the outcome. Fifth, despite our efforts to include recruited patients from two centers and conduct a meta-analysis to improve patient volume, only seventeen patients (23.3%) underwent delayed RT in our study, the small number of patients negatively impacted the outcome of this study.