This study retrospectively compared the efficacy and safety of different first-line treatments for unresectable stage III NSCLC after grouping patients according to negative or positive driver genes. In negative driver genes group, the presence of radiotherapy significantly improved efficacy. Single-modality radiotherapy was the standard for unresectable stage III NSCLC in the 1980s based on the RTOG 7301 trail (Perez et al. 1980). Additionally, some following studies demonstrated improvement in symptoms after radiation treatment (Shang et al. 2022). Our results are consistent with these results, which suggests that radiotherapy is associated with improved survival in patients with unresected stage III NSCLC. And further multivariate analysis showed that radiotherapy was indeed a significant factor affecting the PFS in the negative driver genes group (P༜0.001).
In order to meet the urgent need for better efficacy, there has been progress in the treatment modalities for unresectable stage III NSCLC. Recently, immunotherapy has shown striking survival improvement in unresectable stage III NSCLC. Our study showed similar positive findings. Further subgroup analysis showed that immunotherapy had significantly better survival compared to chemotherapy whether patients with or without radiotherapy in negative driver genes group. And the most obvious improvement was found in the immunotherapy in combination with CRT group, which further confirm the results of the PACIFIC trail. The potential reason might be that the drugs of PD-1/PD-L1 checkpoint inhibition could synergize the effect of CRT. Since radiotherapy generates in situ vaccination which can be substantially potentiated by immunotherapy, the abscopal effect of radiotherapy has become more meaningful (Liu et al. 2018). Furthermore, radiotherapy can stimulate anti-tumor adaptive immunity, modulating the tumor microenvironment and induce tumor PD-L1 levels (Liu et al. 2018) (Wang et al. 2018) (Dovedi et al. 2014).
Collectively, for patients with negative driver genes, the combination of radiotherapy and immunotherapy are critical components of definitive treatment to significantly improve outcomes. At present, there are some clinical trials to explore further progress based on the success of the combination of CRT and immunotherapy. An exploratory analysis of the PACIFIC study also suggests that durvalumab treatment given earlier (≤ 14 days) after cCRT may benefit more. Subgroup analysis found that the subgroup initiated with durvalumab ≤ 2 weeks after radiotherapy significantly delayed disease progression. This suggests the potential for simultaneous immunotherapy with CRT, but this model is still in the exploratory stage. Preliminary data from the Phase II clinical study DETERRED show that atezolizumab is feasible when administered concurrently with CRT followed by chemotherapy-atezolizumab consolidation. This treatment strategy did not increase the incidence of radiation-related pneumonia in terms of safety. In terms of effectiveness, the rates of 1-year PFS and OS are 66% and 77%, respectively. It appears to be better on the rate of 1-year PFS (55.9%) compared to the PACIFIC, but the rate of 1-year OS (83.1%) is slightly worse(Lin et al. 2018). At the same time, the ETOPNICOLAS Phase II clinical study also showed that cCRT synchronization with nivolumab and then nivolumab maintenance in unresectable stage III NSCLC was feasible. And no increased risk of unintended adverse events or severe pneumonia was observed. The median PFS was 12.7 months, the median OS was 38.8 months, and the 1-year PFS and OS rates were 53.7% and 75.7%, respectively (Peters et al. 2021). In our trial, there was no statistical difference in mPFS and the rate of pneumonia between the two groups. Our trial, like previous trials, suggests the potential for simultaneous immunotherapy with CRT. Several large-scale Phase III trials of immunosynchronous therapy modalities are ongoing, including NCT 03519971 and NCT-04092283.
There is concern that toxicity could be further aggravated when immunotherapy and radiotherapy are given. Although the radiotherapy group increased the rate of pneumonia at any grade (9.43%), there was no statistical differences in the incidence of grade 3/4 pneumonia between the two groups. Furthermore, in PACIFIC trail, rates of grade 3/4 AEs of any cause were similar for durvalumab compared with placebo (29.9% vs. 26.1%) (Sj et al. 2018). Several prospective trails (LUN14-179; BTCRC LUN16-081) have also confirmed that the toxicity of consolidation immunotherapy after CRT is tolerable (Ga et al. 2020) (Yan et al. 2019). Similarly, our study showed no differences in grade 3/4 AEs between immunotherapy group and cCRT or chemotherapy group.
About patients with EGFR mutations, the subgroup analysis of PACIFIC trail showed that them might not benefit from maintenance immunotherapy. ESMO expert consensus does not recommend the use of adjunctive durvalumab in patients with EGFR mutations. Another treatment should thus be explored for this population. Some studies suggest many stage III NSCLC patients have driver mutations such as EGFR (10–30% of patients) (Jiang et al. 2020). In our study, EGFR-mutant patients account for about 50% in positive driver genes group while others have anaplastic lymphoma kinase gene rearrangements (ALK+), v-raf murine sarcoma viral oncogene homolog B (BRAF) mutations and so on. Among patients with advanced NSCLC with oncogenic driver mutations, molecular targeted drugs have been recommended for the first-line therapy, which dramatically changed the standard treatment. Preclinical studies have shown that EGFR tyrosine kinase inhibitors (TKIs) could have a radio sensitizing effect, which showed the combination of EGFR-TKIs and radiotherapy seems to be a reasonable approach (Anakura et al. 2019) (Zhuang et al. 2009). However, there are few recommendations indicating whether radiotherapy is effective for patients with positive driver genes. Thus, it was worth to explore the efficacy of radiotherapy for this population given that it significantly improved the survival for patients with negative driver genes. In our study, there were no differences in short-term efficacy among radiotherapy subgroup, targeted therapy subgroup and radiotherapy plus targeted therapy group, which showed radiotherapy seemly failed to improve outcomes whether combined with targeted therapy. Although several phase II clinical experiments (RECEL trail; WJOG 6911L trail) showed the potential value of concurrent targeted therapy with radiotherapy (Xing et al. 2021)(Akamatsu et al. 2019), no phase III trails have yet demonstrated similar results. Based on the above results, it may not urgent to add radiotherapy to first-line treatment to improve the efficacy for patients with positive gene driver. However, the limited number of patients and the retrospective nature of this analysis do not lead to obtain firm conclusions, further prospective studies should aim to confirm these results.
There are several limitations in this study. This analysis was based on a small sample from a single institution. And the study was retrospective in design, which is inherently affected by selection bias and missing data. Therefore, our results suggest the possibility of clinical treatment, rather than reaching definitive conclusions. Larger prospective studies are needed to confirm our findings.