Title:“Combination of Radiotherapy and Immunotherapy in Advanced Non–Small Cell Lung Cancer”
Authors: Han Zhou, Si-Chao Wang, Teddy Tai Loy Lee
Background
The combination of radiotherapy and immunotherapy has become an important area of research in advanced non–small cell lung cancer (NSCLC). Immune checkpoint inhibitors (ICIs) have changed the treatment landscape for advanced NSCLC, improving survival for many patients. At the same time, radiotherapy remains a key treatment option for local disease control, symptom relief, and selected patients with limited metastatic burden. Biologically, radiotherapy may also enhance antitumor immune activity by increasing tumor antigen release, improving immune recognition, and modifying the tumor microenvironment. However, the best way to combine radiotherapy with immunotherapy remains unclear. A major clinical question is whether radiotherapy should be delivered at the same time as immunotherapy or in a sequential approach. The value of adding chemotherapy to this strategy is also not well defined, especially in real-world patients with newly diagnosed advanced or refractory NSCLC.
A territory-wide cohort study published in JAMA Oncology evaluated these questions using real-world data from Hong Kong. The study, known as OCEANUS, investigated survival outcomes in patients with NSCLC who received immunotherapy and radiotherapy, with a focus on treatment sequencing, immune checkpoint inhibitor maintenance after radiotherapy, and the role of chemotherapy.
Methods
This cohort study used data from the Hong Kong Hospital Authority Clinical Data Analysis and Reporting System, which covers more than 90% of the population. Patients with NSCLC diagnosed between January 1, 2010, and December 31, 2021, were included if they later received immunotherapy combined with radiotherapy for either newly diagnosed advanced disease or refractory disease.
The investigators compared real-world overall survival between sequential and concurrent immunotherapy-radiotherapy approaches in patients with newly diagnosed advanced NSCLC. They also assessed whether immune checkpoint inhibitor maintenance after radiotherapy was associated with improved outcomes in patients with refractory NSCLC. In addition, the study evaluated the survival association of chemotherapy when used as part of the treatment strategy.
To reduce treatment-selection bias, the investigators used propensity score–based methods. Overlap weighting was the primary method, while inverse probability of treatment weighting was used as a sensitivity analysis. Real-world overall survival after a landmark time point was the primary outcome. Survival was estimated using weighted Kaplan-Meier analyses and Cox models. When proportional hazards assumptions were not met, restricted mean survival time was used to summarize treatment effects.
Study Design
The OCEANUS study included 3,522 patients with NSCLC who received immune checkpoint inhibitors. Among them, 335 patients also received radiotherapy and were included in the main analysis. This group included 155 patients with newly diagnosed advanced NSCLC and 180 patients with refractory NSCLC.
The median age of patients was 64 years, with a range from 34 to 90 years. Most patients were male, with 247 of 335 patients, or 73.7%, being men. The study population represents a real-world group of patients rather than the highly selected population often seen in randomized clinical trials. This is important because patients with advanced NSCLC frequently have variable disease burden, comorbidities, prior treatments, performance status differences, and differences in treatment access.
The study focused on two main clinical settings. The first was newly diagnosed advanced NSCLC, where the main question was whether sequential radiotherapy and immunotherapy could improve survival compared with concurrent treatment. The second was refractory NSCLC, where the investigators assessed whether continuing immune checkpoint inhibitor maintenance after radiotherapy could improve survival compared with radiotherapy without ICI maintenance.
Results
In patients with newly diagnosed advanced NSCLC, sequential immunotherapy and radiotherapy was associated with significantly longer real-world overall survival compared with concurrent treatment. Median real-world overall survival was 20.3 months in the sequential group, with a 95% confidence interval of 13.3 months to not reached. In comparison, median overall survival was 16.0 months in the concurrent group, with a 95% confidence interval of 8.3 to 30.0 months.
The adjusted hazard ratio for overall survival was 0.68, with a 95% confidence interval of 0.47 to 0.99, and the result was statistically significant with a P value of .045. This suggests that sequential treatment was associated with a 32% lower risk of death compared with concurrent immunotherapy and radiotherapy in this real-world cohort.
The survival benefit appeared stronger among patients who received definitive radiotherapy, although formal interaction testing was not statistically significant. This means that the study observed a possible signal that radiotherapy intent may matter, but the data were not strong enough to confirm a clear subgroup interaction.
Chemotherapy was also associated with longer survival in patients with newly diagnosed advanced NSCLC. This finding suggests that systemic treatment partners may remain important even in the era of immunotherapy and radiotherapy combinations.
In patients with refractory NSCLC, radiotherapy followed by immune checkpoint inhibitor maintenance was associated with a numerically longer median real-world overall survival compared with radiotherapy without ICI maintenance. Median survival was 11.2 months with ICI maintenance versus 6.7 months without ICI maintenance. However, this difference was not statistically significant, with a P value of .20. Therefore, while the result is clinically interesting, it should be interpreted cautiously.
In refractory disease, the addition of chemotherapy was not significantly associated with improved real-world overall survival. Sensitivity analyses using inverse probability of treatment weighting produced similar estimates, supporting the consistency of the main findings.
Key Findings
The most important finding of this study is that treatment sequencing may matter in advanced NSCLC. In newly diagnosed advanced disease, sequential immunotherapy and radiotherapy was associated with longer real-world overall survival than concurrent treatment. The difference in median overall survival was 20.3 months versus 16.0 months, favoring the sequential approach.
Another key finding is that chemotherapy remained associated with longer survival in newly diagnosed advanced NSCLC. This is clinically relevant because many current treatment strategies use immunotherapy in combination with chemotherapy, and this real-world analysis supports the idea that chemotherapy may still have an important role when radiotherapy is also part of treatment.
For refractory NSCLC, immune checkpoint inhibitor maintenance after radiotherapy showed a numerical survival advantage, with median overall survival of 11.2 months compared with 6.7 months without maintenance. However, because this result was not statistically significant, it should be viewed as hypothesis generating rather than practice changing.
The study also highlights the need for prospective randomized trials. Although the data were adjusted using advanced statistical methods, this was still an observational cohort study. Real-world studies can identify important clinical signals, but they cannot fully replace randomized evidence.
Key Takeaway Messages
Sequential radiotherapy and immunotherapy may be a preferred strategy for patients with newly diagnosed advanced NSCLC when combining these modalities.
In this cohort, sequential immunotherapy-radiotherapy was associated with longer overall survival than concurrent treatment, with a median survival of 20.3 months versus 16.0 months.
Chemotherapy was also associated with improved survival in newly diagnosed advanced NSCLC, suggesting that systemic treatment partners remain important.
In refractory NSCLC, immune checkpoint inhibitor maintenance after radiotherapy showed a numerical but not statistically significant survival benefit.
The findings are hypothesis generating and support the need for randomized clinical trials to define the optimal sequencing of radiotherapy, immunotherapy, and chemotherapy in advanced NSCLC.
Conclusion
This territory-wide real-world cohort study provides important evidence on how radiotherapy and immunotherapy may be best combined in advanced non–small cell lung cancer. Among patients with newly diagnosed advanced NSCLC, sequential immunotherapy and radiotherapy was associated with longer overall survival compared with concurrent treatment. The benefit was supported by adjusted analyses and sensitivity testing, making the signal clinically meaningful, although not definitive.
The study also found that chemotherapy was associated with longer survival in newly diagnosed advanced disease, reinforcing the importance of multimodality systemic therapy in appropriate patients. In refractory NSCLC, radiotherapy with ICI maintenance showed a numerical improvement in survival, but the association was not statistically significant.
Overall, these findings suggest that the timing of radiotherapy relative to immunotherapy may influence outcomes in advanced NSCLC. Sequential treatment may offer a survival advantage compared with concurrent treatment, especially in newly diagnosed advanced disease. However, because the study was observational, the results should be interpreted as hypothesis generating. Prospective randomized trials are needed to confirm the optimal sequencing of radiotherapy and immunotherapy and to clarify the role of chemotherapy and ICI maintenance in different NSCLC treatment settings.
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Written by Aren Karapetyan, MD