Radiotherapy combined with immunotherapy has become a significant focus in the treatment of unresectable lung cancer, but many key clinical questions remain unresolved. Establishing a consensus is crucial to guide standardized clinical practice. To address these needs, Academician Jinming Yu from Shandong Cancer Hospital, Dr. Ying Cheng from Jilin Cancer Hospital, and Dr. Lian’an Chen from Chinese PLA General Hospital led a multidisciplinary effort to review evidence in this field. Together with expert members from key national organizations, they have developed the 2024 Consensus on Radiotherapy Combined with Immunotherapy for Unresectable Lung Cancer.

In an interview with Oncology Frontier, Dr. Ying Cheng, who chaired the expert group responsible for the consensus, discussed the significance of the new guidelines, key topics in the field, and future directions.

Q1. Oncology Frontier: As the chair of the expert group, could you share the background and significance of releasing the 2024 Consensus on Radiotherapy Combined with Immunotherapy for Unresectable Lung Cancer?

Dr. Ying Cheng: In recent years, efforts have focused on exploring multimodal treatment strategies for unresectable lung cancer. Despite the increasing application of immune checkpoint inhibitors (ICIs), nearly 50% of patients do not respond, highlighting the immense potential of combining radiotherapy and immunotherapy. This area of research has garnered significant attention, and combining radiotherapy with immunotherapy after chemoradiotherapy has already become a standard treatment for unresectable non-small cell lung cancer (NSCLC), providing notable survival benefits. Meanwhile, for limited-stage and extensive-stage small cell lung cancer (LS-SCLC and ES-SCLC), the role of this combination is being actively explored, with numerous studies showing encouraging results in support of the combined approach.

However, new treatment models come with challenges. Key questions such as identifying the right patient population, determining optimal timing and dosage, and managing potential adverse events remain top priorities for clinicians.

Based on these developments and the needs of clinical practice, we have compiled the latest research and clinical insights to address critical questions, such as patient selection, radiotherapy dosing, and timing of immunotherapy. This consensus aims to provide scientific, standardized, and practical recommendations for clinicians, ultimately improving patient survival outcomes.

Q2. Oncology Frontier: Immunotherapy combined with chemotherapy has become the standard first-line treatment for extensive-stage small cell lung cancer (ES-SCLC). However, controversies remain regarding thoracic radiotherapy, optimal dosing, and timing. Based on current data, which ES-SCLC patients might benefit from thoracic radiotherapy, and how can the combination of thoracic radiotherapy and immunotherapy be optimized?

Dr. Ying Cheng: In the chemotherapy era, the CREST study demonstrated survival benefits in patients with ES-SCLC who achieved complete or partial response with chemotherapy and received thoracic radiotherapy. Further analysis showed that patients with fewer than three metastases had significantly better progression-free survival (PFS). Now that chemo-immunotherapy has become the standard first-line treatment, the role of thoracic radiotherapy in this context is gaining attention. This consensus recommends thoracic radiotherapy for ES-SCLC patients who show a positive response to chemo-immunotherapy, provided that the benefit-risk ratio is favorable.

Accumulated evidence from phase I-II clinical studies provides insights for further optimization. Firstly, safety remains a concern. Different studies using various immune checkpoint inhibitors and radiotherapy doses have yielded varying results in terms of safety and tolerability. Some studies have shown good tolerability with low-dose radiotherapy, indicating that more exploration is needed to enhance safety. Secondly, patient selection is critical. For example, studies combining nivolumab and ipilimumab with radiotherapy did not demonstrate PFS benefits, but they did find that CTX infiltration and migration in tumors correlated with longer PFS and overall survival (OS). This suggests the need for biomarkers to help stratify patients. Lastly, optimizing the timing, dosage, and combination of these treatments is essential. The consensus suggests adjusting radiotherapy doses based on factors such as target area size, tumor burden, and patient condition, with radiotherapy generally recommended after induction chemo-immunotherapy. While these issues currently lack high-quality evidence, future studies may provide new strategies to enhance efficacy and minimize adverse effects.

Q3. Oncology Frontier: For limited-stage small cell lung cancer (LS-SCLC) patients, concurrent chemoradiotherapy is the current standard of care. Based on the current applications of immunotherapy in SCLC and your involvement in various registration studies, what is your view on the role of immunotherapy in LS-SCLC? Can both concurrent chemoradiotherapy combined with immunotherapy and consolidation immunotherapy offer benefits to patients?

Dr. Ying Cheng: Concurrent chemoradiotherapy, the standard treatment for LS-SCLC, offers a median survival of only 20–30 months, with a 5-year survival rate of around 30%. This treatment model has remained unchanged for over 30 years. Immunotherapy has reshaped the treatment landscape for ES-SCLC, and it is now an essential area of exploration for LS-SCLC.

The ADRIATIC study is the first global phase III study evaluating consolidation durvalumab after concurrent chemoradiotherapy for LS-SCLC. In the oral presentation at ASCO this year, the study showed that consolidation durvalumab extended median PFS by 7.4 months and reduced the risk of progression by 24%, while also extending median OS by 22.5 months and reducing the risk of death by 27%. The study also improved 2-year PFS and OS rates by around 10 percentage points each, with good safety outcomes. Published in The New England Journal of Medicine, this study marks a revolutionary advancement in LS-SCLC treatment, establishing a new model of consolidation immunotherapy after induction chemoradiotherapy. In addition, we are exploring the efficacy and safety of introducing immunotherapy at the start of induction treatment in LS-SCLC. The SHR-1316-III-302 phase III study, which I lead, is investigating atezolizumab combined with concurrent chemoradiotherapy. Preliminary safety data show an objective response rate (ORR) of 92.9%, a PFS of 17.9 months, and good tolerability, indicating the potential advantages of the combined strategy.

Although both models show promising prospects in LS-SCLC, the current consensus recommends consolidation immunotherapy after chemoradiotherapy based on available evidence, while concurrent chemo-immunotherapy lacks definitive data and should be considered within clinical trials where possible.

Q4. Oncology Frontier: Despite progress in combining radiotherapy with immunotherapy for unresectable lung cancer, many questions remain unanswered. In future research, what issues in radiotherapy dosing, drug selection for immunotherapy, and patient stratification need to be addressed? Are there any ongoing clinical trials that could change current treatment paradigms?

Dr. Ying Cheng: Radiotherapy combined with immunotherapy shows great potential in both NSCLC and SCLC, but this approach involves multiple variables and complexities. To achieve optimal individualized combination therapy, several key questions need to be answered:

1. Accurately identifying patient populations through biomarkers and stratification models.
2. Determining optimal radiotherapy doses and fractionation modes, as well as the best timing for radiotherapy and immunotherapy.
3. Managing adverse effects effectively in clinical practice.

These critical issues require further investigation through large-scale clinical trials and real-world studies. Ongoing pivotal studies are expected to provide additional safety and efficacy evidence. For instance, the phase II-III NRG-LU007 study in ES-SCLC is evaluating the benefits of sequential radiotherapy following first-line standard therapy in a larger patient population. The phase III TRIPLEX study is exploring whether adding radiotherapy to first-line immuno-chemotherapy can further enhance outcomes. Additionally, the second phase of the SHR-1316-III-302 study is progressing steadily, testing the strategy of concurrent chemo-immunotherapy in Chinese patients. In advanced NSCLC, the phase II/III Alliance A082002 study is examining whether combining systemic therapy with SBRT in the first-line setting can provide further benefits. With these high-quality studies accumulating evidence, the combination of radiotherapy and immunotherapy may soon reshape the treatment landscape for unresectable lung cancer.

Dr. Ying Cheng

• Professor of the highest rank, PhD advisor, and postdoctoral mentor
• Recipient of the State Council Special Allowance, recognized as an Outstanding Young and Middle-aged Expert by the Ministry of Health
• Director of the Integrated Clinical Research Center for Malignant Tumors, Jilin Cancer Hospital
• Director of the Jilin Cancer Center and the Jilin Lung Cancer Center
• Vice-Chairperson of the Supervisory Board of the Chinese Society of Clinical Oncology (CSCO)
• Member of the Rare Tumor (SCLC) Committee of the International Association for the Study of Lung Cancer (IASLC)
• Chairperson of the CSCO Small Cell Lung Cancer Expert Committee
• Chair-Elect of the CSCO Clinical Research Expert Committee
• Chair-Elect of the Lung Cancer Committee of the Chinese Anti-Cancer Association
• Vice-Chairperson of the CSCO NSCLC Expert Committee
• Vice-Chairperson of the Lung Cancer Committee of the Chinese Medical Association Oncology Branch
• Vice-Chairperson of the Multidisciplinary Tumor Diagnosis and Treatment Committee of the Chinese Medical Doctor Association
• Named as one of the “World’s Highly Cited Scientists in Clinical Medicine” for 2023