With the development of immune checkpoint inhibitors (ICIs) and the widespread application of immunotherapy, the treatment paradigm for driver mutation-negative lung cancer has been fundamentally transformed. Multiple studies have demonstrated that radiotherapy (RT) can regulate both local and systemic immune responses, triggering anti-tumor immune effects. As a result, the immunomodulatory properties of RT and its synergistic effects when combined with immunotherapy have garnered significant attention within the medical community.

Recently, the 14th International Symposium on Respiratory Endoscopy and Lung Cancer (ISRELC) was successfully held in Shanghai. At the main forum, Dr. You Lu from West China Hospital, Sichuan University delivered a keynote speech titled “Transformative Clinical Research in Adaptive Immuno-Radiotherapy,” providing an in-depth analysis of the relationship between radiotherapy and immunotherapy, as well as progress and challenges in adaptive immuno-radiotherapy clinical research.

Part 1: The Relationship Between Radiotherapy and Immunotherapy

Dr. You Lu emphasized that the connection between radiotherapy and immunotherapy has existed for over a century. The introduction of PD-1/PD-L1 inhibitors at the 2012 ASCO Annual Meeting revolutionized the field of oncology, placing immunotherapy at the forefront of cancer treatment.

In 2020, Dr. You Lu’s team published groundbreaking research on the synergistic effects of low-dose radiotherapy (LDRT) and anti-PD-1 therapy in regulating the tumor microenvironment. The study, along with similar research, was featured in a special issue of the Int J Radiat Oncol Biol Phys. Editor-in-Chief AL Zietman described this convergence of radiotherapy and immunotherapy as a pivotal moment, marking the beginning of a scientific revolution.

Part 2: Progress and Challenges in Transformative Clinical Research on Adaptive Immuno-Radiotherapy

1. SBRT + IO: Enhancing the Abscopal Effect of RT

Stereotactic body radiotherapy (SBRT) is a high-precision, high-dose radiotherapy technique that delivers concentrated radiation to tumor regions over a short period, typically used for small, localized tumors. The relationship between radiotherapy and immune response highlights the importance of the abscopal effect (AE), a phenomenon where radiation not only destroys the directly irradiated tumor lesions but also leads to the regression of untreated lesions.

Dr. You Lu explained that as early as 1977, studies reported AE in lymphoma patients who underwent Mantle field and Waldeyer’s ring radiotherapy. One month after receiving 30 Gy, imaging showed shrinkage or resolution of abdominal and pelvic lymph nodes that had not been directly irradiated. Despite this, over the next few decades, cases of AE induced by radiotherapy alone remained sporadic and lacked large-scale clinical validation.

In 2012, a New England Journal of Medicine case report described immune checkpoint inhibitor (ICI) therapy combined with SBRT for melanoma, which elicited a strong immune-mediated abscopal effect. This report sparked widespread interest in AE within the oncology field. Over the next 2–3 years, more than 200 clinical trials investigating SBRT combined with immunotherapy were registered on ClinicalTrials.gov, marking a surge in AE research.

PEMBRO-RT Trial: SBRT + ICI (Pembrolizumab) for Advanced NSCLC

In 2019, JAMA Oncology published the results of the PEMBRO-RT study, which explored the efficacy and safety of SBRT followed by pembrolizumab in advanced non-small cell lung cancer (NSCLC). This multicenter, Phase II randomized controlled trial found that while the overall response rate (ORR) at 12 weeks was 18% in the pembrolizumab group compared to 36% in the SBRT + pembrolizumab group, the difference was not statistically significant. Similarly, no significant differences were observed in progression-free survival (PFS) or overall survival (OS) between the groups.

The researchers attributed these negative results to the study’s small sample size. To further investigate, data from PEMBRO-RT and another Phase II trial conducted at MD Anderson Cancer Center were pooled. In 2020, a meta-analysis published in The Lancet Respiratory Medicine revealed that combining pembrolizumab with RT significantly improved the response rate of non-irradiated lesions, resulting in notable PFS and OS benefits. Although this combination shows promise as a treatment option for metastatic NSCLC, prospective Phase III trials are required for validation.

I-SABR Trial: Phase II Randomized Controlled Trial

In 2023, The Lancet published the results of the I-SABR trial led by Dr. Yu-Jiao Zhang’s team at MD Anderson Cancer Center. This study evaluated the safety and efficacy of SBRT combined with PD-1 inhibitors in early-stage NSCLC. The results demonstrated that compared to SBRT alone, I-SABR significantly improved the four-year event-free survival (EFS) of patients with early-stage or node-negative NSCLC with isolated lung recurrence, while maintaining a manageable safety profile.

Despite these positive outcomes, Dr. You Lu cautioned that the findings should be interpreted carefully. The study population was limited to patients with early-stage or oligometastatic NSCLC, and the observed benefits may be attributed more to SBRT’s high-dose ablative or potentially curative effects on small lesions rather than an immune-mediated abscopal effect. Additionally, three specific subgroup concerns emerged in the forest plot analysis—dose distribution for smaller fields, PD-L1 expression, and EGFR mutations—requiring further clarification through rigorously designed Phase III trials.

Con-SBRT + IO Trial Update: Failure of the Phase III Keynote-867 Study

On August 29, 2024, Merck announced the termination of the Keynote-867 Phase III trial, which aimed to evaluate pembrolizumab combined with SBRT versus SBRT plus placebo for treating unresectable early-stage NSCLC (Stages I and II [IIB N0, M0]). The trial was halted because interim analysis failed to demonstrate improvements in EFS or OS in the pembrolizumab group. While related Phase III trial data remain undisclosed, the outlook appears unfavorable.

These findings underscore the need to unravel the molecular mechanisms underlying the abscopal effect and address the clinical practicality of applying SBRT to all lesions.

The Role of Immunogenic Cell Death (ICD) and Future Directions

Dr. You Lu emphasized that exploring RT’s biological mechanisms involves understanding immunogenic cell death (ICD). The immune consequences of cell death largely depend on environmental factors such as the tumor microenvironment (TME) and the host’s systemic immune status. Critical unresolved questions for clinical application include visualizing necroptotic cells and damage-associated molecular patterns (DAMPs) and integrating necroptotic induction with pre-existing treatments.

Additionally, defining SBRT’s applicability and feasibility remains a challenge. Current dose guidelines often designate a 3 cm diameter as the standard small-field limit, leaving the management of large tumors with SBRT uncertain.

While SBRT combined with immunotherapy has achieved some promising advancements, significant controversies and challenges persist. Future trials must refine enrollment criteria based on driver mutations (EGFR/ALK), PD-L1 expression, and optimized SBRT protocols to improve clinical efficacy.

2. The “Double-Edged Sword” Effect of Radiotherapy on Immunotherapy

Previous Phase III trials indicate that the timing of RT relative to immunotherapy profoundly influences treatment outcomes. Sequential combinations of RT and ICIs, such as those validated in the PACIFIC trial for NSCLC and the ADRIATIC trial for SCLC, demonstrate significant synergistic benefits. However, concurrent approaches, including PACIFIC-2, CheckMate73L, and NRG-LU005 trials, have yielded negative results.

Promising Results from Induction Therapy

At the 2024 World Conference on Lung Cancer (WCLC), the APOLO Phase II trial reported notable results for induction chemotherapy combined with atezolizumab, followed by concurrent chemoradiotherapy and maintenance atezolizumab in locally advanced NSCLC. With a 12-month PFS of 68.4% and OS of 86.8%, the study highlighted the potential of this sequential approach.

Another study, the SPRINT trial, evaluated pembrolizumab induction therapy for PD-L1 TPS ≥50% locally advanced NSCLC, followed by PET/CT-guided targeted RT and sequential pembrolizumab consolidation. The results showed one- and two-year OS rates of 92% and 76%, respectively, with excellent safety profiles. These findings suggest that RT without chemotherapy may be a safe and effective strategy for selected patients.

Challenges in SCLC

While high PD-L1 expression NSCLC patients benefit from RT combined with immunotherapy, safety concerns remain in SCLC. The TREASURE trial was terminated due to increased toxicity, while another study led by Jinming Yu’s team demonstrated significant benefits of atezolizumab combined with RT and chemotherapy for extensive-stage SCLC, achieving a median OS of 21.4 months with good tolerability. Ongoing Phase III trials like JCOG2002 are expected to provide further clarity.

The dual nature of RT, as both an immune-enhancing and immune-suppressive modality, emphasizes the critical role of timing and sequencing in maximizing therapeutic synergy while minimizing adverse effects.

3. Classic RT vs. Adaptive Immuno-Radiotherapy

Dr. You Lu explained that classic RT approaches may not meet the demands of immunotherapy in the modern era. Adaptive treatments consider TME heterogeneity and the evolving characteristics of tumors during therapy, offering a dynamic approach to optimize outcomes.

Adaptive Immuno-Radiotherapy (AIRT): A New Frontier

The concept of adaptive radiotherapy emerged two decades ago, initially focused on precision dose delivery using image-guided RT (IGRT). Subsequently, PET/CT-guided dose adjustments were explored, but trials like NRG-RTOG1106 failed to demonstrate improved two-year local control rates for advanced NSCLC.

Later studies attributed improved outcomes to the combination of RT with immunotherapy rather than dose intensification alone. For instance, the PACIFIC trial established sequential immunotherapy as a game-changer in treating unresectable Stage III NSCLC, achieving a five-year OS rate of 42.9%.

Building on this, the LAURA study led by Jun Lu investigated EGFR-TKI consolidation therapy after curative RT for EGFR-mutant Stage III NSCLC, showing a dramatic improvement in median PFS (39.1 months vs. 5.6 months). This paradigm shift highlights the importance of integrating targeted therapies post-RT.

AIRT Research by Dr. You Lu’s Team

Over the past decade, Dr. You Lu’s team has pioneered AIRT research with the following clinical trials:

HX-1: SBRT + LDRT + ICI — Addressing the Therapeutic Bottleneck in Advanced NSCLC

This Phase I clinical trial adopted a novel “chemotherapy-free” design for advanced non-small cell lung cancer (NSCLC), utilizing stereotactic body radiotherapy (SBRT) for small lesions combined with low-dose radiotherapy (LDRT) for larger lesions, alongside immune checkpoint inhibitors (ICIs). The study initially validated that SBRT at ablative doses could stimulate local immune activation, while LDRT reshaped the tumor microenvironment, generating a homing effect. ICIs further amplified systemic immune responses. Moreover, LDRT demonstrated a modest and safe integrated dose effect on large distant target lesions, potentially converting subclinical abscopal effects into observable clinical benefits.

HX-2: SBRT Embedded in LDRT + ICI ± Chemotherapy (iERT) — Targeting Refractory Large Tumors in Advanced Cases

When faced with large, inoperable tumors unresponsive to conventional treatment options or intolerant to standard radiotherapy, Dr. You Lu’s team developed a strategy embedding one or two SBRT sessions within LDRT, combined with ICIs (termed iERT). This approach provided enhanced clinical benefits and created a viable window for subsequent drug therapies. Results from the iERT trial and its Phase I partial findings were presented at the 2023 ASTRO meeting, garnering international attention. Notably, similar studies conducted by foreign researchers yielded consistent findings, effectively serving as a blinded validation of the approach.

HX-3: Concurrent LDRT + ICI/CT — Addressing Challenges in Treating “Orphan Diseases” Like ES-SCLC in the Immunotherapy Era

In the context of extensive-stage small cell lung cancer (ES-SCLC), Dr. You Lu’s team initiated the first domestic multicenter Phase II clinical trial (MATCH study, NCT04622228) combining LDRT with immunotherapy. The study was designed to incorporate LDRT (15 Gy/5 fractions) during the first cycle of the standard chemotherapy + immunotherapy regimen (IMpower133). Results demonstrated that the 12-month progression-free survival (PFS) and overall survival (OS) rates for LDRT combined with atezolizumab and chemotherapy exceeded historical data for immunotherapy-chemotherapy combinations, with favorable tolerability. These findings, published in Med, a flagship journal of Cell Press, introduced a pioneering strategy of combining radiotherapy with immunotherapy for ES-SCLC patients. Long-term efficacy results are currently being prepared for publication.

Conclusion

Dr. You Lu concluded that deepening our understanding of the heterogeneity and complexity of the tumor immune microenvironment and its impact on immunotherapy has brought new hope to clinical radiotherapy, albeit with significant challenges. In the era of immunotherapy, classical radiotherapy schemes fall short of meeting modern clinical demands. The exploration of adaptive immuno-radiotherapy (AIRT) models and protocols must focus on amplifying innate or adoptive immune responses, enhancing systemic effects while improving local efficacy. Continuous optimization of radiotherapy protocols will be essential to bring greater clinical benefits to lung cancer patients.

About Dr. You Lu

• Vice Director, Cancer Center, and Director, Thoracic Oncology Department, Sichuan University West China Hospital
• Deputy Director, Institute of Oncology at West China Hospital, and Director, Clinical Cell Therapy Laboratory
• Vice Chair, NSCLC Expert Committee, Chinese Society of Clinical Oncology (CSCO)
• Vice Chair, Geriatric Oncology Prevention Expert Committee, CSCO
• Vice Chair, Supportive and Rehabilitation Oncology Expert Committee, CSCO
• Member, Oncology Division, Chinese Medical Association
• Vice Leader, Immuno-Radiotherapy Group, Chinese Society of Radiation Oncology
• Standing Member, Multidisciplinary Tumor Diagnosis and Treatment Committee, Chinese Anti-Cancer Association
• Member, Radiation Oncology Committee, Chinese Anti-Cancer Association
• Chair, Radiation Oncology Division, Sichuan Medical Association
• President, Sichuan Province Oncology Physicians Association
• Expert Contributor to Guidelines: Primary Lung Cancer Diagnosis and Treatment Guidelines (China), CSCO NSCLC and SCLC Guidelines, NCCN-Asia NSCLC Consensus, among others

Published over 100 SCI-indexed papers in Nature Medicine, Journal of Clinical Oncology, Clinical Cancer Research, Int J Radiat Oncol Biol Phys, and others