Advances in the research on radiotherapy for lung cancer: a 2025 review

Introduction

Lung cancer remains the leading cause of cancer-related mortality worldwide, with radiotherapy serving as a cornerstone of multimodal treatment. The year 2025 has witnessed remarkable progress in radiotherapy and combination strategies, significantly improving clinical outcomes and quality of life (QoL) for patients. This review encompasses the abstracts from the 2025 World Conference on Lung Cancer (WCLC), American Society of Clinical Oncology (ASCO), American Society for Radiation Oncology (ASTRO), and European Society for Medical Oncology (ESMO) congresses, along with key advancements in lung cancer radiotherapy reported in high-impact journals in 2025.

Methods

We compiled radiotherapy-related studies on lung cancer presented at the 2025 major international conferences, including ASCO, WCLC, ESMO, ASTRO, or published in high-impact oncology journals.

Research progress in non-small cell lung cancer (NSCLC)

Early-stage NSCLC

SWOG/NRG S1914 trial

SWOG/NRG S1914 is a randomized phase III clinical trial designed to evaluate the efficacy and safety of combining stereotactic body radiotherapy (SBRT) with atezolizumab (a checkpoint inhibitor) vs. SBRT alone in patients with high-risk early-stage NSCLC (1). Results showed that there were no significant differences in overall survival (OS) and progression-free survival (PFS) between the combination therapy group and the SBRT group: the hazard ratio (HR) for OS was 1.02 [95% confidence interval (CI): 0.60–1.73; P=0.54], with 2-year OS rates of 80.5% and 81.2% in the two groups, respectively; the HR for PFS was 1.14 (95% CI: 0.75–1.73; P=0.73), with 2-year PFS rates of 70.4% and 62.7%, respectively. The incidence of grade ≥3 treatment-related adverse events (TRAEs) in the combination therapy group was 12%, which was significantly higher than the 2% in the SBRT standard therapy group, including one case of grade 5 respiratory failure. Notably, the phase III SWOG/NRG S1914 study explored the role of Atezolizumab in combination with SBRT in early-stage NSCLC but reported negative results, indicating that not all patients benefit from SBRT plus immunotherapy, highlighting the need for personalized risk stratification.

Locally advanced NSCLC

EA5181 trial

A pivotal study clarifying the optimal timing of immunotherapy relative to radiation is the phase III EA5181 trial, presented as a plenary abstract at the 2025 WCLC (2). The trial enrolled 662 patients with unresectable stage III NSCLC, randomizing them to two regimens: durvalumab administered concurrently with definitive chemoradiotherapy (dCRT) followed by 12 months of durvalumab consolidation (chemoradiotherapy + immunotherapy arm), or dCRT followed by 12 months of durvalumab consolidation alone (chemoradiotherapy arm, consistent with the PACIFIC regimen). No significant differences in OS (median: 41.5 vs. 39.4 months; P=0.83; HR =1.03) or PFS (median: 15.5 vs. 16.8 months; P=0.65; HR =1.05) were observed between the chemoradiotherapy-immunotherapy and chemoradiotherapy arms. Notably, the local recurrence rates were 24.2% vs. 22% (P=0.52), respectively. And the radiation in-field recurrences were noted as 7.6% and 6.6%, respectively (P=0.65). As to the best response rates, including complete response (CR) and partial response (PR), there were no significant differences (P>0.05).

The EA5181 trial provides definitive evidence that adding concurrent durvalumab to dCRT does not improve survival outcomes but increases treatment-related toxicity, reinforcing the PACIFIC regimen (consolidation-only) as the standard of care for locally advanced NSCLC. This finding addresses a longstanding clinical debate about the value of concurrent immunotherapy administration during thoracic radiotherapy (TRT), where theoretical synergies (e.g., enhanced immunogenic cell death) are not translated into clinical benefit, likely due to increased immune-related tissue damage in critical organs like the lungs or the esophagus.

SKYSCRAPER-03 trial

Additionally, the SKYSCRAPER-03 study presented at 2025 ESMO explored atezolizumab + tiragolumab combination following concurrent chemoradiation therapy (cCRT) vs. the PACIFIC regimen in locally advanced NSCLC, providing new options for consolidation therapy (3). As of October 2025, with a median follow-up of 30.7 months, the combination of atezolizumab plus tiragolumab did not demonstrate superiority over durvalumab in either primary endpoint. In the programmed death-ligand 1 (PD-L1) all-comers group, for independent review facility-assessed PFS (IRF-PFS), the median values were 14.2 months in the combination group vs. 13.8 months in the durvalumab group (HR =1.00; 95% CI: 0.84–1.19). For OS, the median values were 45.6 vs. 45.8 months, respectively (HR =0.98; 95% CI: 0.80–1.20). The incidence of any-grade AEs was comparable between the two groups. For grade 3–4 AEs, the overall rates were similar (26.5% vs. 25.7%). Additionally, any-grade adverse events of special interest (AESIs) occurred more often with the combination group (76.4% vs. 62.2%), as did the need for systemic corticosteroids (33.7% vs. 23.5%) and immunosuppressant treatment (2.7% vs. 1.0%). In a word, as the consolidation immune therapy following cCRT, the combination of atezolizumab + tiragolumab exhibited a tolerable safety profile, which is consistent with the previously observed safety profile. However, the combination did not significantly improve IRF-PFS.

NCT03141359: SBRT followed by cCRT and immunotherapy

A notable phase 2 trial published in Lancet Oncol in January 2025 further enriched the combination strategy landscape for locally advanced NSCLC (4). This multicenter study evaluated a novel sequential regimen: full-dose SBRT to the primary lung tumor (50–54 Gy in 3–5 fractions) followed by conventional mediastinal chemoradiotherapy (up to 60 Gy in 30 fractions with concurrent platinum doublet chemotherapy) and subsequent consolidation durvalumab. Among 61 enrolled patients, 47 received durvalumab consolidation, with a median follow-up of 29.5 months. Although the primary endpoint of 1-year PFS in the enrolled population (62.7%, 90% CI: 51.2–73.2%) did not meet the predefined threshold, the regimen showed promising activity: median PFS (mPFS) reached 25.3 months, median OS was 47.1 months, 1-year PFS in the durvalumab subgroup was 69.6%, 2-year OS in the durvalumab subgroup was 71.3%, 2-year regional control rate was 89.7%, and 2-year local control rate of the primary tumor was as high as 96.3%. Notably, the safety profile was favorable compared with standard chemoradiotherapy: grade 3–4 pneumonitis occurred in only 5% of patients, and grade 3–4 esophagitis was seen in just 2% of patients, which were lower than historical data from the PACIFIC trial. This study highlighted that focusing SBRT dose on the primary tumor (while avoiding high-dose exposure to mediastinal lymph nodes adjacent to critical organs) could optimize local control while mitigating toxicity, laying the foundation for the ongoing phase 3 NRG Oncology LU008 trial (NCT05624996) that will validate this regimen against the standard care.

R-ALPS trial

Complementing these findings, the phase III R-ALPS trial led by Ming Chen—presented as Late Breaking Abstract 8004 at 2025 ASCO—unveiled a novel “immunomodulator + anti-angiogenic” consolidation model that synergizes with dCRT in locally advanced NSCLC (5). Enrolling 553 patients with disease control after dCRT, the trial randomized participants to three arms: (I) benmelstobart (PD-L1 agonist) + anlotinib [multi-targeted tyrosine kinase inhibitor (TKI)]; (II) benmelstobart monotherapy; and (III) placebo. At data cutoff (November 30, 2023): independent review committee (IRC)-assessed mPFS: combination arm, 15.15 vs. 4.17 months with placebo (HR =0.49; log-rank P<0.001); monotherapy, 9.69 vs. 4.17 months with placebo (HR =0.53; log-rank P<0.001). At data cutoff (July 8, 2024): IRC-assessed mPFS: combination arm, 17.38 vs. 11.20 months with monotherapy (HR =0.82; log-rank P=0.12). Analysis of secondary endpoints further corroborated the superiority of the combination therapy. In terms of objective response rate (ORR), the combination group achieved 25.6%, which was numerically superior to 23.5% in the benmelstobart monotherapy group and 12.9% in the placebo group. Regarding disease control rate (DCR), the combination group reached 84.5%, which was also significantly superior to 70.5% in the placebo group. Safety analysis demonstrated that the combination therapy was well-tolerated. The incidence of grade ≥3 treatment-emergent adverse events (TEAEs) was 49.8% in the combination therapy group, 31.8% in the benmelstobart monotherapy group, and 21.2% in the placebo group. Most TRAEs were manageable with appropriate interventions, and no new safety signals were observed.

This synergy addresses a key limitation of the PACIFIC regimen—primary resistance to PD-L1 inhibitors—by targeting multiple immune and microenvironmental pathways. Also, the IRC-assessed mPFS (17.38 months) numerically exceeded the PFS of 16.9 months observed in the PACIFIC trial, establishing a new efficacy benchmark for the consolidation therapy of locally advanced unresectable NSCLC.

Late-stage NSCLC

NROG-002 trial

For driver-gene mutated NSCLC, integrating targeted therapy with radiotherapy requires further optimization, and a landmark phase III trial led by Baosheng Li (NROG-002) published in J Clin Oncol in February 2025 provides definitive evidence to guide this integration (6). This multicenter study focused on epidermal growth factor receptor (EGFR)-mutated oligo-organ metastatic NSCLC (defined as ≤3 metastatic organs, regardless of metastatic sites), randomizing 118 patients to first-line EGFR-TKI (icotinib) alone or concurrent TKI plus TRT (60 Gy in 30 fractions to primary tumor and regional lymph nodes). The trial demonstrated that TKI + TRT significantly improved mPFS from 10.6 to 17.1 months (HR =0.57; P=0.004) and OS from 26.2 to 34.4 months (HR =0.62; P=0.03), with the survival benefit attributed primarily to enhanced locoregional control (locoregional PFS: HR =0.35; P<0.001). While severe TRAEs (grade 3 or 4) were higher in the combination arm (11.9% vs. 5.1%), including radiation esophagitis (6.8%) and pneumonitis (5.1%), these were manageable with supportive care. Notably, the study expanded the traditional “oligometastasis” definition from “oligo-sites” to “oligo-organs”, encompassing over 60% of newly diagnosed EGFR-mutated stage IV NSCLC patients, and confirmed survival benefits even in those with up to 3 metastatic organs or >10 metastatic sites—challenging the conventional notion that only limited metastatic sites benefit from local therapy.

NorthStar trial

The NorthStar study (NCT03410043) is a randomized, multicenter, phase II trial investigating the efficacy and safety of osimertinib combined with local consolidation therapy (LCT) vs. osimertinib monotherapy in patients with advanced EGFR-mutant NSCLC (7). A total of 119 patients were successfully randomized (63 to osimertinib monotherapy, 56 to the combination group), with balanced baseline characteristics. The study population exhibited high real-world disease burden: ~70% had polymetastatic disease (>3 lesions), one-third had baseline brain metastases (BMs), and over 70% of polymetastatic patients had ≥5 lesions (30% had >10 lesions). The primary endpoint of PFS was significantly improved in the combination arm: 25.3 vs. 17.5 months in the osimertinib-alone group (HR =0.66; P=0.03). Notably, the benefit was consistent across subgroups, including mutation types (exon 19 deletion or L858R) and metastatic burdens [oligometastatic (≤3 lesions) with mPFS 33.1 vs. 22.4 months; polymetastatic (>3 lesions) with mPFS 19.7 vs. 15.9 months], suggesting LCT value extends beyond traditionally defined oligometastatic disease. Toxicity was manageable: adverse events (e.g., diarrhea, rash) were mostly known osimertinib-related reactions, while LCT-specific events were primarily low-grade pneumonia or dyspnea; no grade 4 or 5 LCT-related severe toxicities were observed.

Among patients who were initially multiple metastatic, if they successfully received complete LCT after treatment, the mPFS was as high as 27.9 months. In contrast, among multiple metastatic patients who received incomplete LCT (i.e., residual lesions remained untreated), the mPFS was only 14.5 months. A key finding was that the “completeness of consolidation therapy” is a critical predictor of LCT efficacy, outweighing initial metastatic burden. The finding challenges traditional notions, brings hope to more patients initially presenting with polymetastasis, and provides a new direction for future clinical practice and research design.

NRG-BN014 trial

Leptomeningeal metastasis (LM) is a devastating complication of NSCLC, with a median OS of only 4–6 months with standard involved-field radiation therapy (IFRT). In November 2025, the NRG-BN014 (“Radiate-LM”) trial was activated to evaluate proton craniospinal radiation therapy (pCSI) vs. IFRT in NSCLC and breast cancer patients with LM (8). At the planned interim analysis, a significant benefit in central nervous system (CNS)-PFS was observed with pCSI compared with IFRT, leading to the early discontinuation of the trial. In the final analysis, a significant benefit was continually observed in CNS-PFS with pCSI (median: 8.2 months) vs. IFRT (median: 2.3 months; P<0.001). A statistically significant and clinically meaningful OS benefit with pCSI (median: 11.3 months) vs. IFRT (median: 4.9 months; P=0.04) was also observed. For the exploratory pCSI cohort (n=35), the median CNS-PFS was 5.8 months and OS was 7.0 months.

Proton therapy’s unique dose-distribution profile allows for targeted dose delivery to the leptomeninges while sparing critical nervous system structures, potentially improving survival and reducing neurotoxicity. The NRG-BN014 trial will stratify patients by histology, systemic disease status, and prior systemic therapy use, with OS as the primary endpoint, representing a critical step forward in LM management.

METIS trial

Complementing this, the METIS study—presented at the 2025 ASTRO Annual Meeting and published in Int J Radiat Oncol Biol Phys in September 2025—explored tumor treating fields (TTFields; a non-invasive electric field therapy) as an adjunct to stereotactic radiosurgery (SRS) for lung cancer BMs (9). This phase III randomized 298 patients 1:1 to SRS followed by TTFields (150 kHz) or SRS alone, with the primary endpoint of time to intracranial progression (TTIP). Key findings demonstrated that TTFields significantly delayed TTIP (HR =0.72; P=0.04). Intracranial progression rates at months 12 and 24 were 46.9% vs. 59.4% (P=0.02) and 53.6% vs. 65.2% (P=0.03). In the 118 patients receiving immune checkpoint inhibitors (ICIs) for their primary disease, TTIP benefit was more pronounced (HR =0.63; Cox P=0.049; Fine-Gray test P=0.06). Notably, TTFields demonstrated an excellent safety profile: device-related AEs were mainly grade ≤2 skin events. TTFields did not cause QoL deterioration, and improvements in deterioration-free survival and time to deterioration of global health status, physical functioning, and fatigue were observed. Due to its non-invasive nature, TTFields addresses a critical barrier for patients with limited performance status or multiple BM recurrences, who may be ineligible for re-irradiation.

Research progress in small cell lung cancer (SCLC)

Hypofractionated radiotherapy (HyPORT) in limited-stage SCLC (LS-SCLC)

A multicenter randomized phase III trial presented at the 2025 International Association for the Study of Lung Cancer (IASLC) WCLC established the role of HyPORT in LS-SCLC (10). The study enrolled 530 patients across 16 hospitals in China, randomly assigning them to receive either HyPORT (45 Gy in 15 daily fractions over 3 weeks) or conventional fractionated radiotherapy (ConvRT; 60 Gy in 30 daily fractions over 6 weeks), both combined with concurrent cisplatin/carboplatin-etoposide chemotherapy.

At a median follow-up of 43.4 months, median OS was 40.2 months in the HyPORT arm vs. 47.9 months in the ConvRT arm (HR =1.04; P=0.75), indicating non-inferior survival. PFS was similar between groups in the HyPORT trial (16.5 vs. 18 months; HR =1.06; P=0.57), while the key benefit was a significant reduction in severe toxicities: acute grade ≥3 adverse events occurred in 48.7% of HyPORT patients compared to 67.7% in the ConvRT group, which was mainly attributed to the decrease in hematological toxicity. Notably, during concurrent chemoradiotherapy, the incidence of grade ≥2 lymphopenia in the HypoRT group was lower (60.5% vs. 88.8%, P<0.001), and it was also significantly reduced at 1 month (34.3% vs. 48.7%, P=0.01) and 6 months (14.4% vs. 28.7%, P=0.008) after radiotherapy. The incidence of grade ≥2 radiation pneumonitis in the HypoRT group was also significantly lower (7.7% vs. 14.5%, P=0.01). No significant difference was observed in the spectrum of late toxicities.

Hippocampal avoidance prophylactic cranial irradiation (HA-PCI)

NRG-CC003 trial

A landmark advancement in mitigating neurocognitive toxicity—an unmet need in SCLC management—comes from the phase II/III NRG-CC003 trial, published in J Clin Oncol in November 2025 (11). This multicenter study enrolled 393 SCLC patients without BMs who responded to chemotherapy, randomizing them to PCI or HA-PCI. The primary objectives were to verify non-inferior 12-month intracranial relapse (ICR) with HA-PCI and reduce 6-month neurocognitive dysfunction, measured by Hopkins Verbal Learning Test-Revised (HVLT-R) Delayed Recall (DR) failure. Critical findings included non-inferior 12-month ICR rates between HA-PCI and standard PCI (14.7% vs. 14.8%), confirming that hippocampal sparing does not compromise intracranial disease control. While the primary end point of 6-month HVLT-R DR preservation was not met (25.5% vs. 30.0% failure, P=0.28), HA-PCI demonstrated a clinically meaningful 22% relative risk reduction in overall neurocognitive function (NCF) failure (adjusted HR =0.78; 95% CI: 0.61–0.99; P=0.04) when evaluating composite NCF tests (including learning, memory, processing speed, and executive function). Notably, OS (median: 20.7 vs. 24.9 months; adjusted HR =0.88; P=0.33) and grade ≥3 toxicity rates (30.7% vs. 31.4%, P=0.88) were comparable between arms, confirming the safety of HA-PCI.

All the above trials are summarized in Table 1.

Conclusions

In early-stage NSCLC, combining SBRT with atezolizumab does not enhance survival outcomes but increases toxicities. Substantial biological heterogeneity, including tumor gene mutation profiles and immune cell infiltration, may vary among patients, and these factors could affect the efficacy of immunotherapy and radiotherapy. In locally advanced NSCLC, concurrent durvalumab with dCRT fails to improve OS or PFS compared to the PACIFIC regimen, reinforcing the latter as the standard of care. The increased incidence of grade ≥3 pneumonitis further underscores the extreme complexity of the timing and toxicity management of concurrent strategies. Promising radiation-immunotherapy combination strategies are already underway: sequential SBRT to primary tumor plus PACIFIC achieved favorable local control with reduced toxicities. Additionally, “immunomodulator + anti-angiogenic” consolidation model (benmelstobart + anlotinib) not only numerically improved mPFS (17.38 months), setting a new record in this field, but also provided important optimization insights for the PACIFIC regimen. In late-stage EGFR-mutant NSCLC, two landmark trials expanded the role of local therapy that prolonged mPFS in oligo-organ metastatic and polymetastatic patients. Results challenged the conventional notion that only limited metastatic sites benefit from local therapy. The “completeness of consolidation therapy” is a critical predictor of LCT efficacy, outweighing initial metastatic burden and bringing hope to more patients initially presenting with polymetastasis.

In SCLC, HyPORT (45 Gy in 15 fractions) is non-inferior to conventional radiotherapy (60 Gy in 30 fractions) in OS while significantly reducing severe toxicities. HA-PCI achieved non-inferior 12-month ICR rates while reducing the relative risk of NCF failure in comparison with PCI.

Acknowledgments

None.

Footnote

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-1-0034/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-1-0034/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Simone CB, Daly ME, Redman MW, et al. SWOG/NRG S1914: Randomized phase III trial of induction/consolidation atezolizumab+ SBRT versus SBRT alone in high risk, early-stage NSCLC. J Clin Oncol 2025;43:8003.
2. Subramanian K. EA5181 Confirms Durvalumab After CRT is SOC for Unresectable Stage III NSCLC. 2025. Available online: https://www.ilcn.org/ea5181-confirms-durvalumab-after-crt-is-soc-for-unresectable-stage-iii-nsclc/
3. Dziadziuszko R, Ahn MJ, Bradley JD, et al. LBA69 SKYSCRAPER-03: Phase III, open-label, randomised study of atezolizumab (atezo)+ tiragolumab (tira) vs durvalumab (durva) in locally advanced, unresectable, stage III non-small cell lung cancer (NSCLC) after platinum-based concurrent chemoradiation (cCRT). Ann Oncol 2025;36:S1725-6.
4. Heinzerling JH, Mileham KF, Robinson MM, et al. Primary lung tumour stereotactic body radiotherapy followed by concurrent mediastinal chemoradiotherapy and adjuvant immunotherapy for locally advanced non-small-cell lung cancer: a multicentre, single-arm, phase 2 trial. Lancet Oncol 2025;26:85-97. [Crossref] [PubMed]
5. Chen M, Ji Y, Chen L, et al. R-ALPS: A randomized, double-blind, placebo-controlled, multicenter phase III clinical trial of TQB2450 with or without anlotinib as maintenance treatment in patients with locally advanced and unresectable (stage III) NSCLC without progression following concurrent or sequential chemoradiotherapy. J Clin Oncol 2025;43:LBA8004. [Crossref] [PubMed]
6. Sun H, Li M, Huang W, et al. Thoracic Radiotherapy Improves the Survival in Patients With EGFR-Mutated Oligo-Organ Metastatic Non-Small Cell Lung Cancer Treated With Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitors: A Multicenter, Randomized, Controlled, Phase III Trial. J Clin Oncol 2025;43:412-21. [Crossref] [PubMed]
7. Elamin YY, Gandhi S, Antonoff M, et al. LBA72 NorthStar: a phase II randomized study of osimertinib (OSI) with or without local consolidative therapy (LCT) for metastatic EGFR-mutant non-small cell lung cancer (NSCLC). Ann Oncol 2025;36:S1729.
8. Yang JT, Yerramilli D, Pentsova E, et al. Proton Craniospinal Irradiation for Patients With Leptomeningeal Metastasis: A Randomized Clinical Trial. JAMA Oncol 2025;11:1293-301. [Crossref] [PubMed]
9. Mehta MP, Gondi V, Ahluwalia MS, et al. Tumor Treating Fields Therapy After Stereotactic Radiosurgery for Brain Metastases From Non-Small Cell Lung Cancer: Final Results of the Phase 3 METIS Study. Int J Radiat Oncol Biol Phys 2026;124:278-93. [Crossref] [PubMed]
10. Subramanian K. HypoRT with Concurrent Chemo Shows Favorable Safety Profile. 2025. Available online: https://www.ilcn.org/hyport-with-concurrent-chemo-shows-favorable-safety-profile/
11. Gondi V, Pugh SL, Mehta MP, et al. Hippocampal Avoidance During Prophylactic Cranial Irradiation for Patients With Small Cell Lung Cancer: Randomized Phase II/III Trial NRG-CC003. J Clin Oncol 2025;43:3516-25. [Crossref] [PubMed]