Chemoimmunotherapy Before Radiation Improves Survival in Stage III NSCLC

Sequencing chemoimmunotherapy prior to definitive chemoradiotherapy (CRT) significantly improved survival outcomes compared with adjuvant immunotherapy among patients with stage III non–small cell lung cancer (NSCLC), according to findings from a real-world study published in Lung Cancer.¹

Data showed a median progression-free survival (PFS) of 25.0 months (95% CI, 22.2-32.2) among patients who received neoadjuvant chemoimmunotherapy compared with 16.3 months (95% CI, 13.8-19.4) among those who received adjuvant immunotherapy (HR, 0.57; 95% CI, 0.43-0.74; P <.001). Additionally, the median overall survival (OS) was not reached (NR) vs 41.1 months in each respective population (HR, 0.54; 95% CI, 0.37-0.78; P = .001).

Performing propensity-score matching between the cohorts revealed sustained improvements in PFS and OS with the neoadjuvant regimen vs adjuvant immunotherapy. When accounting for potential clustering effects and reduced sample sizes after matching, investigators continued to note significant improvements for PFS (HR, 0.53; 95% CI, 0.37-0.74; P <.001) and OS (HR, 0.47; 95% CI, 0.28-0.78; P = .003) with the neoadjuvant combination.

Regarding patterns of disease recurrence in the neoadjuvant therapy cohort, 44.4% had isolated locoregional progression, 42.9% had distant metastasis only, and 12.7% had locoregional and distant progression. Among patients in the adjuvant therapy group, 46.4% had distant failure, 33.3% experienced isolated locoregional failure, and 20.2% experienced combined failure.

“[O]ur large-scale real-world study provides robust evidence that the neoadjuvant/induction immunotherapy approach followed by [concurrent] CRT and consolidation is associated with significantly improved survival outcomes compared with the phase 3 PACIFIC [NCT02125461] regimen, without a definitive increase in severe pneumonitis risk,” lead study author Guoyin Li, from the Fuxi Laboratory at College of Life Science and Agronomy of Zhoukou Normal University, wrote with coauthors in the publication.^1,2 “Future research should not only focus on confirming efficacy but also on identifying biomarkers to select patients most likely to benefit from this intensive modality while minimizing toxicity. The optimal number of induction cycles, the choice of immune agents, and the integration of novel combinations represent key areas for further exploration.”

Investigators of this real-world retrospective analysis evaluated 463 patients who underwent treatment at 9 centers between January 1, 2020, and December 31, 2023. A total of 142 patients received adjuvant immunotherapy after definitive CRT, and 321 patients received neoadjuvant immunotherapy before definitive CRT.

Chemotherapy consisted of platinum-containing doublets, with agents including cisplatin, carboplatin, and nedaplatin; non-platinum therapies included pemetrexed, docetaxel, gemcitabine, etoposide, and paclitaxel. Immunotherapy comprised PD-L and PD-L1 inhibitors such as tislelizumab-jsgr (Tevimbra), sintilimab (Tyvyt), pembrolizumab (Keytruda), and durvalumab (Imfinzi).

The study’s primary end points were PFS and OS. Secondary end points included treatment patterns, recurrence modes, and incidence of pneumonitis.

Patients with pathologically confirmed NSCLC, stage III disease, at least 1 cycle of immunotherapy before or after radiotherapy, and a minimum follow-up of 6 months after radiotherapy were eligible for inclusion in the study. Those with EGFR mutations or EML4-ALK rearrangements were ineligible for study entry due to potential confounding effects from targeted agents.

In the neoadjuvant and adjuvant therapy groups, respectively, most patients were male (91.9% vs 90.1%) and younger than 65 years (59.8% vs 58.5%). Additionally, most in each cohort had an ECOG performance status of 0 or 1 (96.9% vs 93.0%), a history of smoking (76.0% vs 75.4%), squamous histology (80.1% vs 76.1%), and stage IIIB disease (50.8% vs 47.9%).

Radiation pneumonitis of any grade occurred in 57.9% of the adjuvant therapy group vs 49.4% of the neoadjuvant therapy group, although this difference did not show statistical significance (P = .123). In each respective group, the rates of grade 2 or higher radiation pneumonitis were 30.8% vs 31.8% (P = .925), and the rates of grade 3 or higher pneumonitis were 7.5% vs 14.0% (P = .071). Regarding checkpoint inhibitor pneumonitis, 9.3% of the neoadjuvant therapy group experienced any-grade events compared with 5.3% of the adjuvant therapy group (P = .179).

References

1. Li G, Liu C, Xi P, et al. Neoadjuvant immunotherapy plus chemotherapy in locally advanced stage III NSCLC patients undergoing definitive chemo-radiotherapy---a real‑world multicenter retrospective study. Lung Cancer. Published online December 17, 2025. doi:10.1016/j.lungcan.2025.108883
2. Antonia SJ, Villegas A, Daniel D, et al. Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer. N Engl J Med. 2017;377(20):1919-1929. doi:10.1056/NEJMoa1709937