Induction chemo-immunotherapy followed by surgery or radiotherapy for locally-advanced III stage non-small cell lung cancer: prospective single center non-randomized study (preliminary results)

Background. The evolving modalities of systemic treatment for non-small cell lung cancer (NSCLC) promotes the need to redefine different strategies for combined treatment in stage III and borderline-resectable lung cancer. Hereby we present the outcomes of a neoadjuvant chemo-immunotherapy regimen with subsequent individualized local control strategy of patients with locally advanced NSCLC.
Materials. Prospective, single-center, non-randomized observational study enrolled patients with the following criteria: age > 18 years, histologically confirmed NSCLC without driver mutations (EGFR, ALK, ROS1), clinically staged as IIIA–IIIC per the 8th edition TNM classification, including cases deemed resectable and borderline-resectable, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2. The protocol comprised 4 cycles of neoadjuvant chemo-immunotherapy following MDT-based definition of surgical resection or radiotherapy — based on a technical resectability and a risk of cardiopulmonary complications.
Results. From September 2021 to October 2025, 119 patients were enrolled with male: female ratio 103:16 and median age 65 years (IQR, 59–69). Clinical stage distribution was: IIIA — 63 (52.9 %), IIIB — 51 (42.9 %), IIIC — 4 (3.4 %) and IIb — 1 (0.8 %). Histologically, adenocarcinoma and squamous cell carcinoma accounted for 41 (34.4 %) and 78 (65.6 %) cases respectively. The full course of neoadjuvant / induction therapy was completed by 109 (91.6 %) patients. Radiological response assessment by RECIST criteria revealed a partial (iPR), complete response (iCR) or stable disease (iSD) in 68 (57 %), 11 (9.2 %) and 35 (29.4 %) cases respectively. For local control 76 (63.9 %) patients underwent surgical resection and 26 (21.9 %) received radiotherapy. Postoperative complications (Clavien — Dindo classification) occurred in 11 of 76 surgical patients (14.5 %; 95 % CI, 8.3–24.1). A major pathological response (MPR) and complete response (pCR) were achieved in 21 (27.6 %) and 30 (39.5 %) cases respectively. Median overall survival (OS) and event-free survival (EFS) in the surgical cohort have not been reached, whereas in the radiotherapy group, median OS was 29 months (95 % CI, 17.3; not estimable) and median EFS was 15.5 months (95 % CI, 12.7; not estimable).
Conclusion. Our findings support consideration of induction / neoadjuvant chemo-immunotherapy for selected cohort of patients with locally-advanced and borderline-resectable stage III NSCLC. Future investigations are needed to explore the benefits of proposed strategy.

1. The state of oncological care for the population of Russia in 2023. Eds.: A.D. Kaprin, V.V. Starinsky, A.O. Shakhzadova. Moscow: P.A. Herzen Moscow State Medical Research Institute – branch of the Federal State Budgetary Institution “NMIC of Radiology” Ministry of Health of Russia, 2024.262 p. (in Russ)

2. Casal-Mouriño A., Ruano-Ravina A., Lorenzo-González M., et al. Epidemiology of stage III lung cancer: frequency, diagnostic characteristics, and survival. Transl Lung Cancer Res 2021;10(1):506–518. https://doi.org/10.21037/tlcr.2020.03.40

3. Kim S.S., Cooke D.T., Kidane B., et al. The society of thoracic surgeons expert consensus on the multidisciplinary management and resectability of locally advanced non-small cell lung cancer. Ann Thorac Surg 2025;119(1):16–33. https://doi.org/10.1016/j.athoracsur.2024.09.041

4. Antonia S.J., Villegas A., Daniel D., et al. Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC. N Engl J Med 2018;379(24):2342–2350. https://doi.org/10.1056/NEJMoa1809697

5. Forde P.M., Spicer J.D., Provencio M., et al. Overall survival with neoadjuvant nivolumab plus chemotherapy in lung cancer. N Engl J Med 2025;393(8):741–752. https://doi.org/10.1056/NEJMoa2502931

6. Wakelee H., Liberman M., Kato T., et al. Perioperative pembrolizumab for early-stage non–small-cell lung cancer. N Engl J Med 2023;389(6):491–503. https://doi.org/10.1056/NEJMoa2302983

7. Heymach J.V., Harpole D., Mitsudomi T., et al. Perioperative durvalumab for resectable non–small-cell lung cancer. N Engl J Med 2023;389(18):1672–1684. https://doi.org/10.1056/NEJMoa2304875

8. Reck M., Nadal E., Girard N., et al. Neoadjuvant durvalumab plus chemotherapy followed by either surgery and adjuvant durvalumab or chemoradiotherapy and consolidation durvalumab in resectable or borderline-resectable stage IIB–IIIB NSCLC. Clin Lung Cancer 2024;25:587–593.e3. https://doi.org/10.1016/j.cllc.2024.06.007

9. Kristenson K., Hylander J., Boros M., Hedman K. VE/VCO2 slope threshold optimization for preoperative evaluation in lung cancer surgery: identifying true high- and low-risk groups. J Thorac Dis 2024;16(1):123–132. https://doi.org/10.21037/jtd-23-1292

10. Cottrell T.R., Thompson E.D., Forde P.M., et al. Pathologic features of response to neoadjuvant anti-PD-1 in resected non-small-cell lung carcinoma: a proposal for quantitative immune-related pathologic response criteria (irPRC). Ann Oncol 2018;29(8):1853–1860. https://doi.org/10.1093/annonc/mdy218

11. Rodriguez-Ąuintero J.H., Jindani R., \hu R., et al. Surgery for patients with cT3/4N2M0, stage IIIB NSCLC. Is It time to redefine resectability? JTO Clin Res Rep 2024;6(1):100766. https://doi.org/10.1016/j.jtocrr.2024.100766

12. Sorin M., Prosty C., Ghaleb L., et al. Neoadjuvant Chemoimmunotherapy for NSCLC: a systematic review and meta-analysis. JAMA Oncol 2024;10(5):621–633. https://doi.org/10.1001/jamaoncol.2024.0057

13. Cascone T., Awad M.M., Spicer J.D., et al. Phase III study comparing neoadjuvant nivolumab (NIVO) plus chemotherapy (chemo) vs neoadjuvant placebo plus chemo followed by surgery and adjuvant NIVO or placebo for previously untreated, resectable stage II–IIIb NSCLC. Ann Oncol 2023;34:S1295. https://doi.org/10.1016/j.annonc.2023.10.050

14. Provencio M., Nadal E., Insa A., et al. Neoadjuvant chemotherapy and nivolumab in resectable non-small-cell lung cancer (NADIM): an open-label, multicentre, single-arm, phase 2 trial. Lancet Oncol 2020;21(11):1413–1422. https://doi.org/10.1016/S1470-2045(20)30453-8

15. Spicer J.D., Gao S., Liberman M., et al. LBA56 Overall survival in the KEYNOTE-671 study of perioperative pembrolizumab for early-stage non-small-cell lung cancer (NSCLC). Ann Oncol 2023;34:S1297–S1298. https://doi.org/10.1016/j.annonc.2023.10.052

16. Hines J.B., Cameron R.B., Esposito A., et al. Evaluation of major pathologic response and pathologic complete response as surrogate end points for survival in randomized controlled trials of neoadjuvant immune checkpoint blockade in resectable in NSCLC. Journal of Thoracic Oncology 2024;19(7):1108–1116. https://doi.org/10.1016/j.jtho.2024.03.010

17. Spigel D.R., Faivre-Finn C., Gray J.E., et al. Five-year survival outcomes from the PACIFIC trial: durvalumab after chemoradiotherapy in stage III non–small-cell lung cancer. J Clin Oncol 2022;40(12):1301–1311. https://doi.org/10.1200/JCO.21.01308

18. Laktionov K.K., Artamonova E.V., Breder V.V., et al. Non-small cell lung cancer. RUSSCO practical recommendations, part 1.1. \lokachestvennie opuholi = Malignant Tumors 2024;14(3s2):65–104 (In Russ.). https://doi.org/10.18027/2224-5057-2024-14-3s2-1.1-04

19. Kumar A., Srinivasan D., Potter A.L., et al. Induction chemoimmunotherapy with surgery versus concurrent chemoradiation followed by immunotherapy for stage III-N2 non–small cell lung cancer. J Thorac Cardiovasc Surg 2024;167(6):1895–1905.e2. https://doi.org/10.1016/j.jtcvs.2023.09.029

20. Qi Y., \hai X., Xu Q., et al. Comparison of neoadjuvant chemoimmunotherapy with planned surgery and concurrent chemoradiation followed by immunotherapy for potentially resectable stage III non-small-cell lung cancer: a retrospective study. Cancer Immunol Immunother 2025;74(4):119. https://doi.org/10.1007/s00262-025-03961-0

21. Wang, S., Bian, D., Guo, Q., et al. 1818MO Surgery versus radiotherapy after induction therapy with serplulimab combined with chemotherapy for unresectable stage IIIB–IIIC non-small cell lung cancer: A randomized controlled, open-label, phase II trial. Ann Oncol 2025;36:S1052–S1053. https://doi.org/10.1016/j.annonc.2025.08.2444

22. Houda I., Bahce I., Dickhoff C., et al. OA06.03 An International EORTC survey on resectability of stage III non-small cell lung cancer. Journal of Thoracic Oncology 2023;18(11):S55–S56. https://doi.org/10.1016/j.jtho.2023.09.044

23. Wang S., Bian D., Guo Q., et al. 1818MO Surgery versus radiotherapy aGer induction therapy with serplulimab combined with chemotherapy for unresectable stage IIIB–IIIC non-small cell lung cancer: A randomized controlled, open-label, phase II trial [conference abstract. Ann Oncol 2025;36(suppl_2):S1052-S1053. https://doi.org/10.1016/j.annonc.2025.08.2444.