Objective  To investigate the clinical efficacy and prognosis of cross-line immunotherapy for driver gene-negative advanced non-small cell lung cancer (NSCLC).

Methods  Clinical data of patients with advanced NSCLC in Zhongnan Hospital of Wuhan University from June 2019 to December 2023 were retrospectively analyzed. For first-line treatment for the patients, programmed cell death receptor-1 (PD-1) monoclonal antibody combined with platinum-based doublet chemotherapy was adopted, and for second-line treatment, PD-1 monoclonal antibody combined with chemotherapy was used. The Kaplan-Meier method was employed to draw survival curves, and the Log-rank test was used to evaluate the differences in survival. The Cox proportional hazards regression model was used to analyze the risk factors that affect prognosis and subgroup analyses were conducted to explore the impact on patients' prognosis.

Results  A total of 112 advanced NSCLC patients with negative driver genes were included. The overall response rate (ORR) of cross-line immunotherapy was 20.54%, and the disease control rate (DCR) of cross-line immunotherapy reached 49.11%. The median overall survival (OS) was 26.6 months. The median progression free survival of first-line treatment (PFS-1) was 7.3 months, and that of second-line treatment (PFS-2) was 5.4 months. The subgroup analysis showed that, compared with patients with PFS-1≤10 months, patients with PFS-1>10 months had longer median OS [44.3 months vs. 13.8 months, P<0.001] and median PFS-2 [10.0 months vs. 3.5 months, P<0.01]. Patients with BMI>25  kg/m² had longer median PFS-2 than those with BMI≤25 kg/m² [10.0 months vs. 4.2 months, P<0.05]. Moreover, in contrast to patients with low expression of PD-L1 (<1% PD-L1 on tumor cells or tissues), patients with high expression of PD-L1 had a longer median PFS-2 [6.9 months vs. 2.5 months, P<0.01]. In the multivariate Cox proportional hazards regression analysis, compared with patients with PFS-1≤10 months, patients with PFS-1>10 months had a 52% reduction in the risk of progression [HR=0.48, 95%CI(0.27, 0.87), P<0.05].

Conclusion  The benefits of cross-line immunotherapy might not be remarkable for advanced non-small cell lung cancer with negative driver genes. However, patients with PFS-1>10 months may have a better prognosis.

1.Bray F, Laversanne M, Sung H, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA Cancer J Clin, 2024, 74(3): 229-263. DOI: 10.3322/caac.21834.

2.Bourreau C, Treps L, Faure S, et al. Therapeutic strategies for non-small cell lung cancer: experimental models and emerging biomarkers to monitor drug efficacies[J]. Pharmacol Ther, 2023, 242: 108347. DOI: 10.1016/j.pharmthera.2023.108347.

3.Huang Z, Su W, Lu T, et al. First-line immune-checkpoint inhibitors in non-small cell lung cancer: current landscape and future progress[J]. Front Pharmacol, 2020, 11: 578091. DOI: 10.3389/fphar.2020.578091.

4.Ettinger DS, Wood DE, Aisner DL, et al. NCCN guidelines® insights: non-small cell lung cancer, version 2.2023[J]. J Natl Compr Canc Netw, 2023, 21(4): 340-350. DOI: 10.6004/jnccn.2023.0020.

5.周彩存,王洁,程颖,等. 基因驱动阴性非小细胞肺癌二线治疗中国专家共识[J]. 中国肺癌杂志, 2024, 27(2): 81-87. [Zhou CC, Wang J, Cheng Y, et al. Chinese expert consensus on second-line treatment for non-small cell lung cancer with negative driver gene mutations[J]. Chinese Journal of Lung Cancer, 2024, 27(2): 81-87.] DOI: 10.3779/j.issn.1009-3419.2024.102.10.

6.Herbst RS, Garon EB, Kim DW, et al. Long-term outcomes and retreatment among patients with previously treated, programmed death-ligand 1‒positive, advanced non-small-cell lung cancer in the KEYNOTE-010 study[J]. J Clin Oncol, 2020, 38(14): 1580-1590. DOI: 10.1200/JCO.19.02446.

7.Ricciuti B, Genova C, Bassanelli M, et al. Safety and efficacy of nivolumab in patients with advanced non-small-cell lung cancer treated beyond progression[J]. Clin Lung Cancer, 2019, 20(3): 178-185. DOI: 10.1016/j.cllc.2019.02.001.

8.Stinchcombe TE, Miksad RA, Gossai A, et al. Real-world outcomes for advanced non-small cell lung cancer patients treated with a PD-L1 inhibitor beyond progression[J]. Clin Lung Cancer, 2020, 21(5): 389-394. e3. DOI: 10.1016/j.cllc.2020.04.008.

9.Jia W, Wang M, Zhu H, et al. Clinical outcomes for immunotherapy beyond progression in patients with advanced non-small cell lung cancer[J]. J Clin Oncol, 2023, 41(16_suppl): e21222. DOI: 10.1200/JCO.2023.41.16_suppl.e21222.

10.Won SE, Park HJ, Byun S, et al. Impact of pseudoprogression and treatment beyond progression on outcome in patients with non-small cell lung cancer treated with immune checkpoint inhibitors[J]. Oncoimmunology, 2020, 9(1): 1776058. DOI: 10.1080/2162402X.2020.1776058.

11.Enomoto T, Tamiya A, Matsumoto K, et al. Nivolumab treatment beyond progressive disease in advanced non-small cell lung cancer[J]. Clin Transl Oncol, 2021, 23(3): 582-590. DOI: 10.1007/s12094-020-02452-1.

12.Metro G, Addeo A, Signorelli D, et al. Outcomes from salvage chemotherapy or pembrolizumab beyond progression with or without local ablative therapies for advanced non-small cell lung cancers with PD-L1≥50% who progress on first-line immunotherapy: real-world data from a European cohort[J]. J Thorac Dis, 2019, 11(12): 4972-4981. DOI: 10.21037/JTD.2019.12.23.

13.Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1)[J]. Eur J Cancer, 2009, 45(2): 228-247. DOI: 10.1016/j.ejca.2008.10.026.

14.Gandhi L, Rodríguez-Abreu D, Gadgeel S, et al. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer[J]. N Engl J Med, 2018, 378(22): 2078-2092. DOI: 10.1056/NEJMoa1801005.

15.Reck M, Rodríguez-Abreu D, Robinson AG, et al. KEYNOTE-024: Pembrolizumab (pembro) vs platinum-based chemotherapy (chemo) as first-line therapy for advanced NSCLC with a PD-L1 tumor proportion score (TPS)≥50%[J]. Annals of Oncology, 2016, 27(suppl_6). DOI: 10.1093/annonc/mdw435.40.

16.Gadgeel S, Rodríguez-Abreu D, Speranza G, et al. Updated analysis from KEYNOTE-189: pembrolizumab or placebo plus pemetrexed and platinum for previously untreated metastatic nonsquamous non-small-cell lung cancer[J]. J Clin Oncol, 2020, 38(14): 1505-1517. DOI: 10.1200/JCO.19.03136.

17.王婧怡, 钟雨玲, 邬麟. 晚期非小细胞肺癌免疫治疗: 研究进展和展望[J]. 肿瘤防治研究, 2024, 51(6): 409-418. [Wang  JY, Zhong YL, Wu L. Immunotherapy for advanced non-small cell lung cancer: research progress and prospects[J]. Cancer Research on Prevention and Treatment, 2024, 51(6): 409-418.] DOI: 10.3971/j.issn.1000-8578.2024.24.0090.

18.Han B, Jiao S, Chen J, et al. 59MO Final analysis of AK105-302: a randomized, double-blind, placebo-controlled, phase III trial of penpulimab plus carboplatin and paclitaxel as first-line treatment for advanced squamous NSCLC[J]. Immuno-Oncology and Technology, 2022, 16. DOI: 10.1016/j.iotech.2022.100164.

19.Wang Z, Wu L, Li B, et al. Toripalimab plus chemotherapy for patients with treatment-naive advanced non-small-cell lung cancer: a multicenter randomized phase III trial (CHOICE-01) [J]. J Clin Oncol, 2023, 41(3): 651-663. DOI: 10.1200/JCO.22. 00727.

20.Zhou C, Wang Z, Sun Y, et al. Sugemalimab versus placebo, in combination with platinum-based chemotherapy, as first-line treatment of metastatic non-small-cell lung cancer (GEMSTONE-302): interim and final analyses of a double-blind, randomised, phase 3 clinical trial[J]. Lancet Oncol, 2022, 23(2): 220-233. DOI: 10.1016/S1470-2045(21)00650-1.

21.Zhou C, Huang D, Fan Y, et al. Tislelizumab versus docetaxel in patients with previously treated advanced NSCLC (rationale-303): a phase 3, open-label, randomized controlled trial[J]. J Thorac Oncol, 2023, 18(1): 93-105. DOI: 10.1016/j.jtho. 2022.09.217.

22.Xu M, Hao Y, Zeng X, et al. Immune checkpoint inhibitors beyond first-line progression with prior immunotherapy in patients with advanced non-small cell lung cancer[J]. J Thorac Dis, 2023, 15(4): 1648-1657. DOI: 10.21037/jtd-22-1611.

23.Hu J, Zhang L, Xia H, et al. Tumor microenvironment remodeling after neoadjuvant immunotherapy in non-small cell lung cancer revealed by single-cell RNA sequencing[J]. Genome Med, 2023, 15(1): 14. DOI: 10.1186/s13073-023-01164-9.

24.Qian BZ, Pollard JW. Macrophage diversity enhances tumor progression and metastasis[J]. Cell, 2010, 141(1): 39-51. DOI: 10.1016/j.cell.2010.03.014.

25.de Visser KE, Joyce JA. The evolving tumor microenvironment: from cancer initiation to metastatic outgrowth[J]. Cancer Cell, 2023, 41(3): 374-403. DOI: 10.1016/j.ccell.2023.02.016.

26.van der Leun AM, Thommen DS, Schumacher TN. CD8+ T cell states in human cancer: insights from single-cell analysis[J]. Nat Rev Cancer, 2020, 20(4): 218-232. DOI: 10.1038/s41568-019-0235-4.

27.Purdy AK, Campbell KS. Natural killer cells and cancer: regulation by the killer cell Ig-like receptors (KIR)[J]. Cancer Biol Ther, 2009, 8(23): 2211-2220. DOI: 10.4161/cbt.8.23.10455.

28.Sugiyama D, Hinohara K, Nishikawa H. Significance of regulatory T cells in cancer immunology and immunotherapy[J]. Exp Dermatol, 2023, 32(3): 256-263. DOI: 10.1111/exd.14721.

29.Yarchoan M, Hopkins A, Jaffee EM. Tumor mutational burden and response rate to PD-1 inhibition[J]. N Engl J Med, 2017, 377(25): 2500-2501. DOI: 10.1056/NEJMc1713444.

30.Yu D, Zheng W, Johansson M, et al. Overall and central obesity and risk of lung cancer: a pooled analysis[J]. J Natl Cancer Inst, 2018, 110(8): 831-842. DOI: 10.1093/jnci/djx286.

31.Shepshelovich D, Xu W, Lu L, et al. Body mass index (BMI), BMI change, and overall survival in patients with SCLC and NSCLC: a pooled analysis of the international lung cancer consortium[J]. J Thorac Oncol, 2019, 14(9): 1594-1607. DOI: 10.1016/j.jtho.2019.05.031.

32.张晓楠, 熊雅俊, 许爱国. 基于老年营养风险指数构建老年非小细胞肺癌患者的预后模型[J]. 中国肺癌杂志, 2023, 26(7): 497-506. [Zhang XN, Xiong YJ, Xu AG. A prognostic model of elderly patients with non-small cell lung cancer based on geriatric nutritional risk index[J]. Chinese Journal of Lung Cancer, 2023, 26(7): 497-506.] DOI: 10.3779/j.issn.1009-3419.2023.106.14.

33.Lam VK, Bentzen SM, Mohindra P, et al. Obesity is associated with long-term improved survival in definitively treated locally advanced non-small cell lung cancer (NSCLC)[J]. Lung Cancer, 2017, 104: 52-57. DOI: 10.1016/j.lungcan.2016.11.017.

34.Petrelli F, Cortellini A, Indini A, et al. Obesity paradox in patients with cancer: a systematic review and Meta-analysis of 6,320,365 patients[J]. medRxiv, 2020: 2020-2024. DOI: 10.1101/2020.04.28.20082800.

35.Massimo M, Foivos I, Peng HT. Complex interaction of adiponectin-mediated pathways on cancer treatment: a novel therapeutic target[J]. Journal of Cancer Metastasis and Treatment, 2019, 3: 108-130. DOI: 10.20517/2394-4722.2018.79.

36.Gelibter A, Occhipinti M, Pisegna S, et al. Status of correlation between BMI and response to immunocheck-point inhibitor in advanced non-small-cell lung cancer[J]. Lung Cancer Manag, 2020, 9(2): LMT26. DOI: 10.2217/lmt-2019-0016.

37.Wang Z, Aguilar EG, Luna JI, et al. Paradoxical effects of obesity on T cell function during tumor progression and PD-1 checkpoint blockade[J]. Nat Med, 2019, 25(1): 141-151. DOI: 10.1038/s41591-018-0221-5.

38.Rizvi NA, Hellmann MD, Snyder A, et al. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer[J]. Science, 2015, 348(6230): 124-128. DOI: 10.1126/science.aaa1348.

39.Theelen WSME, Chen D, Verma V, et al. Pembrolizumab with or without radiotherapy for metastatic non-small-cell lung cancer: a pooled analysis of two randomised trials[J]. Lancet Respir Med, 2021, 9(5): 467-475. DOI: 10.1016/S2213-2600(20)30391-X.

40.Juloori A, Bestvina CM, Pointer KB, et al. OA22.03 the addition of multisite SBRT to ipilimumab and nivolumab in first line metastatic NSCLC: the COSINR trial[J]. Journal of Thoracic Oncology, 2023, 18(11): S95-S96. DOI: 10.1016/j.jtho.2023. 09.108.