肺癌新辅助免疫治疗研究进展

doi:10.3760/cma.j.cn371439-20220323-00070

摘要/Abstract

摘要：

新辅助免疫治疗可降低可切除肺癌患者术后复发或远处转移风险,延长患者生存期,其疗效优于新辅助化疗。小样本研究表明新辅助免疫治疗联合化疗方案相比于新辅助免疫单药方案的主要病理缓解率更高,但其治疗相关不良事件发生率也更高、治疗周期更长,可导致手术的延迟、增加术中并发症的风险。新辅助免疫治疗的方案选择、手术时机、疗效评估等问题仍未有定论,多项新辅助免疫治疗单药及联合方案的Ⅲ期临床研究正在进行中,期待通过长期随访数据进一步验证新辅助免疫治疗的疗效。

关键词: 肺肿瘤, 免疫疗法, 治疗结果, 新辅助疗法

Abstract:

Neoadjuvant immunotherapy can reduce the risk of postoperative recurrence or distant metastasis in patients with resectable lung cancer, prolong the survival of patients, and has better efficacy compared to neoadjuvant chemotherapy. Existing clinical trials with a small sample size indicate that neoadjuvant immunotherapy combined with chemotherapy has a higher rate of major pathologic response compared to single-agent immunotherapy, but it is also accompanied by a higher incidence of treatment-related adverse events and a longer treatment cycle, which may lead to delayed surgery or increased risk of intraoperative complications. The selection of therapeutic regimens, surgical timing, efficacy evaluation, and other issues have not been determined. Several phase Ⅲ clinical studies of a single drug and combined regimen of neoadjuvant immunotherapy are ongoing, and the efficacy of neoadjuvant immunotherapy is expected to be further verified through follow-up data.

Key words: Lung neoplasms, Immunotherapy, Treatment outcome, Neoadjuvant therapy

蔡刚祥, 李境, 许斌. 肺癌新辅助免疫治疗研究进展[J]. 国际肿瘤学杂志, 2022, 49(6): 366-370.

Cai Gangxiang, Li Jing, Xu Bin. Advances in neoadjuvant immunotherapy for lung cancer[J]. Journal of International Oncology, 2022, 49(6): 366-370.

参考文献 35

[1]	Ferris RL, Blumenschein G Jr, Fayette J, et al. Nivolumab for recurrent squamous-cell carcinoma of the head and neck[J]. N Engl J Med, 2016, 375(19): 1856-1867. DOI: 10.1056/NEJMoa1602252. doi: 10.1056/NEJMoa1602252
[2]	Seiwert TY, Burtness B, Mehra R, et al. Safety and clinical activity of pembrolizumab for treatment of recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-012): an open-label, multicentre, phase 1b trial[J]. Lancet Oncol, 2016, 17(7): 956-965. DOI: 10.1016/S1470-2045(16)30066-3. doi: S1470-2045(16)30066-3 pmid: 27247226
[3]	Li B, Chan HL, Chen P. Immune checkpoint inhibitors: basics and challenges[J]. Curr Med Chem, 2019, 26(17): 3009-3025. DOI: 10.2174/0929867324666170804143706. doi: 10.2174/0929867324666170804143706
[4]	Liu J, Blake SJ, Yong MC, et al. Improved efficacy of neoadjuvant compared to adjuvant immunotherapy to eradicate metastatic disease[J]. Cancer Discov, 2016, 6(12): 1382-1399. DOI: 10.1158/2159-8290.CD-16-0577. doi: 10.1158/2159-8290.CD-16-0577
[5]	Forde PM, Chaft JE, Smith KN, et al. Neoadjuvant PD-1 blockade in resectable lung cancer[J]. N Engl J Med, 2018, 378(21): 1976-1986. DOI: 10.1056/NEJMoa1716078. doi: 10.1056/NEJMoa1716078
[6]	Lee J, Chaft J, Nicholas A, et al. Surgical outcomes of a multicenter phase Ⅱ trial of neoadjuvant atezolizumab in resectable stages ⅠB-ⅢB NSCLC: update on LCMC3 clinical trial[J]. J Thorac Oncol, 2019, 14(10): S744. DOI: 10.1016/j.jtho.2019.08.1593. doi: 10.1016/j.jtho.2019.08.1593
[7]	Carbone D, Lee J, Kris M, et al. Clinical/biomarker data for neoad-juvant atezolizumab in resectable stage ⅠB-ⅢB NSCLC: primary analysis in the LCMC3 study[J]. J Thorac Oncol, 2021, 16(3): S115-S116. DOI: 10.1016/j.jtho.2021.01.294. doi: 10.1016/j.jtho.2021.01.294
[8]	Waldman AD, Fritz JM, Lenardo MJ. A guide to cancer immunotherapy: from T cell basic science to clinical practice[J]. Nat Rev Immunol, 2020, 20(11): 651-668. DOI: 10.1038/s41577-020-0306-5. doi: 10.1038/s41577-020-0306-5
[9]	Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy[J]. Nat Rev Cancer, 2012, 12(4): 252-264. DOI: 10.1038/nrc3239. doi: 10.1038/nrc3239 pmid: 22437870
[10]	Wei SC, Anang NAS, Sharma R, et al. combination anti-CTLA-4 plus anti-PD-1 checkpoint blockade utilizes cellular mechanisms partially distinct from monotherapies[J]. Proc Natl Acad Sci U S A, 2019, 116(45): 22699-22709. DOI: 10.1073/pnas.1821218116. doi: 10.1073/pnas.1821218116
[11]	Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Five-year survival with combined nivolumab and ipilimumab in advanced melanoma[J]. N Engl J Med, 2019, 381(16): 1535-1546. DOI: 10.1056/NEJMoa1910836. doi: 10.1056/NEJMoa1910836
[12]	Hellmann MD, Paz-Ares L, Bernabe Caro R, et al. Nivolumab plus ipilimumab in advanced non-small-cell lung cancer[J]. N Engl J Med, 2019, 381(21): 2020-2031. DOI: 10.1056/NEJMoa1910231. doi: 10.1056/NEJMoa1910231
[13]	Motzer RJ, Rini BI, McDermott DF, et al. Nivolumab plus ipili-mumab versus sunitinib in first-line treatment for advanced renal cell carcinoma: extended follow-up of efficacy and safety results from a randomised, controlled, phase 3 trial[J]. Lancet Oncol, 2019, 20(10): 1370-1385. DOI: 10.1016/S1470-2045(19)30413-9. doi: 10.1016/S1470-2045(19)30413-9
[14]	Overman MJ, Lonardi S, Wong KYM, et al. Durable clinical benefit with nivolumab plus ipilimumab in DNA mismatch repair-deficient/microsatellite instability-high metastatic colorectal cancer[J]. J Clin Oncol, 2018, 36(8): 773-779. DOI: 10.1200/JCO.2017.76.9901. doi: 10.1200/JCO.2017.76.9901
[15]	Cascone T, William WN Jr, Weissferdt A, et al. Neoadjuvant nivo-lumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial[J]. Nat Med, 2021, 27(3): 504-514. DOI: 10.1038/s41591-020-01224-2. doi: 10.1038/s41591-020-01224-2 pmid: 33603241
[16]	Heinhuis KM, Ros W, Kok M, et al. Enhancing antitumor res-ponse by combining immune checkpoint inhibitors with chemotherapy in solid tumors[J]. Ann Oncol, 2019, 30(2): 219-235. DOI: 10.1093/annonc/mdy551. doi: S0923-7534(19)31044-0 pmid: 31987419
[17]	Leonetti A, Wever B, Mazzaschi G, et al. Molecular basis and rationale for combining immune checkpoint inhibitors with chemotherapy in non-small cell lung cancer[J]. Drug Resist Updat, 2019, 46: 100644. DOI: 10.1016/j.drup.2019.100644. doi: 10.1016/j.drup.2019.100644
[18]	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[J]. Lancet Oncol, 2020, 21(11): 1413-1422. DOI: 10.1016/S1470-2045(20)30453-8. doi: 10.1016/S1470-2045(20)30453-8 pmid: 32979984
[19]	Shu CA, Gainor JF, Awad MM, et al. Neoadjuvant atezolizumab and chemotherapy in patients with resectable non-small-cell lung cancer: an open-label, multicentre, single-arm, phase 2 trial[J]. Lancet Oncol, 2020, 21(6): 786-795. DOI: 10.1016/S1470-2045(20)30140-6. doi: 10.1016/S1470-2045(20)30140-6
[20]	Forde PM, Spicer J, Lu S, et al. Abstract CT003: nivolumab (NIVO)+ platinum-doublet chemotherapy (chemo) vs chemo as neoadjuvant treatment (tx) for resectable (ⅠB-ⅢA) non-small cell lung cancer (NSCLC) in the phase 3 CheckMate 816 trial[J]. Cancer Res, 2021, 81(Suppl-13): CT003. DOI: 10.1158/1538-7445.AM2021-CT003. doi: 10.1158/1538-7445.AM2021-CT003
[21]	Schumann C, Cascone T, Provencio M, et al. CheckMate 77 T: a phase 3 trial of neoadjuvant nivolumab (NIVO)+chemotherapy (chemo) followed by adjuvant NIVO in resectable early-stage non-small cell lung cancer (NSCLC)[J]. Pneumologie, 2021, 75(S01): S16. DOI: 10.1055/s-0041-1723292. doi: 10.1055/s-0041-1723292
[22]	Tsuboi M, Luft A, Ursol G, et al. Perioperative pembrolizumab+platinum-based chemotherapy for resectable locally advanced non-small cell lung cancer: the phase Ⅲ KEYNOTE-671 study[J]. Ann Oncol, 2020, 31(Suppl-4): S801-S802. DOI: 10.1016/j.annonc.2020.08.1437. doi: 10.1016/j.annonc.2020.08.1437
[23]	Peters S, Kim AW, Solomon B, et al. IMpower030: phase Ⅲ study evaluating neoadjuvant treatment of resectable stage Ⅱ-ⅢB non-small cell lung cancer (NSCLC) with atezolizumab (atezo)+chemotherapy[J]. Ann Oncol, 2019, 30(Suppl-2): ii30. DOI: 10.1093/annonc/mdz064.014. doi: 10.1093/annonc/mdz064.014
[24]	Krishnamoorthy M, Lenehan JG, Maleki Vareki S. Neoadjuvant immunotherapy for high-risk, resectable malignancies: scientific rationale and clinical challenges[J]. J Natl Cancer Inst, 2021, 113(7): 823-832. DOI: 10.1093/jnci/djaa216. doi: 10.1093/jnci/djaa216 pmid: 33432320
[25]	Kang J, Zhang C, Zhong WZ. Neoadjuvant immunotherapy for non-small cell lung cancer: state of the art[J]. Cancer Commun (Lond), 2021, 41(4): 287-302. DOI: 10.1002/cac2.12153. doi: 10.1002/cac2.12153
[26]	Hamada A, Soh J, Hata A, et al. Phase Ⅱ study of neoadjuvant concurrent chemo-immuno-radiation therapy followed by surgery and adjuvant immunotherapy for resectable stage ⅢA-B (discrete N₂) non-small-cell lung cancer: SQUAT trial (WJOG 12119L)[J]. Clin Lung Cancer, 2021, 22(6): 596-600. DOI: 10.1016/j.cllc.2021.04.006. doi: 10.1016/j.cllc.2021.04.006 pmid: 34034990
[27]	Wyld L, Audisio RA, Poston GJ. The evolution of cancer surgery and future perspectives[J]. Nat Rev Clin Oncol, 2015, 12(2): 115-124. DOI: 10.1038/nrclinonc.2014.191. doi: 10.1038/nrclinonc.2014.191
[28]	O'Donnell JS, Hoefsmit EP, Smyth MJ, et al. The promise of neoadjuvant immunotherapy and surgery for cancer treatment[J]. Clin Cancer Res, 2019, 25(19): 5743-5751. DOI: 10.1158/1078-0432.CCR-18-2641. doi: 10.1158/1078-0432.CCR-18-2641 pmid: 31040150
[29]	Melero I, Berraondo P, Rodríguez-Ruiz ME, et al. Making the most of cancer surgery with neoadjuvant immunotherapy[J]. Can-cer Discov, 2016, 6(12): 1312-1314. DOI: 10.1158/2159-8290.CD-16-1109. doi: 10.1158/2159-8290.CD-16-1109
[30]	Liu J, O'Donnell JS, Yan JM, et al. Timing of neoadjuvant im-munotherapy in relation to surgery is crucial for outcome[J]. Oncoi-mmunology, 2019, 8(5): e1581530. DOI: 10.1080/2162402X.2019.1581530. doi: 10.1080/2162402X.2019.1581530
[31]	Huang AC, Orlowski RJ, Xu X, et al. A single dose of neoadjuvant PD-1 blockade predicts clinical outcomes in resectable melanoma[J]. Nat Med, 2019, 25(3): 454-461. DOI: 10.1038/s41591-019-0357-y. doi: 10.1038/s41591-019-0357-y
[32]	Simoni Y, Becht E, Fehlings M, et al. Bystander CD8⁺ T cells are abundant and phenotypically distinct in human tumour infiltrates[J]. Nature, 2018, 557(7706): 575-579. DOI: 10.1038/s41586-018-0130-2. doi: 10.1038/s41586-018-0130-2
[33]	Shen D, Wang J, Wu J, et al. Neoadjuvant pembrolizumab with chemotherapy for the treatment of stage ⅡB-ⅢB resectable lung squamous cell carcinoma[J]. J Thorac Dis, 2021, 13(3): 1760-1768. DOI: 10.21037/jtd-21-103. doi: 10.21037/jtd-21-103
[34]	Liang W, Cai K, Chen C, et al. Expert consensus on neoadjuvant immunotherapy for non-small cell lung cancer[J]. Transl Lung Cancer Res, 2020, 9(6): 2696-2715. DOI: 10.21037/tlcr-2020-63. doi: 10.21037/tlcr-2020-63
[35]	Cottrell TR, Thompson ED, Forde PM, 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)[J]. Ann Oncol, 2018, 29(8): 1853-1860. DOI: 10.1093/annonc/mdy218. doi: S0923-7534(19)34134-1 pmid: 29982279